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A protein superfamily is the largest grouping (clade) of proteins for which common ancestry can be inferred (see homology). Usually this common ancestry is inferred from structural alignment and mechanistic similarity, even if no sequence similarity is evident. Sequence homology can then be deduced even if not apparent (due to low sequence similarity). Superfamilies typically contain several protein families which show sequence similarity within each family. The term protein clan is commonly used for protease and glycosyl hydrolases superfamilies based on the MEROPS and CAZy classification systems.
== Identification ==
Superfamilies of proteins are identified using a number of methods. Closely related members can be identified by different methods to those needed to group the most evolutionarily divergent members.
=== Sequence similarity ===
Historically, the similarity of different amino acid sequences has been the most common method of inferring homology. Sequence similarity is considered a good predictor of relatedness, since similar sequences are more likely the result of gene duplication and divergent evolution, rather than the result of convergent evolution. Amino acid sequence is typically more conserved than DNA sequence (due to the degenerate genetic code), so it is a more sensitive detection method. Since some of the amino acids have similar properties (e.g., charge, hydrophobicity, size), conservative mutations that interchange them are often neutral to function. The most conserved sequence regions of a protein often correspond to functionally important regions like catalytic sites and binding sites, since these regions are less tolerant to sequence changes.
Using sequence similarity to infer homology has several limitations. There is no minimum level of sequence similarity guaranteed to produce identical structures. Over long periods of evolution, related proteins may show no detectable sequence similarity to one another. Sequences with many insertions and deletions can also sometimes be difficult to align and so identify the homologous sequence regions. In the PA clan of proteases, for example, not a single residue is conserved through the superfamily, not even those in the catalytic triad. Conversely, the individual families that make up a superfamily are defined on the basis of their sequence alignment, for example the C04 protease family within the PA clan.
Nevertheless, sequence similarity is the most commonly used form of evidence to infer relatedness, since the number of known sequences vastly outnumbers the number of known tertiary structures. In the absence of structural information, sequence similarity constrains the limits of which proteins can be assigned to a superfamily.
=== Structural similarity ===
Structure is much more evolutionarily conserved than sequence, such that proteins with highly similar structures can have entirely different sequences. Over very long evolutionary timescales, very few residues show detectable amino acid sequence conservation, however secondary structural elements and tertiary structural motifs are highly conserved. Some protein dynamics and conformational changes of the protein structure may also be conserved, as is seen in the serpin superfamily. Consequently, protein tertiary structure can be used to detect homology between proteins even when no evidence of relatedness remains in their sequences. Structural alignment programs, such as DALI, use the 3D structure of a protein of interest to find proteins with similar folds. However, on rare occasions, related proteins may evolve to be structurally dissimilar and relatedness can only be inferred by other methods.
=== Mechanistic similarity ===
The catalytic mechanism of enzymes within a superfamily is commonly conserved, although substrate specificity may be significantly different. Catalytic residues also tend to occur in the same order in the protein sequence. For the families within the PA clan of proteases, although there has been divergent evolution of the catalytic triad residues used to perform catalysis, all members use a similar mechanism to perform covalent, nucleophilic catalysis on proteins, peptides or amino acids. However, mechanism alone is not sufficient to infer relatedness. Some catalytic mechanisms have been convergently evolved multiple times independently, and so form separate superfamilies, and in some superfamilies display a range of different (though often chemically similar) mechanisms.
== Evolutionary significance ==
Protein superfamilies represent the current limits of our ability to identify common ancestry. They are the largest evolutionary grouping based on direct evidence that is currently possible. They are therefore amongst the most ancient evolutionary events currently studied. Some superfamilies have members present in all kingdoms of life, indicating that the last common ancestor of that superfamily was in the last universal common ancestor of all life (LUCA).
Superfamily members may be in different species, with the ancestral protein being the form of the protein that existed in the ancestral species (orthology). Conversely, the proteins may be in the same species, but evolved from a single protein whose gene was duplicated in the genome (paralogy).
=== Diversification ===
A majority of proteins contain multiple domains. Between 66-80% of eukaryotic proteins have multiple domains while about 40-60% of prokaryotic proteins have multiple domains. Over time, many of the superfamilies of domains have mixed together. In fact, it is very rare to find “consistently isolated superfamilies”. When domains do combine, the N- to C-terminal domain order (the "domain architecture") is typically well conserved. Additionally, the number of domain combinations seen in nature is small compared to the number of possibilities, suggesting that selection acts on all combinations.
== Examples ==
α/β hydrolase superfamily
Members share an α/β sheet, containing 8 strands connected by helices, with catalytic triad residues in the same order, activities include proteases, lipases, peroxidases, esterases, epoxide hydrolases and dehalogenases.
Alkaline phosphatase superfamily
Members share an αβα sandwich structure as well as performing common promiscuous reactions by a common mechanism.
Globin superfamily
Members share an 8-alpha helix globular globin fold.
Immunoglobulin superfamily
Members share a sandwich-like structure of two sheets of antiparallel β strands (Ig-fold), and are involved in recognition, binding, and adhesion.
PA clan
Members share a chymotrypsin-like double β-barrel fold and similar proteolysis mechanisms but sequence identity of <10%. The clan contains both cysteine and serine proteases (different nucleophiles).
Ras superfamily
Members share a common catalytic G domain of a 6-strand β sheet surrounded by 5 α-helices.
RSH superfamily
Members share capability to hydrolyze and/or synthesize ppGpp alarmones in the stringent response.
Serpin superfamily
Members share a high-energy, stressed fold which can undergo a large conformational change, which is typically used to inhibit serine and cysteine proteases by disrupting their structure.
TIM barrel superfamily
Members share a large α8β8 barrel structure. It is one of the most common protein folds and the monophylicity of this superfamily is still contested.
== Protein superfamily resources ==
Several biological databases document protein superfamilies and protein folds, for example:
Pfam - Protein families database of alignments and HMMs
PROSITE - Database of protein domains, families and functional sites
PIRSF - SuperFamily Classification System
PASS2 - Protein Alignment as Structural Superfamilies v2
SUPERFAMILY - Library of HMMs representing superfamilies and database of (superfamily and family) annotations for all completely sequenced organisms
SCOP and CATH - Classifications of protein structures into superfamilies, families and domains
Similarly there are algorithms that search the PDB for proteins with structural homology to a target structure, for example:
DALI - Structural alignment based on a distance alignment matrix method
== See also ==
== References ==
== External links ==
Media related to Protein superfamilies at Wikimedia Commons | Wikipedia/Protein_superfamilies |
The Enzyme Function Initiative (EFI) is a large-scale collaborative project aiming to develop and disseminate a robust strategy to determine enzyme function through an integrated sequence–structure-based approach. The project was funded in May 2010 by the National Institute of General Medical Sciences as a Glue Grant which supports the research of complex biological problems that cannot be solved by a single research group. The EFI was largely spurred by the need to develop methods to identify the functions of the enormous number proteins discovered through genomic sequencing projects.
== Motivation ==
The dramatic increase in genome sequencing technology has caused the number of protein sequences deposited into public databases to grow apparently exponentially. To cope with the influx of sequences, databases use computational predictions to auto-annotate individual protein's functions. While these computational methods offer the advantages of being extremely high-throughput and generally provide accurate broad classifications, exclusive use has led to a significant level of misannotation of enzyme function in protein databases. Thus although the information now available represents an unprecedented opportunity to understand cellular metabolism across a wide variety of organisms, which includes the ability to identify molecules and/or reactions that may benefit human quality of life, the potential has not been fully actualized. The biological community's ability to characterize newly discovered proteins has been outstripped by the rate of genome sequencing, and the task of assigning function is now considered the rate-limiting step in understanding biological systems in detail.
== Integrated strategy for functional assignment ==
The EFI is developing an integrated sequence-structure based strategy for functional assignment by predicting the substrate specificities of unknown members of mechanistically diverse enzyme superfamilies. The approach leverages conserved features within a given superfamily such as known chemistry, identity of active site functional groups, and composition of specificity-determining residues, motifs, or structures to predict function but relies on multidisciplinary expertise to streamline, refine, and test the predictions. The integrated sequence-strategy under development will be generally applicable to deciphering the ligand specificities of any functionally unknown protein.
== Organization ==
By NIGMS program mandate, Glue Grant consortia must contain core resources and bridging projects. The EFI consists of six scientific cores which provide bioinformatic, structural, computational, and data management expertise to facilitate functional predictions for enzymes of unknown function targeted by the EFI. At the beginning of the grant, these predictions were tested by five Bridging Projects representing the amidohydrolase, enolase, GST, HAD, and isoprenoid synthase enzyme superfamilies. Three Bridging Projects now remain. In addition, the Anaerobic Enzymology Pilot Project was added in 2014 to explore the Radical SAM superfamily and Glycyl Radical Enzyme superfamily.
=== Scientific cores ===
The bioinformatics core contributes bioinformatic analysis by collecting and curating complete sequence data sets, generating sequence similarity networks, and classification of superfamily members into subgroups and families for subsequent annotation transfer and evaluation as targets for functional characterization.
The protein core develops cloning, expression, and protein purification strategies for the enzymes targeted for study.
The structure core fulfills the structural biology component for EFI by providing high resolution structures of targeted enzymes.
The computation core performs in silico docking to generate rank-ordered lists of predicted substrates for targeted enzymes using both experimentally determined and/or homology modeled protein structures.
The microbiology core examines in vivo functions using genetic techniques and metabolomics to complement in vitro functions determined by the Bridging Projects.
The data and dissemination core maintains a public database for experimental data (EFI-DB).
=== Bridging projects ===
The enolase superfamily contains evolutionarily related enzymes with a (β/α)7β‑barrel (TIM‑barrel) fold which primarily catalyze metal-assisted epimerization/racemization or β-elimination of carboxylate substrates.
The Haloacid dehydrogenase superfamily contains evolutionarily related enzymes with a Rossmanoid α/β fold with an inserted "cap" region which primarily catalyze metal-assisted nucleophilic catalysis, most frequently resulting in phosphoryl group transfer.
The isoprenoid synthase (I) superfamily contains evolutionarily related enzymes with a mostly all α-helical fold and primarily catalyze trans-prenyl transfer reactions to form elongated or cyclized isoprene products.
The Anaerobic Enzymology bridging project will explore radical-dependent enzymology, which allows the execution of unusual chemical transformations via an iron-sulfur cluster cleaving S-Adenosyl methionine (SAM) and producing a radical intermediate, or alternatively, abstraction of a hydrogen from glycine producing a glycyl radical. The superfamilies containing these enzymes are largely unexplored and thus, ripe with the potential for functional discoveries. The acquisition of an anaerobic protein production pipeline coupled with the installation of a Biosafety Level 2 anaerobic chamber for culturing human gut microbes has readied the EFI to pursue anaerobic enzymology.
=== Participating investigators ===
Twelve investigators with expertise in various disciplines make up the EFI.
== Deliverables ==
The EFI's primary deliverable is development and dissemination of an integrated sequence/structure strategy for functional assignment. The EFI now offers access to two high-throughput docking tools, a web tool for comparing protein sequences within entire protein families, and a web tool for composing a genome context inventory based on a protein sequence similarity network. Additionally, as the strategy is developed, data and clones generated by the EFI are made freely available via several online resources.
== Funding ==
The EFI was established in May 2010 with $33.9 million in funding over a five-year period (grant number GM093342).
== References ==
== External links ==
Enzyme Function Initiative
Structure-Function Linkage Database
EFI-DB
NIGMS Glue Grant Consortia | Wikipedia/Enzyme_Function_Initiative |
In molecular biology, an intrinsically disordered protein (IDP) is a protein that lacks a fixed or ordered three-dimensional structure, typically in the absence of its macromolecular interaction partners, such as other proteins or RNA. IDPs range from fully unstructured to partially structured and include random coil, molten globule-like aggregates, or flexible linkers in large multi-domain proteins. They are sometimes considered as a separate class of proteins along with globular, fibrous and membrane proteins.
IDPs are a very large and functionally important class of proteins. They are most numerous in eukaryotes, with an estimated 30-40% of residues in the eukaryotic proteome located in disordered regions. Disorder is present in around 70% of proteins, either in the form of disordered tails or flexible linkers. Proteins can also be entirely disordered and lack a defined secondary and/or tertiary structure. Their discovery has disproved the idea that three-dimensional structures of proteins must be fixed to accomplish their biological functions. For example, IDPs have been identified to participate in weak multivalent interactions that are highly cooperative and dynamic, lending them importance in DNA regulation and in cell signaling. Many IDPs can also adopt a fixed three-dimensional structure after binding to other macromolecules. Overall, IDPs are different from structured proteins in many ways and tend to have distinctive function, structure, sequence, interactions, evolution and regulation.
== History ==
In the 1930s-1950s, the first protein structures were solved by protein crystallography. These early structures suggested that a fixed three-dimensional structure might be generally required to mediate biological functions of proteins. These publications solidified the central dogma of molecular biology in that the amino acid sequence of a protein determines its structure which, in turn, determines its function. In 1950, Karush wrote about 'Configurational Adaptability' contradicting this assumption. He was convinced that proteins have more than one configuration at the same energy level and can choose one when binding to other substrates. In the 1960s, Levinthal's paradox suggested that the systematic conformational search of a long polypeptide is unlikely to yield a single folded protein structure on biologically relevant timescales (i.e. microseconds to minutes). Curiously, for many (small) proteins or protein domains, relatively rapid and efficient refolding can be observed in vitro. As stated in Anfinsen's Dogma from 1973, the fixed 3D structure of these proteins is uniquely encoded in its primary structure (the amino acid sequence), is kinetically accessible and stable under a range of (near) physiological conditions, and can therefore be considered as the native state of such "ordered" proteins.
During the subsequent decades, however, many large protein regions could not be assigned in x-ray datasets, indicating that they occupy multiple positions, which average out in electron density maps. The lack of fixed, unique positions relative to the crystal lattice suggested that these regions were "disordered". Nuclear magnetic resonance spectroscopy of proteins also demonstrated the presence of large flexible linkers and termini in many solved structural ensembles.
In 2001, Dunker questioned whether the newly found information was ignored for 50 years with more quantitative analyses becoming available in the 2000s. In the 2010s it became clear that IDPs are common among disease-related proteins, such as alpha-synuclein and tau.
== Abundance ==
It is now generally accepted that proteins exist as an ensemble of similar structures with some regions more constrained than others. IDPs occupy the extreme end of this spectrum of flexibility and include proteins of considerable local structure tendency or flexible multidomain assemblies.
Intrinsic disorder is particularly elevated among proteins that regulate chromatin and transcription, and bioinformatic predictions indicate that is more common in genomes and proteomes than in known structures in the protein database. Based on DISOPRED2 prediction, long (>30 residue) disordered segments occur in 2.0% of archaean, 4.2% of eubacterial and 33.0% of eukaryotic proteins, including certain disease-related proteins.
== Biological roles ==
Highly dynamic disordered regions of proteins have been linked to functionally important phenomena such as allosteric regulation and enzyme catalysis. Many disordered proteins have the binding affinity with their receptors regulated by post-translational modification, thus it has been proposed that the flexibility of disordered proteins facilitates the different conformational requirements for binding the modifying enzymes as well as their receptors. Intrinsic disorder is particularly enriched in proteins implicated in cell signaling and transcription, as well as chromatin remodeling functions. Genes that have recently been born de novo tend to have higher disorder. In animals, genes with high disorder are lost at higher rates during evolution.
=== Flexible linkers ===
Disordered regions are often found as flexible linkers or loops connecting domains. Linker sequences vary greatly in length but are typically rich in polar uncharged amino acids. Flexible linkers allow the connecting domains to freely twist and rotate to recruit their binding partners via protein domain dynamics. They also allow their binding partners to induce larger scale conformational changes by long-range allostery. The flexible linker of FBP25 which connects two domains of FKBP25 is important for the binding of FKBP25 with DNA.
=== Linear motifs ===
Linear motifs are short disordered segments of proteins that mediate functional interactions with other proteins or other biomolecules (RNA, DNA, sugars etc.). Many roles of linear motifs are associated with cell regulation, for instance in control of cell shape, subcellular localisation of individual proteins and regulated protein turnover. Often, post-translational modifications such as phosphorylation tune the affinity (not rarely by several orders of magnitude) of individual linear motifs for specific interactions. Relatively rapid evolution and a relatively small number of structural restraints for establishing novel (low-affinity) interfaces make it particularly challenging to detect linear motifs but their widespread biological roles and the fact that many viruses mimick/hijack linear motifs to efficiently recode infected cells underlines the timely urgency of research on this very challenging and exciting topic.
=== Pre-structured motifs ===
Unlike globular proteins, IDPs do not have spatially-disposed active pockets. Fascinatingly, 80% of target-unbound IDPs (~4 dozens) subjected to detailed structural characterization by NMR possess linear motifs termed PresMos (pre-structured motifs) that are transient secondary structural elements primed for target recognition. In several cases it has been demonstrated that these transient structures become full and stable secondary structures, e.g., helices, upon target binding. Hence, PresMos are the putative active sites in IDPs.
=== Coupled folding and binding ===
Many unstructured proteins undergo transitions to more ordered states upon binding to their targets (e.g. molecular recognition features (MoRFs)). The coupled folding and binding may be local, involving only a few interacting residues, or it might involve an entire protein domain. It was recently shown that the coupled folding and binding allows the burial of a large surface area that would be possible only for fully structured proteins if they were much larger. Moreover, certain disordered regions might serve as "molecular switches" in regulating certain biological function by switching to ordered conformation upon molecular recognition like small molecule-binding, DNA/RNA binding, ion interactions etc.
The ability of disordered proteins to bind, and thus to exert a function, shows that stability is not a required condition. Many short functional sites, for example short linear motifs are over-represented in disordered proteins. Disordered proteins and short linear motifs are particularly abundant in many RNA viruses such as Hendra virus, HCV, HIV-1 and human papillomaviruses. This enables such viruses to overcome their informationally limited genomes by facilitating binding, and manipulation of, a large number of host cell proteins.
=== Disorder in the bound state (fuzzy complexes) ===
Intrinsically disordered proteins can retain their conformational freedom even when they bind specifically to other proteins. The structural disorder in bound state can be static or dynamic. In fuzzy complexes structural multiplicity is required for function and the manipulation of the bound disordered region changes activity. The conformational ensemble of the complex is modulated via post-translational modifications or protein interactions. Specificity of DNA binding proteins often depends on the length of fuzzy regions, which is varied by alternative splicing. Some fuzzy complexes may exhibit high binding affinity, although other studies showed different affinity values for the same system in a different concentration regime.
== Structural aspects ==
Intrinsically disordered proteins adapt a dynamic range of rapidly interchanging conformations in vivo according to the cell's conditions, creating a structural or conformational ensemble.
Therefore, their structures are strongly function-related. However, only few proteins are fully disordered in their native state. Disorder is mostly found in intrinsically disordered regions (IDRs) within an otherwise well-structured protein. The term intrinsically disordered protein (IDP) therefore includes proteins that contain IDRs as well as fully disordered proteins.
The existence and kind of protein disorder is encoded in its amino acid sequence. In general, IDPs are characterized by a low content of bulky hydrophobic amino acids and a high proportion of polar and charged amino acids, usually referred to as low hydrophobicity. This property leads to good interactions with water. Furthermore, high net charges promote disorder because of electrostatic repulsion resulting from equally charged residues. Thus disordered sequences cannot sufficiently bury a hydrophobic core to fold into stable globular proteins. In some cases, hydrophobic clusters in disordered sequences provide the clues for identifying the regions that undergo coupled folding and binding (refer to biological roles). Many disordered proteins reveal regions without any regular secondary structure. These regions can be termed as flexible, compared to structured loops. While the latter are rigid and contain only one set of Ramachandran angles, IDPs involve multiple sets of angles. The term flexibility is also used for well-structured proteins, but describes a different phenomenon in the context of disordered proteins. Flexibility in structured proteins is bound to an equilibrium state, while it is not so in IDPs. Many disordered proteins also reveal low complexity sequences, i.e. sequences with over-representation of a few residues. While low complexity sequences are a strong indication of disorder, the reverse is not necessarily true, that is, not all disordered proteins have low complexity sequences. Disordered proteins have a low content of predicted secondary structure.
Due to the disordered nature of these proteins, topological approaches have been developed to search for conformational patterns in their dynamics. For instance, circuit topology has been applied to track the dynamics of disordered protein domains. By employing a topological approach, one can categorize motifs according to their topological buildup and the timescale of their formation.
A common aspect of IDP structural ensembles is the ability or tendency to fold upon an interaction to a binding partner in the cell. Examples of IDP folding in a binding context are binding-coupled folding, and formation of fuzzy complexes. However, it is also possible for proteins to remain entirely disordered in a binding scenario.
== Experimental validation ==
IDPs can be validated in several contexts. Most approaches for experimental validation of IDPs are restricted to extracted or purified proteins while some new experimental strategies aim to explore in vivo conformations and structural variations of IDPs inside intact living cells and systematic comparisons between their dynamics in vivo and in vitro.
=== In vivo approaches ===
The first direct evidence for in vivo persistence of intrinsic disorder has been achieved by in-cell NMR upon electroporation of a purified IDP and recovery of cells to an intact state.
Larger-scale in vivo validation of IDR predictions is now possible using biotin 'painting'.
=== In vitro approaches ===
Intrinsically unfolded proteins, once purified, can be identified by various experimental methods. The primary method to obtain information on disordered regions of a protein is NMR spectroscopy. The lack of electron density in X-ray crystallographic studies may also be a sign of disorder.
Folded proteins have a high density (partial specific volume of 0.72-0.74 mL/g) and commensurately small radius of gyration. Hence, unfolded proteins can be detected by methods that are sensitive to molecular size, density or hydrodynamic drag, such as size exclusion chromatography, analytical ultracentrifugation, small angle X-ray scattering (SAXS), and measurements of the diffusion constant. Unfolded proteins are also characterized by their lack of secondary structure, as assessed by far-UV (170–250 nm) circular dichroism (esp. a pronounced minimum at ~200 nm) or infrared spectroscopy. Unfolded proteins also have exposed backbone peptide groups exposed to solvent, so that they are readily cleaved by proteases, undergo rapid hydrogen-deuterium exchange and exhibit a small dispersion (<1 ppm) in their 1H amide chemical shifts as measured by NMR. (Folded proteins typically show dispersions as large as 5 ppm for the amide protons.) Recently, new methods including fast parallel proteolysis (FASTpp) have been introduced, which allow to determine the fraction folded/disordered without the need for purification. Even subtle differences in the stability of missense mutations, protein partner binding and (self)polymerisation-induced folding of (e.g.) coiled-coils can be detected using FASTpp as recently demonstrated using the tropomyosin-troponin protein interaction. Fully unstructured protein regions can be experimentally validated by their hypersusceptibility to proteolysis using short digestion times and low protease concentrations.
Bulk methods to study IDP structure and dynamics include SAXS for ensemble shape information, NMR for atomistic ensemble refinement, fluorescence for visualising molecular interactions and conformational transitions, x-ray crystallography to highlight more mobile regions in otherwise rigid protein crystals, cryo-EM to reveal less fixed parts of proteins, light scattering to monitor size distributions of IDPs or their aggregation kinetics, NMR chemical shift and circular dichroism to monitor secondary structure of IDPs.
Single-molecule methods to study IDPs include spFRET to study conformational flexibility of IDPs and the kinetics of structural transitions, optical tweezers for high-resolution insights into the ensembles of IDPs and their oligomers or aggregates, nanopores to reveal global shape distributions of IDPs, magnetic tweezers to study structural transitions for long times at low forces, high-speed atomic force microscopy (AFM) to visualise the spatio-temporal flexibility of IDPs directly.
== Disorder annotation ==
Intrinsic disorder can be either annotated from experimental information or predicted with specialized software. Disorder prediction algorithms can predict intrinsic disorder (ID) propensity with high accuracy (approaching around 80%) based on primary sequence composition, similarity to unassigned segments in protein x-ray datasets, flexible regions in NMR studies and physico-chemical properties of amino acids.
=== Disorder databases ===
Databases have been established to annotate protein sequences with intrinsic disorder information. The DisProt database contains a collection of manually curated protein segments which have been experimentally determined to be disordered. MobiDB is a database combining experimentally curated disorder annotations (e.g. from DisProt) with data derived from missing residues in X-ray crystallographic structures and flexible regions in NMR structures.
=== Predicting IDPs by sequence ===
Separating disordered from ordered proteins is essential for disorder prediction. One of the first steps to find a factor that distinguishes IDPs from non-IDPs is to specify biases within the amino acid composition. The following hydrophilic, charged amino acids A, R, G, Q, S, P, E and K have been characterized as disorder-promoting amino acids, while order-promoting amino acids W, C, F, I, Y, V, L, and N are hydrophobic and uncharged. The remaining amino acids H, M, T and D are ambiguous, found in both ordered and unstructured regions. A more recent analysis ranked amino acids by their propensity to form disordered regions as follows (order promoting to disorder promoting): W, F, Y, I, M, L, V, N, C, T, A, G, R, D, H, Q, K, S, E, P. As it can be seen from the list, small, charged, hydrophilic residues often promote disorder, while large and hydrophobic residues promote order.
This information is the basis of most sequence-based predictors. Regions with little to no secondary structure, also known as NORS (no regular secondary structure) regions, and low-complexity regions can easily be detected. However, not all disordered proteins contain such low complexity sequences.
=== Prediction methods ===
Determining disordered regions from biochemical methods is very costly and time-consuming. Due to the variable nature of IDPs, only certain aspects of their structure can be detected, so that a full characterization requires a large number of different methods and experiments. This further increases the expense of IDP determination. In order to overcome this obstacle, computer-based methods are created for predicting protein structure and function. It is one of the main goals of bioinformatics to derive knowledge by prediction. Predictors for IDP function are also being developed, but mainly use structural information such as linear motif sites. There are different approaches for predicting IDP structure, such as neural networks or matrix calculations, based on different structural and/or biophysical properties.
Many computational methods exploit sequence information to predict whether a protein is disordered. Notable examples of such software include IUPRED and Disopred. Different methods may use different definitions of disorder. Meta-predictors show a new concept, combining different primary predictors to create a more competent and exact predictor.
Due to the different approaches of predicting disordered proteins, estimating their relative accuracy is fairly difficult. For example, neural networks are often trained on different datasets. The disorder prediction category is a part of biannual CASP experiment that is designed to test methods according accuracy in finding regions with missing 3D structure (marked in PDB files as REMARK465, missing electron densities in X-ray structures).
== Disorder and disease ==
Intrinsically unstructured proteins have been implicated in a number of diseases. Aggregation of misfolded proteins is the cause of many synucleinopathies and toxicity as those proteins start binding to each other randomly and can lead to cancer or cardiovascular diseases. Thereby, misfolding can happen spontaneously because millions of copies of proteins are made during the lifetime of an organism. The aggregation of the intrinsically unstructured protein α-synuclein is thought to be responsible. The structural flexibility of this protein together with its susceptibility to modification in the cell leads to misfolding and aggregation. Genetics, oxidative and nitrative stress as well as mitochondrial impairment impact the structural flexibility of the unstructured α-synuclein protein and associated disease mechanisms. Many key tumour suppressors have large intrinsically unstructured regions, for example p53 and BRCA1. These regions of the proteins are responsible for mediating many of their interactions. Taking the cell's native defense mechanisms as a model drugs can be developed, trying to block the place of noxious substrates and inhibiting them, and thus counteracting the disease.
== Computer simulations ==
Owing to high structural heterogeneity, NMR/SAXS experimental parameters obtained will be an average over a large number of highly diverse and disordered states (an ensemble of disordered states). Hence, to understand the structural implications of these experimental parameters, there is a necessity for accurate representation of these ensembles by computer simulations. All-atom molecular dynamic simulations can be used for this purpose but their use is limited by the accuracy of current force-fields in representing disordered proteins. Nevertheless, some force-fields have been explicitly developed for studying disordered proteins by optimising force-field parameters using available NMR data for disordered proteins. (examples are CHARMM 22*, CHARMM 32, Amber ff03* etc.)
MD simulations restrained by experimental parameters (restrained-MD) have also been used to characterise disordered proteins. In principle, one can sample the whole conformational space given an MD simulation (with accurate Force-field) is run long enough. Because of very high structural heterogeneity, the time scales that needs to be run for this purpose are very large and are limited by computational power. However, other computational techniques such as accelerated-MD simulations, replica exchange simulations, metadynamics, multicanonical MD simulations, or methods using coarse-grained representation with implicit and explicit solvents have been used to sample broader conformational space in smaller time scales.
Moreover, various protocols and methods of analyzing IDPs, such as studies based on quantitative analysis of GC content in genes and their respective chromosomal bands, have been used to understand functional IDP segments.
== See also ==
IDPbyNMR
DisProt database
MobiDB database
Molten globule
Prion
Random coil
Dark proteome
== References ==
== External links ==
Intrinsically disordered protein at Proteopedia
MobiDB: a comprehensive database of intrinsic protein disorder annotations
IDEAL - Intrinsically Disordered proteins with Extensive Annotations and Literature Archived 2020-05-02 at the Wayback Machine
D2P2 Database of Disordered Protein Predictions
Gallery of images of intrinsically disordered proteins
First IDP journal covering all topics of IDP research
IDP Journal
Database of experimentally validated IDPs
IDP ensemble database Archived 2018-03-10 at the Wayback Machine | Wikipedia/Intrinsically_disordered_proteins |
The Worldwide Protein Data Bank (wwPDB) is an organization that maintains the archive of macromolecular structure. Its mission is to maintain a single Protein Data Bank Archive of macromolecular structural data that is freely and publicly available to the global community.
The organization has five members:
Research Collaboratory for Structural Bioinformatics Protein Database (RCSB PDB)
Protein Data Bank in Europe (PDBe)
Protein Data Bank Japan (PDBj)
Biological Magnetic Resonance Data Bank (BMRB)
Electron Microscopy Data Bank (EMDB).
The wwPDB was founded in 2003 by RCSB PDB (USA), PDBe (Europe) and PDBj (Japan). In 2006 BMRB (USA) joined the wwPDB. EMDB (UK) joined in 2021.
Each member's site can accept structural data and process the data. The processed data is sent to the "archive keeper". The RCSB PDB presently acts as the "archive keeper". This ensures that there is only one version of the data which is identical for all users. The modified database is then made available to the other wwPDB members, each of whom makes the resulting structure files available through their websites to the public. (Data is accessed from the wwPDB website itself only through links to the member websites.) The member sites are more than just mirrors of the archive keeper, because the members offer different tools on their websites for analysing the structures in the database.
Accomplishments
2008 The wwPDB now requires that, in addition to atomic coordinates, structure factor amplitudes and intensities (for crystal structure depositions) and NMR restraints (for NMR structure depositions) must be deposited as a prerequisite for receiving a PDB ID.
2007 Rolled out a remediated PDB. Remediation included changing the nomenclature to conform to IUPAC standards.
== References ==
== External links ==
Official website
Member organizations
RCSB PDB, Research Collaboratory for Structural Bioinformatics Protein Databank (USA)
PDBe, Protein Data Bank in Europe
PDBj, Protein Data Bank Japan
BMRB, Biological Magnetic Resonance Data Bank (USA)
Electron Microscopy Data Bank | Wikipedia/Worldwide_Protein_Data_Bank |
In biology, a protein structure database is a database that is modeled around the various experimentally determined protein structures. The aim of most protein structure databases is to organize and annotate the protein structures, providing the biological community access to the experimental data in a useful way. Data included in protein structure databases often includes three-dimensional coordinates as well as experimental information, such as unit cell dimensions and angles for x-ray crystallography determined structures. Though most instances, in this case either proteins or a specific structure determinations of a protein, also contain sequence information and some databases even provide means for performing sequence based queries, the primary attribute of a structure database is structural information, whereas sequence databases focus on sequence information, and contain no structural information for the majority of entries. Protein structure databases are critical for many efforts in computational biology such as structure based drug design, both in developing the computational methods used and in providing a large experimental dataset used by some methods to provide insights about the function of a protein.
== The Protein Data Bank ==
The Protein Data Bank (PDB) was established in 1971 as the central archive of all experimentally determined protein structure data. Today the PDB is maintained by an international consortia collectively known as the Worldwide Protein Data Bank (wwPDB). The mission of the wwPDB is to maintain a single archive of macromolecular structural data that is freely and publicly available to the global community.
== List of other protein structure databases ==
Because the PDB releases data into the public domain, the data has been used in various other protein structure databases.
Examples of protein structure databases include (in alphabetical order);
Database of Macromolecular Movements
describes the motions that occur in proteins and other macromolecules, particularly using movies
Dynameomics
a data warehouse of molecular dynamics simulations and analyses of proteins representing all known protein fold families
JenaLib
the Jena Library of Biological Macromolecules is aimed at a better dissemination of information on three-dimensional biopolymer structures with an emphasis on visualization and analysis.
ModBase
a database of three-dimensional protein models calculated by comparative modeling
OCA
a browser-database for protein structure/function - The OCA integrates information from KEGG, OMIM, PDBselect, Pfam, PubMed, SCOP, SwissProt, and others.
OPM
provides spatial positions of protein three-dimensional structures with respect to the lipid bilayer.
PDB Lite
derived from OCA, PDB Lite was provided to make it as easy as possible to find and view a macromolecule within the PDB
PDBsum
provides an overview macromolecular structures in the PDB, giving schematic diagrams of the molecules in each structure and of the interactions between them
PDBTM
the Protein Data Bank of Transmembrane Proteins — a selection of the PDB.
PDBWiki
a community annotated knowledge base of biological molecular structures [1]
ProtCID
The Protein Common Interface Database (ProtCID) is a database of similar protein–protein interfaces in crystal structures of homologous proteins.
Protein
the NIH protein database, a collection of sequences from several sources, including translations from annotated coding regions in GenBank, RefSeq and Third Party Annotation, as well as records from SwissProt, PIR, PRF, and PDB
Proteopedia
the collaborative, 3D encyclopedia of proteins and other molecules. A wiki that contains a page for every entry in the PDB (>100,000 pages), with a Jmol view that highlights functional sites and ligands. Offers an easy-to-use scene-authoring tool so you don't have to learn Jmol script language to create customized molecular scenes. Custom scenes are easily attached to "green links" in descriptive text that display those scenes in Jmol.
ProteinLounge
a protein databases that includes visuals of protein structure. Also, includes protein pathways and gene sequences including other tools.
SCOP
the Structural Classification of Proteins [2] a detailed and comprehensive description of the structural and evolutionary relationships between all proteins whose structure is known.
SWISS-MODEL Repository
a database of annotated protein models calculated by homology modeling
TOPSAN
the Open Protein Structure Annotation Network — a wiki designed to collect, share and distribute information about protein three-dimensional structures.
== References == | Wikipedia/Protein_structure_database |
The Zebrafish Information Network (ZFIN) is an online biological database of information about the zebrafish (Danio rerio). The zebrafish is a widely used model organism for genetic, genomic, and developmental studies, and ZFIN provides an integrated interface for querying and displaying the large volume of data generated by this research. To facilitate use of the zebrafish as a model of human biology, ZFIN links these data to corresponding information about other model organisms (e.g., mouse) and to human disease databases. Abundant links to external sequence databases (e.g., GenBank) and to genome browsers are included. Gene product, gene expression, and phenotype data are annotated with terms from biomedical ontologies. ZFIN is based at the University of Oregon in the United States, with funding provided by the National Institutes of Health (NIH).
== Contents ==
ZFIN consists of two principal parts:
a website of community news and announcements, as well as biological resources such as laboratory protocols, a gene nomenclature guide, and anatomy information
a relational database containing biological data that are curated from the scientific literature and that are directly submitted by zebrafish research laboratories (e.g., Thisse high-throughput gene expression analysis).
Information in ZFIN is tightly linked to the web resources of the Zebrafish International Resource Center (ZIRC), the China Zebrafish Resource Center (CZRC), and so on, which maintain and provide zebrafish-related research resources, materials and services.
ZFIN's relational database interface provides query forms and display pages for the following biological data types:
Genes, markers, and clones
Gene expression
Antibodies
Sequence alignments (BLAST)
Mutants and transgenic lines
Anatomy
Genetic maps
ZFIN also maintains a database of zebrafish-related publications, laboratories, people, and companies.
In addition to its specialized search interfaces, ZFIN provides a Google-like global site search.
ZFIN's community wiki gives zebrafish researchers the ability to share information about laboratory protocols and antibodies.
== Notes and references ==
== External links ==
ZFIN The Zebrafish Model Organism Database
Vega Zebrafish Genome Annotation
FishMap : The Zebrafish Community Genomics Browser maintained at the Institute of Genomics and Integrative Biology
Zebrafish GenomeWiki Beta Preview maintained at the Institute of Genomics and Integrative Biology
== See also ==
Wormbase
Flybase
Xenbase | Wikipedia/Zebrafish_Information_Network |
Intelligent Systems for Molecular Biology (ISMB) is an annual academic conference on the subjects of bioinformatics and computational biology organised by the International Society for Computational Biology (ISCB). The principal focus of the conference is on the development and application of advanced computational methods for biological problems. The conference has been held every year since 1993 and has grown to become one of the largest and most prestigious meetings in these fields, hosting over 2,000 delegates in 2004. From the first meeting, ISMB has been held in locations worldwide; since 2007, meetings have been located in Europe and North America in alternating years. Since 2004, European meetings have been held jointly with the European Conference on Computational Biology (ECCB).
The main ISMB conference is usually held over three days and consists of presentations, poster sessions and keynote talks. Most presentations are given in multiple parallel tracks; however, keynote talks are presented in a single track and are chosen to reflect outstanding research in bioinformatics. Notable ISMB keynote speakers have included eight Nobel laureates. The recipients of the ISCB Overton Prize and ISCB Accomplishment by a Senior Scientist Award are invited to give keynote talks as part of the programme. The proceedings of the conference are currently published by the journal Bioinformatics.
== History ==
=== Early meetings ===
The origins of the ISMB conference lie in a workshop for artificial intelligence researchers with an interest in molecular biology held in November 1991. The workshop was organised by American researcher Lawrence Hunter, then director of the Machine Learning Project at the United States National Institutes of Health's National Library of Medicine (NLM) in Bethesda, Maryland. A subsequent workshop on the same topic held in 1992, hosted by the NLM and the National Science Foundation, made it clear that a regular international conference for the field was required. Such a conference would be dedicated to molecular biology as a rapidly emerging application of artificial intelligence. Having successfully applied for grants from AAAI, NIH and the Department of Energy Office of Health and Environmental Research, the first ISMB conference was held in July 1993, at the NLM. The conference was chaired by Hunter, David Searls (research associate professor at University of Pennsylvania School of Medicine) and Jude Shavlik (assistant professor of computer science at University of Wisconsin–Madison) and attracted over 200 attendees from 13 countries, submitting 69 scientific papers.
The success of the first conference prompted the announcement of a second ISMB conference at the end of the meeting. ISMB 1994 was initially planned to be held in Seattle. However, a competing meeting forced ISMB to change venues at short notice. The conference was held at Stanford University in August 1994 and was organised by Russ Altman, a research scientist at Stanford University School of Medicine. To emphasise the international aspect of the conference, ISMB 1995 was held at Robinson College, Cambridge. ISMB 1995 also marked a shift in the focus of the conference. ISCB Board member and Director of the Spanish National Bioinformatics Institute Alfonso Valencia has stated that, in 1995, "the conference changed from a computer science-based conference to a point where everyone realized that, if you want to make progress, there has to be more focus in biology."
=== Formation of ISCB and expansion ===
ISMB 1997 was held in Halkidiki, Greece and marked the foundation of the International Society for Computational Biology (ISCB). ISCB was formed with a focus on managing all scientific, organizational and financial aspects of the ISMB conference and to provide a forum for scientists to address the emerging role of computers in the biological sciences. ISCB has assisted in organising the ISMB conference series since 1998. The period following the formation of ISCB also marked an expansion in the number of ISMB attendees: ISMB 2000 (held at the University of California, San Diego) was attended by over 1,000 delegates, submitting 141 scientific papers. This meeting was also the last time ISMB would be held at a university, due to size limitations.
=== Partnership with ECCB ===
In 2004, ISMB was jointly held with the European Conference on Computational Biology for the first time. The conference was also co-located with the Genes, Proteins and Computers conference. This meeting, held in Glasgow, UK, was the largest bioinformatics conference ever held, attended by 2,136 delegates, submitting 496 scientific papers. Alfonso Valencia considers ISMB/ECCB 2004 to be an important milestone in the history of ISMB: "it was the first one where the balance between Europe and the States became an important part of the conference. It was here that we established the rules and the ways and the spirit of collaboration between the Americans and the Europeans." The success of the joint conference paved the way for future European ISMB meetings to be held jointly with ECCB.
=== Recent meetings ===
By the end of 2006, ISCB was in financial difficulty. Two conferences (ISMB 2003, in Brisbane and ISMB 2006, in Fortaleza) had drastically reduced numbers of participants due to their location, with a corresponding reduction in income. To allow more delegates to attend, it was decided to limit conference locations to North America and Europe. In January 2007, ISMB and ECCB agreed to hold joint conferences in Europe every other year, beginning with ISMB/ECCB 2007. ISMB would be held in North America in the years between joint meetings. As of 2016, this pattern has been confirmed to continue until at least 2019. ISMB/ECCB 2007 (held in Vienna, Austria) marked the first conference for which ISCB took full responsibility for organising. Vienna became the first city to host ISMB twice with ISMB/ECCB 2011. This 'return visit' was an experiment intended to reduce the increasing effort required to find suitable conference venues. Although the return to Vienna was only deemed partially successful due to price increases, Boston (which hosted ISMB 2010 and 2014) is predicted to become a 'safe' site which ISMB can periodically return to.
ISMB celebrated its 20th meeting with ISMB 2012, held in Long Beach, California. This event attracted around 1,600 delegates, submitting 268 scientific papers. Richard H. Lathrop and Lawrence Hunter presented a special keynote presentation, looking back at previous ISMB meetings and attempting to predict where the field of bioinformatics may head in the future. ISMB/ECCB 2013 was held in Berlin, Germany and was attended by around 2,000 delegates, submitting 233 scientific papers.
== Format ==
=== Main conference ===
The main ISMB conference is usually held over three days and consists of presentations, poster sessions and keynote talks.
Academic papers at ISMB were traditionally presented in a single track. Presentations at ISMB 1994 were split further into three themed days, focusing on protein secondary structure prediction, sequence analysis and AI techniques and biochemical applications, respectively. As attendance at ISMB increased, the single track approach became increasingly unsustainable and two parallel tracks were introduced at ISMB/ECCB 2004. Further expansion meant that, by ISMB 2012, over 200 talks were presented in nine parallel tracks including multiple proceedings tracks, a highlights track and a technology track. The introduction of parallel tracks to ISMB was controversial. Christopher Rawlings (head of Computational and Systems Biology at Rothamsted Research and organiser of ISMB 1995) has said: "There were a lot of people who wanted to keep it more strongly in the AI intelligent systems model and have a meeting where everybody would go to everything. But it just grew too big. We just couldn’t." As the number of submitted proceedings papers has increased, the acceptance rate has decreased dramatically, from 75% in 1994 to 13% in 2012. ISMB proceedings from 1993-2000 were published by AAAI Press. Since ISMB 2001, proceedings have been published in the journal Bioinformatics. The number of posters presented at ISMB has also increased dramatically. 25 posters were presented at ISMB 1994; at recent ISMB meetings, 500–1,000 posters have been presented in multiple poster sessions.
Keynote talks are presented in a single track and generally attract the largest audience. These presentations are chosen to highlight outstanding research in the field of bioinformatics. Notable ISMB keynote speakers have included eight Nobel laureates: Richard J. Roberts (keynote speaker in 1994, 2006), John Sulston (1995), Manfred Eigen (1999), Gerald Edelman (2000), Sydney Brenner (2003), Kurt Wüthrich (2006), Robert Huber (2006) and Michael Levitt (2015).
As of 2012, ISMB runs on a budget in excess of $1.5M and, in terms of proceeds, brings in four times that of the other ISCB conferences (ISCB-Latin America, ISCB-Africa, ISCB-Asia, Rocky Mountain Bioinformatics Conference, CSHALS and the Great Lakes Bioinformatics Conference) combined. Standard registration fees (as of 2013) are around $1,000 for academics who are ISCB members ($1,350 for non-members), with lower rates for students and higher rates for corporate delegates respectively. Discounts are provided for early registration.
=== Satellite events ===
Pre-conference tutorials have played an important role in ISMB since the first conference. Tutorials at ISMB 1994 included introductions to genetic algorithms, neural networks, AI for molecular biologists and molecular biology for computer scientists. Tutorials on computational mass spectrometry-based proteomics and ENCODE data access were presented at ISMB/ECCB 2013.
As attendance at ISMB grew in the late 1990s, several satellite meetings and special interest group (SIG) meetings formed alongside the main conference. SIG meetings are held over one or two days before the main conference and focus on a specific topic, allowing more detailed discussion than there would be time for in the main conference. Notable SIG meetings include the Bioinformatics Open Source Conference (BOSC), which has been held annually since 2000 and Bio-Ontologies, which has been held annually since 1998. Satellite meetings are usually two days long and are held in conjunction with ISMB. The 12th CAMDA conference and the 9th 3DSIG meeting were held as satellite meetings of ISMB/ECCB 2013.
== List of conferences ==
=== Planned events ===
== See also ==
European Conference on Computational Biology (ECCB)
Pacific Symposium on Biocomputing (PSB)
Research in Computational Molecular Biology (RECOMB)
== References == | Wikipedia/Intelligent_Systems_for_Molecular_Biology |
The Protein Information Resource (PIR), located at Georgetown University Medical Center, is an integrated public bioinformatics resource to support genomic and proteomic research, and scientific studies. It contains protein sequences databases
== History ==
PIR was established in 1984 by the National Biomedical Research Foundation as a resource to assist researchers and customers in the identification and interpretation of protein sequence information. Prior to that, the foundation compiled the first comprehensive collection of macromolecular sequences in the Atlas of Protein Sequence and Structure, published from 1964 to 1974 under the editorship of Margaret Dayhoff. Dayhoff and her research group pioneered in the development of computer methods for the comparison of protein sequences, for the detection of distantly related sequences and duplications within sequences, and for the inference of evolutionary histories from alignments of protein sequences.
Winona Barker and Robert Ledley assumed leadership of the project after the death of Dayhoff in 1983. In 1999, Cathy H. Wu joined the National Biomedical Research Foundation, and later on Georgetown University Medical Center, to head the bioinformatics efforts of PIR, and has served first as Principal Investigator and, since 2001, as Director.
For four decades, PIR has provided many protein databases and analysis tools freely accessible to the scientific community, including the Protein Sequence Database, the first international database (see PIR-International), which grew out of Atlas of Protein Sequences and Structure.
In 2002, PIR – along with its international partners, the European Bioinformatics Institute and the Swiss Institute of Bioinformatics – were awarded a grant from NIH to create UniProt, a single worldwide database of protein sequence and function, by unifying the Protein Information Resource-Protein Sequence Database, Swiss-Prot, and TrEMBL databases. As of 2010, PIR offers a wide variety of resources mainly oriented to assist the propagation and standardization of protein annotation: PIRSF, iProClass, and iProLINK.
The Protein Ontology is another popular database released by the Protein Information Resource.
== References == | Wikipedia/Protein_Information_Resource |
The Protein Data Bank (PDB) file format is a textual file format describing the three-dimensional structures of molecules held in the Protein Data Bank, now succeeded by the mmCIF format. The PDB format accordingly provides for description and annotation of protein and nucleic acid structures including atomic coordinates, secondary structure assignments, as well as atomic connectivity. In addition experimental metadata are stored. The PDB format is the legacy file format for the Protein Data Bank which has kept data on biological macromolecules in the newer PDBx/mmCIF file format since 2014.
== History ==
The PDB file format was invented in 1972 as a human-readable file that would allow researchers to exchange the atomic coordinates in a given protein through a database system. Its fixed-column width format is limited to 80 or 140 columns, which was based on the width of the computer punch cards that were previously used to exchange the coordinates. Through the years the file format has undergone many changes and revisions. The final update to the PDB file format was in November 2012 with version 3.30.
== Example ==
A typical PDB file describing a protein consists of hundreds to thousands of lines like the following (taken from a file describing the structure of a synthetic collagen-like peptide):
HEADER EXTRACELLULAR MATRIX 22-JAN-98 1A3I
TITLE X-RAY CRYSTALLOGRAPHIC DETERMINATION OF A COLLAGEN-LIKE
TITLE 2 PEPTIDE WITH THE REPEATING SEQUENCE (PRO-PRO-GLY)
...
EXPDTA X-RAY DIFFRACTION
AUTHOR R.Z.KRAMER,L.VITAGLIANO,J.BELLA,R.BERISIO,L.MAZZARELLA,
AUTHOR 2 B.BRODSKY,A.ZAGARI,H.M.BERMAN
...
REMARK 350 BIOMOLECULE: 1
REMARK 350 APPLY THE FOLLOWING TO CHAINS: A, B, C
REMARK 350 BIOMT1 1 1.000000 0.000000 0.000000 0.00000
REMARK 350 BIOMT2 1 0.000000 1.000000 0.000000 0.00000
...
SEQRES 1 A 9 PRO PRO GLY PRO PRO GLY PRO PRO GLY
SEQRES 1 B 6 PRO PRO GLY PRO PRO GLY
SEQRES 1 C 6 PRO PRO GLY PRO PRO GLY
...
ATOM 1 N PRO A 1 8.316 21.206 21.530 1.00 17.44 N
ATOM 2 CA PRO A 1 7.608 20.729 20.336 1.00 17.44 C
ATOM 3 C PRO A 1 8.487 20.707 19.092 1.00 17.44 C
ATOM 4 O PRO A 1 9.466 21.457 19.005 1.00 17.44 O
ATOM 5 CB PRO A 1 6.460 21.723 20.211 1.00 22.26 C
...
HETATM 130 C ACY 401 3.682 22.541 11.236 1.00 21.19 C
HETATM 131 O ACY 401 2.807 23.097 10.553 1.00 21.19 O
HETATM 132 OXT ACY 401 4.306 23.101 12.291 1.00 21.19 O
...
HEADER, TITLE and AUTHOR records
provide information about the researchers who defined the structure; numerous other types of records are available to provide other types of information.
REMARK records
can contain free-form annotation, but they also accommodate standardized information; for example, the REMARK 350 BIOMT records describe how to compute the coordinates of the experimentally observed multimer from those of the explicitly specified ones of a single repeating unit.
SEQRES records
give the sequences of the three peptide chains (named A, B and C), which are very short in this example but usually span multiple lines.
ATOM records
describe the coordinates of the atoms that are part of the protein. For example, the first ATOM line above describes the alpha-N atom of the first residue of peptide chain A, which is a proline residue; the first three floating point numbers are its x, y and z coordinates and are in units of Ångströms. The next three columns are the occupancy, temperature factor, and the element name, respectively.
HETATM records
describe coordinates of hetero-atoms, that is those atoms which are not part of the protein molecule.
== Molecular visualization software capable of displaying PDB files ==
== 3d Animation software capable of displaying PDB files ==
== See also ==
Chemical file format
ScientificPython — provides an interface for Python
Software for molecular mechanics modeling
== References ==
== External links ==
PDB Format Guide This is the current version (3.3) of the PDB format specification.
PDBML A more recent, alternative XML-based file format for molecular coordinates.
The RCSB Protein Data Bank
Protein Data Bank in Europe
The Molecular Modeling DataBase (MMDB) from NCBI
The wwPDB remediation Project from wwPDB
MakeMultimer An online tool for expanding BIOMT records in PDB files
Molecules iPad/iPhone App to display PDB files
Python Macromolecular Library (mmLib) — a Python library capable of reading and writing PDB file formats | Wikipedia/Protein_Data_Bank_(file_format) |
Before the emergence of electron microscopy in the 1950s, scientists did not know the structure of a cell membrane or what its components were; biologists and other researchers used indirect evidence to identify membranes before they could actually be visualized. Specifically, it was through the models of Overton, Langmuir, Gorter and Grendel, and Davson and Danielli, that it was deduced that membranes have lipids, proteins, and a bilayer. The advent of the electron microscope, the findings of J. David Robertson, the proposal of Singer and Nicolson, and additional work of Unwin and Henderson all contributed to the development of the modern membrane model. However, understanding of past membrane models elucidates present-day perception of membrane characteristics. Following intense experimental research, the membrane models of the preceding century gave way to the fluid mosaic model that is generally accepted as a partial description.
== Gorter and Grendel's membrane theory (1925) ==
Evert Gorter and François Grendel (Dutch physiologists) approached the discovery of our present model of the plasma membrane structure as a lipid bi-layer. They simply hypothesized that if the plasma membrane is a bi-layer, then the surface area of the mono-layer of lipids measured would be double the surface area of the plasma membrane. To examine their hypothesis, they performed an experiment in which they extracted lipids from a known number of red blood cells (erythrocytes) of different mammalian sources, such as humans, goats, sheep, etc. and then spreading the lipids as a mono-layer in a Langmuir-Blodgett trough. They measured the total surface area of the plasma membrane of red blood cells, and using Langmuir's method, they measured the area of the monolayer of lipids. In comparing the two, they calculated an estimated ratio of 2:1 Mono-layer of lipids: Plasma membrane. This supported their hypothesis, which led to the conclusion that cell membranes are composed of two opposing molecular layers. The two scientists proposed a structure for this bi-layer, with the polar hydrophilic heads facing outwards towards the aqueous environment and the hydrophobic tails facing inwards away from the aqueous surroundings on both sides of the membrane. Although they arrived at the right conclusions, some of the experimental data were incorrect such as the miscalculation of the area and pressure of the lipid monolayer and the incompleteness of lipid extraction. They also failed to describe membrane function and had false assumptions such as that of plasma membranes consisting mostly of lipids. However, on the whole, this envisioning of the lipid bi-layer structure became the basic underlying assumption for each successive refinement in a modern understanding of membrane function.
== The Davson and Danielli model with backup from Robertson (1940–1960) ==
Following the proposal of Gorter and Grendel, doubts inevitably arose over the veracity of having just a simple lipid bi-layer as a membrane. For instance, their model could not provide answers to questions on surface tension, permeability, and the electric resistance of membranes. Therefore, physiologist Hugh Davson and biologist James Danielli suggested that membranes indeed do have proteins. According to them, the existence of these "membrane proteins" explained that which couldn't be answered by the Gorter-Grendel model.
In 1935, Davson and Danielli proposed that biological membranes are made up of lipid bi-layers that are coated on both sides with thin sheets of protein and they simplified their model into the "pauci-molecular" theory. This theory declared that all biological membranes have a "lipoid" center surrounded by mono-layers of lipid that are covered by protein mono-layers. In short, their model was illustrated as a "sandwich" of protein-lipid-protein. The Davson-Danielli model threw new light on the understanding of cell membranes, by stressing the important role played by proteins in biological membranes.
By the 1950s, cell biologists verified the existence of plasma membranes through the use of electron microscopy (which accounted for higher resolutions). J. David Robertson used this method to propose the unit membrane model. Basically, he suggested that all cellular membranes share a similar underlying structure, the unit membrane. Using heavy metal staining, Robertson's proposal also seemed to agree instantaneously with the Davson-Danielli model. According to the trilaminar pattern of the cellular membrane viewed by Robertson, he suggested that the membranes consist of a lipid bi-layer covered on both surfaces with thin sheets of proteins(mucoprotiens). This suggestion was a great boost to the proposal of Davson and Danielli. However, even with Robertson's substantiation, the Davson-Danielli model had serious complications, a major one being that the proteins studied were mainly globular and couldn't therefore fit into the model's claim of thin protein sheets. These difficulties with the model stimulated new research in membrane organization and paved the way for the fluid mosaic model, which was proposed in 1972.
== Singer and Nicolson's fluid mosaic model (1972) ==
In 1972, S. Jonathan Singer and Garth Nicolson developed new ideas for membrane structure. Their proposal was the fluid mosaic model, which is one of the dominant models now. It has two key features—a mosaic of proteins embedded in the membrane, and the membrane being a fluid bi-layer of lipids. The lipid bi-layer suggestion agrees with previous models but views proteins as globular entities embedded in the layer instead of thin sheets on the surface.
According to the model, membrane proteins are in three classes based on how they are linked to the lipid bi-layer:
Integral proteins: Immersed in the bi-layer and held in place by the affinity of hydrophobic parts of the protein for the hydrophobic tails of phospholipids on interior of the layer.
Peripheral proteins: More hydrophilic, and thus are non-covalently linked to the polar heads of phospholipids and other hydrophilic parts of other membrane proteins on the surface of the membrane.
Lipid anchored proteins: Essentially hydrophilic, so, are also located on the surface of the membrane, and are covalently attached to lipid molecules embedded in the layer.
As for the fluid nature of the membrane, the lipid components are capable of moving parallel to the membrane surface and are in constant motion. Many proteins are also capable of that motion within the membrane. However, some are restricted in their mobility due to them being anchored to structural elements such as the cytoskeleton on either side of the membrane.
In general, this model explains most of the criticisms of the Davson–Danielli model. It eliminated the need to accommodate membrane proteins in thin surface layers, proposed that the variability in the protein/lipid ratios of different membranes simply means that different membranes vary in the amount of protein they contain, and showed how the exposure of lipid-head groups at the membrane surface is compatible with their sensitivity to phospholipase digestion. Also, the fluidity of the lipid bi-layers and the intermingling of their components within the membrane make it easy to visualize the mobility of both lipids and proteins.
== Henderson and Unwin's membrane theory ==
Henderson and Unwin have studied the purple membrane by electron microscopy, using a method for determining the projected structures of unstained crystalline specimens. By applying the method to tilted specimens, and using the principles put forward by DeRosier and Klug for the combination of such two-dimensional views, they obtained a 3-dimensional map of the membrane at 7 Å resolution. The map reveals the location of the protein and lipid components, the arrangement of the polypeptide chains within each protein molecule, and the relationship of the protein molecules in the lattice.
High-resolution micrographs of crystalline arrays of membrane proteins, taken at a low dose of electrons to minimize radiation damage, have been exploited to determine the three-dimensional structure by a Fourier transform.
Recent studies on negatively stained rat hepatocyte Gap™ junctions subjected to 3-dimensional Fourier reconstructions (of low-dose electron micrographs) indicate that the six protein sub-units are arranged in a cylinder slightly tilted tangentially, enclosing a channel 2 nm wide at the extracellular region. The dimensions of the channel within the membrane were narrower but could not be resolved (Unwin and Zampighi, 1980). A small radical movement of the sub-units at the cytoplasmic ends could reduce the sub-unit inclination tangential to six-fold axis and close the channel.
Further details of the molecular organization should emerge as more methods of preparation become available, so that high-resolution 3-dimensional images comparable to the purple membranes are obtained. By using ingenious procedures for the analysis of periodic arrays of biological macromolecules, in which data from low-dose electron images and diffraction patterns were combined, Henderson and Unwin (1975) reconstructed a three-dimensional image of purple membranes at 0.7 nm resolution. Glucose embedding was employed to alleviate dehydration damage and low doses (< 0.5 e/A*) to reduce the irradiation damage. The electron micrographs of unstained membranes were recorded such that the only source of contrast was a weak phase contrast induced by defocusing.
In their experiment, Unwin and Henderson found that protein extends to both sides of the lipid bi-layer and is composed of seven α-helices packed about 1–1.2 nm apart, 3.5–4.0 nm in length, running perpendicular to the plane of membrane. The molecules are organized around a 3-fold axis with a 2 nm-wide space at the center that is filled with lipids. This elegant work represents the most significant step forward thus far, as it has for the first time provided us with the structure of an integral membrane protein in situ.
The availability of the amino acid sequence, together with information about the electron scattering density from the work of Henderson and Unwin, has stimulated model-building efforts (Engleman et al., 1980) to fit the bacteriorhodopsin sequence information into a series of α-helical segments.
== Kervin and Overduin's proteolipid code (2024) ==
Building on the fluid mosaic model, a framework called the proteolipid code was proposed in order to explain membrane organization. The proteolipid code relies on the concept of a zone, which is a functional region of membrane that is assembled and stabilized with both protein and lipid dependency. Integral and lipid-anchored proteins are proposed to form three types of zones: proteins with an associated lipid fingerprint, protein islands, and lipid-only voids. Although the latter do not contain proteins as part of their internal particle set or primary structure, they do contain proteins in their quaternary association with the former two zone types which influence the composition of the void. The idea that lipids can cluster independently of proteins through lipid-lipid interactions and then recruit integral proteins is forbidden in the framework, although lipid clustering is allowed and is designated as zone secondary structure.
== See also ==
Cell biology
Cell theory
History of cell membrane theory
Membrane protein
== References == | Wikipedia/Membrane_models |
In chemistry, a solution is defined by IUPAC as "A liquid or solid phase containing more than one substance, when for convenience one (or more) substance, which is called the solvent, is treated differently from the other substances, which are called solutes. When, as is often but not necessarily the case, the sum of the mole fractions of solutes is small compared with unity, the solution is called a dilute solution. A superscript attached to the ∞ symbol for a property of a solution denotes the property in the limit of infinite dilution." One important parameter of a solution is the concentration, which is a measure of the amount of solute in a given amount of solution or solvent. The term "aqueous solution" is used when one of the solvents is water.
== Types ==
Homogeneous means that the components of the mixture form a single phase. Heterogeneous means that the components of the mixture are of different phase. The properties of the mixture (such as concentration, temperature, and density) can be uniformly distributed through the volume but only in absence of diffusion phenomena or after their completion. Usually, the substance present in the greatest amount is considered the solvent. Solvents can be gases, liquids, or solids. One or more components present in the solution other than the solvent are called solutes. The solution has the same physical state as the solvent.
=== Gaseous mixtures ===
If the solvent is a gas, only gases (non-condensable) or vapors (condensable) are dissolved under a given set of conditions. An example of a gaseous solution is air (oxygen and other gases dissolved in nitrogen). Since interactions between gaseous molecules play almost no role, non-condensable gases form rather trivial solutions. In the literature, they are not even classified as solutions, but simply addressed as homogeneous mixtures of gases. The Brownian motion and the permanent molecular agitation of gas molecules guarantee the homogeneity of the gaseous systems. Non-condensable gaseous mixtures (e.g., air/CO2, or air/xenon) do not spontaneously demix, nor sediment, as distinctly stratified and separate gas layers as a function of their relative density. Diffusion forces efficiently counteract gravitation forces under normal conditions prevailing on Earth. The case of condensable vapors is different: once the saturation vapor pressure at a given temperature is reached, vapor excess condenses into the liquid state.
=== Liquid solutions ===
Liquids dissolve gases, other liquids, and solids. An example of a dissolved gas is oxygen in water, which allows fish to breathe under water. An examples of a dissolved liquid is ethanol in water, as found in alcoholic beverages. An example of a dissolved solid is sugar water, which contains dissolved sucrose.
=== Solid solutions ===
If the solvent is a solid, then gases, liquids, and solids can be dissolved.
Gas in solids:
Hydrogen dissolves rather well in metals, especially in palladium; this is studied as a means of hydrogen storage.
Liquid in solid:
Mercury in gold, forming an amalgam
Water in solid salt or sugar, forming moist solids
Hexane in paraffin wax
Polymers containing plasticizers such as phthalate (liquid) in PVC (solid)
Solid in solid:
Steel, basically a solution of carbon atoms in a crystalline matrix of iron atoms
Alloys like bronze and many others
Radium sulfate dissolved in barium sulfate: a true solid solution of Ra in BaSO4
== Solubility ==
The ability of one compound to dissolve in another compound is called solubility. When a liquid can completely dissolve in another liquid the two liquids are miscible. Two substances that can never mix to form a solution are said to be immiscible.
All solutions have a positive entropy of mixing. The interactions between different molecules or ions may be energetically favored or not. If interactions are unfavorable, then the free energy decreases with increasing solute concentration. At some point, the energy loss outweighs the entropy gain, and no more solute particles can be dissolved; the solution is said to be saturated. However, the point at which a solution can become saturated can change significantly with different environmental factors, such as temperature, pressure, and contamination. For some solute-solvent combinations, a supersaturated solution can be prepared by raising the solubility (for example by increasing the temperature) to dissolve more solute and then lowering it (for example by cooling).
Usually, the greater the temperature of the solvent, the more of a given solid solute it can dissolve. However, most gases and some compounds exhibit solubilities that decrease with increased temperature. Such behavior is a result of an exothermic enthalpy of solution. Some surfactants exhibit this behaviour. The solubility of liquids in liquids is generally less temperature-sensitive than that of solids or gases.
== Properties ==
The physical properties of compounds such as melting point and boiling point change when other compounds are added. Together they are called colligative properties. There are several ways to quantify the amount of one compound dissolved in the other compounds collectively called concentration. Examples include molarity, volume fraction, and mole fraction.
The properties of ideal solutions can be calculated by the linear combination of the properties of its components. If both solute and solvent exist in equal quantities (such as in a 50% ethanol, 50% water solution), the concepts of "solute" and "solvent" become less relevant, but the substance that is more often used as a solvent is normally designated as the solvent (in this example, water).
== Liquid solution characteristics ==
In principle, all types of liquids can behave as solvents: liquid noble gases, molten metals, molten salts, molten covalent networks, and molecular liquids. In the practice of chemistry and biochemistry, most solvents are molecular liquids. They can be classified into polar and non-polar, according to whether their molecules possess a permanent electric dipole moment. Another distinction is whether their molecules can form hydrogen bonds (protic and aprotic solvents). Water, the most commonly used solvent, is both polar and sustains hydrogen bonds.
Salts dissolve in polar solvents, forming positive and negative ions that are attracted to the negative and positive ends of the solvent molecule, respectively. If the solvent is water, hydration occurs when the charged solute ions become surrounded by water molecules. A standard example is aqueous saltwater. Such solutions are called electrolytes. Whenever salt dissolves in water ion association has to be taken into account.
Polar solutes dissolve in polar solvents, forming polar bonds or hydrogen bonds. As an example, all alcoholic beverages are aqueous solutions of ethanol. On the other hand, non-polar solutes dissolve better in non-polar solvents. Examples are hydrocarbons such as oil and grease that easily mix, while being incompatible with water.
An example of the immiscibility of oil and water is a leak of petroleum from a damaged tanker, that does not dissolve in the ocean water but rather floats on the surface.
== See also ==
Molar solution – Measure of concentration of a chemicalPages displaying short descriptions of redirect targets
Percentage solution (disambiguation)
Solubility equilibrium – Thermodynamic equilibrium between a solid and a solution of the same compound
Total dissolved solids – Measurement in environmental chemistry is a common term in a range of disciplines, and can have different meanings depending on the analytical method used. In water quality, it refers to the amount of residue remaining after the evaporation of water from a sample.
Upper critical solution temperature – Critical temperature of miscibility in a mixture
Lower critical solution temperature – Critical temperature below which components of a mixture are miscible for all compositions
Coil–globule transition – Collapse of a macromolecule from an expanded coil state to a collapsed globule state
== References ==
IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version: (2006–) "solution". doi:10.1351/goldbook.S05746
== External links ==
Media related to Solutions at Wikimedia Commons | Wikipedia/Dilute_solution |
The Protein Data Bank (PDB) is a database for the three-dimensional structural data of large biological molecules such as proteins and nucleic acids, which is overseen by the Worldwide Protein Data Bank (wwPDB). This structural data is obtained and deposited by biologists and biochemists worldwide through the use of experimental methodologies such as X-ray crystallography, NMR spectroscopy, and, increasingly, cryo-electron microscopy. All submitted data are reviewed by expert biocurators and, once approved, are made freely available on the Internet under the CC0 Public Domain Dedication. Global access to the data is provided by the websites of the wwPDB member organizations (PDBe, PDBj, RCSB PDB, and BMRB).
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Historically, the number of structures in the PDB has grown at an approximately exponential rate, with 100 registered structures in 1982, 1,000 structures in 1993, 10,000 in 1999, 100,000 in 2014, and 200,000 in January 2023.
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Crystallographic database
Protein structure
Protein structure prediction
Protein structure database
PDBREPORT lists all anomalies (also errors) in PDB structures
PDBsum—extracts data from other databases about PDB structures
Proteopedia—a collaborative 3D encyclopedia of proteins and other molecules
== References ==
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The Worldwide Protein Data Bank (wwPDB)—parent site to regional hosts (below)
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Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly inherited. It typically presents as a triad of progressive psychiatric, cognitive, and motor symptoms. The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities, which precede the motor symptoms for many people. The definitive physical symptoms, including a general lack of coordination and an unsteady gait, eventually follow. Over time, the basal ganglia region of the brain gradually becomes damaged. The disease is primarily characterized by a distinctive hyperkinetic movement disorder known as chorea. Chorea classically presents as uncoordinated, involuntary, "dance-like" body movements that become more apparent as the disease advances. Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk. Mental abilities generally decline into dementia, depression, apathy, and impulsivity at times. The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40. The disease may develop earlier in each successive generation. About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea.
HD is typically inherited from an affected parent, who carries a mutation in the huntingtin gene (HTT). However, up to 10% of cases are due to a new mutation. The huntingtin gene provides the genetic information for huntingtin protein (Htt). Expansion of CAG repeats of cytosine-adenine-guanine (known as a trinucleotide repeat expansion) in the gene coding for the huntingtin protein results in an abnormal mutant protein (mHtt), which gradually damages brain cells through a number of possible mechanisms. The mutant protein is dominant, so having one parent who is a carrier of the trait is sufficient to trigger the disease in their children. Diagnosis is by genetic testing, which can be carried out at any time, regardless of whether or not symptoms are present. This fact raises several ethical debates: the age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results.
No cure for HD is known, and full-time care is required in the later stages. Treatments can relieve some symptoms and possibly improve quality of life. The best evidence for treatment of the movement problems is with tetrabenazine. HD affects about 4 to 15 in 100,000 people of European descent. It is rare among the Finnish and Japanese, while the occurrence rate in Africa is unknown. The disease affects males and females equally. Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy; although fatal aspiration pneumonia is commonly cited as the ultimate cause of death for those with the condition. Suicide is the cause of death in about 9% of cases. Death typically occurs 15–20 years from when the disease was first detected.
The earliest known description of the disease was in 1841 by American physician Charles Oscar Waters. The condition was described in further detail in 1872 by American physician George Huntington. The genetic basis was discovered in 1993 by an international collaborative effort led by the Hereditary Disease Foundation. Research and support organizations began forming in the late 1960s to increase public awareness, provide support for individuals and their families and promote research. Research directions include determining the exact mechanism of the disease, improving animal models to aid with research, testing of medications and their delivery to treat symptoms or slow the progression of the disease, and studying procedures such as stem-cell therapy with the goal of replacing damaged or lost neurons.
== Signs and symptoms ==
Signs and symptoms of Huntington's disease most commonly become noticeable between the ages of 30 and 50 years, but they can begin at any age and present as a triad of motor, cognitive, and psychiatric symptoms. When developed in an early stage, it is known as juvenile Huntington's disease. In 50% of cases, the psychiatric symptoms appear first. These can precede the motor symptoms by many years. Disease progression is often described in early stages, middle stages and late stages with an earlier prodromal phase. In the early stages, subtle personality changes, problems in cognition and physical skills, irritability and mood swings occur, all of which may go unnoticed. Almost everyone with HD eventually exhibits similar physical symptoms, but the onset, progression, and extent of cognitive and behavioral symptoms vary significantly between individuals.
The most characteristic initial physical symptoms are jerky, random and uncontrollable movements called chorea. Many people are not aware of their involuntary movements, or impeded by them. Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed saccadic eye movements. These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years. The clear appearance of symptoms such as rigidity, writhing motions, or abnormal posturing appear as the disorder progresses. These are signs that the system in the brain that is responsible for movement has been affected. Psychomotor functions become increasingly impaired, such that any action that requires muscle control is affected. When muscle control is affected such as rigidity or muscle contracture this is known as dystonia. Dystonia is a neurological hyperkinetic movement disorder that results in twisting or repetitive movements, that may resemble a tremor. Common consequences are physical instability, abnormal facial expression, and difficulties chewing, swallowing and speaking. Sleep disturbances and weight loss are also associated symptoms, and difficulty eating may cause weight loss and malnutrition. Juvenile HD generally progresses at a faster rate with greater cognitive decline, and chorea is exhibited briefly, if at all; the Westphal variant of slowness of movement, rigidity, and tremors is more typical in juvenile HD, as are seizures.
Cognitive abilities are progressively impaired and tend to generally decline into dementia. Especially affected are executive functions, which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiation of appropriate actions, and inhibition of inappropriate actions. Different cognitive impairments include difficulty focusing on tasks, lack of flexibility, a lack of impulse, a lack of awareness of one's own behaviors and abilities and difficulty learning or processing new information. As the disease progresses, memory deficits tend to appear. Reported impairments range from short-term memory deficits to long-term memory difficulties, including deficits in episodic (memory of one's life), procedural (memory of the body of how to perform an activity), and working memory.
Reported neuropsychiatric signs are anxiety, depression, a reduced display of emotions, egocentrism, aggression, and compulsive behavior and hallucination and delusion. Other common psychiatric disorders could include obsessive–compulsive disorder, mania, insomnia and bipolar disorder. Difficulties in recognizing other people's negative expressions have also been observed. The prevalence of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of psychiatric disorders between 33 and 76%. For many with the disease and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization. Early behavioral changes in HD result in an increased risk of suicide. Often, individuals have reduced awareness of chorea, cognitive, and emotional impairments.
== Genetics ==
Everyone has two copies of the huntingtin gene (HTT), which codes for the huntingtin protein (Htt). HTT is also called the HD gene, and the IT15 gene, (interesting transcript 15). Part of this gene is a repeated section called a trinucleotide repeat expansion – a short repeat, which varies in length between individuals, and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes, which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant; mutation of either of a person's HTT alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene; hence its severity can be influenced by the sex of the affected parent.
=== Genetic mutation ===
HD is one of several trinucleotide repeat disorders that are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4 at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the three-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the polyQ region.
Generally, people have fewer than 36 repeated glutamines in the polyQ region, which results in the production of the cytoplasmic protein huntingtin. However, a sequence of 36 or more glutamines results in the production of a protein with different characteristics. This altered form, called mutant huntingtin (mHtt), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these types of neurons and are affected accordingly. Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to the environment and other genes that modify the mechanism of HD. About 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that symptoms are never noticed. With very large repeat counts (more than 60), HD onset can occur below the age of 20, known as juvenile HD. Juvenile HD is typically of the Westphal variant that is characterized by slowness of movement, rigidity, and tremors. This accounts for about 7% of HD carriers.
=== Inheritance ===
Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. Since the penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and developing the disease (see figure). This probability is sex-independent since the huntingtin gene is not located on the X or Y chromosomes.
Trinucleotide CAG repeats numbering over 28 are unstable during replication, and this instability increases with the number of repeats present. This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat. This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD. The earlier age of onset and greater severity of disease in successive generations due to increases in the number of repeats is known as genetic anticipation. Instability is greater in spermatogenesis than oogenesis; maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length. Rarely is Huntington's disease caused by a new mutation, where neither parent has over 36 CAG repeats.
In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100%. Individuals with both genes affected are rare. For some time, HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression, but it has since been found that it can affect the phenotype and the rate of progression.
== Mechanisms ==
Huntingtin protein interacts with over 100 other proteins, and appears to have multiple functions. The behavior of the mutated protein (mHtt) is not completely understood, but it is toxic to certain cell types, particularly brain cells. Early damage is most evident in the subcortical basal ganglia, initially in the striatum, but as the disease progresses, other areas of the brain are also affected, including regions of the cerebral cortex. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood, and higher cognitive function. DNA methylation also appears to be changed in HD.
In 2025, scientists affiliated with Harvard and MIT published a study examining the mechanism behind the onset of symptoms. They found that the length of the repeated trinucleotide sequence increases with age due to accumulated errors in DNA mismatch repair processes after transcription, and that this becomes toxic once the sequence expands beyond 150 repeats.
=== Huntingtin function ===
Htt is expressed in all cells, with the highest concentrations found in the brain and testes, and moderate amounts in the liver, heart, and lungs. Although its full range of functions is not yet understood, Htt interacts with proteins involved in transcription, cell signaling, and intracellular transport. Studies in genetically modified animals have shown that wild-type Htt is essential for embryonic development, as complete absence of the gene results in embryonic death. Htt also plays a protective role in mature neurons: it regulates the production of brain-derived neurotrophic factor, supports synaptic vesicular transport and synaptic transmission, controls neuronal gene transcription, and prevents programmed cell death by inhibiting apoptotic enzymes such as caspases. In contrast to these protective roles, the mutant form of the protein (mHtt) interferes with the ubiquitin-proteasome system, which promotes caspase activation, contributing to neurodegeneration. Increasing the expression of Htt can promote brain cell survival and ameliorate the effects of mHtt, whereas reducing it can exacerbate those effects. Accordingly, the disease is thought not to be caused by inadequate expression of Htt, but by a toxic gain-of-function of mHtt in the body. The mutant protein is expressed throughout the body and associated with abnormalities in peripheral tissues outside of the brain, which can include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis, and testicular atrophy.
=== Cellular changes ===
The toxic action of mHtt may manifest and produce the HD pathology through multiple cellular changes. In its mutant (polyglutamine expanded) form, the protein is more prone to cleavage that creates shorter fragments containing the polyglutamine expansion. These protein fragments have a propensity to undergo misfolding and aggregation, yielding fibrillar aggregates in which non-native polyglutamine β-strands from multiple proteins are bonded together by hydrogen bonds. These aggregates share the same fundamental cross-beta amyloid architecture seen in other protein deposition diseases. Over time, the aggregates accumulate to form inclusion bodies within cells, ultimately interfering with neuronal function. Inclusion bodies have been found in both the cell nucleus and cytoplasm. Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be toxic for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.
Several pathways by which mHtt may cause cell death have been identified. These include effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with caspases, which play a role in the process of removing cells; the toxic effects of glutamine on nerve cells; impairment of energy production within cells; and effects on the expression of genes.
Mutant huntingtin protein has been found to play a key role in mitochondrial dysfunction. The impairment of mitochondrial electron transport can result in higher levels of oxidative stress and release of reactive oxygen species.
Glutamine is known to be excitotoxic when present in large amounts, that can cause damage to numerous cellular structures. Excessive glutamine is not found in HD, but the interactions of the altered huntingtin protein with numerous proteins in neurons lead to an increased vulnerability to glutamine. The increased vulnerability is thought to result in excitotoxic effects from normal glutamine levels.
A somatic expansion of CAG repeats is involved in the progression of the disease. Over decades, the HTT gene first sees its CAG repeats expand to about 80 copies: the 35+ CAG locus causes additional slippage errors that expand the repeat. Then the process accelerates, reaching 150 copies within years. There is no significant toxic effect on the cell until 150 copies, at which point a large number of genes become progressively dysregulated. Over months, the medium spiny neuron slowly loses its cell identity until cell death pathways are activated.
=== Macroscopic changes ===
Initially, damage to the brain is regionally specific with the dorsal striatum in the subcortical basal ganglia being primarily affected, followed later by cortical involvement in all areas. Other areas of the basal ganglia affected include the substantia nigra; cortical involvement includes cortical layers 3, 5, and 6; also evident is involvement of the hippocampus, Purkinje cells in the cerebellum, lateral tuberal nuclei of the hypothalamus and parts of the thalamus. These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells. Striatal medium spiny neurons are the most vulnerable, particularly ones with projections towards the external globus pallidus, with interneurons and spiny cells projecting to the internal globus pallidus being less affected. HD also causes an abnormal increase in astrocytes and activation of the brain's immune cells, microglia.
The basal ganglia play a key role in movement and behavior control. Their functions are not fully understood, but theories propose that they are part of the cognitive executive system and the motor circuit. The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to the motion or motions to be unintentionally initiated or in a motion to be halted before or beyond its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD known as chorea, a dyskinesia. Because of the basal ganglia's inability to inhibit movements, individuals affected by it inevitably experience a reduced ability to produce speech and swallow foods and liquids (dysphagia).
=== Transcriptional dysregulation ===
CREB-binding protein (CBP), a transcriptional coregulator, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways. CBP contains an acetyltransferase domain to which HTT binds through its polyglutamine-containing domain. Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP. In addition, when CBP is overexpressed, polyglutamine-induced death is diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.
== Diagnosis ==
Diagnosis of the onset of HD can be made following the appearance of physical symptoms specific to the disease. Genetic testing can be used to confirm a physical diagnosis if no family history of HD exists. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat (CAG) in the HTT gene that causes the disease. Genetic counseling is available to provide advice and guidance throughout the testing procedure and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family-planning decisions, relatives, and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.
=== Clinical ===
A physical examination, sometimes combined with a psychological examination, can determine whether the onset of the disease has begun. Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or behavioral symptoms are rarely the first symptoms diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the unified Huntington's disease rating scale, which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments. Medical imaging, such as a CT scan or MRI scan, can show atrophy of the caudate nuclei early in the disease, as seen in the illustration to the right, but these changes are not, by themselves, diagnostic of HD. Cerebral atrophy can be seen in the advanced stages of the disease. Functional neuroimaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), can show changes in brain activity before the onset of physical symptoms, but they are experimental tools and are not used clinically.
=== Predictive genetic testing ===
Because HD follows an autosomal dominant pattern of inheritance, a strong motivation exists for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a blood test, which counts the numbers of CAG repeats in each of the HTT alleles. Cutoffs are given as follows:
At 40 or more CAG repeats, full penetrance allele (FPA) exists. A "positive test" or "positive result" generally refers to this case. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD. The test will tell a person who originally had a 50% chance of inheriting the disease if their risk goes up to 100% or is eliminated. Persons who test positive for the disease will develop HD sometime within their lifetimes, provided they live long enough for the disease to appear.
At 36 to 39 repeats, incomplete or reduced penetrance allele (RPA) may cause symptoms, usually later in the adult life. The maximum risk is 60% that a person with an RPA will be symptomatic at age 65, and 70% at 75.
At 27 to 35 repeats, intermediate allele (IA), or large normal allele, is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.
With 26 or fewer repeats, the result is not associated with HD.
Testing before the onset of symptoms is a life-changing event and a very personal decision. The main reason given for choosing to test for HD is to aid in career and family decisions. Predictive testing for Huntington's disease has been available via linkage analysis (which requires testing multiple family members) since 1986 and via direct mutation analysis since 1993. At that time, surveys indicated that 50–70% of at-risk individuals would have been interested in receiving testing, but since predictive testing has been offered far fewer choose to be tested. Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because it has no treatment. A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result. Irrespective of the result, stress levels are lower two years after being tested, but the risk of suicide is increased after a positive test result. Individuals found to have not inherited the disorder may experience survivor guilt about family members who are affected. Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it. In one study, genetic discrimination was found in 46% of individuals at risk for Huntington's disease. It occurred at higher rates within personal relationships than health insurance or employment relations. Genetic counseling in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process. Because of the implications of this test, patients who wish to undergo testing must complete three counseling sessions which provide information about Huntington's.
Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar ataxia. Presymptomatic testing for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial Alzheimer's disease and breast cancer. The European Molecular Genetics Quality Network have published yearly external quality assessment scheme for molecular genetic testing for this disease and have developed best practice guidelines for genetic testing for HD to assist in testing and reporting of results.
=== Preimplantation genetic diagnosis ===
Embryos produced using in vitro fertilization may be genetically tested for HD using preimplantation genetic diagnosis. This technique, where one or two cells are extracted from a typically 4- to 8-cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos affected with HD genes are not implanted, so any offspring will not inherit the disease. Some forms of preimplantation genetic diagnosis—non-disclosure or exclusion testing—allow at-risk people to have HD-free offspring without revealing their own parental genotype, giving no information about whether they themselves are destined to develop HD. In exclusion testing, the embryo's DNA is compared with that of the parents and grandparents to avoid inheritance of the chromosomal region containing the HD gene from the affected grandparent. In nondisclosure testing, only disease-free embryos are replaced in the uterus while the parental genotype and hence parental risk for HD are never disclosed.
=== Prenatal testing ===
Obtaining a prenatal diagnosis for an embryo or fetus in the womb is also possible, using fetal genetic material acquired through chorionic villus sampling. An amniocentesis can be performed if the pregnancy is further along, within 14–18 weeks. This procedure looks at the amniotic fluid surrounding the baby for indicators of the HD mutation. This, too, can be paired with exclusion testing to avoid disclosure of parental genotype. Prenatal testing can be done when parents have been diagnosed with HD, when they have had genetic testing showing the expansion of the HTT gene, or when they have a 50% chance of inheriting the disease. The parents can be counseled on their options, which include termination of pregnancy, and on the difficulties of a child with the identified gene.
In addition, in at-risk pregnancies due to an affected male partner, noninvasive prenatal diagnosis can be performed by analyzing cell-free fetal DNA in a blood sample taken from the mother (via venipuncture) between six and 12 weeks of pregnancy. It has no procedure-related risk of miscarriage.
=== Differential diagnosis ===
About 99% of HD diagnoses based on the typical symptoms and a family history of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called HD-like (HDL) syndromes. The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the prion protein gene (HDL1), the junctophilin 3 gene (HDL2), a recessively inherited unknown gene (HDL3—only found in two families and poorly understood), and the gene encoding the TATA box-binding protein (SCA17, sometimes called HDL4). Other autosomal dominant diseases that can be misdiagnosed as HD are dentatorubral-pallidoluysian atrophy and neuroferritinopathy. Also, some autosomal recessive disorders resemble sporadic cases of HD. These include chorea acanthocytosis and pantothenate kinase-associated neurodegeneration. One X-linked disorder of this type is McLeod syndrome.
== Management ==
Treatments are available to reduce the severity of some HD symptoms. For many of these treatments, evidence to confirm their effectiveness in treating symptoms of HD specifically are incomplete. As the disease progresses, the ability to care for oneself declines, and carefully managed multidisciplinary caregiving becomes increasingly necessary. Although relatively few studies of exercises and therapies have shown to be helpful to rehabilitate cognitive symptoms of HD, some evidence shows the usefulness of physical therapy, occupational therapy, and speech therapy.
=== Therapy ===
Weight loss and problems in eating due to dysphagia and other muscle discoordination are common, making nutrition management increasingly important as the disease advances. Thickening agents can be added to liquids, as thicker fluids are easier and safer to swallow. Reminding the affected person to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking. If eating becomes too hazardous or uncomfortable, the option of using a percutaneous endoscopic gastrostomy is available. This feeding tube, permanently attached through the abdomen into the stomach, reduces the risk of aspirating food and provides better nutritional management. Assessment and management by speech-language pathologists with experience in Huntington's disease is recommended.
People with Huntington's disease may see a physical therapist for noninvasive and nonmedication-based ways of managing the physical symptoms. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. Walking aids may be prescribed as appropriate. Physical therapists also prescribe breathing exercises and airway clearance techniques with the development of respiratory problems. Consensus guidelines on physiotherapy in Huntington's disease have been produced by the European HD Network. Goals of early rehabilitation interventions are prevention of loss of function. Participation in rehabilitation programs during the early to middle stage of the disease may be beneficial as it translates into long-term maintenance of motor and functional performance. Rehabilitation during the late stage aims to compensate for motor and functional losses. For long-term independent management, the therapist may develop home exercise programs for appropriate people.
Additionally, an increasing number of people with HD are turning to palliative care, which aims to improve quality of life through the treatment of the symptoms and stress of serious illness, in addition to their other treatments.
=== Medications ===
Tetrabenazine was approved in 2000 for treatment of chorea in Huntington's disease in the EU, and in 2008 in the US. Although other drugs had been used "off label", tetrabenazine was the first approved treatment for Huntington's disease in the U.S. The compound has been known since the 1950s. In 2017, deutetrabenazine, a heavier form of tetrabenazine medication for the treatment of chorea in HD, was approved by the FDA. This is marketed as Austedo. Valbenazine (Ingrezza) was also approved by the FDA for the treatment of Huntington's disease chorea in 2023. Tetrabenazine, deutetrabenazine, and valbenazine are all vesicular monoamine transporter 2 (VMAT2) inhibitors, which work by depleting dopamine in the brain, lessening involuntary movements. These are the only drugs that have been approved specifically for Huntington's disease (namely the chorea associated with it).
Other drugs that help to reduce chorea include antipsychotics and benzodiazepines. Hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid. Tentative evidence has found ethyl eicosapentaenoic acid to improve motor symptoms at one year. Amantadine has also been used to treat chorea, but there is limited evidence for its safety and efficacy.
Psychiatric symptoms can be treated with medications similar to those used in the general population. Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotics are recommended for psychosis and behavioral problems. Specialist neuropsychiatric input is recommended since people may require long-term treatment with multiple medications in combination.
=== Plant-based medications ===
There has been a number of alternative therapies experimented in ayurvedic medicine with plant-based products, although none have provided good evidence of efficacy. A recent study showed that the stromal processing peptidase (SPP), a synthetic enzyme found in plant chloroplasts, prevented the aggregation of proteins associated with Huntington's disease. However, repeat studies and clinical validation are needed to confirm its true therapeutic potential.
=== Education ===
The families of individuals, and society at large, who have inherited or are at risk of inheriting HD have generations of experience of HD but may be unaware of recent breakthroughs in understanding the disease, and of the availability of genetic testing. Genetic counseling benefits these individuals by updating their knowledge, seeking to dispel any unfounded beliefs that they may have, and helping them consider their future options and plans. The Patient Education Program for Huntington's Disease has been created to help educate family members, caretakers, and those diagnosed with Huntington's disease. Also covered is information concerning family planning choices, care management, and other considerations.
== Prognosis ==
The length of the trinucleotide repeat accounts for 60% of the variation of the age of symptoms onset and their rate of progress. A longer repeat results in an earlier age of onset and a faster progression of symptoms. Individuals with more than sixty repeats often develop the disease before age 20, while those with fewer than 40 repeats may remain asymptomatic. The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.
Life expectancy in HD is generally around 10 to 30 years following the onset of visible symptoms. Juvenile Huntington's disease has a life expectancy rate of 10 years after onset of visible symptoms. People with Huntington's disease usually have a reduced lifespan of around 58-63 years (mean), although it varies considerably, and different studies give slightly different ages. Most life-threatening complications result from muscle coordination, and to a lesser extent, behavioral changes induced by declining cognitive function. The largest risk is pneumonia, which causes death in one third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs, and an increased risk of aspirating food or drink both increase the risk of contracting pneumonia. The second-greatest risk is heart disease, which causes almost a quarter of fatalities of those with HD. Suicide is the third greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. To what extent suicidal thoughts are influenced by behavioral symptoms is unclear, as they signify a desire to avoid the later stages of the disease. Suicide is the greatest risk of this disease before the diagnosis is made and in the middle stages of development throughout the disease. Other associated risks include choking; due to the inability to swallow, physical injury from falls, and malnutrition.
== Epidemiology ==
The late onset of Huntington's disease means it does not usually affect reproduction. The worldwide prevalence of HD is 5–10 cases per 100,000 persons, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around seven per 100,000 people, and is lower in the rest of the world; e.g., one per million people of Asian and African descent. A 2013 epidemiological study of the prevalence of Huntington's disease in the UK between 1990 and 2010 found that the average prevalence for the UK was 12.3 per 100,000. Additionally, some localized areas have a much higher prevalence than their regional average. One of the highest incidences is in the isolated populations of the Lake Maracaibo region of Venezuela, where HD affects up to 700 per 100,000 persons. Other areas of high localization have been found in Tasmania and specific regions of Scotland, Wales and Sweden. Increased prevalence in some cases occurs due to a local founder effect, a historical migration of carriers into an area of geographic isolation. Some of these carriers have been traced back hundreds of years using genealogical studies. Genetic haplotypes can also give clues for the geographic variations of prevalence. Iceland, on the contrary, has a rather low prevalence of 1 per 100,000, despite the fact that Icelanders as a people are descended from the early Germanic tribes of Scandinavia which also gave rise to the Swedes; all cases with the exception of one going back nearly two centuries having derived from the offspring of a couple living early in the 19th century. Finland, as well, has a low incidence of only 2.2 per 100,000 people.
Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics; and, as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.
== History ==
In centuries past, various kinds of chorea were at times called by names such as Saint Vitus' dance, with little or no understanding of their cause or type in each case.
The first definite mention of HD was in a letter by Charles Oscar Waters (1816–1892), published in the first edition of Robley Dunglison's Practice of Medicine in 1842. Waters described "a form of chorea, vulgarly called magrums", including accurate descriptions of the chorea, its progression, and the strong heredity of the disease. In 1846 Charles Rollin Gorman (1817–1879) observed how higher prevalence seemed to occur in localized regions. Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical College in Philadelphia, Johan Christian Lund (1830–1906) also produced an early description in 1860. He specifically noted that in Setesdalen, a secluded mountain valley in Norway, the high prevalence of dementia was associated with a pattern of jerking movement disorders that ran in families.
The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of Mendelian inheritance.
Of its hereditary nature. When either or both the parents have shown manifestations of the disease ... one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.
Sir William Osler was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating, "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described." Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community. Great interest was shown by scientists in Europe, including Louis Théophile Joseph Landouzy, Désiré-Magloire Bourneville, Camillo Golgi, and Joseph Jules Dejerine, and until the end of the century, much of the research into HD was European in origin. By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.
During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance. English biologist William Bateson used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern. The strong inheritance pattern prompted several researchers, including Smith Ely Jelliffe, to attempt to trace and connect family members of previous studies. Jelliffe collected information from across New York and published several articles regarding the genealogy of HD in New England. Jelliffe's research roused the interest of his college friend, Charles Davenport, who commissioned Elizabeth Muncey to produce the first field study on the East Coast of the United States of families with HD and to construct their pedigrees. Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the US could be traced back to a handful of individuals. This research was further embellished in 1932 by P. R. Vessie, who popularized the idea that three brothers who left England in 1630 bound for Boston were the progenitors of HD in the US. The claim that the earliest progenitors had been established and eugenic bias of Muncey's, Davenport's, and Vessie's work contributed to misunderstandings and prejudice about HD. Muncey and Davenport also popularized the idea that in the past, some with HD may have been thought to be possessed by spirits or victims of witchcraft, and were sometimes shunned or exiled by society. This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.
The search for the cause of this condition was enhanced considerably in 1968, when the Hereditary Disease Foundation (HDF) was created by Milton Wexler, a psychoanalyst based in Los Angeles, California, whose wife Leonore Sabin had been diagnosed earlier that year with Huntington's disease. The three brothers of Wexler's wife also had this disease.
The foundation was involved in the recruitment of more than 100 scientists in the US-Venezuela Huntington's Disease Collaborative Project, which over a 10-year period from 1979, worked to locate the genetic cause. This was achieved in 1983 when a causal gene was approximately located, and in 1993, the gene was precisely located at chromosome 4 (4p16.3). The study had focused on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of HD, and involved over 18,000 people, mostly from a single extended family, and resulted in making HD the first autosomal disease locus found using genetic linkage analysis. Among other innovations, the project developed DNA-marking methods which were an important step in making the Human Genome Project possible.
In the same time, key discoveries concerning the mechanisms of the disorder were being made, including the findings by Anita Harding's research group on the effects of the gene's length.
Modelling the disease in various types of animals, such as the transgenic mouse developed in 1996, enabled larger-scale experiments. As these animals have faster metabolisms and much shorter lifespans than humans results from experiments are received sooner, speeding research. The 1997 discovery that mHtt fragments misfold led to the discovery of the nuclear inclusions they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.
The networks of care and support that had developed in Venezuela and Colombia during the research projects there in the 1970s through 2000s were eventually eroded by various forces, such as the ongoing crisis in Venezuela and the death of a lead researcher in Colombia (Jorge Daza Barriga). Doctors are working toward rekindling these networks because the people who have contributed to the science of Huntington's disease by participating in these studies deserve adequate follow-up care; societies elsewhere in the world who benefit from the scientific advances thus achieved owe at least that much to those who participated in the research.
The condition was formerly called Huntington's chorea, but this term has been replaced by Huntington's disease because not all patients develop chorea and due to the importance of cognitive and behavioral problems.
== Society and culture ==
=== Ethics ===
Genetic testing for Huntington's disease has raised several ethical issues. The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters. There was controversy when Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain diseases, including HD, as part of the eugenics movement. In vitro fertilization has some issues regarding its use of embryos. Some HD research has ethical issues due to its use of animal testing and embryonic stem cells.
The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.
Many guidelines and testing procedures have strict procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results and also to whom the results are made available. Insurance companies and businesses are faced with the question of whether to use genetic test results when assessing an individual, such as for life insurance or employment. The United Kingdom's insurance companies agreed with the Department of Health and Social Care that until 2017 customers would not need to disclose predictive genetics tests to them, but this agreement explicitly excluded the government-approved test for Huntington's when writing policies with a value over £500,000. As with other untreatable genetic conditions with a later onset, it is ethically questionable to perform presymptomatic testing on a child or adolescent since there would be no medical benefit for that individual. There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of effective treatment, testing a person under legal age who is not judged to be competent is considered unethical in most cases.
There are ethical concerns related to prenatal genetic testing or preimplantation genetic diagnosis to ensure a child is not born with a given disease. For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some. As it is a dominant disease, there are difficulties in situations in which a parent does not want to know his or her own diagnosis. This would require parts of the process to be kept secret from the parent.
=== Support organizations ===
In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF), with the aim of curing genetic illnesses by coordinating and supporting research. The foundation and Wexler's daughter, Nancy Wexler, were key parts of the research team in Venezuela which discovered the HD gene.
At roughly the same time as the HDF formed, Marjorie Guthrie helped to found the committee to Combat Huntington's Disease (now the Huntington's Disease Society of America), after her husband, folk singer-songwriter Woody Guthrie died from complications of HD.
Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the European HD network. Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, 6 June is designated "National Huntington's Disease Awareness Day" by the US Senate. Many organizations exist to support and inform those affected by HD, including the Huntington's Disease Association in the UK. The largest funder of research is provided by the Cure Huntington's Disease Initiative Foundation (CHDI).
== Research directions ==
Research into the mechanism of HD is focused on identifying the functioning of Htt, how mHtt differs or interferes with it, and the brain pathology that the disease produces. Research is conducted using in vitro methods, genetically modified animals, (also called transgenic animal models), and human volunteers. Animal models are critical for understanding the fundamental mechanisms causing the disease, and for supporting the early stages of drug development. The identification of the causative gene has enabled the development of many genetically modified organisms including nematodes (roundworms), Drosophila fruit flies, and genetically modified mammals including mice, rats, sheep, pigs and monkeys that express mutant huntingtin and develop progressive neurodegeneration and HD-like symptoms.
Research is being conducted using many approaches to either prevent Huntington's disease or slow its progression. Disease-modifying strategies can be broadly grouped into three categories: reducing the level of the mutant huntingtin protein (including gene splicing and gene silencing); approaches aimed at improving neuronal survival by reducing the harm caused by the protein to specific cellular pathways and mechanisms (including protein homeostasis and histone deacetylase inhibition); and strategies to replace lost neurons. In addition, novel therapies to improve brain functioning are under development; these seek to produce symptomatic rather than disease-modifying therapies, and include phosphodiesterase inhibitors.
The CHDI Foundation funds a great many research initiatives providing many publications. The CHDI foundation is the largest funder of Huntington's disease research globally and aims to find and develop drugs that will slow the progression of HD. CHDI was formerly known as the High Q Foundation. In 2006, it spent $50 million on Huntington's disease research. CHDI collaborates with many academic and commercial laboratories globally and engages in oversight and management of research projects as well as funding.
=== Reducing huntingtin production ===
Gene silencing aims to reduce the production of the mutant protein, since HD is caused by a single dominant gene encoding a toxic protein. Gene silencing experiments in mouse models have shown that when the expression of mHtt is reduced, symptoms improve. The safety of RNA interference, and allele-specific oligonucleotide (ASO) methods of gene silencing has been demonstrated in mice and the larger primate macaque brain. Allele-specific silencing attempts to silence mutant htt while leaving wild-type Htt untouched. One way of accomplishing this is to identify polymorphisms present on only one allele and produce gene silencing drugs that target polymorphisms in only the mutant allele. The first gene silencing trial involving humans with HD began in 2015, testing the safety of IONIS-HTTRx, produced by Ionis Pharmaceuticals and led by UCL Institute of Neurology. Mutant huntingtin was detected and quantified for the first time in cerebrospinal fluid from Huntington's disease mutation-carriers in 2015 using a novel "single-molecule counting" immunoassay, providing a direct way to assess whether huntingtin-lowering treatments are achieving the desired effect. A phase 3 trial of this compound, renamed tominersen and sponsored by Roche Pharmaceuticals, began in 2019 but was halted in 2021 after the safety monitoring board concluded that the risk-benefit balance was unfavourable. A huntingtin-lowering gene therapy trial run by Uniqure began in 2019, and several trials of orally administered huntingtin-lowering splicing modulator compounds have been announced. Gene splicing techniques are being looked at to try to repair a genome with the erroneous gene that causes HD, using tools such as CRISPR/Cas9. PTC Therapeutics is evaluating small molecules that induce poison exon inclusion in HTT transcript as a therapeutic strategy to lower HTT expression.
=== Increasing huntingtin clearance ===
Another strategy to reduce the level of mutant huntingtin is to increase the rate at which cells are able to clear it. As mHtt (and many other protein aggregates) are degraded by autophagy, increasing the rate of autophagy has the potential to reduce levels of mHtt and thereby ameliorate disease. Pharmacological and genetic inducers of autophagy have been tested in a variety of Huntington's disease models; many have been shown to reduce mHtt levels and decrease toxicity.
=== Improving cell survival ===
Among the approaches aimed at improving cell survival in the presence of mutant huntingtin are correction of transcriptional regulation using histone deacetylase inhibitors, modulating aggregation of huntingtin, improving metabolism and mitochondrial function and restoring function of synapses.
=== Neuronal replacement ===
Stem-cell therapy is used to replace damaged neurons by transplantation of stem cells into affected regions of the brain. Experiments in animal models (rats and mice only) have yielded positive results.
Whatever their future therapeutic potential, stem cells are already a valuable tool for studying Huntington's disease in the laboratory.
=== Ferroptosis ===
Ferroptosis is a form of regulated cell death characterized by the iron-dependent accumulation of lipid hydroperoxides to lethal levels. ALOX5-mediated ferroptosis acts as a cell death pathway upon oxidative stress in Huntington's disease. Inhibitors of ferroptosis are protective in models of degenerative brain disorders, including
Parkinson's, Huntington's, and Alzheimer's Diseases.
=== Clinical trials ===
In 2020, there were 197 clinical trials related to varied therapies and biomarkers for Huntington's disease listed as either underway, recruiting or newly completed. Compounds trialled that have failed to prevent or slow the progression of Huntington's disease include remacemide, coenzyme Q10, riluzole, creatine, minocycline, ethyl-EPA, phenylbutyrate and dimebon.
== See also ==
AB-1001
Childhood dementia
== References ==
== External links ==
HOPES project Archived 27 August 2020 at the Wayback Machine – Stanford University's HD information project
HDBuzz – HD research news written by scientists in plain language
HD Drug Works – news about current treatments and planned trials | Wikipedia/Huntington's_disease |
Protein disulfide isomerase (EC 5.3.4.1), or PDI, is an enzyme in the endoplasmic reticulum (ER) in eukaryotes and the periplasm of bacteria that catalyzes the formation and breakage of disulfide bonds between cysteine residues within proteins as they fold. This allows proteins to quickly find the correct arrangement of disulfide bonds in their fully folded state, and therefore the enzyme acts to catalyze protein folding.
== Structure ==
Protein disulfide-isomerase has two catalytic thioredoxin-like domains (active sites), each containing the canonical CGHC motif, and two non catalytic domains. This structure is similar to the structure of enzymes responsible for oxidative folding in the intermembrane space of the mitochondria; an example of this is mitochondrial IMS import and assembly (Mia40), which has 2 catalytic domains that contain a CX9C, which is similar to the CGHC domain of PDI. Bacterial DsbA, responsible for oxidative folding, also has a thioredoxin CXXC domain.
== Function ==
=== Protein folding ===
PDI displays oxidoreductase and isomerase properties, both of which depend on the type of substrate that binds to protein disulfide-isomerase and changes in protein disulfide-isomerase's redox state. These types of activities allow for oxidative folding of proteins. Oxidative folding involves the oxidation of reduced cysteine residues of nascent proteins; upon oxidation of these cysteine residues, disulfide bridges are formed, which stabilizes proteins and allows for native structures (namely tertiary and quaternary structures).
==== Regular oxidative folding mechanism and pathway ====
PDI is specifically responsible for folding proteins in the ER. In an unfolded protein, a cysteine residue forms a mixed disulfide with a cysteine residue in an active site (CGHC motif) of protein disulfide-isomerase. A second cysteine residue then forms a stable disulfide bridge within the substrate, leaving protein disulfide-isomerase's two active-site cysteine residues in a reduced state.
Afterwards, PDI can be regenerated to its oxidized form in the endoplasmic reticulum by transferring electrons to reoxidizing proteins such ER oxidoreductin 1 (Ero 1), VKOR (vitamin K epoxide reductase), glutathione peroxidase (Gpx7/8), and PrxIV (peroxiredoxin IV). Ero1 is thought to be the main reoxidizing protein of PDI, and the pathway of reoxidation of PDI for Ero1 is more understood than that of other proteins. Ero1 accepts electrons from PDI and donates these electrons to oxygen molecules in the ER, which leads to the formation of hydrogen peroxide.
==== Misfolded protein mechanism ====
The reduced (dithiol) form of protein disulfide-isomerase is able to catalyze a reduction of a misformed disulfide bridge of a substrate through either reductase activity or isomerase activity. For the reductase method, a misfolded substrate disulfide bond is converted to a pair of reduced cysteine residues by the transfer of electrons from glutathione and NADPH. Afterwards, normal folding occurs with oxidative disulfide bond formation between the correct pairs of substrate cysteine residues, leading to a properly folded protein. For the isomerase method, intramolecular rearrangement of substrate functional groups is catalyzed near the N terminus of each active site. Therefore, protein disulfide-isomerase is capable of catalyzing the post-translational modification disulfide exchange.
=== Redox signaling ===
In the chloroplasts of the unicellular algae Chlamydomonas reinhardtii the protein disulfide-isomerase RB60 serves as a redox sensor component of an mRNA-binding protein complex implicated in the photoregulation of the translation of psbA, the RNA encoding for the photosystem II core protein D1. Protein disulfide-isomerase has also been suggested to play a role in the formation of regulatory disulfide bonds in chloroplasts.
=== Other functions ===
==== Immune system ====
Protein disulfide-isomerase helps load antigenic peptides into MHC class I molecules. These molecules (MHC I) are related to the peptide presentation by antigen-presenting cells in the immune response.
Protein disulfide-isomerase has been found to be involved in the breaking of bonds on the HIV gp120 protein during HIV infection of CD4 positive cells, and is required for HIV infection of lymphocytes and monocytes. Some studies have shown it to be available for HIV infection on the surface of the cell clustered around the CD4 protein. Yet conflicting studies have shown that it is not available on the cell surface, but instead is found in significant amounts in the blood plasma.
==== Chaperone activity ====
Another major function of protein disulfide-isomerase relates to its activity as a chaperone; its b' domain aids in the binding of misfolded protein for subsequent degradation. This is regulated by three ER membrane proteins, Protein Kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring kinase 1 (IRE1), and activating transcription factor 6 (ATF6). They respond to high levels of misfolded proteins in the ER through intracellular signaling cascades that can activate PDI's chaperone activity. These signals can also inactivate translation of these misfolded proteins, because the cascade travels from the ER to the nucleus.
== Activity assays ==
Insulin turbidity assay: protein disulfide-isomerase breaks the two disulfide bonds between two insulin (a and b) chains that results in precipitation of b chain. This precipitation can be monitored at 650 nm, which is indirectly used to monitor protein disulfide-isomerase activity. Sensitivity of this assay is in micromolar range.
ScRNase assay: protein disulfide-isomerase converts scrambled (inactive) RNase into native (active) RNase that further acts on its substrate. The sensitivity is in micromolar range.
Di-E-GSSG assay: This is the fluorometric assay that can detect picomolar quantities of protein disulfide-isomerase and therefore is the most sensitive assay to date for detecting protein disulfide-isomerase activity. Di-E-GSSG has two eosin molecules attached to oxidized glutathione (GSSG). The proximity of eosin molecules leads to the quenching of its fluorescence. However, upon breakage of disulfide bond by protein disulfide-isomerase, fluorescence increases 70-fold.
== Stress and inhibition ==
=== Effects of nitrosative stress ===
Redox dysregulation leads to increases in nitrosative stress in the endoplasmic reticulum. Such adverse changes in the normal cellular environment of susceptible cells, such as neurons, leads to nonfunctioning thiol-containing enzymes. More specifically, protein disulfide-isomerase can no longer fix misfolded proteins once its thiol group in its active site has a nitric monoxide group attached to it; as a result, accumulation of misfolded proteins occurs in neurons, which has been associated with the development of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
=== Inhibition ===
Due to the role of protein disulfide-isomerase in a number of disease states, small molecule inhibitors of protein disulfide-isomerase have been developed. These molecules can either target the active site of protein disulfide-isomerase irreversibly or reversibly.
It has been shown that protein disulfide-isomerase activity is inhibited by red wine and grape juice, which could be the explanation for the French paradox.
== Members ==
Human genes encoding protein disulfide isomerases include:
== References ==
== External links ==
Protein Disulfide-Isomerase at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Protein_disulfide_isomerase |
Medical model is the term coined by psychiatrist R. D. Laing in his The Politics of the Family and Other Essays (1971), for the "set of procedures in which all doctors are trained". It includes complaint, history, physical examination, ancillary tests if needed, diagnosis, treatment, and prognosis with and without treatment.
The medical model embodies basic assumptions about medicine that drive research and theorizing about physical or psychological difficulties on a basis of causation and remediation.
It can be contrasted with other models that make different basic assumptions. Examples include holistic model of the alternative health movement and the social model of the disability rights movement, as well as to biopsychosocial and recovery models of mental disorders. For example, Gregory Bateson's double bind theory of schizophrenia focuses on environmental rather than medical causes. These models are not mutually exclusive. A model is not a statement of absolute reality or a belief system but a tool for helping patients. Thus, utility is the main criterion, and the utility of a model depends on context.
== Other uses ==
=== In psychology ===
In psychology, the term medical model refers to the assumption that psychopathology is the result of one's biology, that is to say, a physical/organic problem in brain structures, neurotransmitters, genetics, the endocrine system, etc., as with traumatic brain injury, Alzheimer's disease, or Down's syndrome. The medical model is useful in these situations as a guide for diagnosis, prognosis, and research. However, for most mental disorders, exclusive reliance on the medical model leads to an incomplete understanding, and, frequently, to incomplete or ineffective treatment interventions. The current Diagnostic and Statistical Manual of Mental Disorders (DSM-5), addresses this point in part, stating, However, in the absence of clear biological markers or clinically useful measurements of severity for many mental disorders, it has not been possible to completely separate normal and pathological symptom expressions contained in diagnostic criteria. This gap in information is particularly problematic in clinical situations in which the patient's symptom presentation by itself (particularly in mild forms) is not inherently pathological and may be encountered in individuals for whom a diagnosis of "mental disorder" would be inappropriate.
The Critical Psychiatry Network, a group of psychiatrists who critique the practice of psychiatry on many grounds, feel that the medical model for mental illness can result in poor treatment choices.
=== Germ theory of disease ===
The rise of modern scientific medicine during the 19th century has a great impact on the development of the medical model. Especially important was the development of the "germ theory" of disease by European medical researchers such as Louis Pasteur and Robert Koch. During the late 19th and early 20th centuries, the physical causes of a variety of diseases were uncovered, which, in turn, led to the development of effective forms of treatment.
== Concept of "disease" and "injury" ==
The concepts of "disease" and "injury" are central to the medical model. In general, "disease" or "injury" refer to some deviation from normal body functioning that has undesirable consequences for the affected individual. An important aspect of the medical model is that it regards signs (objective indicators such as an elevated temperature) and symptoms (subjective feelings of distress expressed by the patient) as indicative of an underlying physical abnormality (pathology) within the individual. According to the medical model, medical treatment, wherever possible, should be directed at the underlying pathology in an attempt to correct the abnormality and cure the disease. In regard to many mental illnesses, for example, the assumption is that the cause of the disorder lies in abnormalities within the affected individual's brain (especially their brain neurochemistry). That carries the implicit conclusion that disordered behaviors are not learned but are spontaneously generated by the disordered brain. According to the medical model, for treatment (such as drugs), to be effective, it should be directed as closely as possible at correcting the theorized chemical imbalance in the brain of the person with mental illness.
=== Importance of diagnosis ===
Proper diagnosis (that is, the categorization of illness signs and symptoms into meaning disease groupings) is essential to the medical model. Placing the patient's signs and symptoms into the correct diagnostic category can:
Provide the physician with clinically useful information about the course of the illness over time (its prognosis);
Point to (or at least suggest) a specific underlying cause or causes for the disorder; and
Direct the physician to specific treatment or treatments for the condition.
For example, if a patient presents to a primary care provider with symptoms of a given illness, by taking a thorough history, performing assessments (such as auscultation and palpation), and, in some cases, ordering diagnostic tests the primary care provider can make a reasonable conclusion about the cause of the symptoms. Based on clinical experience and available evidence, the healthcare professional can identify treatment options that are likely to be successful.
== Other important aspects ==
Finally, adherence to the medical model has a number of other consequences for the patient and society as a whole, both positive and negative:
In the medical model, the physician was traditionally seen as the expert, and patients were expected to comply with the advice. The physician assumes an authoritarian position in relation to the patient. Because of the specific expertise of the physician, according to the medical model, it is necessary and to be expected. However, in recent years, the move towards patient-centered care has resulted in greater patient involvement in many cases.
In the medical model, the physician may be viewed as the dominant health care professional, who is the professional trained in diagnosis and treatment.
An ill patient should not be held responsible for the condition. The patient should not be blamed or stigmatized for the illness.
Under the medical model, the disease condition of the patient is of major importance. Social, psychological, and other "external" factors, which may influence patient behavior, may be given less attention.
== See also ==
Andersen healthcare utilization model
Biomedical model
Medical model of disability
Reductionism
Social constructionism
== References ==
== External links ==
'Medical model' vs 'social model' British Film Institute Education.
Disability Awareness at the University of Sheffield, UK
Medical model Open university UK | Wikipedia/Disease_model |
In molecular biology, protein aggregation is a phenomenon in which intrinsically-disordered or mis-folded proteins aggregate (i.e., accumulate and clump together) either intra- or extracellularly. Protein aggregates have been implicated in a wide variety of diseases known as amyloidoses, including ALS, Alzheimer's, Parkinson's and prion disease.
After synthesis, proteins typically fold into a particular three-dimensional conformation that is the most thermodynamically favorable: their native state. This folding process is driven by the hydrophobic effect: a tendency for hydrophobic (water-fearing) portions of the protein to shield themselves from the hydrophilic (water-loving) environment of the cell by burying into the interior of the protein. Thus, the exterior of a protein is typically hydrophilic, whereas the interior is typically hydrophobic.
Protein structures are stabilized by non-covalent interactions and disulfide bonds between two cysteine residues. The non-covalent interactions include ionic interactions and weak van der Waals interactions. Ionic interactions form between an anion and a cation and form salt bridges that help stabilize the protein. Van der Waals interactions include nonpolar interactions (i.e. London dispersion force) and polar interactions (i.e. hydrogen bonds, dipole-dipole bond). These play an important role in a protein's secondary structure, such as forming an alpha helix or a beta sheet, and tertiary structure. Interactions between amino acid residues in a specific protein are very important in that protein's final structure.
When there are changes in the non-covalent interactions, as may happen with a change in the amino acid sequence, the protein is susceptible to misfolding or unfolding. In these cases, if the cell does not assist the protein in re-folding, or degrade the unfolded protein, the unfolded/misfolded protein may aggregate, in which the exposed hydrophobic portions of the protein may interact with the exposed hydrophobic patches of other proteins. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils.
== Causes ==
Protein aggregation can occur due to a variety of causes. There are four classes that these causes can be categorized into, which are detailed below.
=== Mutations ===
Mutations that occur in the DNA sequence may or may not affect the amino acid sequence of the protein. When the sequence is affected, a different amino acid may change the interactions between the side chains that affect the folding of the protein. This can lead to exposed hydrophobic regions of the protein that aggregate with the same misfolded/unfolded protein or a different protein.
In addition to mutations in the affected proteins themselves, protein aggregation could also be caused indirectly through mutations in proteins in regulatory pathways such as the refolding pathway (molecular chaperones) or the ubiquitin-proteasome pathway (ubiquitin ligases). Chaperones help with protein refolding by providing a safe environment for the protein to fold. Ubiquitin ligases target proteins for degradation through ubiquitin modification.
=== Problems with protein synthesis ===
Protein aggregation can be caused by problems that occur during transcription or translation. During transcription, DNA is copied into mRNA, forming a strand of pre-mRNA that undergoes RNA processing to form mRNA. During translation, ribosomes and tRNA help translate the mRNA sequence into an amino acid sequence. If problems arise during either step, making an incorrect mRNA strand and/or an incorrect amino acid sequence, this can cause the protein to misfold, leading to protein aggregation.
=== Environmental stresses ===
Environmental stresses such as extreme temperatures and pH or oxidative stress can also lead to protein aggregation. One such disease is cryoglobulinemia.
Extreme temperatures can weaken and destabilize the non-covalent interactions between the amino acid residues. pHs outside of the protein's pH range can change the protonation state of the amino acids, which can increase or decrease the non-covalent interactions. This can also lead to less stable interactions and result in protein unfolding.
Oxidative stress can be caused by radicals such as reactive oxygen species (ROS). These unstable radicals can attack the amino acid residues, leading to oxidation of side chains (e.g. aromatic side chains, methionine side chains) and/or cleavage of the polypeptide bonds. This can affect the non-covalent interactions that hold the protein together correctly, which can cause protein destabilization, and may cause the protein to unfold.
=== Aging ===
Cells have mechanisms that can refold or degrade protein aggregates. However, as cells age, these control mechanisms are weakened and the cell is less able to resolve the aggregates.
The hypothesis that protein aggregation is a causative process in aging is testable now since some models of delayed aging are in hand. If the development of protein aggregates was an aging independent process, slowing down aging will show no
effect on the rate of proteotoxicity over time. However, if aging is associated
with decline in the activity of protective mechanisms against proteotoxicity,
the slow aging models would show reduced aggregation and proteotoxicity. To
address this problem several toxicity assays have been done in C. elegans.
These studies indicated that reducing the activity of insulin/IGF signaling
(IIS), a prominent aging regulatory pathway protects from
neurodegeneration-linked toxic protein aggregation. The validity of this approach
has been tested and confirmed in mammals as reducing the activity of the IGF-1
signaling pathway protected Alzheimer's model mice from the behavioral and
biochemical impairments associated with the disease.
== Aggregate localization ==
Several studies have shown that cellular responses to protein aggregation are well-regulated and organized. Protein aggregates localize to specific areas in the cell, and research has been done on these localizations in prokaryotes (E.coli) and eukaryotes (yeast, mammalian cells). From the macroscopic point of view, positron emission tomography tracers are used for certain misfolded proitein. Recently, a team of researchers led by Dr. Alessandro Crimi has proposed a machine learning method to predict future deposition in the brain.
=== Bacteria ===
The aggregates in bacteria asymmetrically end up at one of the poles of the cell, the "older pole." After the cell divides, the daughter cells with the older pole gets the protein aggregate and grows more slowly than daughter cells without the aggregate. This provides a natural selection mechanism for reducing protein aggregates in the bacterial population.
=== Yeast ===
Most of the protein aggregates in yeast cells get refolded by molecular chaperones. However, some aggregates, such as the oxidatively damaged proteins or the proteins marked for degradation, cannot be refolded. Rather, there are two compartments that they can end up in. Protein aggregates can be localized at the Juxtanuclear quality-control compartment (JUNQ), which is near the nuclear membrane, or at the Insoluble Protein deposit (IPOD), near the vacuole in yeast cells. Protein aggregates localize at JUNQ when they are ubiquitinated and targeted for degradation. The aggregated and insoluble proteins localize at IPOD as a more permanent deposition. There is evidence that the proteins here may be removed by autophagy. These two pathways work together in that the proteins tend to come to the IPOD when the proteasome pathway is being overworked.
=== Mammalian cells ===
In mammalian cells, these protein aggregates are termed "aggresomes" and they are formed when the cell is diseased. This is because aggregates tend to form when there are heterologous proteins present in the cell, which can arise when the cell is mutated. Different mutates of the same protein may form aggresomes of different morphologies, ranging from diffuse dispersion of soluble species to large puncta, which in turn bear different pathogenicity. The E3 ubiquitin ligase is able to recognize misfolded proteins and ubiquinate them. HDAC6 can then bind to the ubiquitin and the motor protein dynein to bring the marked aggregates to the microtubule organizing center (MTOC). There, they pack together into a sphere that surrounds the MTOC. They bring over chaperones and proteasomes and activate autophagy.
== Elimination ==
There are two main protein quality control systems in the cell that are responsible for eliminating protein aggregates. Misfolded proteins can get refolded by the bi-chaperone system or degraded by the ubiquitin proteasome system or autophagy.
=== Refolding ===
The bi-chaperone system utilizes the Hsp70 (DnaK-DnaJ-GrpE in E. coli and Ssa1-Ydj1/Sis1-Sse1/Fe1 in yeast) and Hsp100 (ClpB in E. coli and Hsp104 in yeast) chaperones for protein disaggregation and refolding.
Hsp70 interacts with the protein aggregates and recruits Hsp100. Hsp70 stabilizes an activated Hsp100. Hsp100 proteins have aromatic pore loops that are used for threading activity to disentangle single polypeptides. This threading activity can be initiated at the N-terminus, C-terminus or in the middle of the polypeptide. The polypeptide gets translocated through Hsp100 in a series of steps, utilizing an ATP at each step. The polypeptide unfolds and is then allowed to refold either by itself or with the help of heat shock proteins.
=== Degradation ===
Misfolded proteins can be eliminated through the ubiquitin-proteasome system (UPS). This consists of an E1-E2-E3 pathway that ubiquinates proteins to mark them for degradation. In eukaryotes, the proteins get degraded by the 26S proteasome. In mammalian cells, the E3 ligase, carboxy-terminal Hsp70 interacting protein (CHIP), targets Hsp70-bound proteins. In yeast, the E3 ligases Doa10 and Hrd1 have similar functions on endoplasmic reticulum proteins. On the molecular level, degradation rate of aggregates vary from protein to protein due to their different internal environments, and thus different accessibility for protease molecules.
Misfolded proteins can also be eliminated through autophagy, in which the protein aggregates are delivered to the lysosome.
== Toxicity ==
Although it has been thought that the mature protein aggregates themselves are toxic, evidence suggests that it is in fact immature protein aggregates that are most toxic. The hydrophobic patches of these aggregates can interact with other components of the cell and damage them. The hypotheses are that the toxicity of protein aggregates is related to mechanisms of the sequestration of cellular components, the generation of reactive oxygen species and the binding to specific receptors in the membrane or through the disruption of membranes. A quantitative assay has been used to determine that higher molecular weight species are responsible for the membrane permeation. It is known that protein aggregates in vitro can destabilize artificial phospholipid bilayers, leading to permeabilization of the membrane.
== In biomanufacturing ==
Protein aggregation is also a common phenomenon in the biopharmaceutical manufacturing process, which may pose risks to patients via generating adverse immune responses.
== See also ==
Amyloid
Proteopathy
Amyloidosis
JUNQ and IPOD
Protein aggregation predictors
== References == | Wikipedia/Protein_aggregation |
A protein contact map represents the distance between all possible amino acid residue pairs of a three-dimensional protein structure using a binary two-dimensional matrix. For two residues
i
{\displaystyle i}
and
j
{\displaystyle j}
, the
i
j
{\displaystyle ij}
element of the matrix is 1 if the two residues are closer than a predetermined threshold, and 0 otherwise. Various contact definitions have been proposed: The distance between the Cα-Cα atom with threshold 6-12 Å; distance between Cβ-Cβ atoms with threshold 6-12 Å (Cα is used for Glycine); and distance between the side-chain centers of mass.
== Overview ==
Contact maps provide a more reduced representation of a protein structure than its full 3D atomic coordinates. The advantage is that contact maps are invariant to rotations and translations. They are more easily predicted by machine learning methods. It has also been shown that under certain circumstances (e.g. low content of erroneously predicted contacts) it is possible to reconstruct the 3D coordinates of a protein using its contact map.
Contact maps are also used for protein superimposition and to describe similarity between protein structures. They are either predicted from protein sequence or calculated from a given structure.
== Contact map prediction ==
With the availability of high numbers of genomic sequences it becomes feasible to analyze such sequences for coevolving residues. The effectiveness of this approach results from the fact that a mutation in position i of a protein is more likely to be associated with a mutation in position j than with a back-mutation in i if both positions are functionally coupled (e.g. by taking part in an enzymatic domain, or by being adjacent in a folded protein, or even by being adjacent in an oligomer of that protein).
Several statistical methods exist to extract from a multiple sequence alignment such coupled residue pairs: observed versus expected frequencies of residue pairs (OMES); the McLachlan Based Substitution correlation (McBASC); statistical coupling analysis; Mutual Information (MI) based methods; and recently direct coupling analysis (DCA).
Machine learning algorithms have been able to enhance MSA analysis methods, especially for non-homologous proteins (ie. shallow MSA's).
Predicted contact maps have been used in the prediction of membrane proteins where helix-helix interactions are targeted.
== HB Plot ==
Knowledge of the relationship between a protein's structure and its dynamic behavior is essential for understanding protein function. The description of a protein three dimensional structure as a network of hydrogen bonding interactions (HB plot) was introduced as a tool for exploring protein structure and function. By analyzing the network of tertiary interactions, the possible spread of information within a protein can be investigated.
HB plot offers a simple way of analyzing protein secondary structure and tertiary structure. Hydrogen bonds stabilizing secondary structural elements (secondary hydrogen bonds) and those formed between distant amino acid residues - defined as tertiary hydrogen bonds - can be easily distinguished in HB plot, thus, amino acid residues involved in stabilizing protein structure and function can be identified.
=== Features ===
The plot distinguishes between main chain-main chain, main chain-side chain and side chain-side chain hydrogen bonding interactions. Bifurcated hydrogen bonds and multiple hydrogen bonds between amino acid residues; and intra- and interchain hydrogen bonds are also indicated on the plots. Three classes of hydrogen bondings are distinguished by color-coding; short (distance smaller than 2.5 Å between donor and acceptor), intermediate (between 2.5 Å and 3.2 Å) and long hydrogen bonds (greater than 3.2 Å).
=== Secondary structure elements in HB plot ===
In representations of the HB plot, characteristic patterns of secondary structure elements can be recognised easily, as follows:
Helices can be identified as strips directly adjacent to the diagonal.
Antiparallel beta sheets appear in HB plot as cross-diagonal.
Parallel beta sheets appears in the HB plot as parallel to the diagonal.
Loops appear as breaks in the diagonal between the cross-diagonal beta-sheet motifs.
=== Examples of usage ===
==== Cytochrome P450s ====
The cytochrome P450s (P450s) are xenobiotic-metabolizing membrane-bound heme-containing enzymes that use molecular oxygen and electrons from NADPH cytochrome P450 reductase to oxidize their substrates. CYP2B4, a member of the cytochrome P450 family is the only protein within this family, whose X-ray structure in both open 11 and closed form 12 is published. The comparison of the open and closed structures of CYP2B4 structures reveals large-scale conformational rearrangement between the two states, with the greatest conformational change around the residues 215-225, which is widely open in ligand-free state and shut after ligand binding; and the region around loop C near the heme.
Examining the HB plot of the closed and open state of CYP2B4 revealed that the rearrangement of tertiary hydrogen bonds was in excellent agreement with the current knowledge of the cytochrome P450 catalytic cycle.
The first step in P450 catalytic cycle is identified as substrate binding. Preliminary binding of a ligand near to the entrance breaks hydrogen bonds S212-E474, S207-H172 in the open form of CYP2B4 and hydrogen bonds E218-A102, Q215-L51 are formed that fix the entrance in the closed form as the HB plot reveals.
The second step is the transfer of the first electron from NADPH via an electron transfer chain. For the electron transfer a conformational change occurs that triggers interaction of the P450 with the NADPH cytochrome P450 reductase. Breaking of hydrogen bonds between S128-N287, S128-T291, L124-N287 and forming S96-R434, A116-R434, R125-I435, D82-R400 at the NADPH cytochrome P450 reductase binding site—as seen in HB plot—transform CYP2B4 to a conformation state, where binding of NADPH cytochrome P450 reductase occurs.
In the third step, oxygen enters CYP2B4 in the closed state - the state where newly formed hydrogen bonds S176-T300, H172-S304, N167-R308 open a tunnel which is exactly the size and shape of an oxygen molecule.
==== Lipocalin family ====
The lipocalin family is a large and diverse family of proteins with functions as small hydrophobic molecule transporters. Beta-lactoglobulin is a typical member of the lipocalin family. Beta-lactoglobulin was found to have a role in the transport of hydrophobic ligands such as retinol or fatty acids. Its crystal structure were determined [e.g. Qin, 1998] with different ligands and in ligand-free form as well. The crystal structures determined so far reveal that the typical lipocalin contains eight-stranded antiparallel-barrel arranged to form a conical central cavity in which the hydrophobic ligand is bound. The structure of beta-lactoglobulin reveals that the barrel-form structure with the central cavity of the protein has an "entrance" surrounded by five beta-loops with centers around 26, 35, 63, 87, and 111, which undergo a conformational change during the ligand binding and close the cavity.
The overall shape of beta-lactoglobulin is characteristic of the lipocalin family. In the absence of alpha-helices, the main diagonal almost disappears and the cross-diagonals representing the beta-sheets dominate the plot. Relatively low number of tertiary hydrogen bonds can be found in the plot, with three high-density regions, one of which is connected to a loop at the residues around 63, a second is connected to the loop around 87, and a third region which is connected to the regions 26 and 35. The fifth loop around 111 is represented only one tertiary hydrogen bond in the HB plot.
In the three-dimensional structure, tertiary hydrogen bonds are formed (1) near to the entrance, directly involved in conformational rearrangement during ligand binding; and (2) at the bottom of the "barrel".
HB plots of the open and closed forms of beta-lactoglobulin are very similar, all unique motifs can be recognized in both forms. Difference in HB plots of open and ligand-bound form show few important individual changes in tertiary hydrogen bonding pattern. Especially, the formation of hydrogen bonds between Y20-E157 and S21-H161 in closed form might be crucial in conformational rearrangement. These hydrogen bonds lie at the bottom of the cavity, which suggests that the closure of the entrance of a lipocalin starts when a ligand reached the bottom of the cavity and broke hydrogen bonds R123-Y99, R123-T18, and V41-Q120. Lipocalins are known to have very low sequence similarity with high structural similarity. The only conserved regions are exactly the region around 20 and 160 with an unknown role.
== See also ==
Ramachandran plot
Circuit topology
Structural classification of proteins
CATH
HB plot
Dot plot (bioinformatics)
Self-similarity matrix
== References ==
== External links ==
DISTILL— prediction of protein structural features (including protein residue contact maps)
Structural Proteomics Tools — includes amino acid contact maps
ProfCon — prediction of inter-residue contacts
TMHcon — prediction of helix-helix contacts specifically within the transmembrane parts of membrane proteins
TMhit — A new transmembrane helix-helix interaction prediction method based on residue contacts
CMAPpro — A protein contact map prediction server
[1] —A Tool for Protein Contact-Map Visualization in jerseysforcheapshop | Wikipedia/Protein_contact_map |
Nuclear magnetic resonance spectroscopy of proteins (usually abbreviated protein NMR) is a field of structural biology in which NMR spectroscopy is used to obtain information about the structure and dynamics of proteins, and also nucleic acids, and their complexes. The field was pioneered by Richard R. Ernst and Kurt Wüthrich at the ETH, and by Ad Bax, Marius Clore, Angela Gronenborn at the NIH, and Gerhard Wagner at Harvard University, among others. Structure determination by NMR spectroscopy usually consists of several phases, each using a separate set of highly specialized techniques. The sample is prepared, measurements are made, interpretive approaches are applied, and a structure is calculated and validated.
NMR involves the quantum-mechanical properties of the central core ("nucleus") of the atom. These properties depend on the local molecular environment, and their measurement provides a map of how the atoms are linked chemically, how close they are in space, and how rapidly they move with respect to each other. These properties are fundamentally the same as those used in the more familiar magnetic resonance imaging (MRI), but the molecular applications use a somewhat different approach, appropriate to the change of scale from millimeters (of interest to radiologists) to nanometers (bonded atoms are typically a fraction of a nanometer apart), a factor of a million. This change of scale requires much higher sensitivity of detection and stability for long term measurement. In contrast to MRI, structural biology studies do not directly generate an image, but rely on complex computer calculations to generate three-dimensional molecular models.
Currently most samples are examined in a solution in water, but methods are being developed to also work with solid samples. Data collection relies on placing the sample inside a powerful magnet, sending radio frequency signals through the sample, and measuring the absorption of those signals. Depending on the environment of atoms within the protein, the nuclei of individual atoms will absorb different frequencies of radio signals. Furthermore, the absorption signals of different nuclei may be perturbed by adjacent nuclei. This information can be used to determine the distance between nuclei. These distances in turn can be used to determine the overall structure of the protein.
A typical study might involve how two proteins interact with each other, possibly with a view to developing small molecules that can be used to probe the normal biology of the interaction ("chemical biology") or to provide possible leads for pharmaceutical use (drug development). Frequently, the interacting pair of proteins may have been identified by studies of human genetics, indicating the interaction can be disrupted by unfavorable mutations, or they may play a key role in the normal biology of a "model" organism like the fruit fly, yeast, the worm C. elegans, or mice. To prepare a sample, methods of molecular biology are typically used to make quantities by bacterial fermentation. This also permits changing the isotopic composition of the molecule, which is desirable because the isotopes behave differently and provide methods for identifying overlapping NMR signals.
== Sample preparation ==
Protein nuclear magnetic resonance is performed on aqueous samples of highly purified protein. Usually, the sample consists of between 300 and 600 microlitres with a protein concentration in the range 0.1 – 3 millimolar. The source of the protein can be either natural or produced in a production system using recombinant DNA techniques through genetic engineering. Recombinantly expressed proteins are usually easier to produce in sufficient quantity, and this method makes isotopic labeling possible.
The purified protein is usually dissolved in a buffer solution and adjusted to the desired solvent conditions. The NMR sample is prepared in a thin-walled glass tube.
== Data collection ==
Protein NMR utilizes multidimensional nuclear magnetic resonance experiments to obtain information about the protein. Ideally, each distinct nucleus in the molecule experiences a distinct electronic environment and thus has a distinct chemical shift by which it can be recognized. However, in large molecules such as proteins the number of resonances can typically be several thousand and a one-dimensional spectrum inevitably has incidental overlaps. Therefore, multidimensional experiments that correlate the frequencies of distinct nuclei are performed. The additional dimensions decrease the chance of overlap and have a larger information content, since they correlate signals from nuclei within a specific part of the molecule. Magnetization is transferred into the sample using pulses of electromagnetic (radiofrequency) energy and between nuclei using delays; the process is described with so-called pulse sequences. Pulse sequences allow the experimenter to investigate and select specific types of connections between nuclei. The array of nuclear magnetic resonance experiments used on proteins fall in two main categories — one where magnetization is transferred through the chemical bonds, and one where the transfer is through space, irrespective of the bonding structure. The first category is used to assign the different chemical shifts to a specific nucleus, and the second is primarily used to generate the distance restraints used in the structure calculation, and in the assignment with unlabelled protein.
Depending on the concentration of the sample, the magnetic field of the spectrometer, and the type of experiment, a single multidimensional nuclear magnetic resonance experiment on a protein sample may take hours or even several days to obtain suitable signal-to-noise ratio through signal averaging, and to allow for sufficient evolution of magnetization transfer through the various dimensions of the experiment. Other things being equal, higher-dimensional experiments will take longer than lower-dimensional experiments.
Typically, the first experiment to be measured with an isotope-labelled protein is a 2D heteronuclear single quantum correlation (HSQC) spectrum, where "heteronuclear" refers to nuclei other than 1H. In theory, the heteronuclear single quantum correlation has one peak for each H bound to a heteronucleus. Thus, in the 15N-HSQC, with a 15N labelled protein, one signal is expected for each nitrogen atom in the back bone, with the exception of proline, which has no amide-hydrogen due to the cyclic nature of its backbone. Additional 15N-HSQC signals are contributed by each residue with a nitrogen-hydrogen bond in its side chain (W, N, Q, R, H, K). The 15N-HSQC is often referred to as the fingerprint of a protein because each protein has a unique pattern of signal positions. Analysis of the 15N-HSQC allows researchers to evaluate whether the expected number of peaks is present and thus to identify possible problems due to multiple conformations or sample heterogeneity. The relatively quick heteronuclear single quantum correlation experiment helps determine the feasibility of doing subsequent longer, more expensive, and more elaborate experiments. It is not possible to assign peaks to specific atoms from the heteronuclear single quantum correlation alone.
== Resonance assignment ==
In order to analyze the nuclear magnetic resonance data, it is important to get a resonance assignment for the protein, that is to find out which chemical shift corresponds to which atom. This is typically achieved by sequential walking using information derived from several different types of NMR experiment. The exact procedure depends on whether the protein is isotopically labelled or not, since a lot of the assignment experiments depend on carbon-13 and nitrogen-15.
=== Homonuclear nuclear magnetic resonance ===
With unlabelled protein the usual procedure is to record a set of two-dimensional homonuclear nuclear magnetic resonance experiments through correlation spectroscopy (COSY), of which several types include conventional correlation spectroscopy, total correlation spectroscopy (TOCSY) and nuclear Overhauser effect spectroscopy (NOESY). A two-dimensional nuclear magnetic resonance experiment produces a two-dimensional spectrum. The units of both axes are chemical shifts. The COSY and TOCSY transfer magnetization through the chemical bonds between adjacent protons. The conventional correlation spectroscopy experiment is only able to transfer magnetization between protons on adjacent atoms, whereas in the total correlation spectroscopy experiment the protons are able to relay the magnetization, so it is transferred among all the protons that are connected by adjacent atoms. Thus in a conventional correlation spectroscopy, an alpha proton transfers magnetization to the beta protons, the beta protons transfers to the alpha and gamma protons, if any are present, then the gamma proton transfers to the beta and the delta protons, and the process continues. In total correlation spectroscopy, the alpha and all the other protons are able to transfer magnetization to the beta, gamma, delta, epsilon if they are connected by a continuous chain of protons. The continuous chain of protons are the sidechain of the individual amino acids. Thus these two experiments are used to build so called spin systems, that is build a list of resonances of the chemical shift of the peptide proton, the alpha protons and all the protons from each residue’s sidechain. Which chemical shifts corresponds to which nuclei in the spin system is determined by the conventional correlation spectroscopy connectivities and the fact that different types of protons have characteristic chemical shifts. To connect the different spinsystems in a sequential order, the nuclear Overhauser effect spectroscopy experiment has to be used. Because this experiment transfers magnetization through space, it will show crosspeaks for all protons that are close in space regardless of whether they are in the same spin system or not. The neighbouring residues are inherently close in space, so the assignments can be made by the peaks in the NOESY with other spin systems.
One important problem using homonuclear nuclear magnetic resonance is overlap between peaks. This occurs when different protons have the same or very similar chemical shifts. This problem becomes greater as the protein becomes larger, so homonuclear nuclear magnetic resonance is usually restricted to small proteins or peptides.
=== Nitrogen-15 nuclear magnetic resonance ===
The most commonly performed 15N experiment is the 1H-15N HSQC. The experiment is highly sensitive and therefore can be performed relatively quickly. It is often used to check the suitability of a protein for structure determination using NMR, as well as for the optimization of the sample conditions. It is one of the standard suite of experiments used for the determination of the solution structure of protein. The HSQC can be further expanded into three- and four dimensional NMR experiments, such as 15N-TOCSY-HSQC and 15N-NOESY-HSQC.
=== Carbon-13 and nitrogen-15 nuclear magnetic resonance ===
When the protein is labelled with carbon-13 and nitrogen-15 it is possible to record triple resonance experiments that transfer magnetisation over the peptide bond, and thus connect different spin systems through bonds. This is usually done using some of the following experiments, HNCO, HN(CA)CO}, HNCA, HN(CO)CA, HNCACB and CBCA(CO)NH. All six experiments consist of a 1H-15N plane (similar to a HSQC spectrum) expanded with a carbon dimension. In the HN(CA)CO, each HN plane contains the peaks from the carbonyl carbon from its residue as well the preceding one in the sequence. The HNCO contains the carbonyl carbon chemical shift from only the preceding residue, but is much more sensitive than HN(CA)CO. These experiments allow each 1H-15N peak to be linked to the preceding carbonyl carbon, and sequential assignment can then be undertaken by matching the shifts of each spin system's own and previous carbons. The HNCA and HN(CO)CA works similarly, just with the alpha carbons (Cα) rather than the carbonyls, and the HNCACB and the CBCA(CO)NH contains both the alpha carbon and the beta carbon (Cβ). Usually several of these experiments are required to resolve overlap in the carbon dimension. This procedure is usually less ambiguous than the NOESY-based method since it is based on through bond transfer. In the NOESY-based methods, additional peaks corresponding to atoms that are close in space but that do not belong to sequential residues will appear, confusing the assignment process. Following the initial sequential resonance assignment, it is usually possible to extend the assignment from the Cα and Cβ to the rest of the sidechain using experiments such as HCCH-TOCSY, which is basically a TOCSY experiment resolved in an additional carbon dimension.
== Restraint generation ==
In order to make structure calculations, a number of experimentally determined restraints have to be generated. These fall into different categories; the most widely used are distance restraints and angle restraints.
=== Distance restraints ===
A crosspeak in a NOESY experiment signifies spatial proximity between the two nuclei in question. Thus each peak can be converted into a maximum distance between the nuclei, usually between 1.8 and 6 angstroms. The intensity of a NOESY peak is proportional to the distance to the minus 6th power, so the distance is determined according to the intensity of the peak. The intensity-distance relationship is not exact, so usually a distance range is used.
It is of great importance to assign the NOESY peaks to the correct nuclei based on the chemical shifts. If this task is performed manually it is usually very labor-intensive, since proteins usually have thousands of NOESY peaks. Some computer programs such as PASD/XPLOR-NIH, UNIO, CYANA, ARIA/CNS, and AUDANA/PONDEROSA-C/S in the Integrative NMR platform perform this task automatically on manually pre-processed listings of peak positions and peak volumes, coupled to a structure calculation. Direct access to the raw NOESY data without the cumbersome need of iteratively refined peak lists is so far only granted by the PASD algorithm implemented in XPLOR-NIH, the ATNOS/CANDID approach implemented in the UNIO software package, and the PONDEROSA-C/S and thus indeed guarantees objective and efficient NOESY spectral analysis.
To obtain as accurate assignments as possible, it is a great advantage to have access to carbon-13 and nitrogen-15 NOESY experiments, since they help to resolve overlap in the proton dimension. This leads to faster and more reliable assignments, and in turn to better structures.
=== Angle restraints ===
In addition to distance restraints, restraints on the torsion angles of the chemical bonds, typically the psi and phi angles, can be generated. One approach is to use the Karplus equation, to generate angle restraints from coupling constants. Another approach uses the chemical shifts to generate angle restraints. Both methods use the fact that the geometry around the alpha carbon affects the coupling constants and chemical shifts, so given the coupling constants or the chemical shifts, a qualified guess can be made about the torsion angles.
=== Orientation restraints ===
The analyte molecules in a sample can be partially ordered with respect to the external magnetic field of the spectrometer by manipulating the sample conditions. Common techniques include addition of bacteriophages or bicelles to the sample, or preparation of the sample in a stretched polyacrylamide gel. This creates a local environment that favours certain orientations of nonspherical molecules. Normally in solution NMR the dipolar couplings between nuclei are averaged out because of the fast tumbling of the molecule. The slight overpopulation of one orientation means that a residual dipolar coupling remains to be observed. The dipolar coupling is commonly used in solid state NMR and provides information about the relative orientation of the bond vectors relative to a single global reference frame. Typically the orientation of the N-H vector is probed in an HSQC-like experiment. Initially, residual dipolar couplings were used for refinement of previously determined structures, but attempts at de novo structure determination have also been made.
== Hydrogen–deuterium exchange ==
NMR spectroscopy is nucleus specific. Thus, it can distinguish between hydrogen and deuterium. The amide protons in the protein exchange readily with the solvent, and, if the solvent contains a different isotope, typically deuterium, the reaction can be monitored by NMR spectroscopy. How rapidly a given amide exchanges reflects its solvent accessibility. Thus amide exchange rates can give information on which parts of the protein are buried, hydrogen-bonded, etc. A common application is to compare the exchange of a free form versus a complex. The amides that become protected in the complex, are assumed to be in the interaction interface.
== Structure calculation ==
The experimentally determined restraints can be used as input for the structure calculation process. Researchers, using computer programs such as XPLOR-NIH, CYANA, GeNMR, or RosettaNMR attempt to satisfy as many of the restraints as possible, in addition to general properties of proteins such as bond lengths and angles. The algorithms convert the restraints and the general protein properties into energy terms, and then try to minimize this energy. The process results in an ensemble of structures that, if the data were sufficient to dictate a certain fold, will converge.
== Structure validation ==
The ensemble of structures obtained is an "experimental model", i.e., a representation of certain kind of experimental data. To acknowledge this fact is important because it means that the model could be a good or bad representation of that experimental data. In general, the quality of a model will depend on both the quantity and quality of experimental data used to generate it and the correct interpretation of such data.
Every experiment has associated errors. Random errors will affect the reproducibility and precision of the resulting structures. If the errors are systematic, the accuracy of the model will be affected. The precision indicates the degree of reproducibility of the measurement and is often expressed as the variance of the measured data set under the same conditions. The accuracy, however, indicates the degree to which a measurement approaches its "true" value.
Ideally, a model of a protein will be more accurate the more fit the actual molecule that represents and will be more precise as there is less uncertainty about the positions of their atoms. In practice there is no "standard molecule" against which to compare models of proteins, so the accuracy of a model is given by the degree of agreement between the model and a set of experimental data. Historically, the structures determined by NMR have been, in general, of lower quality than those determined by X-ray diffraction. This is due, in part, to the lower amount of information contained in data obtained by NMR. Because of this fact, it has become common practice to establish the quality of NMR ensembles, by comparing it against the unique conformation determined by X-ray diffraction, for the same protein. However, the X-ray diffraction structure may not exist, and, since the proteins in solution are flexible molecules, a protein represented by a single structure may lead to underestimate the intrinsic variation of the atomic positions of a protein. A set of conformations, determined by NMR or X-ray crystallography may be a better representation of the experimental data of a protein than a unique conformation.
The utility of a model will be given, at least in part, by the degree of accuracy and precision of the model. An accurate model with relatively poor precision could be useful to study the evolutionary relationships between the structures of a set of proteins, whereas the rational drug design requires both precise and accurate models. A model that is not accurate, regardless of the degree of precision with which it was obtained will not be very useful.
Since protein structures are experimental models that can contain errors, it is very important to be able to detect these errors. The process aimed at the detection of errors is known as validation.
There are several methods to validate structures, some are statistical like PROCHECK and WHAT IF while others are based on physical principles as CheShift, or a mixture of statistical and physics principles PSVS.
== Dynamics ==
In addition to structures, nuclear magnetic resonance can yield information on the dynamics of various parts of the protein. This usually involves measuring relaxation times such as T1 and T2 to determine order parameters, correlation times, and chemical exchange rates. NMR relaxation is a consequence of local fluctuating magnetic fields within a molecule. Local fluctuating magnetic fields are generated by molecular motions. In this way, measurements of relaxation times can provide information of motions within a molecule on the atomic level. In NMR studies of protein dynamics, the nitrogen-15 isotope is the preferred nucleus to study because its relaxation times are relatively simple to relate to molecular motions. This, however, requires isotope labeling of the protein. The T1 and T2 relaxation times can be measured using various types of HSQC-based experiments. The types of motions that can be detected are motions that occur on a time-scale ranging from about 10 picoseconds to about 10 nanoseconds. In addition, slower motions, which take place on a time-scale ranging from about 10 microseconds to 100 milliseconds, can also be studied. However, since nitrogen atoms are found mainly in the backbone of a protein, the results mainly reflect the motions of the backbone, which is the most rigid part of a protein molecule. Thus, the results obtained from nitrogen-15 relaxation measurements may not be representative of the whole protein. Therefore, techniques utilising relaxation measurements of carbon-13 and deuterium have recently been developed, which enables systematic studies of motions of the amino acid side-chains in proteins.
A challenging and special case of study regarding dynamics and flexibility of peptides and full-length proteins is represented by disordered structures. Nowadays, it is an accepted concept that proteins can exhibit a more flexible behaviour known as disorder or lack of structure; however, it is possible to describe an ensemble of structures instead of a static picture representing a fully functional state of the protein. Many advances are represented in this field in particular in terms of new pulse sequences, technological improvement, and rigorous training of researchers in the field.
== NMR spectroscopy on large proteins ==
Traditionally, nuclear magnetic resonance spectroscopy has been limited to relatively small proteins or protein domains. This is in part caused by problems resolving overlapping peaks in larger proteins, but this has been alleviated by the introduction of isotope labelling and multidimensional experiments. Another more serious problem is the fact that in large proteins the magnetization relaxes faster, which means there is less time to detect the signal. This in turn causes the peaks to become broader and weaker, and eventually disappear. Two techniques have been introduced to attenuate the relaxation: transverse relaxation optimized spectroscopy (TROSY) and deuteration of proteins. By using these techniques it has been possible to study proteins in complex with the 900 kDa chaperone GroES-GroEL.
== Automation of the process ==
Structure determination by NMR has traditionally been a time-consuming process, requiring interactive analysis of the data by a highly trained scientist. There has been considerable interest in automating the process to increase the throughput of structure determination and to make protein NMR accessible to non-experts (See structural genomics). The two most time-consuming processes involved are the sequence-specific resonance assignment (backbone and side-chain assignment) and the NOE assignment tasks. Several different computer programs have been published that target individual parts of the overall NMR structure determination process in an automated fashion. Most progress has been achieved for the task of automated NOE assignment. So far, only the FLYA and the UNIO approach were proposed to perform the entire protein NMR structure determination process in an automated manner without any human intervention. Modules in the NMRFAM-SPARKY such as APES (two-letter-code: ae), I-PINE/PINE-SPARKY (two-letter-code: ep; I-PINE web server) and PONDEROSA (two-letter-code: c3, up; PONDEROSA web server) are integrated so that it offers full automation with visual verification capability in each step. Efforts have also been made to standardize the structure calculation protocol to make it quicker and more amenable to automation. Recently, the POKY suite, the successor of programs mentioned above, has been released to provide modern GUI tools and AI/ML features.
== See also ==
NMR spectroscopy
Nuclear magnetic resonance
Nuclear magnetic resonance spectroscopy of carbohydrates
Nuclear magnetic resonance spectroscopy of nucleic acids
Protein crystallization
Protein dynamics
Relaxation (NMR)
X-ray crystallography
== References ==
== Further reading ==
== External links ==
NOESY-Based Strategy for Assignments of Backbone and Side Chain Resonances of Large Proteins without Deuteration (a protocol)
relax Software for the analysis of NMR dynamics
ProSA-web Archived 2011-05-11 at the Wayback Machine Web service for the recognition of errors in experimentally or theoretically determined protein structures
Protein structure determination from sparse experimental data - an introductory presentation
Protein NMR Protein NMR experiments | Wikipedia/Protein_NMR |
In molecular biology, molecular chaperones are proteins that assist the conformational folding or unfolding of large proteins or macromolecular protein complexes. There are a number of classes of molecular chaperones, all of which function to assist large proteins in proper protein folding during or after synthesis, and after partial denaturation. Chaperones are also involved in the translocation of proteins for proteolysis.
The first molecular chaperones discovered were a type of assembly chaperones which assist in the assembly of nucleosomes from folded histones and DNA. One major function of molecular chaperones is to prevent the aggregation of misfolded proteins, thus many chaperone proteins are classified as heat shock proteins, as the tendency for protein aggregation is increased by heat stress.
The majority of molecular chaperones do not convey any steric information for protein folding, and instead assist in protein folding by binding to and stabilizing folding intermediates until the polypeptide chain is fully translated. The specific mode of function of chaperones differs based on their target proteins and location. Various approaches have been applied to study the structure, dynamics and functioning of chaperones. Bulk biochemical measurements have informed us on the protein folding efficiency, and prevention of aggregation when chaperones are present during protein folding. Recent advances in single-molecule analysis have brought insights into structural heterogeneity of chaperones, folding intermediates and affinity of chaperones for unstructured and structured protein chains.
== Functions of molecular chaperones ==
Many chaperones are heat shock proteins, that is, proteins expressed in response to elevated temperatures or other cellular stresses. Heat shock protein chaperones are classified based on their observed molecular weights into Hsp60, Hsp70, Hsp90, Hsp104, and small Hsps. The Hsp60 family of protein chaperones are termed chaperonins, and are characterized by a stacked double-ring structure and are found in prokaryotes, in the cytosol of eukaryotes, and in mitochondria.
Some chaperone systems work as foldases: they support the folding of proteins in an ATP-dependent manner (for example, the GroEL/GroES or the DnaK/DnaJ/GrpE system). Although most newly synthesized proteins can fold in absence of chaperones, a minority strictly requires them for the same. Other chaperones work as holdases: they bind folding intermediates to prevent their aggregation, for example DnaJ or Hsp33.
Chaperones can also work as disaggregases, which interact with aberrant protein assemblies and revert them to monomers. Some chaperones can assist in protein degradation, leading proteins to protease systems, such as the ubiquitin-proteasome system in eukaryotes. Chaperone proteins participate in the folding of over half of all mammalian proteins.
Macromolecular crowding may be important in chaperone function. The crowded environment of the cytosol can accelerate the folding process, since a compact folded protein will occupy less volume than an unfolded protein chain. However, crowding can reduce the yield of correctly folded protein by increasing protein aggregation. Crowding may also increase the effectiveness of the chaperone proteins such as GroEL, which could counteract this reduction in folding efficiency. Some highly specific 'steric chaperones' convey unique structural information onto proteins, which cannot be folded spontaneously. Such proteins violate Anfinsen's dogma, requiring protein dynamics to fold correctly.
Other types of chaperones are involved in transport across membranes, for example membranes of the mitochondria and endoplasmic reticulum (ER) in eukaryotes. A bacterial translocation-specific chaperone SecB maintains newly synthesized precursor polypeptide chains in a translocation-competent (generally unfolded) state and guides them to the translocon.
New functions for chaperones continue to be discovered, such as bacterial adhesin activity, induction of aggregation towards non-amyloid aggregates, suppression of toxic protein oligomers via their clustering, and in responding to diseases linked to protein aggregation and cancer maintenance.
== Human chaperone proteins ==
In human cell lines, chaperone proteins were found to make up ~10% of the gross proteome mass, and are ubiquitously and highly expressed across human tissues.
Chaperones are found extensively in the endoplasmic reticulum (ER), since protein synthesis often occurs in this area.
=== Endoplasmic reticulum ===
In the endoplasmic reticulum (ER) there are general, lectin- and non-classical molecular chaperones that moderate protein folding.
General chaperones: GRP78/BiP, GRP94, GRP170.
Lectin chaperones: calnexin and calreticulin
Non-classical molecular chaperones: HSP47 and ERp29
Folding chaperones:
Protein disulfide isomerase (PDI),
Peptidyl prolyl cis-trans isomerase (PPI), Prolyl isomerase
ERp57
== Nomenclature and examples of chaperone families ==
There are many different families of chaperones; each family acts to aid protein folding in a different way. In bacteria like E. coli, many of these proteins are highly expressed under conditions of high stress, for example, when the bacterium is placed in high temperatures, thus heat shock protein chaperones are the most extensive.
A variety of nomenclatures are in use for chaperones. As heat shock proteins, the names are classically formed by "Hsp" followed by the approximate molecular mass in kilodaltons; such names are commonly used for eukaryotes such as yeast. The bacterial names have more varied forms, and refer directly to their apparent function at discovery. For example, "GroEL" originally stands for "phage growth defect, overcome by mutation in phage gene E, large subunit".
=== Hsp10 and Hsp60 ===
Hsp10/60 (GroEL/GroES complex in E. coli) is the best characterized large (~ 1 MDa) chaperone complex. GroEL (Hsp60) is a double-ring 14mer with a hydrophobic patch at its opening; it is so large it can accommodate native folding of 54-kDa GFP in its lumen. GroES (Hsp10) is a single-ring heptamer that binds to GroEL in the presence of ATP or ADP. GroEL/GroES may not be able to undo previous aggregation, but it does compete in the pathway of misfolding and aggregation. Also acts in the mitochondrial matrix as a molecular chaperone.
=== Hsp70 and Hsp40 ===
Hsp70 (DnaK in E. coli) is perhaps the best characterized small (~ 70 kDa) chaperone. The Hsp70 proteins are aided by Hsp40 proteins (DnaJ in E. coli), which increase the ATP consumption rate and activity of the Hsp70s. The two proteins are named "Dna" in bacteria because they were initially identified as being required for E. coli DNA replication.
It has been noted that increased expression of Hsp70 proteins in the cell results in a decreased tendency toward apoptosis. Although a precise mechanistic understanding has yet to be determined, it is known that Hsp70s have a high-affinity bound state to unfolded proteins when bound to ADP, and a low-affinity state when bound to ATP.
It is thought that many Hsp70s crowd around an unfolded substrate, stabilizing it and preventing aggregation until the unfolded molecule folds properly, at which time the Hsp70s lose affinity for the molecule and diffuse away. Hsp70 also acts as a mitochondrial and chloroplastic molecular chaperone in eukaryotes.
=== Hsp90 ===
Hsp90 (HtpG in E. coli) may be the least understood chaperone. Its molecular weight is about 90 kDa, and it is necessary for viability in eukaryotes (possibly for prokaryotes as well). Heat shock protein 90 (Hsp90) is a molecular chaperone essential for activating many signaling proteins in the eukaryotic cell.
Each Hsp90 has an ATP-binding domain, a middle domain, and a dimerization domain. Originally thought to clamp onto their substrate protein (also known as a client protein) upon binding ATP, the recently published structures by Vaughan et al. and Ali et al. indicate that client proteins may bind externally to both the N-terminal and middle domains of Hsp90.
Hsp90 may also require co-chaperones-like immunophilins, Sti1, p50 (Cdc37), and Aha1, and also cooperates with the Hsp70 chaperone system.
=== Hsp100 ===
Hsp100 (Clp family in E. coli) proteins have been studied in vivo and in vitro for their ability to target and unfold tagged and misfolded proteins.
Proteins in the Hsp100/Clp family form large hexameric structures with unfoldase activity in the presence of ATP. These proteins are thought to function as chaperones by processively threading client proteins through a small 20 Å (2 nm) pore, thereby giving each client protein a second chance to fold.
Some of these Hsp100 chaperones, like ClpA and ClpX, associate with the double-ringed tetradecameric serine protease ClpP; instead of catalyzing the refolding of client proteins, these complexes are responsible for the targeted destruction of tagged and misfolded proteins.
Hsp104, the Hsp100 of Saccharomyces cerevisiae, is essential for the propagation of many yeast prions. Deletion of the HSP104 gene results in cells that are unable to propagate certain prions.
== Bacteriophage ==
The genes of bacteriophage (phage) T4 that encode proteins with a role in determining phage T4 structure were identified using conditional lethal mutants. Most of these proteins proved to be either major or minor structural components of the completed phage particle. However among the gene products (gps) necessary for phage assembly, Snustad identified a group of gps that act catalytically rather than being incorporated themselves into the phage structure. These gps were gp26, gp31, gp38, gp51, gp28, and gp4 [gene 4 is synonymous with genes 50 and 65, and thus the gp can be designated gp4(50)(65)]. The first four of these six gene products have since been recognized as being chaperone proteins. Additionally, gp40, gp57A, gp63 and gpwac have also now been identified as chaperones.
Phage T4 morphogenesis is divided into three independent pathways: the head, the tail and the long tail fiber pathways as detailed by Yap and Rossman. With regard to head morphogenesis, chaperone gp31 interacts with the bacterial host chaperone GroEL to promote proper folding of the major head capsid protein gp23. Chaperone gp40 participates in the assembly of gp20, thus aiding in the formation of the connector complex that initiates head procapsid assembly. Gp4(50)(65), although not specifically listed as a chaperone, acts catalytically as a nuclease that appears to be essential for morphogenesis by cleaving packaged DNA to enable the joining of heads to tails.
During overall tail assembly, chaperone proteins gp26 and gp51 are necessary for baseplate hub assembly. Gp57A is required for correct folding of gp12, a structural component of the baseplate short tail fibers.
Synthesis of the long tail fibers depends on the chaperone protein gp57A that is needed for the trimerization of gp34 and gp37, the major structural proteins of the tail fibers. The chaperone protein gp38 is also required for the proper folding of gp37. Chaperone proteins gp63 and gpwac are employed in attachment of the long tail fibers to the tail baseplate.
== History ==
The investigation of chaperones has a long history. The term "molecular chaperone" appeared first in the literature in 1978, and was invented by Ron Laskey to describe the ability of a nuclear protein called nucleoplasmin to prevent the aggregation of folded histone proteins with DNA during the assembly of nucleosomes. The term was later extended by R. John Ellis in 1987 to describe proteins that mediated the post-translational assembly of protein complexes. In 1988, it was realised that similar proteins mediated this process in both prokaryotes and eukaryotes. The details of this process were determined in 1989, when the ATP-dependent protein folding was demonstrated in vitro.
== Clinical significance ==
There are many disorders associated with mutations in genes encoding chaperones (i.e. multisystem proteinopathy) that can affect muscle, bone and/or the central nervous system.
== See also ==
Media related to Chaperone proteins at Wikimedia Commons
== Notes ==
== References == | Wikipedia/Chaperone_(protein) |
In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "coassembles") with others to form a protein complex.
Large assemblies of proteins such as viruses often use a small number of types of protein subunits as building blocks.
A subunit is often named with a Greek or Roman letter, and the numbers of this type of subunit in a protein is indicated by a subscript. For example, ATP synthase has a type of subunit called α. Three of these are present in the ATP synthase molecule, leading to the designation α3. Larger groups of subunits can also be specified, like α3β3-hexamer and c-ring.
Naturally occurring proteins that have a relatively small number of subunits are referred to as oligomeric. For example, hemoglobin is a symmetrical arrangement of two identical α-globin subunits and two identical β-globin subunits. Longer multimeric proteins such as microtubules and other cytoskeleton proteins may consist of very large numbers of subunits. For example, dynein is a multimeric protein complex involving two heavy chains (DHCs), two intermediate chains (ICs), two light-intermediate chains (LICs) and several light chains (LCs).
The subunits of a protein complex may be identical, homologous or totally dissimilar and dedicated to disparate tasks.
In some protein assemblies, one subunit may be a "catalytic subunit" that enzymatically catalyzes a reaction, whereas a "regulatory subunit" will facilitate or inhibit the activity. Although telomerase has telomerase reverse transcriptase as a catalytic subunit, regulation is accomplished by factors outside the protein.
An enzyme composed of both regulatory and catalytic subunits when assembled is often referred to as a holoenzyme. For example, class I phosphoinositide 3-kinase is composed of a p110 catalytic subunit and a p85 regulatory subunit. One subunit is made of one polypeptide chain. A polypeptide chain has one gene coding for it – meaning that a protein must have one gene for each unique subunit.
== See also ==
Fusion protein
Subunit vaccine
Protein quaternary structure
Allostery
Cooperativity
Monomer
== References == | Wikipedia/Protein_subunit |
Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. They were first described in relation to heat shock, but are now known to also be expressed during other stresses including exposure to cold, UV light and during wound healing or tissue remodeling. Many members of this group perform chaperone functions by stabilizing new proteins to ensure correct folding or by helping to refold proteins that were damaged by the cell stress. This increase in expression is transcriptionally regulated. The dramatic upregulation of the heat shock proteins is a key part of the heat shock response and is induced primarily by heat shock factor (HSF). HSPs are found in virtually all living organisms, from bacteria to humans.
Heat shock proteins are named according to their molecular weight. For example, Hsp60, Hsp70 and Hsp90 (the most widely studied HSPs) refer to families of heat shock proteins on the order of 60, 70 and 90 kilodaltons in size, respectively. The small 8-kilodalton protein ubiquitin, which marks proteins for degradation, also has features of a heat shock protein. A conserved protein binding domain of approximately 80 amino-acid alpha crystallins are known as small heat shock proteins (sHSP).
== Discovery ==
It is known that rapid heat hardening can be elicited by a brief exposure of cells to sub-lethal high temperature, which in turn provides protection from subsequent and more severe temperature. In 1962, Italian geneticist Ferruccio Ritossa reported that heat and the metabolic uncoupler 2,4-dinitrophenol induced a characteristic pattern of "puffing" in the chromosomes of Drosophila. This discovery eventually led to the identification of the heat-shock proteins (HSP) or stress proteins whose expression this puffing represented. Increased synthesis of selected proteins in Drosophila cells following stresses such as heat shock was first reported in 1974. In 1974, Tissieres, Mitchell and Tracy discovered that heat-shock induces the production of a small number of proteins and inhibits the production of most others. This initial biochemical finding gave rise to a large number of studies on the induction of heat shock and its biological role. Heat shock proteins often function as chaperones in the refolding of proteins damaged by heat stress. Heat shock proteins have been found in all species examined, from bacteria to humans, suggesting that they evolved very early and have an important function.
== Function ==
According to Marvin et al. sHSPs independently express not only in heat shock response but also have developmental roles in embryonic or juvenile stages of mammals, teleost fish and some lower vertebral genomes. hspb1 (HSP27) is expressed during stress and during the development of embryo, somites, mid-hindbrain, heart and lens in zebrafish. Expression of the hspb4 gene, which codes for alpha crystallin, increases considerably in the lens in response to heat shock.
=== Upregulation in stress ===
Production of high levels of heat shock proteins can also be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the cell to harmful materials (ethanol, arsenic, and trace metals, among many others), ultraviolet light, starvation, hypoxia (oxygen deprivation), nitrogen deficiency (in plants) or water deprivation. As a consequence, the heat shock proteins are also referred to as stress proteins and their upregulation is sometimes described more generally as part of the stress response.
The mechanism by which heat shock (or other environmental stressors) activates the heat shock factor has been determined in bacteria. During heat stress, outer membrane proteins (OMPs) do not fold and cannot insert correctly into the outer membrane. They accumulate in the periplasmic space. These OMPs are detected by DegS, an inner membrane protease, that passes the signal through the membrane to the sigmaE transcription factor. However, some studies suggest that an increase in damaged or abnormal proteins brings HSPs into action.
Some bacterial heat shock proteins are upregulated via a mechanism involving RNA thermometers such as the FourU thermometer, ROSE element and the Hsp90 cis-regulatory element.
Petersen and Mitchell found that in D. melanogaster a mild heat shock pretreatment which induces heat shock gene expression (and greatly enhances survival after a subsequent higher temperature heat shock) primarily affects translation of messenger RNA rather than transcription of RNA. Heat shock proteins are also synthesized in D. melanogaster during recovery from prolonged exposure to cold in the absence of heat shock. A mild heat shock pretreatment of the same kind that protects against death from subsequent heat shock also prevents death from exposure to cold.
=== Role as chaperone ===
Several heat shock proteins function as intra-cellular chaperones for other proteins. They play an important role in protein–protein interactions such as folding and assisting in the establishment of proper protein conformation (shape) and prevention of unwanted protein aggregation. By helping to stabilize partially unfolded proteins, HSPs aid in transporting proteins across membranes within the cell.
Some members of the HSP family are expressed at low to moderate levels in all organisms because of their essential role in protein maintenance.
=== Management ===
Heat-shock proteins also occur under non-stressful conditions, simply "monitoring" the cell's proteins. Some examples of their role as "monitors" are that they carry old proteins to the cell's "recycling bin" (proteasome) and they help newly synthesised proteins fold properly.
These activities are part of a cell's own repair system, called the "cellular stress response" or the "heat-shock response".
Recently, there are several studies that suggest a correlation between HSPs and dual frequency ultrasound as demonstrated by the use of LDM-MED machine.
Heat shock proteins appear to be more susceptible to self-degradation than other proteins due to slow proteolytic action on themselves.
=== Cardiovascular ===
Heat shock proteins appear to serve a significant cardiovascular role. Hsp90, hsp84, hsp70, hsp27, hsp20, and alpha B crystallin all have been reported as having roles in the cardiovasculature.
Hsp90 binds both endothelial nitric oxide synthase and soluble guanylate cyclase, which in turn are involved in vascular relaxation.
The subset of hsp70, extracellular hsp70 (ehsp70) and intracellular hsp70 (ihsp70), has been shown to have a pivotal role in managing oxidative stress and other physiological factors.
Krief et al. referred hspb7 (cvHSP - cardiovascular Heat shock protein) as cardiac heat shock protein. Gata4 is an essential gene responsible for cardiac morphogenesis. It also regulates the gene expression of hspb7 and hspb12. Gata4 depletion can result in reduced transcript levels of hspb7 and hspb12 and this could result in cardiac myopathies in zebrafish embryos as observed by Gabriel et al.
hspb7 also acts in the downregulation of Kupffer vesicles which is responsible for regulation of left-right asymmetry of heart in zebrafish. Along with hspb7, hspb12 is involved in cardiac laterality determination. A kinase of the nitric oxide cell signalling pathway, protein kinase G, phosphorylates a small heat shock protein, hsp20. Hsp20 phosphorylation correlates well with smooth muscle relaxation and is one significant phosphoprotein involved in the process. Hsp20 appears significant in development of the smooth muscle phenotype during development. Hsp20 also serves a significant role in preventing platelet aggregation, cardiac myocyte function and prevention of apoptosis after ischemic injury, and skeletal muscle function and muscle insulin response.
Hsp27 is a major phosphoprotein during women's contractions. Hsp27 functions in small muscle migrations and appears to serve an integral role.
=== Immunity ===
Function of heat-shock proteins in immunity is based on their ability to bind not only whole proteins, but also peptides. The affinity and specificity of this interaction is typically low.
It was shown, that at least some of the HSPs possess this ability, mainly hsp70, hsp90, gp96 and calreticulin, and their peptide-binding sites were identified. In the case of gp96 it is not clear whether it can bind peptides in vivo, although its peptide-binding site has been found. But gp96 immune function could be peptide-independent, because it is involved in proper folding of many immune receptors, like TLR or integrins.
Apart from that, HSPs can stimulate immune receptors and are important in proper folding of proteins involved in pro-inflammatory signaling pathways.
==== Antigen presentation ====
HSPs are indispensable components of antigen presentation pathways - the classical ones and also cross-presentation and autophagy.
===== MHCI presentation =====
In the simplified view of this pathway HSPs are usually not mentioned: antigenic peptides are generated in proteasome, transported into ER through protein transporter TAP and loaded onto MHCI, which then goes through secretory pathway on plasma membrane.
But HSPs play an important part in transfer of unfolded proteins to proteasome and generated peptides to MHCI. Hsp90 can associate with proteasome and take over generated peptides. Afterwards, it can associate with hsp70, which can take the peptide further to the TAP. After passing through TAP, ER chaperons are getting important - calreticulin binds peptides and together with gp96 form peptide loading complex for MHCI.
This handing over with peptides is important, because HSPs can shield hydrophobic residues in peptides which would be otherwise problematic in aquatic cytosol. Also simple diffusion of peptides would be too ineffective.
===== MHCII presentation =====
In MHCII presentation, HSPs are involved in clathrin-dependent endocytosis. Also when HSPs are extracellular, they can guide their associated peptides into MHCII pathway, although it is not known how they are distinguished from the cross-presented ones (see below).
===== Autophagy =====
HSPs are involved in classical macroautophagy, when protein aggregates are enclosed by double membrane and degraded afterwards. They are also involved in a special type of autophagy called chaperone-mediated autophagy, when they enable cytosolic proteins to get into lysosomes.
===== Cross-presentation =====
When HSPs are extracellular, they can bind to specific receptors on dendritic cells (DC) and promote cross-presentation of their carried peptides. The most important receptors in this case are scavenger receptors, mainly SRECI and LOX-1. CD91 scavenger receptor has been previously proposed as the common HSP receptor. But now its relevance is controversial because the majority of DC types does not express CD91 in relevant amounts and the binding capacity for many HSPs has not been proved. Stimulation of some scavenger receptors can even result in immunosuppression, this is the case for SRA.
LOX-1 and SRECI when stimulated guide HSPs with their associated peptides into cross-presentation. LOX-1 binds mainly hsp60 and hsp70. SRECI is now considered to by the common heat-shock protein receptor because it binds hsp60, hsp70, hsp90, hsp110, gp96 and GRP170.
The relevance for this type of cross-presentation is high especially in tumour-immunosurveillance. Thanks to the HSP, the bound peptide is protected against degradation in dendritic cell compartments and the efficiency of cross-presentation is higher. Also internalisation of HSP-peptide complex is more efficient than internalisation of soluble antigens. Tumor cells usually express only a few neo-antigens, which can be targeted by immune system and also not all tumor cells express them. Because of that the amount of tumor antigens is restricted and high efficiency of cross-presentation is necessary for mounting strong immune response.
Hsp70 and hsp90 are also involved intracellulary in cytosolic pathway of cross-presentation where they help antigens to get from endosome into the cytosol.
==== Damage-associated molecular patterns ====
Extracellular heat-shock proteins can be sensed by the immune system as damage-associated molecular patterns (DAMPs). They are able to interact with pattern recognition receptors like TLR2 or TLR4 and activate antigen presenting cells by upregulation of co-stimulation molecules (CD80, CD86, CD40), MHC molecules and pro-inflammatory and Th1 cytokines. HSP70 was shown to react to DAMP release, causing an influx of HSP70-positive T-EVs (tumor cells) that initiate anti-tumor immune signaling cascades.
Heat-shock proteins can signal also through scavenger receptors, which can either associate with TLRs, or activate pro-inflammatory intracellular pathways like MAPK or NF-kB. With the exception of SRA, which down-regulates immune response.
==== Transport into extracellular space ====
Heat-shock proteins can be secreted from immune cells or tumour cells by non-canonical secretion pathway, or leaderless pathway, because they do not have the leader peptide, which navigate proteins into endoplasmic reticulum. The non-canonical secretion can be similar to the one, which occurs for IL1b, and it is induced by stress conditions.
Another possibility is release of HSPs during cell necrosis, or secretion of HSPs in exosomes. During special types of apoptotic cell death (for example induced by some chemotherapeutics), HSPs can also appear on the extracellular side of plasma membrane.
There is a debate about how long can HSP keep its peptide in extracellular space, at least for hsp70 the complex with peptide is quite stable.
The role of extracellular HSPs can be miscellaneous. It depends a lot on context of tissue whether HSPs will stimulate the immune system or suppress immunity. They can promote Th17, Th1, Th2 or Treg responses depending on antigen-presenting cells.
As a result, the clinical use of heat-shock proteins is both in cancer treatment (boosting an immune response) and treatment of autoimmune diseases (suppress of immunity).
=== Lens ===
Alpha crystallin (α4- crystallin) or hspb4 is involved in the development of lens in Zebrafish as it is expressed in response to heat shock in the Zebrafish embryo in its developmental stages.
== Clinical significance ==
=== HSF 1 ===
Heat shock factor 1 (HSF 1) is a transcription factor that is involved in the general maintenance and upregulation of Hsp70 protein expression. Recently it was discovered that HSF1 is a powerful multifaceted modifier of carcinogenesis. HSF1 knockout mice show significantly decreased incidence of skin tumor after topical application of DMBA (7,12-dimethylbenzanthracene), a mutagen. Moreover, HSF1 inhibition by a potent RNA aptamer attenuates mitogenic (MAPK) signaling and induces cancer cell apoptosis.
=== Diabetes mellitus ===
Diabetes mellitus (DM) is a immune-disease characterized by the presence of hyperglycemia. Typically these symptoms are brought about by insulin deficiency. However, there have been many recent articles alluding to a correlation between hsp70, in some cases hsp60, and DM. Another recent article discovered the ratio of ehsp70 and ihsp70 could have an effect on DM, leading to a sufficient biomarker. Serum levels of hsp70 have also been shown to increase over time in patients with diabetes.
=== Cancer ===
HSP expression plays a pivotal role in cancer identification. Recent discoveries have shown that high concentrations of eHSP can indicate the presence of contentious tumors. Additionally, HSPs have been shown to benefit oncologist in oral cancer diagnosis. Using techniques such as dot immunoassay and ELISA test researchers have been able to determine that HSP-specific phage antibodies could be beneficial in-vitro cancer diagnosis markers. HSPs have also been shown to interact with cancer adaptations such as drug resistance, tumor cell production and lifespan, and the up-regulation and down-regulation of oncomirs.
== Applications ==
=== Cancer vaccines ===
Given their role in presentation, HSPs are useful as immunologic adjuvants (DAMPS) in boosting the response to a vaccine. Furthermore, some researchers speculate that HSPs may be involved in binding protein fragments from dead malignant cells and presenting them to the immune system. In a recent study published by Sedlacek et al., HSP was shown to effect different signaling pathways involved in carcinogenesis responses such as STAT1 activation, gp96-activated macrophages, and activation of NK cells. Therefore, HSPs may be useful for increasing the effectiveness of cancer vaccines.
Also isolated HSPs from tumor cells are able to act as a specific anti-tumor vaccine by themselves. Tumour cells express a lot of HSPs because they need to chaperone mutated and over-expressed oncogenes, tumour cells are also in a permanent stress. When HSPs from a tumour are isolated, the peptide repertoire bound by HSPs is somewhat a fingerprint of these particular tumour cells. Application of such HSPs back into patient then stimulate immune system (promotes efficient antigen presentation and act as DAMP) specifically against the tumor and leads to tumor regression. This immunisation is not functional against a different tumour. It was used in autologous manner in clinical studies for gp96 and hsp70, but in vitro this works for all immune-relevant HSPs.
=== Anticancer therapeutics ===
Intracellular heat shock proteins are highly expressed in cancerous cells and are essential to the survival of these cell types due to presence of mutated and over-expressed oncogenes. Many HSPs can also promote invasiveness and metastasis formation in tumours, block apoptosis, or promote resistance to anti-cancer drugs. Hence small molecule inhibitors of HSPs, especially Hsp90 show promise as anticancer agents. The potent Hsp90 inhibitor 17-AAG was in clinical trials for the treatment of several types of cancer, but for various reasons unrelated to efficacy did not go on to Phase 3. HSPgp96 also shows promise as an anticancer treatment and is currently in clinical trials against non-small cell lung cancer.
=== Autoimmunity treatment ===
Acting as DAMPs, HSPs can extracellularly promote autoimmune reactions leading to diseases as rheumatoid arthritis or systemic lupus erythematosus. Nevertheless, it was found, that application of some HSPs into patients is able to induce immune tolerance and treat autoimmune diseases. The underlying mechanism is not known. HSPs (especially hsp60 and hsp70) are used in clinical studies to treat rheumatoid arthritis and type I. diabetes. Current therapeutic research areas in the treatment for DM include: long-term physical exercise, hot tub therapy (HTT), and alfalfa-derived HSP70 (aHSP70).
Hsp90 inhibitors are another possible treatment for autoimmunity, because hsp90 is necessary for proper folding of many pro-inflammatory proteins (components of PI3K, MAPK and NF-kB cascades).
=== Agricultural ===
Researchers are also investigating the role of HSPs in conferring stress tolerance to hybridized plants, hoping to address drought and poor soil conditions for farming.
== Classification ==
The principal heat-shock proteins that have chaperone activity belong to five conserved classes: HSP33, HSP60, HSP70/HSP110, HSP90, HSP100, and the small heat-shock proteins (sHSPs). A standard nomenclature for human HSP genes is available.
Although the most important members of each family are tabulated here, some species may express additional chaperones, co-chaperones, and heat shock proteins not listed. In addition, many of these proteins may have multiple splice variants (Hsp90α and Hsp90β, for instance) or conflicts of nomenclature (Hsp72 is sometimes called Hsp70).
== See also ==
Cellular stress response
Chaperone
Chaperonin
Co-chaperone
Cold-shock domain
FourU thermometer
Hsp90 cis-regulatory element
ROSE element
HSF1
== References ==
== External links ==
Heat-Shock+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Heat_shock_protein |
Fenvalerate is a synthetic pyrethroid insecticide. It is a mixture of four optical isomers which have different insecticidal activities. The 2-S alpha (or SS) configuration, known as esfenvalerate, is the most insecticidally active isomer. Fenvalerate consists of about 23% of this isomer.
Fenvalerate is an insecticide of moderate mammalian toxicity. In laboratory animals, central nervous system toxicity is observed following acute or short-term exposure. Fenvalerate has applications against a wide range of pests including some of the more destructive such as the Helicoverpa assulta. Residue levels are minimized by low application rates. Fenvalerate is most toxic to bees and fish. It is found in some emulsifiable concentrates, ULV, wettable powders, slow release formulations, insecticidal fogs, and granules. It is most commonly used to control insects in food, feed, and cotton products, and for the control of flies and ticks in barns and stables. Fenvalerate does not affect plants, but is active for an extended period of time.
Fenvalerate may irritate the skin and eyes on contact, and is also harmful if swallowed.
== References ==
== External links ==
Pyrethrins and Pyrethroids Fact Sheet - National Pesticide Information Center
Esfenvalerate Pesticide Information Profile - Extension Toxicology Network
Fenvalerate in the Pesticide Properties DataBase (PPDB)
WHO fenvalerate fact page | Wikipedia/Fenvalerate |
Pest Control is an English hardcore punk band from Leeds, West Yorkshire. They have released one studio album, in addition to their 2020 demo. A 2023 article by Metal Hammer writer Dom Lawson called the band "the single most exciting band in the UK right now".
== History ==
Leah Massey-Hay, Joseph Kerry and Ben Jones had previously been a part of the hardcore band Implement, which disbanded amidst the COVID-19 lockdown in the United Kingdom. Soon, Kerry began sending ideas for songs to Massey-Hay and Jones. This culminated in the first Pest Control demo, which was recorded in September 2020, by Massey-Hay on vocals, Joseph Kerry on guitar and Jones on drums. The release was followed shortly by the hiring of bassist Jack Padurariu.
The band began recording for their debut album in 2022. During this time, the band recruited second guitarist Luke Schoonbeek for recording. Once the recording process was completed, they hired Big Cheese bassist Joe Sam Williams as a permanent second guitarist. On 10 February 2023, the band officially released their debut album, titled Don't Test the Pest. During February 2023, they opened for Kreator on their United Kingdom headline tour, alongside Municipal Waste. On 11 August, they released the single "Enjoy the Show", accompanied by a music video. Between 22 August and 11 September, they toured the United Kingdom supporting Obituary. On 6 January 2024, the band played a benefit show for the Leeds venue Boom, alongside Higher Power, the Flex and Static Dress. On 18 May, the band performed at Desert Festival in London.
The band were originally scheduled to play the June 2024 Download Festival. However, on 10 June, four days before the festival, the band announced they had cancelled their appearance due to the festival's sponsorship by Barclaycard who were connected to Israel's role in the Israeli–Palestinian conflict. In the following hours, the band's statement led to Scowl, Zulu, Speed, Negative Frame, Overpower and Ithaca to cancel their appearances at the festival too. Instead, over the following days Pest Control, Scowl, Speed and Zulu organised a fundraising for the Palestinian cause, which was held at Centrala in Birmingham on 14 June. The show included support from Cauldren, Ikhras and Transistrrr. The sponsorship was dropped from the festival on the same day, with negotiations initiated by Enter Shikari.
On 12 August 2024, the band released the single "Time Bomb", announcing it would a part of their Autumn 2024 EP Year Of The Pest.
== Musical style ==
Pest Control have been categorised by critics as crossover thrash and hardcore punk, while also making use of elements of death metal. The band's music incorporates tight and grooving thrash metal guitar riffs and raspy, shouted vocals. The band often avoid the political lyrics commonplace in hardcore and crossover thrash. Instead, lyrics discuss personal themes and mental health, many of which are told through metaphors of insects and infestations.
They have cited influences including Suicidal Tendencies, Anthrax, the Crumbsuckers, Municipal Waste, Metallica, Testament and Ludichrist.
== Members ==
Leah Massey-Hay – vocals (2020–present)
Joseph Kerry – guitar (2020–present)
Ben Jones – drums (2020–present)
Jack Padurariu – bass (2020–present)
Joe Sam Williams – guitar (2022–present)
== Discography ==
Albums
Don't Test the Pest (2023)
EPs
Year Of The Pest (2024)
Demos
Demo 2020
Singles
"Infestation/Rat Race"
"Enjoy the Show"
"Time Bomb"
== References == | Wikipedia/Pest_Control_(band) |
Hunting strategy or hunting method is any specific techniques or tactics that are used to target, pursue, and hunt an animal. The term mostly applies to humans catching and killing wild animals, but can also be used in ethology and nature documentaries to describe predation strategies adopted by carnivores.
The hunting strategy that a hunter uses depends mainly on the type of terrain, as well as game being hunted. Climate, local hunting techniques, and local hunting laws are also taken in consideration. Some of the most common hunting methods that are used include: still hunting, stalking, driving, stand hunting, calling, baiting, hunting with dogs and falconry.
== Strategies ==
Hunting strategies include:
Baiting is the use of decoys, lures, scent or food to attract targeted animals.
Blind or Stand hunting is waiting for animals in a concealed or elevated position.
Calling is the use of noises to attract or drive animals.
Camouflage is concealing oneself visually, or with scent, to blend in with the environment.
Use of hunting dogs to help flush, herd, drive, track, point at, pursue, or retrieve animals.
Game drive system was a prehistoric hunting strategy where game were herded into areas where they could be hunted in groups.
Driving is the herding of animals in a particular direction, as over a cliff or to other hunters.
Flushing is the practice of scaring targets from concealed areas.
Persistence hunting is a variant of pursuit predation in which a predator will bring down a prey item via indirect means, such as exhaustion, heat illness or injury.
Spotlighting is the use of artificial light to find or blind targets before capture. Modern lighting also includes IR and other devices.
Scouting consists of a variety of tasks and techniques for finding animals to hunt.
Stalking is the practice of walking stealthily, often in pursuit of an identified animal.
Tracking is the practice of interpreting physical evidence to pursue animals.
Trapping is the use of devices (e.g., snares, pits, deadfalls) to capture or kill an animal.
== Stalking ==
Though stalking and still-hunting may resemble in many ways, while the still hunter follows game through its haunts following tracks, stalking, or spot and stalk hunting, consists in locating game from afar and trying to approach within shooting distance, taking advantage of the territory's geography, forest, wind direction and sun location, thus, avoiding to be detected through sight, sounds and smells. Stalk hunting is mainly practiced in mountain terrain, inhabited by animals with low tolerance for human presence, such as sheep, goats, and several mountain deer species. In order to be successful, the hunter gets advantage from vantage points from where to spot game in open ground, that provides less concealment than forested areas.
=== Pushing ===
This strategy is widely used to hunt elusive game in heavy covered areas. It is probably one of the first methods of hunting used by primitive tribes, and even used by animals, such as African lions, where male lions show themselves with aid of their smell and roar to spook antelope towards the position where the more agile lioness is concealed. Humans also use the same principle; pushing game out of forest towards a hunter ready to take a shot.
=== Stand hunting ===
Stand hunting is likely the most common form of hunting used today when hunting for most North American big game species, especially in the east. Stand hunting is when the hunter is stationary in one location and waits for the animal to come to them. Hunters often use tree-stands, ground blinds, and tripod stands to make the hunt more comfortable and to make it harder for the wildlife to spot them. The locations where hunters chose to stand hunt varies greatly. Often hunters will set up a stand near a food source that their target animal species is coming to for food. Hunters will also stand hunt along game trails, and even near water sources in drier climates. The stand hunting method is also the fundamental method used when using baiting, and often calling hunting methods.
==== Calling ====
The technique of calling can be a very effective hunting technique. Calling is the process of using game calls or some other instrument to replicate the sounds of the animal that you are hunting. Game calls are especially effective during the desired species' mating season. During this time, animal mating calls can be a sure fire way to lure in an animal that is within earshot of you. The most common calls used when hunting deer are grunt calls, bleat calls, and rattling antlers. The grunt call can be aggressive buck grunts that would attract a buck that is looking to display his dominance, while bleat calls mimic the sound of a doe that is looking for a buck to breed her. Rattling antlers imitate the sound of two bucks fighting and can lure other bucks in to see what the commotion is all about.
==== Baiting ====
While baiting is an extremely popular and very effective way to encounter various species of wildlife, it is important to check local game laws to ensure that baiting is legal in the area. While most places allow baiting, some areas still deem it illegal to bait wildlife. Baiting is pretty simple and is just the act of using an artificial food source that is placed near your hunting stand to attract the species of animal that is being pursued. Some common baits that are used to attract big game in North America are things such as dried field corn, apples, salt, minerals, and even processed foods such as peanut butter and molasses.
=== Still hunting ===
Still hunting is a common method of hunting used to hunt North American big game species such as deer, elk, bear, and feral hogs. Still hunting is the process of hunting an animal by sneaking into habitats where the animal lives and trying to spot the animal before the animal spots you. The process emulates the final procedure of spot and stalk hunting throughout the entire process. The still hunting method of hunting is not the most popular hunting technique because it takes a fair amount of skill and time. Still hunting is an ancient method of hunting that was used by our ancestors to hunt and kill animals to eat. Still hunting is done by tracking animals down by looking for their tracks, droppings, mating signs, etc. and following this sign very carefully. When following the animal sign it is important to walk very slowly and very quietly while constantly scanning for movement and wildlife. It is also important to stop frequently to watch and listen for wildlife around you. Wind direction is another important aspect of still hunting because if the wind is blowing in the direction that you are walking, it is likely that the animal that you are hunting will smell you and scurry before you ever come into contact with the animal.
== References ==
== External links ==
Media related to Hunting methods at Wikimedia Commons | Wikipedia/Hunting_strategy |
Mechanical pest control is the management and control of pests using physical means such as fences, barriers or electronic wires. It includes also weeding and change of temperature to control pests. Many farmers at the moment are trying to find sustainable ways to remove pests without harming the ecosystem.
== Methods ==
=== Handpicking ===
The use of human hands to remove harmful insects or other toxic material is often the most common action by gardeners. It is also classified as the most direct and the quickest way to remove clearly visible pests. However, it also has equal disadvantages as it must be performed before damage to the plant has been done and before the key development of insects.
=== Mechanical traps ===
Mechanical traps or physical attractants are used in three main ways: to efficiently trap insects, to kill them or to estimate how many insects are there in the total landmass using sampling method. However, some traps are expensive to produce and can end up benefiting insects rather than harming them.
== Differences from integrated pest control ==
Integrated pest control refers to the use of any means to control pests once they reach unacceptable levels. Mechanical pest control is but a minor part of integrated pest control. It means only the use of physical means to control pests.
== See also ==
Biological pest control
Kaolin spray
== References ==
== External list ==
Further Information | Wikipedia/Mechanical_pest_control |
Plant disease resistance protects plants from pathogens in two ways: by pre-formed structures and chemicals, and by infection-induced responses of the immune system. Relative to a susceptible plant, disease resistance is the reduction of pathogen growth on or in the plant (and hence a reduction of disease), while the term disease tolerance describes plants that exhibit little disease damage despite substantial pathogen levels. Disease outcome is determined by the three-way interaction of the pathogen, the plant, and the environmental conditions (an interaction known as the disease triangle).
Defense-activating compounds can move cell-to-cell and systematically through the plant's vascular system. However, plants do not have circulating immune cells, so most cell types exhibit a broad suite of antimicrobial defenses. Although obvious qualitative differences in disease resistance can be observed when multiple specimens are compared (allowing classification as "resistant" or "susceptible" after infection by the same pathogen strain at similar inoculum levels in similar environments), a gradation of quantitative differences in disease resistance is more typically observed between plant strains or genotypes. Plants consistently resist certain pathogens but succumb to others; resistance is usually specific to certain pathogen species or pathogen strains.
== Background ==
Plant disease resistance is crucial to the reliable production of food, and it provides significant reductions in agricultural use of land, water, fuel, and other inputs. Plants in both natural and cultivated populations carry inherent disease resistance, but this has not always protected them.
The late blight Great Famine of Ireland of the 1840s was caused by the oomycete Phytophthora infestans. The world's first mass-cultivated banana cultivar Gros Michel was lost in the 1920s to Panama disease caused by the fungus Fusarium oxysporum. The current wheat stem rust, leaf rust, and yellow stripe rust epidemics spreading from East Africa into the Indian subcontinent are caused by rust fungi Puccinia graminis and P. striiformis. Other epidemics include chestnut blight, as well as recurrent severe plant diseases such as rice blast, soybean cyst nematode, and citrus canker.
Plant pathogens can spread rapidly over great distances, vectored by water, wind, insects, and humans. Across large regions and many crop species, it is estimated that diseases typically reduce plant yields by 10% every year in more developed nations or agricultural systems, but yield loss to diseases often exceeds 20% in less developed settings.
However, disease control is reasonably successful for most crops. Disease control is achieved by use of plants that have been bred for good resistance to many diseases, and by plant cultivation approaches such as crop rotation, pathogen-free seed, appropriate planting date and plant density, control of field moisture, and pesticide use.
== Common disease resistance mechanisms ==
=== Pre-formed structures and compounds ===
Plant cuticle/surface
Plant cell walls
Antimicrobial chemicals (for example: polyphenols, sesquiterpene lactones, saponins)
Antimicrobial peptides
Enzyme inhibitors
Detoxifying enzymes that break down pathogen-derived toxins
Receptors that perceive pathogen presence and activate inducible plant defences
=== Inducible post-infection plant defenses ===
Cell wall reinforcement (cellulose, lignin, suberin, callose, cell wall proteins)
Antimicrobial chemicals, including reactive oxygen species such as hydrogen peroxide or peroxynitrite, or more complex phytoalexins such as genistein or camalexin
Antimicrobial proteins such as defensins, thionins, or PR-1
Antimicrobial enzymes such as chitinases, beta-glucanases, or peroxidases
Hypersensitive response – a rapid host cell death response associated with defence induction.
== Immune system ==
The plant immune system carries two interconnected tiers of receptors, one most frequently sensing molecules outside the cell and the other most frequently sensing molecules inside the cell. Both systems sense the intruder and respond by activating antimicrobial defenses in the infected cell and neighboring cells. In some cases, defense-activating signals spread to the rest of the plant or even to neighboring plants. The two systems detect different types of pathogen molecules and classes of plant receptor proteins.
The first tier is primarily governed by pattern recognition receptors that are activated by recognition of evolutionarily conserved pathogen or microbial–associated molecular patterns (PAMPs or MAMPs). Activation of PRRs leads to intracellular signaling, transcriptional reprogramming, and biosynthesis of a complex output response that limits colonization. The system is known as PAMP-triggered immunity or as pattern-triggered immunity (PTI).
The second tier, primarily governed by R gene products, is often termed effector-triggered immunity (ETI). ETI is typically activated by the presence of specific pathogen "effectors" and then triggers strong antimicrobial responses (see R gene section below).
In addition to PTI and ETI, plant defenses can be activated by the sensing of damage-associated compounds (DAMP), such as portions of the plant cell wall released during pathogenic infection.
Responses activated by PTI and ETI receptors include ion channel gating, oxidative burst, cellular redox changes, or protein kinase cascades that directly activate cellular changes (such as cell wall reinforcement or antimicrobial production), or activate changes in gene expression that then elevate other defensive responses.
Plant immune systems show some mechanistic similarities with the immune systems of insects and mammals, but also exhibit many plant-specific characteristics. The two above-described tiers are central to plant immunity but do not fully describe plant immune systems. In addition, many specific examples of apparent PTI or ETI violate common PTI/ETI definitions, suggesting a need for broadened definitions and/or paradigms.
The term quantitative resistance (discussed below) refers to plant disease resistance that is controlled by multiple genes and multiple molecular mechanisms that each have small effects on the overall resistance trait. Quantitative resistance is often contrasted to ETI resistance mediated by single major-effect R genes.
=== Pattern-triggered immunity ===
PAMPs, conserved molecules that inhabit multiple pathogen genera, are referred to as MAMPs by many researchers. The defenses induced by MAMP perception are sufficient to repel most pathogens. However, pathogen effector proteins (see below) are adapted to suppress basal defenses such as PTI. Many receptors for MAMPs (and DAMPs) have been discovered. MAMPs and DAMPs are often detected by transmembrane receptor-kinases that carry LRR or LysM extracellular domains.
=== Effector triggered immunity ===
Effector triggered immunity (ETI) is activated by the presence of pathogen effectors. The ETI response is reliant on R genes, and is activated by specific pathogen strains. Plant ETI often causes an apoptotic hypersensitive response.
=== R genes and R proteins ===
Plants have evolved R genes (resistance genes) whose products mediate resistance to specific virus, bacteria, oomycete, fungus, nematode or insect strains. R gene products are proteins that allow recognition of specific pathogen effectors, either through direct binding or by recognition of the effector's alteration of a host protein. Many R genes encode NB-LRR proteins (proteins with nucleotide-binding and leucine-rich repeat domains, also known as NLR proteins or STAND proteins, among other names). Most plant immune systems carry a repertoire of 100–600 different R gene homologs. Individual R genes have been demonstrated to mediate resistance to specific virus, bacteria, oomycete, fungus, nematode or insect strains. R gene products control a broad set of disease resistance responses whose induction is often sufficient to stop further pathogen growth/spread.
Studied R genes usually confer specificity for particular strains of a pathogen species (those that express the recognized effector). As first noted by Harold Flor in his mid-20th century formulation of the gene-for-gene relationship, a plant R gene has specificity for a pathogen avirulence gene (Avr gene). Avirulence genes are now known to encode effectors. The pathogen Avr gene must have matched specificity with the R gene for that R gene to confer resistance, suggesting a receptor/ligand interaction for Avr and R genes. Alternatively, an effector can modify its host cellular target (or a molecular decoy of that target), and the R gene product (NLR protein) activates defenses when it detects the modified form of the host target or decoy.
=== Effector biology ===
Effectors are central to the pathogenic or symbiotic potential of microbes and microscopic plant-colonizing animals such as nematodes. Effectors typically are proteins that are delivered outside the microbe and into the host cell. These colonist-derived effectors manipulate the host's cell physiology and development. As such, effectors offer examples of co-evolution (example: a fungal protein that functions outside of the fungus but inside of plant cells has evolved to take on plant-specific functions). Pathogen host range is determined, among other things, by the presence of appropriate effectors that allow colonization of a particular host. Pathogen-derived effectors are a powerful tool to identify plant functions that play key roles in disease and in disease resistance. Apparently most effectors function to manipulate host physiology to allow disease to occur. Well-studied bacterial plant pathogens typically express a few dozen effectors, often delivered into the host by a Type III secretion apparatus. Fungal, oomycete and nematode plant pathogens apparently express a few hundred effectors.
So-called "core" effectors are defined operationally by their wide distribution across the population of a particular pathogen and their substantial contribution to pathogen virulence. Genomics can be used to identify core effectors, which can then be used to discover new R gene alleles, which can be used in plant breeding for disease resistance.
=== Small RNAs and RNA interference ===
Plant sRNA pathways are understood to be important components of pathogen-associated molecular pattern (PAMP)-triggered immunity (PTI) and effector-triggered immunity (ETI). Bacteria‐induced microRNAs (miRNAs) in Arabidopsis have been shown to influence hormonal signalling including auxin, abscisic acid (ABA), jasmonic acid (JA) and salicylic acid (SA). Advances in genome‐wide studies revealed a massive adaptation of host miRNA expression patterns after infection by fungal pathogens Fusarium virguliforme, Erysiphe graminis, Verticillium dahliae, and Cronartium quercuum, and the oomycete Phytophthora sojae. Changes to sRNA expression in response to fungal pathogens indicate that gene silencing may be involved in this defense pathway. However, there is also evidence that the antifungal defense response to Colletotrichum spp. infection in maize is not entirely regulated by specific miRNA induction, but may instead act to fine-tune the balance between genetic and metabolic components upon infection.
Transport of sRNAs during infection is likely facilitated by extracellular vesicles (EVs) and multivesicular bodies (MVBs). The composition of RNA in plant EVs has not been fully evaluated, but it is likely that they are, in part, responsible for trafficking RNA. Plants can transport viral RNAs, mRNAs, miRNAs and small interfering RNAs (siRNAs) systemically through the phloem. This process is thought to occur through the plasmodesmata and involves RNA-binding proteins that assist RNA localization in mesophyll cells. Although they have been identified in the phloem with mRNA, there is no determinate evidence that they mediate long-distant transport of RNAs. EVs may therefore contribute to an alternate pathway of RNA loading into the phloem, or could possibly transport RNA through the apoplast. There is also evidence that plant EVs can allow for interspecies transfer of sRNAs by RNA interference such as Host-Induced Gene Silencing (HIGS). The transport of RNA between plants and fungi seems to be bidirectional as sRNAs from the fungal pathogen Botrytis cinerea have been shown to target host defense genes in Arabidopsis and tomato.
=== Species-level resistance ===
In a small number of cases, plant genes are effective against an entire pathogen species, even though that species is pathogenic on other genotypes of that host species. Examples include barley MLO against powdery mildew, wheat Lr34 against leaf rust and wheat Yr36 against wheat stripe rust. An array of mechanisms for this type of resistance may exist depending on the particular gene and plant-pathogen combination. Other reasons for effective plant immunity can include a lack of coadaptation (the pathogen and/or plant lack multiple mechanisms needed for colonization and growth within that host species), or a particularly effective suite of pre-formed defenses.
== Signaling mechanisms ==
=== Perception of pathogen presence ===
Plant defense signaling is activated by the pathogen-detecting receptors that are described in an above section. The activated receptors frequently elicit reactive oxygen and nitric oxide production, calcium, potassium and proton ion fluxes, altered levels of salicylic acid and other hormones and activation of MAP kinases and other specific protein kinases. These events in turn typically lead to the modification of proteins that control gene transcription, and the activation of defense-associated gene expression.
=== Transcription factors and the hormone response ===
Numerous genes and/or proteins as well as other molecules have been identified that mediate plant defense signal transduction. Cytoskeleton and vesicle trafficking dynamics help to orient plant defense responses toward the point of pathogen attack.
==== Mechanisms of transcription factors and hormones ====
Plant immune system activity is regulated in part by signaling hormones such as:
Salicylic acid
Jasmonic acid
Ethylene
There can be substantial cross-talk among these pathways.
=== Regulation by degradation ===
As with many signal transduction pathways, plant gene expression during immune responses can be regulated by degradation. This often occurs when hormone binding to hormone receptors stimulates ubiquitin-associated degradation of repressor proteins that block expression of certain genes. The net result is hormone-activated gene expression. Examples:
Auxin: binds to receptors that then recruit and degrade repressors of transcriptional activators that stimulate auxin-specific gene expression.
Jasmonic acid: similar to auxin, except with jasmonate receptors impacting jasmonate-response signaling mediators such as JAZ proteins.
Gibberellic acid: Gibberellin causes receptor conformational changes and binding and degradation of Della proteins.
Ethylene: Inhibitory phosphorylation of the EIN2 ethylene response activator is blocked by ethylene binding. When this phosphorylation is reduced, EIN2 protein is cleaved and a portion of the protein moves to the nucleus to activate ethylene-response gene expression.
==== Ubiquitin and E3 signaling ====
Ubiquitination plays a central role in cell signaling that regulates processes including protein degradation and immunological response. Although one of the main functions of ubiquitin is to target proteins for destruction, it is also useful in signaling pathways, hormone release, apoptosis and translocation of materials throughout the cell. Ubiquitination is a component of several immune responses. Without ubiquitin's proper functioning, the invasion of pathogens and other harmful molecules would increase dramatically due to weakened immune defenses.
===== E3 signaling =====
The E3 ubiquitin ligase enzyme is a main component that provides specificity in protein degradation pathways, including immune signaling pathways. The E3 enzyme components can be grouped by which domains they contain and include several types.
These include the Ring and U-box single subunit, HECT, and CRLs. Plant signaling pathways including immune responses are controlled by several feedback pathways, which often include negative feedback; and they can be regulated by De-ubiquitination enzymes, degradation of transcription factors and the degradation of negative regulators of transcription.
== Quantitative resistance ==
Differences in plant disease resistance are often incremental or quantitative rather than qualitative. The term quantitative resistance (QR) refers to plant disease resistance that is controlled by multiple genes and multiple molecular mechanisms that each have small or minor effects on the overall resistance trait. QR is important in plant breeding because the resulting resistance is often more durable (effective for more years), and more likely to be effective against most or all strains of a particular pathogen. QR is typically effective against one pathogen species or a group of closely related species, rather than being broadly effective against multiple pathogens. QR is often obtained through plant breeding without knowledge of the causal genetic loci or molecular mechanisms. QR is likely to depend on many of the plant immune system components discussed in this article, as well as traits that are unique to certain plant-pathogen pairings (such as sensitivity to certain pathogen effectors), as well as general plant traits such as leaf surface characteristics or root system or plant canopy architecture. The term QR is synonymous with minor gene resistance.
=== Adult plant resistance and seedling resistance ===
Adult plant resistance (APR) is a specialist term referring to quantitative resistance that is not effective in the seedling stage but is effective throughout many remaining plant growth stages. The difference between adult plant resistance and seedling resistance is especially important in annual crops.
Seedling resistance is resistance which begins in the seedling stage of plant development and continues throughout its lifetime. When used by specialists, the term does not refer to resistance that is only active during the seedling stage. "Seedling resistance" is meant to be synonymous with major gene resistance or all stage resistance (ASR), and is used as a contrast to "adult plant resistance". Seedling resistance is often mediated by single R genes, but not all R genes encode seedling resistance.
== Plant breeding for disease resistance ==
Plant breeders emphasize selection and development of disease-resistant plant lines. Plant diseases can also be partially controlled by use of pesticides and by cultivation practices such as crop rotation, tillage, planting density, disease-free seeds and cleaning of equipment, but plant varieties with inherent (genetically determined) disease resistance are generally preferred. Breeding for disease resistance began when plants were first domesticated. Breeding efforts continue because pathogen populations are under selection pressure and evolve increased virulence, pathogens move (or are moved) to new areas, changing cultivation practices or climate favor some pathogens and can reduce resistance efficacy, and plant breeding for other traits can disrupt prior resistance. A plant line with acceptable resistance against one pathogen may lack resistance against others.
Breeding for resistance typically includes:
Identification of plants that may be less desirable in other ways, but which carry a useful disease resistance trait, including wild plant lines that often express enhanced resistance.
Crossing of a desirable but disease-susceptible variety to a plant that is a source of resistance.
Growth of breeding candidates in a disease-conducive setting, possibly including pathogen inoculation. Attention must be paid to the specific pathogen isolates, to address variability within a single pathogen species.
Selection of disease-resistant individuals that retain other desirable traits such as yield, quality and including other disease resistance traits.
Resistance is termed durable if it continues to be effective over multiple years of widespread use as pathogen populations evolve. "Vertical resistance" is specific to certain races or strains of a pathogen species, is often controlled by single R genes and can be less durable. Horizontal or broad-spectrum resistance against an entire pathogen species is often only incompletely effective, but more durable, and is often controlled by many genes that segregate in breeding populations. Durability of resistance is important even when future improved varieties are expected to be on the way: The average time from human recognition of a new fungal disease threat to the release of a resistant crop for that pathogen is at least twelve years.
Crops such as potato, apple, banana, and sugarcane are often propagated by vegetative reproduction to preserve highly desirable plant varieties, because for these species, outcrossing seriously disrupts the preferred traits. See also asexual propagation. Vegetatively propagated crops may be among the best targets for resistance improvement by the biotechnology method of plant transformation to manage genes that affect disease resistance.
Scientific breeding for disease resistance originated with Sir Rowland Biffen, who identified a single recessive gene for resistance to wheat yellow rust. Nearly every crop was then bred to include disease resistance (R) genes, many by introgression from compatible wild relatives.
=== GM or transgenic engineered disease resistance ===
The term GM ("genetically modified") is often used as a synonym of transgenic to refer to plants modified using recombinant DNA technologies. Plants with transgenic/GM disease resistance against insect pests have been extremely successful as commercial products, especially in maize and cotton, and are planted annually on over 20 million hectares in over 20 countries worldwide (see also genetically modified crops). Transgenic plant disease resistance against microbial pathogens was first demonstrated in 1986. Expression of viral coat protein gene sequences conferred virus resistance via small RNAs. This proved to be a widely applicable mechanism for inhibiting viral replication. Combining coat protein genes from three different viruses, scientists developed squash hybrids with field-validated, multiviral resistance. Similar levels of resistance to this variety of viruses had not been achieved by conventional breeding.
A similar strategy was deployed to combat papaya ringspot virus, which by 1994 threatened to destroy Hawaii's papaya industry. Field trials demonstrated excellent efficacy and high fruit quality. By 1998 the first transgenic virus-resistant papaya was approved for sale. Disease resistance has been durable for over 15 years. Transgenic papaya accounts for ~85% of Hawaiian production. The fruit is approved for sale in the U.S., Canada, and Japan.
Potato lines expressing viral replicase sequences that confer resistance to potato leafroll virus were sold under the trade names NewLeaf Y and NewLeaf Plus, and were widely accepted in commercial production in 1999–2001, until McDonald's Corp. decided not to purchase GM potatoes and Monsanto decided to close their NatureMark potato business. NewLeaf Y and NewLeaf Plus potatoes carried two GM traits, as they also expressed Bt-mediated resistance to Colorado potato beetle.
No other crop with engineered disease resistance against microbial pathogens had reached the market by 2013, although more than a dozen were in some state of development and testing.
==== PRR transfer ====
Research aimed at engineered resistance follows multiple strategies. One is to transfer useful PRRs into species that lack them. Identification of functional PRRs and their transfer to a recipient species that lacks an orthologous receptor could provide a general pathway to additional broadened PRR repertoires. For example, the Arabidopsis PRR EF-Tu receptor (EFR) recognizes the bacterial translation elongation factor EF-Tu. Research performed at Sainsbury Laboratory demonstrated that deployment of EFR into either Nicotiana benthamiana or Solanum lycopersicum (tomato), which cannot recognize EF-Tu, conferred resistance to a wide range of bacterial pathogens. EFR expression in tomato was especially effective against the widespread and devastating soil bacterium Ralstonia solanacearum. Conversely, the tomato PRR Verticillium 1 (Ve1) gene can be transferred from tomato to Arabidopsis, where it confers resistance to race 1 Verticillium isolates.
==== Stacking ====
The second strategy attempts to deploy multiple NLR genes simultaneously, a breeding strategy known as stacking. Cultivars generated by either DNA-assisted molecular breeding or gene transfer will likely display more durable resistance, because pathogens would have to mutate multiple effector genes. DNA sequencing allows researchers to functionally “mine” NLR genes from multiple species/strains.
The avrBs2 effector gene from Xanthomona perforans is the causal agent of bacterial spot disease of pepper and tomato. The first “effector-rationalized” search for a potentially durable R gene followed the finding that avrBs2 is found in most disease-causing Xanthomonas species and is required for pathogen fitness. The Bs2 NLR gene from the wild pepper, Capsicum chacoense, was moved into tomato, where it inhibited pathogen growth. Field trials demonstrated robust resistance without bactericidal chemicals. However, rare strains of Xanthomonas overcame Bs2-mediated resistance in pepper by acquisition of avrBs2 mutations that avoid recognition but retain virulence. Stacking R genes that each recognize a different core effector could delay or prevent adaptation.
More than 50 loci in wheat strains confer disease resistance against wheat stem, leaf and yellow stripe rust pathogens. The Stem rust 35 (Sr35) NLR gene, cloned from a diploid relative of cultivated wheat, Triticum monococcum, provides resistance to wheat rust isolate Ug99. Similarly, Sr33, from the wheat relative Aegilops tauschii, encodes a wheat ortholog to barley Mla powdery mildew–resistance genes. Both genes are unusual in wheat and its relatives. Combined with the Sr2 gene that acts additively with at least Sr33, they could provide durable disease resistance to Ug99 and its derivatives.
==== Executor genes ====
Another class of plant disease resistance genes opens a “trap door” that quickly kills invaded cells, stopping pathogen proliferation. Xanthomonas and Ralstonia transcription activator–like (TAL) effectors are DNA-binding proteins that activate host gene expression to enhance pathogen virulence. Both the rice and pepper lineages independently evolved TAL-effector binding sites that instead act as an executioner that induces hypersensitive host cell death when up-regulated. Xa27 from rice and Bs3 and Bs4c from pepper, are such “executor” (or "executioner") genes that encode non-homologous plant proteins of unknown function. Executor genes are expressed only in the presence of a specific TAL effector.
Engineered executor genes were demonstrated by successfully redesigning the pepper Bs3 promoter to contain two additional binding sites for TAL effectors from disparate pathogen strains. Subsequently, an engineered executor gene was deployed in rice by adding five TAL effector binding sites to the Xa27 promoter. The synthetic Xa27 construct conferred resistance against Xanthomonas bacterial blight and bacterial leaf streak species.
==== Host susceptibility alleles ====
Most plant pathogens reprogram host gene expression patterns to directly benefit the pathogen. Reprogrammed genes required for pathogen survival and proliferation can be thought of as “disease-susceptibility genes.” Recessive resistance genes are disease-susceptibility candidates. For example, a mutation disabled an Arabidopsis gene encoding pectate lyase (involved in cell wall degradation), conferring resistance to the powdery mildew pathogen Golovinomyces cichoracearum. Similarly, the Barley MLO gene and spontaneously mutated pea and tomato MLO orthologs also confer powdery mildew resistance.
Lr34 is a gene that provides partial resistance to leaf and yellow rusts and powdery mildew in wheat. Lr34 encodes an adenosine triphosphate (ATP)–binding cassette (ABC) transporter. The dominant allele that provides disease resistance was recently found in cultivated wheat (not in wild strains) and, like MLO, provides broad-spectrum resistance in barley.
Natural alleles of host translation elongation initiation factors eif4e and eif4g are also recessive viral-resistance genes. Some have been deployed to control potyviruses in barley, rice, tomato, pepper, pea, lettuce, and melon. The discovery prompted a successful mutant screen for chemically induced eif4e alleles in tomato.
Natural promoter variation can lead to the evolution of recessive disease-resistance alleles. For example, the recessive resistance gene xa13 in rice is an allele of Os-8N3. Os-8N3 is transcriptionally activated byXanthomonas oryzae pv. oryzae strains that express the TAL effector PthXo1. The xa13 gene has a mutated effector-binding element in its promoter that eliminates PthXo1 binding and renders these lines resistant to strains that rely on PthXo1. This finding also demonstrated that Os-8N3 is required for susceptibility.
Xa13/Os-8N3 is required for pollen development, showing that such mutant alleles can be problematic should the disease-susceptibility phenotype alter function in other processes. However, mutations in the Os11N3 (OsSWEET14) TAL effector–binding element were made by fusing TAL effectors to nucleases (TALENs). Genome-edited rice plants with altered Os11N3 binding sites remained resistant to Xanthomonas oryzae pv. oryzae, but still provided normal development function.
==== Gene silencing ====
RNA silencing-based resistance is a powerful tool for engineering resistant crops. The advantage of RNAi as a novel gene therapy against fungal, viral, and bacterial infection in plants lies in the fact that it regulates gene expression via messenger RNA degradation, translation repression and chromatin remodelling through small non-coding RNAs. Mechanistically, the silencing processes are guided by processing products of the double-stranded RNA (dsRNA) trigger, which are known as small interfering RNAs and microRNAs.
Temperature Effects on Virus Resistance
Temperature significantly affects plant resistance to viruses. For example, plants with the N gene for tobacco develop tolerance to tobacco mosaic virus (TMV) but become systemically infected at temperatures above 28 °C. Similarly, Capsicum chinense plants carrying the Tsw gene can become systemically infected with Tomato spotted wilt virus (TSWV) at 32 °C. In the case of Beet necrotic yellow vein virus (BNYVV), plants expressing the BvGLYR1 gene showed higher virus accumulation at 22 °C compared to 30 °C, indicating that temperature influences the effectiveness of this gene in virus resistance.
== Host range ==
Among the thousands of species of plant pathogenic microorganisms, only a small minority have the capacity to infect a broad range of plant species. Most pathogens instead exhibit a high degree of host-specificity. Non-host plant species are often said to express non-host resistance. The term host resistance is used when a pathogen species can be pathogenic on the host species but certain strains of that plant species resist certain strains of the pathogen species. The causes of host resistance and non-host resistance can overlap. Pathogen host range is determined, among other things, by the presence of appropriate effectors that allow colonization of a particular host. Pathogen host range can change quite suddenly if, for example, the pathogen's capacity to synthesize a host-specific toxin or effector is gained by gene shuffling/mutation, or by horizontal gene transfer.
== Epidemics and population biology ==
Native populations are often characterized by substantial genotype diversity and dispersed populations (growth in a mixture with many other plant species). They also have undergone of plant-pathogen coevolution. Hence as long as novel pathogens are not introduced/do not evolve, such populations generally exhibit only a low incidence of severe disease epidemics.
Monocrop agricultural systems provide an ideal environment for pathogen evolution, because they offer a high density of target specimens with similar/identical genotypes. The rise in mobility stemming from modern transportation systems provides pathogens with access to more potential targets. Climate change can alter the viable geographic range of pathogen species and cause some diseases to become a problem in areas where the disease was previously less important.
These factors make modern agriculture more prone to disease epidemics. Common solutions include constant breeding for disease resistance, use of pesticides, use of border inspections and plant import restrictions, maintenance of significant genetic diversity within the crop gene pool (see crop diversity), and constant surveillance to accelerate initiation of appropriate responses. Some pathogen species have much greater capacity to overcome plant disease resistance than others, often because of their ability to evolve rapidly and to disperse broadly.
== Case Study of American Chestnut Blight ==
Chestnut blight was first noticed in American Chestnut trees that were growing in what is now known as the Bronx Zoo in the year 1904. For years following this incident, it was argued as to what the identity of the pathogen was, as well as the appropriate approach to its control. The earliest attempts to fix the problem on the chestnut involved chemical solutions or physical ones. They attempted to use fungicides, cut limbs off of trees to stop the infection, and completely remove infected trees from habitations to not allow them to infect the others. All of these strategies ended up unsuccessful. Even quarantine measures were put into place which were helped by the passage of Plant Quarantine Act. Chestnut blight still proved to be a huge problem as it rapidly moved through the densely populated forests of chestnut trees. In 1914, the idea was considered to induce blight resistance to the trees through various different means and breeding mechanisms.
== See also ==
Gene-for-gene relationship
Induced systemic resistance
Plant defense against herbivory
Plant pathology
Plant use of endophytic fungi in defense
Systemic acquired resistance
== References ==
== Further reading ==
Lucas, J.A., "Plant Defence." Chapter 9 in Plant Pathology and Plant Pathogens, 3rd ed. 1998 Blackwell Science. ISBN 0-632-03046-1
Hammond-Kosack, K. and Jones, J.D.G. "Responses to plant pathogens." In: Buchanan, Gruissem and Jones, eds. Biochemistry and Molecular Biology of Plants, Second Edition. 2015. Wiley-Blackwell, Hoboken, NJ. ISBN 9780470714218
Dodds, P.; Rathjen, J. (2010). "Plant immunity: towards an integrated view of plant–pathogen interactions". Nature Reviews Genetics. 11 (8): 539–548. doi:10.1038/nrg2812. hdl:1885/29324. PMID 20585331. S2CID 8989912.
Michelmore, Richard W.; Christopoulou, Marilena; Caldwell, Katherine S. (2013-08-04). "Impacts of Resistance Gene Genetics, Function, and Evolution on a Durable Future". Annual Review of Phytopathology. 51 (1). Annual Reviews: 291–319. doi:10.1146/annurev-phyto-082712-102334. ISSN 0066-4286. PMID 23682913. S2CID 22234708.
Schumann, G. Plant Diseases: Their Biology and Social Impact. 1991 APS Press, St. Paul, Minnesota ISBN 0890541167
== External links ==
APS Home | Wikipedia/Plant_disease_resistance |
Physical pest control is a method of getting rid of insects and small rodents by killing, removing, or setting up barriers that will prevent further destruction of one's plants. These methods are used primarily for crop growing, but some methods can be applied to homes as well.
== Methods ==
=== Barriers ===
Row covers are useful for keeping insects out of one's plants, typically used for horticultural crops. They are made out of either plastic or polyester. They are made thin and light to allow plants to still absorb sunshine and water from the air.
Diatomaceous earth, made from fossilized and pulverized silica shells, can be used in order to damage the protective cuticle layer of insects that have them, such as ants. When this layer is damaged, the insects become vulnerable to drying out. Unfortunately, the effectiveness of Diatomaceous earth decreases if it is wet. Therefore, it must be used often. This method was used back in the 1930s and 1940s when farmers would run dust over their fields. This would have the very same effect as diatomaceous earth.
=== Fire ===
For farmers, fire has been a powerful technique used to destroy insect breeding grounds. It is used to burn the top of the soil in order to kill the insects that lie there. Unfortunately, this can present some drawbacks. Fire can make the soil much less effective or get rid of the insects that are beneficial to the plants. Also, there is no guarantee that it will actually solve the pest problems since there may be larvae below the surface of the soil.
=== Firearms ===
Historically, firearms have been one of the primary methods used for pest control. "Garden Guns" are smooth bore shotguns specifically made to fire .22 caliber snake shot or 9mm Flobert, and are commonly used by gardeners and farmers for pest control. Garden Guns are short range weapons that can do little harm past 15 to 20 yards, and they're relatively quiet when fired with snake shot, compared to a standard ammunition. These guns are especially effective inside of barns and sheds, as the snake shot will not shoot holes in the roof or walls, or more importantly injure livestock with a ricochet. They are also used for pest control at airports, warehouses, stockyards, etc.
The most common shot cartridge is .22 Long Rifle loaded with #12 shot. At a distance of about 10 feet (3 m), which is about the maximum effective range, the pattern is about 8 inches (20 cm) in diameter from a standard rifle. Special smoothbore shotguns, such as the Marlin Model 25MG can produce effective patterns out to 15 or 20 yards using .22 WMR shotshells, which hold 1/8 oz. of #12 shot contained in a plastic capsule.
=== Animals ===
Dogs, cats, ferrets, mongoose and other animals have been historically used for pest control. The Rat Terrier is an American dog breed with a background as a farm dog and hunting companion. Specifically bred for killing rats, today's Rat Terrier is an intelligent and active small dog that is kept both for pest control and as a family pet. Cats are also valued for companionship and for their ability to hunt vermin. Ferrets are used for hunting, or ferreting. With their long, lean build, and inquisitive nature, ferrets are very well equipped for getting down holes and chasing rodents, rabbits and moles out of their burrows. Mongooses have long been celebrated for their ability to handle venomous snakes, as immortalized in the short story Rikki-Tikki-Tavi.
=== Temperature control ===
Placing produce inside of cold storage containers lengthens how long the produce lasts while also hindering the growth of insects inside of them. Another method to use is to heat, as it will kill the insect larvae in certain types of produce. An example would be with mangoes, where they are placed into a hot water bath in order to kill any eggs and larvae.
=== Traps ===
Fly paper or sticky boards are devices used in order to capture insects as they land upon the surface of the trap. They are covered in a substance that attracts insects, but are actually very sticky or poisonous. These traps are commonly used for flies or leafhoppers.
Trap strips are crops that are grown on fields with the intention of using them to attract insects and not have insects infest the other crops that are being grown. The insects can then be dealt with much more easily than if they were to have been spread throughout an entire field. Trap strips are very useful for dealing with the wheat stem sawfly. The sawflies will go only as far as they need to in order to plant their eggs. If solid stemmed plants are planted around the a crop field, then that's where the sawflies will go and the sawflies’ larvae can't survive in the solid stem.
== Large scale usage ==
On a much larger scale, physical control methods become much less effective because of the time that must be invested into it and because it is likely to be less economical. For example, taking care of a single tree is simple, but taking care of 500, like on a farm, would be impossible using physical control.
== See also ==
Pest control
Biological pest control
Garden guns
Mechanical pest control
== References == | Wikipedia/Physical_pest_control |
Phorate is an organophosphate used as an insecticide and acaricide.
== Overview ==
At normal conditions, it is a pale yellow mobile liquid poorly soluble in water but readily soluble in organic solvents. It is relatively stable and hydrolyses only at very acidic or basic conditions. It is very toxic both for target organisms and for mammals including humans. It inhibits acetylcholinesterase and butyrylcholinesterase.
Phorate is most commonly applied in granular form. It is non-biocumulative and has no residual action. But some metabolites may persist in soil. It also damages some seeds.
== Toxicity ==
Phorate (Thimate) is absorbed readily through all ways. Its toxicity is high. Oral LD50 to rats is 1.1 – 3.2 mg/kg, to mice 3.5 – 6.5 mg/kg (technical phorate). Similar values has been found out to birds.
== References ==
== External links ==
Phorate in the Pesticide Properties DataBase (PPDB) | Wikipedia/Phorate |
Pest Control is an exclusive to audio Doctor Who story, produced as part of BBC Books' New Series Adventures line, and the first entry in the series to be produced. Written by author Peter Anghelides and read by series star David Tennant, it is also the first non-televised Doctor Who adventure to feature the companion Donna Noble (the first standard printed books featuring her were released in autumn 2008). Pest Control was released on CD on 8 May 2008 and is also available for download.
The story is accompanied by an original soundtrack and sound effects created by Simon Hunt.
== Plot ==
The Doctor and Donna land on the distant planet of Rescension and find themselves caught in a war between humans and the centaur-like Aquabi. When a far greater threat emerges, the Doctor must convince the two sides to work together before they are all wiped out.
== Featuring ==
Tenth Doctor
Donna Noble
== References == | Wikipedia/Pest_Control_(Doctor_Who) |
A zoonosis ( ; plural zoonoses) or zoonotic disease is an infectious disease of humans caused by a pathogen (an infectious agent, such as a virus, bacterium, parasite, fungi, or prion) that can jump from a non-human vertebrate to a human. When humans infect non-humans, it is called reverse zoonosis or anthroponosis.
Major modern diseases such as Ebola and salmonellosis are zoonoses. HIV was a zoonotic disease transmitted to humans in the early part of the 20th century, though it has now evolved into a separate human-only disease. Human infection with animal influenza viruses is rare, as they do not transmit easily to or among humans. However, avian and swine influenza viruses in particular possess high zoonotic potential, and these occasionally recombine with human strains of the flu and can cause pandemics such as the 2009 swine flu. Zoonoses can be caused by a range of disease pathogens such as emergent viruses, bacteria, fungi and parasites; of 1,415 pathogens known to infect humans, 61% were zoonotic. Most human diseases originated in non-humans; however, only diseases that routinely involve non-human to human transmission, such as rabies, are considered direct zoonoses.
Zoonoses have different modes of transmission. In direct zoonosis the disease is directly transmitted between non-humans and humans through the air (influenza), bites and saliva (rabies), faecal-oral transmission or through contaminated food. Transmission can also occur via an intermediate species (referred to as a vector), which carry the disease pathogen without getting sick. The term is from Ancient Greek ζῷον (zoon) 'animal' and νόσος (nosos) 'sickness'.
Host genetics plays an important role in determining which non-human viruses will be able to make copies of themselves in the human body. Dangerous non-human viruses are those that require few mutations to begin replicating themselves in human cells. These viruses are dangerous since the required combinations of mutations might randomly arise in the natural reservoir.
== Causes ==
The emergence of zoonotic diseases originated with the domestication of animals. Zoonotic transmission can occur in any context in which there is contact with or consumption of animals, animal products, or animal derivatives. This can occur in a companionistic (pets), economic (farming, trade, butchering, etc.), predatory (hunting, butchering, or consuming wild game), or research context.
Recently, there has been a rise in frequency of appearance of new zoonotic diseases. "Approximately 1.67 million undescribed viruses are thought to exist in mammals and birds, up to half of which are estimated to have the potential to spill over into humans", says a study led by researchers at the University of California, Davis. According to a report from the United Nations Environment Programme and International Livestock Research Institute a large part of the causes are environmental like climate change, unsustainable agriculture, exploitation of wildlife, and land use change. Others are linked to changes in human society such as an increase in mobility. The organizations propose a set of measures to stop the rise.
=== Contamination of food or water supply ===
Foodborne zoonotic diseases are caused by a variety of pathogens that can affect both humans and animals. The most significant zoonotic pathogens causing foodborne diseases are:
==== Bacterial pathogens ====
Escherichia coli O157:H7, Campylobacter, Caliciviridae, and Salmonella.
==== Viral pathogens ====
Hepatitis E: Hepatitis E virus (HEV) is primarily transmitted through pork products, especially in developing countries with limited sanitation. The infection can lead to acute liver disease and is particularly dangerous for pregnant women.
Norovirus: Often found in contaminated shellfish and fresh produce, norovirus is a leading cause of foodborne illness globally. It spreads easily and causes symptoms like vomiting, diarrhea, and stomach pain.
==== Parasitic pathogens ====
Toxoplasma gondii: This parasite is commonly found in undercooked meat, especially pork and lamb, and can cause toxoplasmosis. While typically mild, toxoplasmosis can be severe in immunocompromised individuals and pregnant women, potentially leading to complications.
Trichinella spp. is transmitted through undercooked pork and wild game, causing trichinellosis. Symptoms range from mild gastrointestinal distress to severe muscle pain and, in rare cases, can be fatal.
=== Farming, ranching and animal husbandry ===
Contact with farm animals can lead to disease in farmers or others that come into contact with infected farm animals. Glanders primarily affects those who work closely with horses and donkeys. Close contact with cattle can lead to cutaneous anthrax infection, whereas inhalation anthrax infection is more common for workers in slaughterhouses, tanneries, and wool mills. Close contact with sheep who have recently given birth can lead to infection with the bacterium Chlamydia psittaci, causing chlamydiosis (and enzootic abortion in pregnant women), as well as increase the risk of Q fever, toxoplasmosis, and listeriosis, in the pregnant or otherwise immunocompromised. Echinococcosis is caused by a tapeworm, which can spread from infected sheep by food or water contaminated by feces or wool. Avian influenza is common in chickens, and, while it is rare in humans, the main public health worry is that a strain of avian influenza will recombine with a human influenza virus and cause a pandemic like the 1918 Spanish flu. In 2017, free-range chickens in the UK were temporarily ordered to remain inside due to the threat of avian influenza. Cattle are an important reservoir of cryptosporidiosis, which mainly affects the immunocompromised. Reports have shown mink can also become infected. In Western countries, hepatitis E burden is largely dependent on exposure to animal products, and pork is a significant source of infection, in this respect. Similarly, the human coronavirus OC43, the main cause of the common cold, can use the pig as a zoonotic reservoir, constantly reinfecting the human population.
Veterinarians are exposed to unique occupational hazards when it comes to zoonotic disease. In the US, studies have highlighted an increased risk of injuries and lack of veterinary awareness of these hazards. Research has proved the importance for continued clinical veterinarian education on occupational risks associated with musculoskeletal injuries, animal bites, needle-sticks, and cuts.
A July 2020 report by the United Nations Environment Programme stated that the increase in zoonotic pandemics is directly attributable to anthropogenic destruction of nature and the increased global demand for meat and that the industrial farming of pigs and chickens in particular will be a primary risk factor for the spillover of zoonotic diseases in the future. Habitat loss of viral reservoir species has been identified as a significant source in at least one spillover event.
=== Wildlife trade or animal attacks ===
The wildlife trade may increase spillover risk because it directly increases the number of interactions across animal species, sometimes in small spaces. The origin of the COVID-19 pandemic is traced to the wet markets in China.
Zoonotic disease emergence is demonstrably linked to the consumption of wildlife meat, exacerbated by human encroachment into natural habitats and amplified by the unsanitary conditions of wildlife markets. These markets, where diverse species converge, facilitate the mixing and transmission of pathogens, including those responsible for outbreaks of HIV-1, Ebola, and mpox, and potentially even the COVID-19 pandemic. Notably, small mammals often harbor a vast array of zoonotic bacteria and viruses, yet endemic bacterial transmission among wildlife remains largely unexplored. Therefore, accurately determining the pathogenic landscape of traded wildlife is crucial for guiding effective measures to combat zoonotic diseases and documenting the societal and environmental costs associated with this practice.
=== Insect vectors ===
African sleeping sickness
Dirofilariasis
Eastern equine encephalitis
Japanese encephalitis
Saint Louis encephalitis
Scrub typhus
Tularemia
Venezuelan equine encephalitis
West Nile fever
Western equine encephalitis
Zika fever
=== Pets ===
Pets can transmit a number of diseases. Dogs and cats are routinely vaccinated against rabies. Pets can also transmit ringworm and Giardia, which are endemic in both animal and human populations. Toxoplasmosis is a common infection of cats; in humans it is a mild disease although it can be dangerous to pregnant women. Dirofilariasis is caused by Dirofilaria immitis through mosquitoes infected by mammals like dogs and cats. Cat-scratch disease is caused by Bartonella henselae and Bartonella quintana, which are transmitted by fleas that are endemic to cats. Toxocariasis is the infection of humans by any of species of roundworm, including species specific to dogs (Toxocara canis) or cats (Toxocara cati). Cryptosporidiosis can be spread to humans from pet lizards, such as the leopard gecko. Encephalitozoon cuniculi is a microsporidial parasite carried by many mammals, including rabbits, and is an important opportunistic pathogen in people immunocompromised by HIV/AIDS, organ transplantation, or CD4+ T-lymphocyte deficiency.
Pets may also serve as a reservoir of viral disease and contribute to the chronic presence of certain viral diseases in the human population. For instance, approximately 20% of domestic dogs, cats, and horses carry anti-hepatitis E virus antibodies and thus these animals probably contribute to human hepatitis E burden as well. For non-vulnerable populations (e.g., people who are not immunocompromised) the associated disease burden is, however, small. Furthermore, the trade of non domestic animals such as wild animals as pets can also increase the risk of zoonosis spread.
=== Exhibition ===
Outbreaks of zoonoses have been traced to human interaction with, and exposure to, other animals at fairs, live animal markets, petting zoos, and other settings. In 2005, the Centers for Disease Control and Prevention (CDC) issued an updated list of recommendations for preventing zoonosis transmission in public settings. The recommendations, developed in conjunction with the National Association of State Public Health Veterinarians, include educational responsibilities of venue operators, limiting public animal contact, and animal care and management.
=== Hunting and bushmeat ===
Hunting involves humans tracking, chasing, and capturing wild animals, primarily for food or materials like fur. However, other reasons like pest control or managing wildlife populations can also exist. Transmission of zoonotic diseases, those leaping from animals to humans, can occur through various routes: direct physical contact, airborne droplets or particles, bites or vector transport by insects, oral ingestion, or even contact with contaminated environments. Wildlife activities like hunting and trade bring humans closer to dangerous zoonotic pathogens, threatening global health.
According to the Center for Diseases Control and Prevention (CDC) hunting and consuming wild animal meat ("bushmeat") in regions like Africa can expose people to infectious diseases due to the types of animals involved, like bats and primates. Unfortunately, common preservation methods like smoking or drying aren't enough to eliminate these risks. Although bushmeat provides protein and income for many, the practice is intricately linked to numerous emerging infectious diseases like Ebola, HIV, and SARS, raising critical public health concerns.
A review published in 2022 found evidence that zoonotic spillover linked to wildmeat consumption has been reported across all continents.
=== Deforestation, biodiversity loss and environmental degradation ===
Kate Jones, Chair of Ecology and Biodiversity at University College London, says zoonotic diseases are increasingly linked to environmental change and human behavior. The disruption of pristine forests driven by logging, mining, road building through remote places, rapid urbanization, and population growth is bringing people into closer contact with animal species they may never have been near before. The resulting transmission of disease from wildlife to humans, she says, is now "a hidden cost of human economic development". In a guest article, published by IPBES, President of the EcoHealth Alliance and zoologist Peter Daszak, along with three co-chairs of the 2019 Global Assessment Report on Biodiversity and Ecosystem Services, Josef Settele, Sandra Díaz, and Eduardo Brondizio, wrote that "rampant deforestation, uncontrolled expansion of agriculture, intensive farming, mining and infrastructure development, as well as the exploitation of wild species have created a 'perfect storm' for the spillover of diseases from wildlife to people."
Joshua Moon, Clare Wenham, and Sophie Harman said that there is evidence that decreased biodiversity has an effect on the diversity of hosts and frequency of human-animal interactions with potential for pathogenic spillover.
An April 2020 study, published in the Proceedings of the Royal Society's Part B journal, found that increased virus spillover events from animals to humans can be linked to biodiversity loss and environmental degradation, as humans further encroach on wildlands to engage in agriculture, hunting, and resource extraction they become exposed to pathogens which normally would remain in these areas. Such spillover events have been tripling every decade since 1980. An August 2020 study, published in Nature, concludes that the anthropogenic destruction of ecosystems for the purpose of expanding agriculture and human settlements reduces biodiversity and allows for smaller animals such as bats and rats, which are more adaptable to human pressures and also carry the most zoonotic diseases, to proliferate. This in turn can result in more pandemics.
In October 2020, the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services published its report on the 'era of pandemics' by 22 experts in a variety of fields and concluded that anthropogenic destruction of biodiversity is paving the way to the pandemic era and could result in as many as 850,000 viruses being transmitted from animals – in particular birds and mammals – to humans. The increased pressure on ecosystems is being driven by the "exponential rise" in consumption and trade of commodities such as meat, palm oil, and metals, largely facilitated by developed nations, and by a growing human population. According to Peter Daszak, the chair of the group who produced the report, "there is no great mystery about the cause of the Covid-19 pandemic, or of any modern pandemic. The same human activities that drive climate change and biodiversity loss also drive pandemic risk through their impacts on our environment."
=== Climate change ===
According to a report from the United Nations Environment Programme and International Livestock Research Institute, entitled "Preventing the next pandemic – Zoonotic diseases and how to break the chain of transmission", climate change is one of the 7 human-related causes of the increase in the number of zoonotic diseases. The University of Sydney issued a study, in March 2021, that examines factors increasing the likelihood of epidemics and pandemics like the COVID-19 pandemic. The researchers found that "pressure on ecosystems, climate change and economic development are key factors" in doing so. More zoonotic diseases were found in high-income countries.
A 2022 study dedicated to the link between climate change and zoonosis found a strong link between climate change and the epidemic emergence in the last 15 years, as it caused a massive migration of species to new areas, and consequently contact between species which do not normally come in contact with one another. Even in a scenario with weak climatic changes, there will be 15,000 spillover of viruses to new hosts in the next decades. The areas with the most possibilities for spillover are the mountainous tropical regions of Africa and southeast Asia. Southeast Asia is especially vulnerable as it has a large number of bat species that generally do not mix, but could easily if climate change forced them to begin migrating.
A 2021 study found possible links between climate change and transmission of COVID-19 through bats. The authors suggest that climate-driven changes in the distribution and robustness of bat species harboring coronaviruses may have occurred in eastern Asian hotspots (southern China, Myanmar, and Laos), constituting a driver behind the evolution and spread of the virus.
=== Secondary Transmission ===
Zoonotic diseases contribute significantly to the burdened public health system as vulnerable groups such the elderly, children, childbearing women and immune-compromised individuals are at risk. According to the World Health Organization (WHO), any disease or infection that is primarily ‘naturally’ transmissible from vertebrate animals to humans or from humans to animals is classified as a zoonosis. Factors such as climate change, urbanization, animal migration and trade, travel and tourism, vector biology, anthropogenic factors, and natural factors have greatly influenced the emergence, re-emergence, distribution, and patterns of zoonoses.
Zoonotic diseases generally refer to diseases of animal origin in which direct or vector mediated animal-to-human transmission is the usual source of human infection. Animal populations are the principal reservoir of the pathogen and horizontal infection in humans is rare. A few examples in this category include lyssavirus infections, Lyme borreliosis, plague, tularemia, leptospirosis, ehrlichiosis, Nipah virus, West Nile virus (WNV) and hantavirus infections. Secondary transmission encompasses a category of diseases of animal origin in which the actual transmission to humans is a rare event but, once it has occurred, human-to-human transmission maintains the infection cycle for some period of time. Some examples include human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), certain influenza A strains, Ebola virus and severe acute respiratory syndrome (SARS).
One example is Ebola which is spread by direct transmission to humans from handling bushmeat (wild animals hunted for food) and contact with infected bats or close contact with infected animals, including chimpanzees, fruit bats, and forest antelope. Secondary transmission also occurs from human to human by direct contact with blood, bodily fluids, or skin of patients with or who died of Ebola virus disease. Some examples of pathogens with this pattern of secondary transmission are human immunodeficiency virus/acquired immune deficiency syndrome, influenza A, Ebola virus and severe acute respiratory syndrome. Recent infections of these emerging and re-emerging zoonotic infections have occurred as a results of many ecological and sociological changes globally.
== History ==
During most of human prehistory groups of hunter-gatherers were probably very small. Such groups probably made contact with other such bands only rarely. Such isolation would have caused epidemic diseases to be restricted to any given local population, because propagation and expansion of epidemics depend on frequent contact with other individuals who have not yet developed an adequate immune response. To persist in such a population, a pathogen either had to be a chronic infection, staying present and potentially infectious in the infected host for long periods, or it had to have other additional species as reservoir where it can maintain itself until further susceptible hosts are contacted and infected. In fact, for many "human" diseases, the human is actually better viewed as an accidental or incidental victim and a dead-end host. Examples include rabies, anthrax, tularemia, and West Nile fever. Thus, much of human exposure to infectious disease has been zoonotic.
Many diseases, even epidemic ones, have zoonotic origin and measles, smallpox, influenza, HIV, and diphtheria are particular examples. Various forms of the common cold and tuberculosis also are adaptations of strains originating in other species. Some experts have suggested that all human viral infections were originally zoonotic.
Zoonoses are of interest because they are often previously unrecognized diseases or have increased virulence in populations lacking immunity. The West Nile virus first appeared in the United States in 1999, in the New York City area. Bubonic plague is a zoonotic disease, as are salmonellosis, Rocky Mountain spotted fever, and Lyme disease.
A major factor contributing to the appearance of new zoonotic pathogens in human populations is increased contact between humans and wildlife. This can be caused either by encroachment of human activity into wilderness areas or by movement of wild animals into areas of human activity. An example of this is the outbreak of Nipah virus in peninsular Malaysia, in 1999, when intensive pig farming began within the habitat of infected fruit bats. The unidentified infection of these pigs amplified the force of infection, transmitting the virus to farmers, and eventually causing 105 human deaths.
Similarly, in recent times avian influenza and West Nile virus have spilled over into human populations probably due to interactions between the carrier host and domestic animals. Highly mobile animals, such as bats and birds, may present a greater risk of zoonotic transmission than other animals due to the ease with which they can move into areas of human habitation.
Because they depend on the human host for part of their life-cycle, diseases such as African schistosomiasis, river blindness, and elephantiasis are not defined as zoonotic, even though they may depend on transmission by insects or other vectors.
== Use in vaccines ==
The first vaccine against smallpox by Edward Jenner in 1800 was by infection of a zoonotic bovine virus which caused a disease called cowpox. Jenner had noticed that milkmaids were resistant to smallpox. Milkmaids contracted a milder version of the disease from infected cows that conferred cross immunity to the human disease. Jenner abstracted an infectious preparation of 'cowpox' and subsequently used it to inoculate persons against smallpox. As a result of vaccination, smallpox has been eradicated globally, and mass inoculation against this disease ceased in 1981. There are a variety of vaccine types, including traditional inactivated pathogen vaccines, subunit vaccines, live attenuated vaccines. There are also new vaccine technologies such as viral vector vaccines and DNA/RNA vaccines, which include many of the COVID-19 vaccines.
== Lists of diseases ==
== See also ==
== References ==
== Bibliography ==
== External links ==
AVMA Collections: Zoonosis Updates
WHO tropical diseases and zoonoses
Detection and Forensic Analysis of Wildlife and Zoonotic Disease
Publications in Zoonotics and Wildlife Disease
A message from nature: coronavirus. United Nations Environment Programme
UK's One Health Vector-Borne Diseases Hub | Wikipedia/Zoonotic_disease |
People for the Ethical Treatment of Animals (PETA; PEE-tə) is an American animal rights nonprofit organization based in Norfolk, Virginia, and led by Ingrid Newkirk, its international president.
Founded in March 1980 by Newkirk and animal rights activist Alex Pacheco, the organization first gained attention in the summer of 1981 during what became known as the Silver Spring monkeys case. The organization opposes factory farming, fur farming, animal testing, and other activities it considers to be exploitation of animals.
The organization's controversial campaigns have been credited with drawing media attention to animal rights issues, but have also been widely criticized for their disruptive nature. Its use of euthanasia has resulted in legal action and a response from Virginia lawmakers.
== History ==
=== Ingrid Newkirk ===
Ingrid Newkirk was born in England in 1949, and raised in Hertfordshire and later New Delhi, India, where her father—a navigational engineer—was stationed. Newkirk, now an atheist, was educated in a convent, the only British girl there. She moved to the United States as a teenager, first studying to become a stockbroker, but after taking some abandoned kittens to an animal shelter in 1969 and being appalled by the conditions that she found there, she chose a career in animal protection instead. She became an animal-protection officer for Montgomery County, Maryland, and then the District of Columbia's first woman poundmaster. By 1976 she was head of the animal disease control division of D.C.'s Commission on Public Health and in 1980 was among those named as "Washingtonians of the Year".
In 1980, after her divorce, she met Alex Pacheco, a political science major at George Washington University. He volunteered at the shelter where she worked, and they fell in love and began living together. Newkirk read Peter Singer's influential book, Animal Liberation (1975), and in March 1980, she persuaded Pacheco to join her in forming People for the Ethical Treatment of Animals, at that point just "five people in a basement", as Newkirk described it. They were mostly students and members of the local vegetarian society, but the group included a friend of Pacheco's from the UK, Kim Stallwood, a British activist who went on to become the national organizer of the British Union for the Abolition of Vivisection.
=== Silver Spring monkeys ===
The group first came to public attention in 1981 during the Silver Spring monkeys case, a dispute about experiments conducted by researcher Edward Taub on 17 macaque monkeys inside the Institute of Behavioral Research in Silver Spring, Maryland. The case led to the first police raid in the United States on an animal laboratory, triggered an amendment in 1985 to the United States Animal Welfare Act, and became the first animal-testing case to be appealed to the United States Supreme Court, which upheld a Louisiana State Court ruling that denied PETA's request for custody of the monkeys.
Pacheco had taken a job in May 1981 inside a primate research laboratory at the institute, intending to gain firsthand experience of working inside an animal laboratory. Taub had been cutting sensory ganglia that supplied nerves to the monkeys' fingers, hands, arms, and legs—a process called "deafferentation"—so that the monkeys could not feel them; some of the monkeys had had their entire spinal columns deafferented. He then used restraint, electric shock, and withholding of food and water to force the monkeys to use the deafferented parts of their bodies. The research led in part to the discovery of neuroplasticity and a new therapy for stroke victims called constraint-induced movement therapy.
Pacheco went to the laboratory at night, taking photographs that showed the monkeys living in what the Institute for Laboratory Animal Research's ILAR Journal called "filthy conditions". He passed his photographs to the police, who raided the lab and arrested Taub. Taub was convicted of six counts of cruelty to animals, the first such conviction in the United States of an animal researcher; the conviction, though, was overturned on appeal. Norm Phelps writes that the case followed the highly publicized campaign of Henry Spira in 1976 against experiments on cats being performed at the American Museum of Natural History in New York and Spira's subsequent campaign in April 1980 against the Draize test. These and the Silver Spring monkey case jointly put animal rights on the agenda in the United States.
The 10-year battle for custody of the monkeys—described by The Washington Post as a vicious mud fight, during which both sides accused the other of lies and distortion— transformed PETA into a national, then international, movement. By February 1991, it claimed over 350,000 supporters, a paid staff of over 100, and an annual budget of over $7 million.
=== PETA India ===
PETA India was founded in 2000 and is based in Mumbai, India.
PETA and the NGO Animal Rahat, authorized by the Animal Welfare Board of India (AWBI), participated in a nine-month investigation of 16 circuses in India. After it was said that "animals used in circuses were subjected to chronic confinement, physical abuse, and psychological torment", AWBI, in 2013, banned the registration of elephants for performance.
PETA India put up billboards prior to a 2020 annual religious event Eid al-Adha where animals are ritualistically slaughtered. The billboards depicted goats with the words "I am a living being and not just meat. Change your view towards us and become a vegan." and "I am ME, Not Mutton. See the Individual. Go Vegan." Muslim clerics wanted to take down the billboards, saying that it was hurtful to their religious sentiments.
In July 2020, PETA put up billboards saying "This Rakshabandhan, protect me: Go leather-free".
=== Locations ===
PETA was based in Rockville, Maryland, until 1996, when it moved to Norfolk, Virginia. It opened a Los Angeles division in 2006 and also has offices in Washington, D.C., and Oakland, California. In addition, PETA has international affiliates.
== Philosophy and activism ==
=== Profile ===
PETA is an animal rights organization that opposes speciesism, and the abuse of animals in any way, such as for food, clothing, entertainment, or research.
In 2020, PETA's website claimed they had 6.5 million supporters, and received donations of $49 million for 2019.
=== Campaigns and consumer boycotts ===
The organization is known for aggressive media stunts, combined with a solid base of celebrity support—in addition to its honorary directors, Paul McCartney, Alicia Silverstone, Eva Mendes, Charlize Theron, Ellen DeGeneres, and many other notable celebrities have appeared in PETA ads. Every week, Newkirk holds what The New Yorker calls a "war council", with two dozen of her top strategists gathered at a square table in the PETA conference room, with no suggestion considered too "kooky or unkind". PETA also gives an annual prize, called the Proggy Award (for "progress"), to individuals or organizations dedicated to animal welfare or who distinguish themselves through their efforts within the area of animal welfare.
Many of the campaigns have focused on large corporations. Fast food companies such as KFC, Wendy's, and Burger King have been targeted. In the animal-testing industry, PETA's consumer boycotts have focused on Avon, Benetton, Bristol-Myers-Squibb, Chesebrough-Pond's, Dow Chemical, General Motors, and others. The group's modus operandi includes buying shares in target companies such as McDonald's and Kraft Foods to exert influence. The campaigns have delivered results for PETA. McDonald's and Wendy's introduced vegetarian options after PETA targeted them; and Polo Ralph Lauren said it would no longer use fur. Avon, Estée Lauder, Benetton, and Tonka Toy Co. all stopped testing products on animals, the Pentagon stopped shooting pigs and goats in wounds tests, and a slaughterhouse in Texas was closed down.
As part of its anti-fur action, PETA supporters have infiltrated hundreds of fashion shows in the U.S. and Europe and one in China, throwing red paint on the catwalks and unfurling banners. Celebrities and supermodels have posed naked for the group's "I'd Rather Go Naked Than Wear Fur" campaign—some men, but mostly women—triggering criticism from some feminist animal rights advocates. The New Yorker writes that PETA activists have crawled through the streets of Paris wearing leg-hold traps and thrown around money soaked in fake blood at the International Fur Fair. They sometimes engage in pie-throwing—in January 2010, Canadian MP Gerry Byrne compared them to terrorists for throwing a tofu cream pie at Canada's fishery minister Gail Shea in protest of the seal slaughter, a comment Newkirk called a silly chest-beating exercise. "The thing is, we make them gawk" she told Satya magazine, "maybe like a traffic accident that you have to look at."
PETA has also objected to the practice of mulesing (removing strips of wool-bearing skin from around the buttocks of a sheep). In October 2004, PETA launched a boycott against the Australian wool industry, leading some clothing retailers to ban products using Australian wool from their stores. In response, the Australian wool industry sued PETA, arguing among other things that mulesing prevents flystrike, a very painful disease that can affect sheep. A settlement was reached, and PETA agreed to stop the boycott, while the wool industry agreed to seek alternatives to mulesing.
In 2011, PETA named five orcas as plaintiffs and sued SeaWorld over the animals' captivity, seeking their protection under the Thirteenth Amendment. A federal judge heard the case and dismissed it in early 2012. In August 2014, SeaWorld announced it was building new orca tanks that would almost double the size of the existing ones to provide more space for its whales. PETA responded that a "larger prison is still a prison." In 2016, SeaWorld admitted that it had been sending its employees to pose as activists to spy on PETA. Following an investigation by an outside law firm, SeaWorld's Board of Directors directed management to end the practice.
In 2011, Patricia de Leon was the Hispanic spokesperson for PETA's anti-bullfighting campaign.
Some campaigns have been particularly controversial. Newkirk was criticized in 2003 for sending a letter to PLO leader Yasser Arafat asking him to keep animals out of the conflict, after a donkey was blown up during an attack in Jerusalem.
To reduce milk consumption, it created the "Got Beer?" campaign, a parody of the dairy industry's series of Got Milk? ads, which featured celebrities with milk "mustaches" on their upper lips. When the mayor of New York, Rudy Giuliani, was diagnosed with prostate cancer in 2000, PETA ran a photograph of him with a white mustache and the words "Got prostate cancer?" to illustrate their claim that dairy products contribute to cancer, an ad that caused an outcry in the United States. After PETA placed ads in school newspapers linking milk to acne, obesity, heart disease, cancer, and strokes, Mothers Against Drunk Driving and college officials complained it encouraged underage drinking; the British Advertising Standards Authority asked that the ads be discontinued after complaints from interest groups such as The National Farmers' Unions.
In August 2011, it was announced that PETA will be launching a soft pornography website in the .xxx domain. PETA spokesperson Lindsay Rajt told the Huffington Post, "We try to use absolutely every outlet to stick up for animals," adding that "We are careful about what we do and wouldn't use nudity or some of our flashier tactics if we didn't know they worked." PETA also used nudity in its "Veggie Love" ad which it prepared for the Super Bowl, only to have it banned by the network. PETA's work has drawn the ire of some feminists who argue that the organization sacrifices women's rights to press its agenda. Lindsay Beyerstein criticized PETA saying "They're the ones drawing disturbing analogies between pornography, misogyny and animal cruelty."
PETA has approached cities to pressure them to change their names, including Fishkill, New York in 1996, Hamburg, New York in 2003, and Commerce City, Colorado in 2007.
PETA sometimes issues isolated statements or press releases, commenting on current events. After Lady Gaga wore a dress made of meat in 2010, PETA issued a statement objecting to the dress. After a fisherman in Florida was bitten by a shark in 2011, PETA proposed an advertisement showing a shark devouring a human, with the caption "Payback Is Hell, Go Vegan". The proposed ad drew criticism from relatives of the injured fisherman. After Minnesota dentist Walter Palmer admitted that he had killed Cecil the lion in Zimbabwe in 2015, PETA's president, Newkirk, issued a statement on behalf of PETA in which she said: Hunting is a coward's pastime. If, as has been reported, this dentist and his guides lured Cecil out of the park with food so as to shoot him on private property, because shooting him in the park would have been illegal, he needs to be extradited, charged, and, preferably, hanged.
=== Undercover work ===
PETA sends its staff undercover into industries and other facilities that use animals to document the alleged abuse of animals. Investigators may spend many months as employees of a facility, making copies of documents and wearing hidden cameras.
==== 1990s ====
In 1984, PETA produced a 26-minute film, Unnecessary Fuss, based on 60 hours of research video footage stolen by the Animal Liberation Front during a break-in at the University of Pennsylvania's head injury clinic. The footage showed experiments on the baboons with a hydraulic device intended to simulate whiplash. The publicity led to investigations, suspension of grant funding, the firing of a veterinarian, the closure of the research lab, and a period of probation for the university.
In 1990, two PETA activists posed as employees of Carolina Biological, where they took pictures and video footage inside the company, alleging that cats were being mistreated. Following the release of PETA's tapes, the USDA conducted its own inspection and subsequently charged the company with seven violations of the Animal Welfare Act. Four years later, an administrative judge ruled that Carolina Biological had not committed any violations.
In 1990, Bobby Berosini, a Las Vegas entertainer, lost his wildlife license as well as (on appeal) a later lawsuit against PETA, after PETA broadcast an undercover film of him slapping and punching orangutans in 1989.
In 1997, PETA made a film from footage obtained by PETA member Michele Rokke, who went undercover to report on UK company Huntingdon Life Sciences, which aired on television. Huntingdon sued PETA, and PETA agreed to drop its campaign against Huntingdon.
In 1999, a North Carolina grand jury indicted three workers at a hog farm after three-months of videotaping by a PETA operative while he was employed at the farm. The veterinarian who oversaw the farm said the video PETA had made from the footage was a distortion and was made by someone who "lied during his employment interview".
==== 2000s ====
In 2004, PETA released video tapes taken from eight-months of undercover filming in a West Virginia slaughterhouse that supplies chicken to the fast food industry. The recordings showed workers stomping on live chickens and throwing dozens against a wall. The parent corporation sent in their inspectors and told the plant to take corrective measures or risk losing their contract. Eleven employees were fired and the company introduced an anti-cruelty pledge for workers to sign.
For 11 months PETA shot footage inside a facility in Virginia operated by Covance (now Fortrea). Alleging that the footage showed primates being choked, hit, and denied medical attention, PETA sent the video and a 253-page complaint to the United States Department of Agriculture. The department investigated and the company was fined $8,720. In June 2005, the company filed a lawsuit in the United States against PETA and the investigator for fraud, breach of employee contract, and conspiracy. PETA agreed to hand over all video footage and written notes to the company, and agreed to a ban on conducting any infiltration of the company for five years.
In 2006, PETA filmed a trainer at Carson & Barnes Circus instructing others to beat the elephants to make them obey. A company spokesman said they stopped using electrical prods on animals after the video was released.
In 2007, the owners of a chinchilla ranch in Michigan sued PETA after pretending in 2004 to be interested buyers and secretly filming them, creating a video "Nightmare on Chinchilla Farm". A judge dismissed the case, writing "Undercover investigations are one of the main ways our criminal justice system operates," and noted that investigative television shows "often conduct undercover investigations to reveal improper, unethical, or criminal behavior."
In 2008, the famous Spanish singer Alaska collaborated with PETA in a joint campaign with AnimaNaturalis, posing nude in a picture to raise awareness for what she considers cruel activity, bullfighting.
==== 2010s ====
In 2013, PETA investigated angora rabbit farms in China and released video footage showing farmers ripping out the wool from live rabbits while they screamed. In 2015, Inditex announced they would discontinue their use of angora and donated their existing inventory to Syrian refugees. Seventy other retailers had also stopped selling angora wool since the release of PETA's graphic video footage.
Between 2012 and 2014, PETA investigated sheep shearing sheds in the wool industry in Australia and the US. PETA sent reports and film footage to local authorities alleging that shearers had kicked and beat sheep, stomped on their heads, necks and legs, punched them with clippers, slammed them onto the floor, and sewed up cuts without pain relief. An American Wool Council spokesperson said "We do not condone or support the actions of anyone that results in the abuse of sheep either intentionally or unintentionally. Rough handling of animals that might result in the injury of a sheep is an unacceptable maneuver during the shearing process or anytime when sheep are handled."
In 2014, PETA conducted an undercover investigation of the horse-racing industry, filming seven hours of footage that, as The New York Times reported, "showed mistreatment of the horses to be widespread and cavalier." Noted trainer Steve Asmussen and his top assistant trainer, Scott Blasi, were accused "of subjecting their horses to cruel and injurious treatments, administering drugs to them for nontherapeutic purposes, and having one of their jockeys use an electrical device to shock horses into running faster." The newspaper noted that this investigation "was PETA's first significant step into advocacy in the horse racing world." In November 2015, as a result of PETA's investigation, Asmussen was fined $10,000 by the New York State Gaming Commission. Robert Williams, executive director of the commission, said, "We recognize PETA for playing a role in bringing about changes necessary to make thoroughbred racing safer and fairer for all." By contrast, the Kentucky Horse Racing Commission, which also received PETA's allegations, found that Asmussen did not violate any of its rules. Asmussen remains under investigation by the U.S. Department of Labor for allegedly violating the Fair Labor Standards Act of 1938. After a thorough investigation, the Kentucky Horse Racing Commission did not bring any charges against Asmussen, stating the allegations "had neither a factual or scientific basis." While the fine from the New York State Gaming Commission was for a minor transgression, the most serious charges were deemed unfounded.
In 2015, as The Washington Post reported, PETA investigated Sweet Stem Farm, a pig farm that supplies meat to Whole Foods. The resulting video footage "featured images of pigs, some allegedly sick and not given appropriate care, crowded into hot pens and roughly handled by employees," contradicting both the farm's own video self-portrait and Whole Foods' claims about "humane meat" (a term that PETA maintains is an oxymoron). The Post notes that "[i]n the wake of the PETA investigation, Whole Foods has removed the Sweet Stem video from its Web site." PETA subsequently filed a class-action lawsuit against Whole Foods, "alleging that the chain's claims about animal welfare amount to a 'sham.'" The lawsuit was dismissed by a federal magistrate, who ruled that the store's signage "amounted to permissible 'puffery'" and that "the statement that 'no cages' were used to raise broiler chickens was not misleading merely because Whole Foods failed to also disclose that poultry suppliers normally do not use cages in the first place."
Other PETA investigations from around this time focused on crocodile and alligator farms in Texas and Zimbabwe, a monkey breeding facility in Florida, pigeon racing in Taiwan, ostrich slaughterhouses and tanneries in South Africa.
CBS News reported in November 2016 that PETA had captured footage from restaurants that serve live octopus, shrimp, and other marine animals. The group's video showed "an octopus writhing as its limbs are severed by a chef at T Equals Fish, a Koreatown sushi restaurant in Los Angeles." PETA noted that octopuses "are considered among the most intelligent invertebrates" and "are capable of feeling pain just as a pig or rabbit would."
In December 2016, PETA released video footage from an investigation at Texas A&M University's dog laboratory, which deliberately breeds dogs to contract muscular dystrophy. PETA claims that for "35 years, dogs have suffered in cruel muscular dystrophy experiments ... which haven't resulted in a cure or treatment for reversing the course of muscular dystrophy in humans." The Houston Press noted that "Texas A&M has been less than transparent about the research, and in some cases has denied that the dogs experience pain or discomfort." Among other efforts, PETA placed a billboard to oppose the ineffectual research on animals.
Bio Corporation, a company that supplies dead animals for study and dissection, was the subject of a November 2017 PETA undercover investigation. It was claimed that video footage showed workers at the company's facility in Alexandria, Minnesota "drowning fully-conscious pigeons, injecting live crayfish with latex and claiming that they sometimes would freeze turtles to death." PETA brought 25 charges of cruelty to animals against the company. Drowning is not considered an acceptable form of euthanasia, according to the American Veterinary Medical Association, and its standards of humane euthanasia must be followed by companies certified by the United States Department of Agriculture such as Bio Corporation. On April 18, 2018, the case was dismissed and all charges dropped based on the Alexandria City Attorney's Office's assessment that the allegations of cruelty against either pigeons or crayfish were not sufficiently supported. Daniel Paden, PETA's director of evidence analysis, said that PETA is "reviewing its options to protect animals killed at Bio Corporation."
In 2018, police raided a PetSmart store in Tennessee, after receiving video footage from PETA. Police confiscated six animals: a guinea pig, mice, and hamsters. PetSmart sued the ex-employee, Jenna Jordan, claiming she was a paid PETA operative who obtained employment at PetSmart stores in Arizona, Florida and Tennessee to obtain recordings which she provided to PETA. Jordan was accused of committing "animal neglect, theft of confidential information, unlawfully surveilled private conversations, and filing false reports with law enforcement under false pretenses in three states." In 2019, PetSmart added PETA as a defendant in the lawsuit.
On May 1, 2018, PETA released an investigation of the mohair industry that led more than 80 retailers, including UNIQLO and Zappos, to drop products made with mohair. The video evidence "depicts goats being thrown around wood floors, dunked in poisonous cleaning solution or having their ears mutilated with pliers. ... [E]mployees are shown cutting goats' throats, breaking their necks, electrically shocking them and beheading them."
=== Ag-gag laws ===
Various U.S. states have passed ag-gag laws to prevent animal rights and animal welfare groups from conducting undercover investigations of operations that use animals. In response, PETA has been involved with other groups bringing lawsuits, citing First Amendment protections for free speech.
In 2017, a federal judge ruled Utah's ag-gag law an unconstitutional violation of the First Amendment in a case brought against the state by PETA, the Animal Legal Defense Fund, and Amy Meyer, the director of the Utah Animal Rights Coalition.
In 2018, Idaho's ag-gag law was struck down as unconstitutional in a case brought by ACLU-Idaho, the ALDF and PETA.
In 2019, a federal judge struck down Iowa's 2012 ag-gag law in a case filed in 2017 by co-plaintiffs PETA, ALDF, ACLU-Iowa, Iowa Citizens for Community Improvement, Bailing Out Benji, and Center for Food Safety.
In 2020, in the case of PETA et al v. Stein, Judge Schroeder struck four subsections of North Carolina's 2015 Property Protection Act, writing "the law is declared unconstitutional as applied to them in their exercise of speech." The plaintiffs included PETA, Center for Food Safety, ALDF, Farm Sanctuary, Food & Water Watch, Government Accountability Project, Farm Forward, and the ASPCA.
=== Legal proceedings ===
Two PETA employees were acquitted in 2007 of cruelty to animals after at least 80 euthanized animals were left in dumpsters in a shopping center in Ahoskie, North Carolina, over the course of a month in 2005; the two employees were seen leaving behind 18 dead animals, and 13 more were found inside their van. The animals had been euthanized after being removed from shelters in Northampton and Bertie counties. A Bertie County Deputy Sheriff stated that the two employees assured the Bertie Animal Shelter that "they were picking up the dogs to take them back to Norfolk where they would find them good homes." During the trial, Daphna Nachminovitch, the supervisor of PETA's Community Animal Project, said PETA began euthanizing animals in some rural North Carolina shelters after it found the shelters killing animals in ways PETA considers inhumane, including by shooting them. She also stated that the dumping of animals did not follow PETA's policy.
In November 2014, a resident of Accomack County, Virginia, produced video evidence that two workers in a van marked with a PETA logo had entered his property in a trailer park and taken his dog, who was then euthanized. He reported the incident to the police, who identified and charged two PETA workers, but the charges were later dropped by the commonwealth attorney on the grounds that it was not possible to prove criminal intent. The trailer park's manager had contacted PETA after a group of residents moved out, leaving their dogs behind, which is why the workers were on the property. The state later determined that PETA had violated state law by failing to ensure that the Chihuahua, who was not wearing a collar or tag, was properly identified and for failing to keep the dog alive for five days before euthanizing the animal. Citing a "severity of this lapse in judgment," the Virginia Department of Agriculture and Consumer Services issued PETA a first-ever violation and imposed a $500 fine. The contract worker who had taken the dog was dismissed by PETA.
In 2015, PETA sued British nature photographer David Slater in US court as a next friend for a wild macaque monkey, whom they named Naruto. PETA argued that the monkey was entitled to the copyright of a selfie it had taken while handling Slater's camera, and naming themselves to be the administrator of any copyright revenue. The monkey selfie copyright dispute was originally dismissed by Judge Orrick who wrote there is no indication that the Copyright Act extends to animals and a monkey could not own a copyright. PETA appealed, but the Court of Appeals found in favor of Slater saying that "PETA's real motivation in this case was to advance its own interests, not Naruto's." The decision cited Cetacean v. Bush (2004) that says animals cannot sue unless Congress makes it clear in the statute that animals can sue, and added that "next friend" representation cannot be applied to animals. The court also wrote: "Puzzlingly, while representing to the world that 'animals are not ours to eat, wear, experiment on, use for entertainment, or abuse in any other way,' PETA seems to employ Naruto as an unwitting pawn in its ideological goals."
=== Video games ===
PETA has created a number of satirical video games with such names as How Green Is My Diet? and KKK or AKC? Spot the Difference. PETA uses these games to spread attention about animal rights and animal welfare and to advocate vegetarian and vegan diets. PETA's head of online marketing Joel Bartlett said "We've found that parody games are extremely popular. By connecting our message with something people are already interested in, we're able to create more buzz."
In 2017, Ingrid Newkirk sent a letter of complaint to Nintendo about their video game 1-2-Switch, during which players get to milk a cow. In her letter, Newkirk called the game "unrealistic" and wrote "you've taken all the cruelty out of milking". She also suggested that "instead of sugarcoating the subject, Nintendo switch to simulating activities in which no animals suffer."
In March 2020, PETA issued a "Vegan Guide to Animal Crossing" for the video game Animal Crossing: New Horizons.
=== Person of the year ===
Each year, PETA selects a "Person of the Year" who has helped advance the cause of animal rights.
2006: Eric Ryan and Adam Lowry (founders of Method Products).
2007: Robert C. Byrd (for his passionate defense of animals throughout six decades of public service).
2008: Oprah Winfrey (for using her powerful voice to defend those without one).
2009: Tim Gunn (Man of the Year) and Ellen DeGeneres (Woman of the Year).
2010: Bill Clinton (for his influence to promote the benefits of following a vegan diet).
2011: Russell Simmons (for tirelessly advocating for animals and setting a positive example for others by promoting a vegan lifestyle).
2012: Anjelica Huston. (for her work to keep animals with their families in the habitats where they belong, instead of being used on production sets and fur farms and to pull carriages).
2013: Ricky Gervais.
2014: Bill de Blasio. (for his defense of tigers, elephants, and horses forced to work in New York and his promotion of vegan eating).
2015: Pope Francis (selected for his encouragement to treat animals with kindness and to respect the environment).
2016: Mary Matalin (chosen for her fight for the humane treatment of farm animals and monkeys).
2017: Naruto (a monkey unaware of his role in a copyright case).
2018: California Wildfire Heroes.
2019: Joaquin Phoenix.
2020: Tabitha Brown.
2021: Billie Eilish.
2022: James Cromwell (for speaking out against the live export of pigs from Ireland, and pressuring Starbucks to end its vegan milk up-charge).
2023: James Gunn.
==== PETA India ====
2011: Hema Malini (for taking a stand and speaking out for animals).
2012: R. Madhavan (for helping make the world a better place for animals).
2013: Shashi Tharoor.
2014: K. S. Panicker Radhakrishnan (Man of the year for a landmark judgement banning Jallikattu) and Jacqueline Fernandez (Woman of the year).
2015: Kapil Sharma (for his dedication in championing the adoption of dogs from animal shelters or the streets).
2016: Sunny Leone (for advocating the support of vegan fashion, vegetarianism, and cat & dog adoption / sterilisation).
2017: Anushka Sharma (for her wide-reaching work for animals, from helping to protect dogs from fireworks to advocating for horses who are forced to pull carriages).
2018: Sonam Kapoor.
2019: Virat Kohli.
2020: John Abraham.
2021: Alia Bhatt (for her continuous work in support of an animal-friendly fashion industry).
2022: Sonakshi Sinha. (for action which helped spare the lives of animals killed for fashion, and her strong advocacy for cats and dogs in need).
==== PETA UK ====
2008: Leona Lewis. (for her campaign against foie gras).
2009: Roger Moore.
2010: Pamela Anderson.
2011: Morrissey.
2012: Brian May (for badger activism).
2014: Tony Benn.
2016: Pamela Anderson.
2017: Roger Moore.
2018: Lewis Hamilton.
2020: Carrie Johnson (for her work to protect endangered animals).
2023: Paul O'Grady (for his lifelong determination to make the world a kinder place for animals).
=== Labels ===
PETA certifies beauty and cosmetics companies with "Beauty without Bunnies" bunny labels in two tiers. In the first tier ("Animal Test-Free"), the entire company does not use animal testing. The company may still produce non-vegan products. In the second tier ("Cruelty-Free"), the company may not produce non-vegan products. The company is animal test-free and also vegan, i.e. does not use any animal-derived ingredients. If a company carries the PETA "animal test-free" or "cruelty-free" label, it must also have signed agreements with its suppliers that they do not use animal testing.
PETA also awards a "vegan" label to clothing and furniture products (instead of entire companies), which means that the products are free from animal-derived ingredients, but the companies can still produce non-vegan products.
== Positions ==
=== Direct action and the ALF ===
Newkirk is outspoken in her support of direct action, writing that no movement for social change has ever succeeded without what she calls the militarism component: "Thinkers may prepare revolutions, but bandits must carry them out." Newkirk is a strong supporter of direct action that removes animals from laboratories and other facilities: "When I hear of anyone walking into a lab and walking out with animals, my heart sings." Newkirk was quoted in 1999, "When you see the resistance to basic humane treatment and to the acknowledgment of animals' social needs, I find it small wonder that the laboratories aren't all burning to the ground. If I had more guts, I'd light a match."
=== Euthanasia ===
PETA is a strong proponent of euthanasia. They oppose the no-kill movement, and rather than adoption programs, PETA prefers to aim for zero births through spaying and neutering. They recommend not breeding pit bulls, and support euthanasia in certain situations for animals in shelters, such as those being housed for long periods in cramped cages.
=== Pet as a derogatory term ===
PETA considers the word pet to be "derogatory and patronises the animal", and prefers the term "companion" or "companion animal". "Animals are not pets", Newkirk has said.
=== Hearing-ear and seeing-eye dogs ===
PETA supports hearing dog programs when animals are sourced from shelters and placed in homes, but opposes seeing-eye-dog programs "because the dogs are bred as if there are no equally intelligent dogs literally dying for homes in shelters, they are kept in harnesses almost 24/7".
=== Animal testing ===
PETA opposes animal testing—whether toxicity testing, basic or applied research, or for education and training—on both moral and practical grounds. Newkirk told the Vogue magazine in 1989 that even if animal testing resulted in a cure for AIDS, PETA would oppose it. The group also believes that it is wasteful, unreliable, and irrelevant to human health, because artificially induced diseases in animals are not identical to human diseases. They say that animal experiments are frequently redundant and lack accountability, oversight, and regulation. They promote alternatives, including embryonic stem cell research and in vitro cell research.
=== National Institute of Allergy and Infectious Diseases/White Coat Waste Project ===
The White Coat Waste Project (WCWP), a group of activists that hold that taxpayers should not have to pay $20 billion every year for experiments on animals, said that the National Institute of Allergy and Infectious Diseases provided $400,000 in taxpayer money to fund experiments in which 28 beagles were infected by disease-causing parasites. The White Coat Project found reports that said dogs taking part in the experiments were "vocalizing in pain" after being injected with foreign substances. Following public outcry, PETA made a call to action that all members of the National Institute of Health resign effective immediately and that there is a "need to find a new NIH director to replace the outgoing Francis Collins who will shut down research that violates the dignity of nonhuman animals." In 2019, the WCWP discovered a USDA funded lab in Beltsville, Maryland which conducted toxoplasmosis experiments on kittens resulting in the deaths of nearly 3,000 kittens over 36 years. This discovery led to the USDA banning all taxpayer funded kitten experiments. In 2024, the WCWP also reported that taxpayer money was used to fund beagle experiments in China, which drew widespread condemnation, including a call from PETA to end taxpayer-funded animal experiments globally.
== Controversies ==
=== High euthanasia rates ===
PETA's euthanasia practices have drawn intense scrutiny from lawmakers and criticism from animal rights activists for years. The consistently high percentage of animals euthanized at PETA's shelter has been controversial.
In 2008, meat industry lobby group the Center for Consumer Freedom (CCF) said in a news release that "[a]n official report filed by PETA itself shows that the animal rights group put to death nearly every dog, cat, and other pet it took in for adoption in 2006," with a kill rate of 97.4 percent. In 2012, the Virginia Department of Agriculture and Consumer Services said that it had in the past considered changing PETA's status from "shelter" to "euthanasia clinic", citing PETA's willingness to take in "anything that comes through the door, and other shelters won't do that." PETA acknowledged that it euthanized 95% of the animals at its shelter in 2011.
PETA calls their shelter in Norfolk, Virginia a "shelter of last resort", claiming they only receive old, sick, injured, badly behaved, and otherwise unadoptable animals. Operating as open admission, they take in animals "no one else will", and consider death "a merciful end". In 2014, PETA euthanized over 80% of the shelter's animals and justified its euthanasia policies as "mercy killings".
Fueled by public outrage from a 2014 incident where PETA workers took a pet chihuahua from its porch and euthanized it the same day, along with documentation that of the 1,606 cats and 1,025 dogs accepted by the shelter that same year, 1,536 cats and 788 dogs were euthanized, the Virginia General Assembly passed Senate Bill 1381 in 2015 aimed at curtailing the operation of PETA's shelter. The bill defines a private animal shelter as "a facility operated for the purpose of finding permanent adoptive homes for animals."
Though risking their legal access to euthanasia drugs, PETA has continued their practices. In the chihuahua case, PETA paid a fine and settled a civil claim with the family three years later.
=== Child targeted messaging ===
PETA has also been criticized for aiming its message at young people. In the past the company has passed out pamphlets such as "Your Daddy Kills Animals", and "Your Mommy Kills Animals", both warning children from letting their "addicted to killing" parents have contact with their pets. The pamphlet was criticized by the Center for Consumer Freedom, who said "There's going to be long-term psychological damage from these kids being exposed to the material that PETA puts in front of them on a regular basis."
As part of its 1999 "McCruelty" campaign, PETA attempted to distribute "Unhappy Meals" to young audiences: a parody of McDonald's Happy Meal. When describing the box, they explained that "PETA's spoof of a McDonald's chicken sandwich box features the image of a knife-wielding Ronald McDonald, along with pictures of birds who have been mutilated and scalded alive. The inside of the Unhappy Meal box is stained with blood and contains a blood-filled packet urging McDonald's to "Ketchup With the Times", a paper cutout of a menacing Ronald McDonald with PETA's parody "I'm Hatin' It" logo, a bloody plastic chicken, and a "Chicken McCruelty" T-shirt wrapped up like a sandwich." The violent imagery was decried by parents who stated "I don't want my son to be around something like this." As part of the same campaign, PETA attempted to place a large statue of a crippled, scalded chicken in front of a McDonalds's in Little Rock, but were denied, and released a short comic book titled Ronald McDonald Kills Animals, in which Ronald McDonald, Grimace, and the Hamburglar unite to kill Birdie's parents, feed them to her unknowingly, then eat her as well.
A similar "Kentucky Fried Cruelty" campaign occurred in 2004, when PETA criticized KFC and distributed "Buckets of Blood" to children: the buckets (meant to mimic KFC's buckets of chicken) included a bag of fake blood, feathers, and bones; a bloody plastic chicken; and a cardboard caricature of a blood-spattered Colonel Sanders holding a butcher knife toward a terrified-looking chicken.
A 2013 ad titled Traditional Thanksgiving Dinner from your Family Butcher, was developed using lenticular technology to show parents a benign Thanksgiving promo, but show their children a mother stabbing a live turkey while her children look on in shock.
=== "It's Still Going On" campaign ===
PETA's "It's Still Going On" campaign features newspaper ads comparing widely publicized murder-cannibalization cases to the deaths of animals in slaughterhouses. The campaign has attracted significant media attention, controversy and generated angry responses from the victims' family members. Ads were released in 1991 describing the deaths of the victims of serial killer Jeffrey Dahmer, in 2002 describing the deaths of the victims of serial killer Robert William Pickton, and in 2008 describing the killing of Tim McLean. In several cases, newspapers have refused to run the ads.
=== "Holocaust on Your Plate" campaign ===
In 2003 PETA composed the "Holocaust on Your Plate" exhibition—eight 60-square-foot (5.6 m2) panels juxtaposing images of Holocaust and concentration camp victims with scenes of factory farming, battery cages, animal carcasses and animals being transported to slaughter, along with captions stating that "Like the Jews murdered in concentration camps, animals are terrorized when they are housed in huge filthy warehouses and rounded up for shipment to slaughter. The leather sofa and handbag are the moral equivalent of the lampshades made from the skins of people killed in the death camps."
The exhibition was quickly criticized by Abraham Foxman and the Anti-Defamation League, who said, "the effort by PETA to compare the deliberate systematic murder of millions of Jews to the issue of animal rights is abhorrent" and "[r]ather than deepen our revulsion against what the Nazis did to the Jews, the project will undermine the struggle to understand the Holocaust and to find a way to make sure such catastrophes never happen again." Alex Herschaft had made similar comparisons in the past, but criticized PETA's use as "careless and reckless" and impersonal. Elie Wiesel was appalled to find the campaign used his own image, calling it possibly the greatest disappointment of his life, and reiterating that "I am not afraid of forgetfulness, I am afraid of banalization, of trivialization and this is part of it." Other detractors included the United States Holocaust Memorial Museum and Wesley Smith.
As a response to critics of the UK campaign asking for a ban or some form of censorship, PETA accused them of book burning to further imply Nazi mentality. In 2004 a complaint was made by Paul Spiegel and the Central Council of Jews in Germany, asking the German court to order PETA to halt the campaign and threatening to sue. In July 2009, the German Federal Constitutional Court ruled that PETA's campaign was not protected by free speech laws and banned it within Germany as an offense against human dignity, and upheld the ban in 2012.
The exhibit had been funded by an anonymous Jewish philanthropist and created by Matt Prescott, who lost several relatives in the Holocaust. Prescott said: "The very same mindset that made the Holocaust possible—that we can do anything we want to those we decide are 'different or inferior'—is what allows us to commit atrocities against animals every single day. ... The fact is, all animals feel pain, fear and loneliness. We're asking people to recognize that what Jews and others went through in the Holocaust is what animals go through every day in factory farms." In addition, PETA claimed a direct influence by the prominent Jewish author Isaac Bashevis Singer, whose grandson, Stephen R. Dujack, supported the exhibition when it traveled to New York, and quotations for the exhibit also pulled from the writings of German philosopher Theodor Adorno. Karen Davis and Gary Yourofsky both voiced their support of the exhibition.
=== "Are Animals the New Slaves?" exhibit ===
In 2005, the NAACP criticized the "Are Animals the New Slaves?" exhibit, which showed images of African-American lynching victims and slaves, Native Americans, child laborers, and women, alongside chained elephants and slaughtered cows. Lee Hall, the then director of Friends of Animals, supported the criticism, stating that, "While African-Americans have been systematically degraded by being compared with nonhuman beings, are we to think that angry responses to the pairing of man and monkey were unanticipated?"
Vakiya Courtney, then executive director of America's Black Holocaust Museum, was outraged; images from the exhibit included one taken at the site of the attempted lynching of the museum founder James Cameron, and the successful lynching of his two friends. "How can you possibly compare the brutality that our ancestors experienced here, and the brutality that people like Dr. Cameron had to overcome, to animal cruelty?" Cameron, himself, had a similar response: "They may have treated us like animals back then, but there is no way we should be compared to animals today."
=== "Got Autism?" campaign ===
In 2008 and in 2014, PETA conducted an advertising campaign linking milk with autism. Their "Got Autism?" campaign, a play on words mocking the milk industry's Got Milk? ad campaign that ran from 1993 to 2014, stated "Studies have shown a link between cow's milk and autism." PETA also claimed milk was strongly linked to cancer, Crohn's disease, and other diseases. When pressed, PETA cited two scientific papers, one from 1995 and one from 2002 using very small samplings of children (36 and 20), and neither showed a correlation nor a causation between milk and autism. Newer studies from 2010 and 2014 came to the same conclusion. Despite having been corrected, in 2014, PETA's Executive Vice President confirmed their position, and additionally stated that dairy consumption contributes to asthma, chronic ear infection, constipation, iron deficiency, anemia, and cancer.
Steven Novella, a clinical neurologist and assistant professor at Yale University School of Medicine, wrote "This is clearly, in my opinion, a campaign of fear mongering based upon a gross distortion of the scientific evidence. The purpose is to advocate for a vegan diet, which fits [PETA's] ideological agenda. They are likely aware that it is easier to spread fears than to reassure with a careful analysis of the scientific evidence."
PETA's campaign has received backlash from the autism community. A 2008 PETA billboard was taken down by the Autistic Self Advocacy Network. In 2017, British food writer, journalist and hunger relief activist Jack Monroe, demanded PETA remove their recipes from their website "with immediate effect coz I wrote them with my autism". PETA removed their recipes, but did not remove the "Got Autism?" article from their website until 2021. It has been argued that the frowny face in the campaign image negatively stereotypes autistic people.
=== "KKK or AKC?" controversy ===
In 2009, PETA members dressed up in Ku Klux Klan robes and protested at the Westminster Kennel Club Dog Show where they passed out brochures implying the Klan and American Kennel Club have the same goal of "pure bloodlines". This protest was continued in the PETA video game KKK or AKC? Spot the Difference.
=== Criticism of Steve Irwin ===
PETA has been critical of Australian wildlife expert and zookeeper Steve Irwin. In 2006, when Irwin died, PETA Vice President Dan Mathews said Irwin had made a career out of antagonizing frightened wild animals. Australian Member of Parliament Bruce Scott was disgusted by the comments and said PETA should apologize to Irwin's family and the rest of Australia, and "Isn't it interesting ... how they [PETA] want to treat animals ethically, but cannot even think for a minute whether or not their outlandish comments are ethical towards their fellow human beings."
In 2019, PETA criticized Google for creating a slideshow Google Doodle of Steve Irwin posthumously honoring his 57th birthday. PETA started a Twitter campaign against Irwin, with several tweets criticizing Google for forwarding a dangerous message, and wrote that Irwin was killed while harassing a stingray and that he forced animals to perform. A Washington Post editor wrote "PETA can add 'insulting a deceased cultural icon' to its infamous repertoire."
=== Anti-carnivore sex strike ===
In 2022, PETA's German division called for a sex strike in which women would refrain from sexual activities with men who ate meat, and also called for men who ate meat to be banned from procreating. When pressed on the ban, Laura Weyman-Jones (the Australian division's marketing manager) said that it was a "conversation starter", and not an actual request or threat. The company did not reverse its position that meat consumption was a form of toxic masculinity, harmful to the environment, increased male impotency, and should be sin-taxed at an additional 41%.
=== Human barbecue stunt protest ===
During Holy Week in the Philippines, a PETA Asia member stripped down to her underwear and laid down on a grill to depict a "human barbecue" in front of Quiapo Church in Quiapo, Manila, calling Filipinos to abstain from eating meat even when not abstaining from meat during Lent. The stunt protest drew attention and controversy from churchgoers, and a complaint was filed by the church with the Manila Police District. No formal complaint was made, and as such, the members involved were eventually released.
== Domain name disputes ==
In February 1995, a parody website calling itself "People Eating Tasty Animals" registered the domain name "peta.org". PETA sued, claiming trademark violation, and won the suit in 2001; the domain is currently owned by PETA. While still engaged in legal proceedings over "peta.org", PETA themselves registered the domains "ringlingbrothers.com" and "voguemagazine.com", using the sites to accuse Ringling Brothers and Barnum & Bailey Circus and Vogue of animal cruelty. PETA later surrendered the domains under threat of similar legal action over trademark infringement.
== Position within the animal rights movement ==
The more radical activists say the group has lost touch with its grass-roots members, is soft on the idea of animal rights, that it should stop the use of media stunts and nudity in its campaigning, and stop "hogging the spotlight at the expense of its allies in the movement".
Robert Garner of the University of Leicester has written that PETA has shaken up the animal rights movement, setting up new groups and radicalizing old ones. According to reviews at Philanthropedia, "PETA paved the way for other national organizations to delve into what used to be controversial issues and are now more mainstream concerns." Michael Specter considers PETA to be the radical that helps the more mainstream message to succeed.
Because of PETA's euthanasia rates at their "shelter of last resort", attorney Nathan Winograd, advocate for the No Kill movement, calls Newkirk of PETA "The Butcher of Norfolk".
Gary L. Francione, professor of law at Rutgers Law School and a proponent of abolitionism, says that PETA is not an animal rights group because of their willingness to work with industries that use animals to achieve incremental change. Francione says PETA trivializes the movement with their "Three Stooges" theory of animal rights, making the public think progress is underway when the changes are only cosmetic. "Their campaigns are selected more for media image than content." Francione has criticized PETA for having caused grassroots animal rights groups to close, groups that were essential for the survival of the animal rights movement, and rejects the centrality of corporate animal charities. Francione wrote that PETA initially set up independent chapters around the United States, but closed them in favor of a top-down, centralized organization, which not only consolidated decision-making power, but centralized donations. Now, local animal rights donations go to PETA, rather than to a local group.
== See also ==
Direct Action Everywhere
European Vegetarian Union
International Vegetarian Union
Mercy for Animals
Women and animal advocacy
List of animal rights advocates
List of animal rights groups
Open rescue
Veganism
== Notes ==
== References ==
== Further reading ==
Pence, Gregory. Classic Cases in Medical Ethics: Accounts of Cases That Have Shaped Medical Ethics. McGraw-Hill, 2007.
Workman, Dave P. Peta Files: The Dark Side of the Animal Rights Movement, Merril Press, 2003.
== External links ==
Official website
Guide to the People for the Ethical Treatment of Animals (PETA) Research Files 1980–2001 | Wikipedia/People_for_the_Ethical_Treatment_of_Animals |
Biological control or biocontrol is a method of controlling pests, whether pest animals such as insects and mites, weeds, or pathogens affecting animals or plants by using other organisms. It relies on predation, parasitism, herbivory, or other natural mechanisms, but typically also involves an active human management role. It can be an important component of integrated pest management (IPM) programs.
There are three basic strategies for biological control: classical (importation), where a natural enemy of a pest is introduced in the hope of achieving control; inductive (augmentation), in which a large population of natural enemies are administered for quick pest control; and inoculative (conservation), in which measures are taken to maintain natural enemies through regular reestablishment.
Natural enemies of insects play an important part in limiting the densities of potential pests. Biological control agents such as these include predators, parasitoids, pathogens, and competitors. Biological control agents of plant diseases are most often referred to as antagonists. Biological control agents of weeds include seed predators, herbivores, and plant pathogens.
Biological control can have side-effects on biodiversity through attacks on non-target species by any of the above mechanisms, especially when a species is introduced without a thorough understanding of the possible consequences.
== History ==
The term "biological control" was first used by Harry Scott Smith at the 1919 meeting of the Pacific Slope Branch of the American Association of Economic Entomologists, in Riverside, California. It was brought into more widespread use by the entomologist Paul H. DeBach (1914–1993) who worked on citrus crop pests throughout his life. However, the practice has previously been used for centuries. The first report of the use of an insect species to control an insect pest comes from "Nanfang Caomu Zhuang" (南方草木狀 Plants of the Southern Regions) (c. 304 AD), attributed to Western Jin dynasty botanist Ji Han (嵇含, 263–307), in which it is mentioned that "Jiaozhi people sell ants and their nests attached to twigs looking like thin cotton envelopes, the reddish-yellow ant being larger than normal. Without such ants, southern citrus fruits will be severely insect-damaged". The ants used are known as huang gan (huang = yellow, gan = citrus) ants (Oecophylla smaragdina). The practice was later reported by Ling Biao Lu Yi (late Tang dynasty or Early Five Dynasties), in Ji Le Pian by Zhuang Jisu (Southern Song dynasty), in the Book of Tree Planting by Yu Zhen Mu (Ming dynasty), in the book Guangdong Xing Yu (17th century), Lingnan by Wu Zhen Fang (Qing dynasty), in Nanyue Miscellanies by Li Diao Yuan, and others.
Biological control techniques as we know them today started to emerge in the 1870s. During this decade, in the US, the Missouri State Entomologist C. V. Riley and the Illinois State Entomologist W. LeBaron began within-state redistribution of parasitoids to control crop pests. The first international shipment of an insect as a biological control agent was made by Charles V. Riley in 1873, shipping to France the predatory mites Tyroglyphus phylloxera to help fight the grapevine phylloxera (Daktulosphaira vitifoliae) that was destroying grapevines in France. The United States Department of Agriculture (USDA) initiated research in classical biological control following the establishment of the Division of Entomology in 1881, with C. V. Riley as Chief. The first importation of a parasitoidal wasp into the United States was that of the braconid Cotesia glomerata in 1883–1884, imported from Europe to control the invasive cabbage white butterfly, Pieris rapae. In 1888–1889 the vedalia beetle, Novius cardinalis, a lady beetle, was introduced from Australia to California to control the cottony cushion scale, Icerya purchasi. This had become a major problem for the newly developed citrus industry in California, but by the end of 1889, the cottony cushion scale population had already declined. This great success led to further introductions of beneficial insects into the US.
In 1905 the USDA initiated its first large-scale biological control program, sending entomologists to Europe and Japan to look for natural enemies of the spongy moth, Lymantria dispar dispar, and the brown-tail moth, Euproctis chrysorrhoea, invasive pests of trees and shrubs. As a result, nine parasitoids (solitary wasps) of the spongy moth, seven of the brown-tail moth, and two predators of both moths became established in the US. Although the spongy moth was not fully controlled by these natural enemies, the frequency, duration, and severity of its outbreaks were reduced and the program was regarded as successful. This program also led to the development of many concepts, principles, and procedures for the implementation of biological control programs.
Prickly pear cacti were introduced into Queensland, Australia as ornamental plants, starting in 1788. They quickly spread to cover over 25 million hectares of Australia by 1920, increasing by 1 million hectares per year. Digging, burning, and crushing all proved ineffective. Two control agents were introduced to help control the spread of the plant, the cactus moth Cactoblastis cactorum, and the scale insect Dactylopius. Between 1926 and 1931, tens of millions of cactus moth eggs were distributed around Queensland with great success, and by 1932, most areas of prickly pear had been destroyed.
The first reported case of a classical biological control attempt in Canada involves the parasitoidal wasp Trichogramma minutum. Individuals were caught in New York State and released in Ontario gardens in 1882 by William Saunders, a trained chemist and first Director of the Dominion Experimental Farms, for controlling the invasive currantworm Nematus ribesii. Between 1884 and 1908, the first Dominion Entomologist, James Fletcher, continued introductions of other parasitoids and pathogens for the control of pests in Canada.
== Types of biological pest control ==
There are three basic biological pest control strategies: importation (classical biological control), augmentation and conservation.
=== Importation ===
Importation or classical biological control involves the introduction of a pest's natural enemies to a new locale where they do not occur naturally. Early instances were often unofficial and not based on research, and some introduced species became serious pests themselves.
To be most effective at controlling a pest, a biological control agent requires a colonizing ability which allows it to keep pace with changes to the habitat in space and time. Control is greatest if the agent has temporal persistence so that it can maintain its population even in the temporary absence of the target species, and if it is an opportunistic forager, enabling it to rapidly exploit a pest population.
One of the earliest successes was in controlling Icerya purchasi (cottony cushion scale) in Australia, using a predatory insect Rodolia cardinalis (the vedalia beetle). This success was repeated in California using the beetle and a parasitoidal fly, Cryptochaetum iceryae. Other successful cases include the control of Antonina graminis in Texas by Neodusmetia sangwani in the 1960s.
Damage from Hypera postica, the alfalfa weevil, a serious introduced pest of forage, was substantially reduced by the introduction of natural enemies. 20 years after their introduction the population of weevils in the alfalfa area treated for alfalfa weevil in the Northeastern United States remained 75 percent down.
Alligator weed was introduced to the United States from South America. It takes root in shallow water, interfering with navigation, irrigation, and flood control. The alligator weed flea beetle and two other biological controls were released in Florida, greatly reducing the amount of land covered by the plant. Another aquatic weed, the giant salvinia (Salvinia molesta) is a serious pest, covering waterways, reducing water flow and harming native species. Control with the salvinia weevil (Cyrtobagous salviniae) and the salvinia stem-borer moth (Samea multiplicalis) is effective in warm climates, and in Zimbabwe, a 99% control of the weed was obtained over a two-year period.
Small, commercially-reared parasitoidal wasps, Trichogramma ostriniae, provide limited and erratic control of the European corn borer (Ostrinia nubilalis), a serious pest. Careful formulations of the bacterium Bacillus thuringiensis are more effective. The O. nubilalis integrated control releasing Tricogramma brassicae (egg parasitoid) and later Bacillus thuringiensis subs. kurstaki (larvicide effect) reduce pest damages more than insecticide treatments
The population of Levuana iridescens, the Levuana moth, a serious coconut pest in Fiji, was brought under control by a classical biological control program in the 1920s.
=== Augmentation ===
Augmentation involves the supplemental release of natural enemies that occur in a particular area, boosting the naturally occurring populations there. In inoculative release, small numbers of the control agents are released at intervals to allow them to reproduce, in the hope of setting up longer-term control and thus keeping the pest down to a low level, constituting prevention rather than cure. In inundative release, in contrast, large numbers are released in the hope of rapidly reducing a damaging pest population, correcting a problem that has already arisen. Augmentation can be effective, but is not guaranteed to work, and depends on the precise details of the interactions between each pest and control agent.
An example of inoculative release occurs in the horticultural production of several crops in greenhouses. Periodic releases of the parasitoidal wasp, Encarsia formosa, are used to control greenhouse whitefly, while the predatory mite Phytoseiulus persimilis is used for control of the two-spotted spider mite.
The egg parasite Trichogramma is frequently released inundatively to control harmful moths. New way for inundative releases are now introduced i.e. use of drones. Egg parasitoids are able to find the eggs of the target host by means of several cues. Kairomones were found on moth scales. Similarly, Bacillus thuringiensis and other microbial insecticides are used in large enough quantities for a rapid effect. Recommended release rates for Trichogramma in vegetable or field crops range from 5,000 to 200,000 per acre (1 to 50 per square metre) per week according to the level of pest infestation. Similarly, nematodes that kill insects (that are entomopathogenic) are released at rates of millions and even billions per acre for control of certain soil-dwelling insect pests.
=== Conservation ===
The conservation of existing natural enemies in an environment is the third method of biological pest control.
Natural enemies are already adapted to the habitat and to the target pest, and their conservation can be simple and cost-effective, as when nectar-producing crop plants are grown in the borders of rice fields. These provide nectar to support parasitoids and predators of planthopper pests and have been demonstrated to be so effective (reducing pest densities by 10- or even 100-fold) that farmers sprayed 70% less insecticides and enjoyed yields boosted by 5%. Predators of aphids were similarly found to be present in tussock grasses by field boundary hedges in England, but they spread too slowly to reach the centers of fields. Control was improved by planting a meter-wide strip of tussock grasses in field centers, enabling aphid predators to overwinter there.
Cropping systems can be modified to favor natural enemies, a practice sometimes referred to as habitat manipulation. Providing a suitable habitat, such as a shelterbelt, hedgerow, or beetle bank where beneficial insects such as parasitoidal wasps can live and reproduce, can help ensure the survival of populations of natural enemies. Things as simple as leaving a layer of fallen leaves or mulch in place provides a suitable food source for worms and provides a shelter for insects, in turn being a food source for such beneficial mammals as hedgehogs and shrews. Compost piles and stacks of wood can provide shelter for invertebrates and small mammals. Long grass and ponds support amphibians. Not removing dead annuals and non-hardy plants in the autumn allow insects to make use of their hollow stems during winter. In California, prune trees are sometimes planted in grape vineyards to provide an improved overwintering habitat or refuge for a key grape pest parasitoid. The providing of artificial shelters in the form of wooden caskets, boxes or flowerpots is also sometimes undertaken, particularly in gardens, to make a cropped area more attractive to natural enemies. For example, earwigs are natural predators that can be encouraged in gardens by hanging upside-down flowerpots filled with straw or wood wool. Green lacewings can be encouraged by using plastic bottles with an open bottom and a roll of cardboard inside. Birdhouses enable insectivorous birds to nest; the most useful birds can be attracted by choosing an opening just large enough for the desired species.
In cotton production, the replacement of broad-spectrum insecticides with selective control measures such as Bt cotton can create a more favorable environment for natural enemies of cotton pests due to reduced insecticide exposure risk. Such predators or parasitoids can control pests not affected by the Bt protein. Reduced prey quality and abundance associated with increased control from Bt cotton can also indirectly decrease natural enemy populations in some cases, but the percentage of pests eaten or parasitized in Bt and non-Bt cotton are often similar.
== Biological control agents ==
=== Predators ===
Predators are mainly free-living species that directly consume a large number of prey during their whole lifetime. Given that many major crop pests are insects, many of the predators used in biological control are insectivorous species. Lady beetles, and in particular their larvae which are active between May and July in the northern hemisphere, are voracious predators of aphids, and also consume mites, scale insects and small caterpillars. The spotted lady beetle (Coleomegilla maculata) is also able to feed on the eggs and larvae of the Colorado potato beetle (Leptinotarsa decemlineata).
The larvae of many hoverfly species principally feed upon aphids, one larva devouring up to 400 in its lifetime. Their effectiveness in commercial crops has not been studied.
The running crab spider Philodromus cespitum also prey heavily on aphids, and act as a biological control agent in European fruit orchards.
Several species of entomopathogenic nematode are important predators of insect and other invertebrate pests. Entomopathogenic nematodes form a stress–resistant stage known as the infective juvenile. These spread in the soil and infect suitable insect hosts. Upon entering the insect they move to the hemolymph where they recover from their stagnated state of development and release their bacterial symbionts. The bacterial symbionts reproduce and release toxins, which then kill the host insect. Phasmarhabditis hermaphrodita is a microscopic nematode that kills slugs. Its complex life cycle includes a free-living, infective stage in the soil where it becomes associated with a pathogenic bacteria such as Moraxella osloensis. The nematode enters the slug through the posterior mantle region, thereafter feeding and reproducing inside, but it is the bacteria that kill the slug. The nematode is available commercially in Europe and is applied by watering onto moist soil. Entomopathogenic nematodes have a limited shelf life because of their limited resistance to high temperature and dry conditions. The type of soil they are applied to may also limit their effectiveness.
Species used to control spider mites include the predatory mites Phytoseiulus persimilis, Neoseilus californicus, and Amblyseius cucumeris, the predatory midge Feltiella acarisuga, and a ladybird Stethorus punctillum. The bug Orius insidiosus has been successfully used against the two-spotted spider mite and the western flower thrips (Frankliniella occidentalis).
Predators including Cactoblastis cactorum (mentioned above) can also be used to destroy invasive plant species. As another example, the poison hemlock moth (Agonopterix alstroemeriana) can be used to control poison hemlock (Conium maculatum). During its larval stage, the moth strictly consumes its host plant, poison hemlock, and can exist at hundreds of larvae per individual host plant, destroying large swathes of the hemlock.
For rodent pests, cats are effective biological control when used in conjunction with reduction of "harborage"/hiding locations. While cats are effective at preventing rodent "population explosions", they are not effective for eliminating pre-existing severe infestations. Barn owls are also sometimes used as biological rodent control. Although there are no quantitative studies of the effectiveness of barn owls for this purpose, they are known rodent predators that can be used in addition to or instead of cats; they can be encouraged into an area with nest boxes.
In Honduras, where the mosquito Aedes aegypti was transmitting dengue fever and other infectious diseases, biological control was attempted by a community action plan; copepods, baby turtles, and juvenile tilapia were added to the wells and tanks where the mosquito breeds and the mosquito larvae were eliminated.
Even amongst arthropods usually thought of as obligate predators of animals (especially other arthropods), floral food sources (nectar and to a lesser degree pollen) are often useful adjunct sources. It had been noticed in one study that adult Adalia bipunctata (predator and common biocontrol of Ephestia kuehniella) could survive on flowers but never completed its life cycle, so a meta-analysis was done to find such an overall trend in previously published data, if it existed. In some cases floral resources are outright necessary. Overall, floral resources (and an imitation, i.e. sugar water) increase longevity and fecundity, meaning even predatory population numbers can depend on non-prey food abundance. Thus biocontrol population maintenance – and success – may depend on nearby flowers.
=== Parasitoids ===
Parasitoids lay their eggs on or in the body of an insect host, which is then used as a food for developing larvae. The host is ultimately killed. Most insect parasitoids are wasps or flies, and many have a very narrow host range. The most important groups are the ichneumonid wasps, which mainly use caterpillars as hosts; braconid wasps, which attack caterpillars and a wide range of other insects including aphids; chalcidoid wasps, which parasitize eggs and larvae of many insect species; and tachinid flies, which parasitize a wide range of insects including caterpillars, beetle adults and larvae, and true bugs. Parasitoids are most effective at reducing pest populations when their host organisms have limited refuges to hide from them.
Parasitoids are among the most widely used biological control agents. Commercially, there are two types of rearing systems: short-term daily output with high production of parasitoids per day, and long-term, low daily output systems. In most instances, production will need to be matched with the appropriate release dates when susceptible host species at a suitable phase of development will be available. Larger production facilities produce on a yearlong basis, whereas some facilities produce only seasonally. Rearing facilities are usually a significant distance from where the agents are to be used in the field, and transporting the parasitoids from the point of production to the point of use can pose problems. Shipping conditions can be too hot, and even vibrations from planes or trucks can adversely affect parasitoids.
Encarsia formosa is a small parasitoid wasp attacking whiteflies, sap-feeding insects which can cause wilting and black sooty moulds in glasshouse vegetable and ornamental crops. It is most effective when dealing with low level infestations, giving protection over a long period of time. The wasp lays its eggs in young whitefly 'scales', turning them black as the parasite larvae pupate. Gonatocerus ashmeadi (Hymenoptera: Mymaridae) has been introduced to control the glassy-winged sharpshooter Homalodisca vitripennis (Hemiptera: Cicadellidae) in French Polynesia and has successfully controlled ~95% of the pest density.
The eastern spruce budworm is an example of a destructive insect in fir and spruce forests. Birds are a natural form of biological control, but the Trichogramma minutum, a species of parasitic wasp, has been investigated as an alternative to more controversial chemical controls.
There are a number of recent studies pursuing sustainable methods for controlling urban cockroaches using parasitic wasps. Since most cockroaches remain in the sewer system and sheltered areas which are inaccessible to insecticides, employing active-hunter wasps is a strategy to try and reduce their populations.
=== Pathogens ===
Pathogenic micro-organisms include bacteria, fungi, and viruses. They kill or debilitate their host and are relatively host-specific. Various microbial insect diseases occur naturally, but may also be used as biological pesticides. When naturally occurring, these outbreaks are density-dependent in that they generally only occur as insect populations become denser.
The use of pathogens against aquatic weeds was unknown until a groundbreaking 1972 proposal by Zettler and Freeman. Up to that point biocontrol of any kind had not been used against any water weeds. In their review of the possibilities, they noted the lack of interest and information thus far, and listed what was known of pests-of-pests – whether pathogens or not. They proposed that this should be relatively straightforward to apply in the same way as other biocontrols. And indeed in the decades since, the same biocontrol methods that are routine on land have become common in the water.
==== Bacteria ====
Bacteria used for biological control infect insects via their digestive tracts, so they offer only limited options for controlling insects with sucking mouth parts such as aphids and scale insects. Bacillus thuringiensis, a soil-dwelling bacterium, is the most widely applied species of bacteria used for biological control, with at least four sub-species used against Lepidopteran (moth, butterfly), Coleopteran (beetle) and Dipteran (true fly) insect pests. The bacterium is available to organic farmers in sachets of dried spores which are mixed with water and sprayed onto vulnerable plants such as brassicas and fruit trees. Genes from B. thuringiensis have also been incorporated into transgenic crops, making the plants express some of the bacterium's toxins, which are proteins. These confer resistance to insect pests and thus reduce the necessity for pesticide use. If pests develop resistance to the toxins in these crops, B. thuringiensis will become useless in organic farming also.
The bacterium Paenibacillus popilliae which causes milky spore disease has been found useful in the control of Japanese beetle, killing the larvae. It is very specific to its host species and is harmless to vertebrates and other invertebrates.
Bacillus spp., fluorescent Pseudomonads, and Streptomycetes are controls of various fungal pathogens.
==== Colombia mosquito control ====
The largest-ever deployment of Wolbachia-infected A. aegypti mosquitoes reduced dengue incidence by 94–97% in the Colombian cities of Bello, Medellín, and Itagüí. The project was executed by non-profit World Mosquito Program (WMP). Wolbachia prevents mosquitos from transmitting viruses such as dengue and zika. The insects pass the bacteria on to their offspring. The project covered a combined area of 135 square kilometres (52 sq mi), home to 3.3 million people. Most of the project area reached the target of infecting 60% of local mosquitoes. The technique is not endorsed by WHO.
=== Fungi ===
Entomopathogenic fungi, which cause disease in insects, include at least 14 species that attack aphids. Beauveria bassiana is mass-produced and used to manage a wide variety of insect pests including whiteflies, thrips, aphids and weevils. Lecanicillium spp. are deployed against white flies, thrips and aphids. Metarhizium spp. are used against pests including beetles, locusts and other grasshoppers, Hemiptera, and spider mites. Paecilomyces fumosoroseus is effective against white flies, thrips and aphids; Purpureocillium lilacinus is used against root-knot nematodes, and 89 Trichoderma species against certain plant pathogens. Trichoderma viride has been used against Dutch elm disease, and has shown some effect in suppressing silver leaf, a disease of stone fruits caused by the pathogenic fungus Chondrostereum purpureum.
Pathogenic fungi may be controlled by other fungi, or bacteria or yeasts, such as: Gliocladium spp., mycoparasitic Pythium spp., binucleate types of Rhizoctonia spp., and Laetisaria spp.
The fungi Cordyceps and Metacordyceps are deployed against a wide spectrum of arthropods. Entomophaga is effective against pests such as the green peach aphid.
Several members of Chytridiomycota and Blastocladiomycota have been explored as agents of biological control. From Chytridiomycota, Synchytrium solstitiale is being considered as a control agent of the yellow star thistle (Centaurea solstitialis) in the United States.
==== Viruses ====
Baculoviruses are specific to individual insect host species and have been shown to be useful in viral biological pest control. For example, the Lymantria dispar multicapsid nuclear polyhedrosis virus has been used to spray large areas of forest in North America where larvae of the spongy moth are causing serious defoliation. The moth larvae are killed by the virus they have eaten and die, the disintegrating cadavers leaving virus particles on the foliage to infect other larvae.
A mammalian virus, the rabbit haemorrhagic disease virus was introduced to Australia to attempt to control the European rabbit populations there. It escaped from quarantine and spread across the country, killing large numbers of rabbits. Very young animals survived, passing immunity to their offspring in due course and eventually producing a virus-resistant population. Introduction into New Zealand in the 1990s was similarly successful at first, but a decade later, immunity had developed and populations had returned to pre-RHD levels.
RNA mycoviruses are controls of various fungal pathogens.
==== Oomycota ====
Lagenidium giganteum is a water-borne mold that parasitizes the larval stage of mosquitoes. When applied to water, the motile spores avoid unsuitable host species and search out suitable mosquito larval hosts. This mold has the advantages of a dormant phase, resistant to desiccation, with slow-release characteristics over several years. Unfortunately, it is susceptible to many chemicals used in mosquito abatement programmes.
=== Competitors ===
The legume vine Mucuna pruriens is used in the countries of Benin and Vietnam as a biological control for problematic Imperata cylindrica grass: the vine is extremely vigorous and suppresses neighbouring plants by out-competing them for space and light. Mucuna pruriens is said not to be invasive outside its cultivated area. Desmodium uncinatum can be used in push-pull farming to stop the parasitic plant, witchweed (Striga).
The Australian bush fly, Musca vetustissima, is a major nuisance pest in Australia, but native decomposers found in Australia are not adapted to feeding on cow dung, which is where bush flies breed. Therefore, the Australian Dung Beetle Project (1965–1985), led by George Bornemissza of the Commonwealth Scientific and Industrial Research Organisation, released forty-nine species of dung beetle, to reduce the amount of dung and therefore also the potential breeding sites of the fly.
=== Combined use of parasitoids and pathogens ===
In cases of massive and severe infection of invasive pests, techniques of pest control are often used in combination. An example is the emerald ash borer, Agrilus planipennis, an invasive beetle from China, which has destroyed tens of millions of ash trees in its introduced range in North America. As part of the campaign against it, from 2003 American scientists and the Chinese Academy of Forestry searched for its natural enemies in the wild, leading to the discovery of several parasitoid wasps, namely Tetrastichus planipennisi, a gregarious larval endoparasitoid, Oobius agrili, a solitary, parthenogenic egg parasitoid, and Spathius agrili, a gregarious larval ectoparasitoid. These have been introduced and released into the United States of America as a possible biological control of the emerald ash borer. Initial results for Tetrastichus planipennisi have shown promise, and it is now being released along with Beauveria bassiana, a fungal pathogen with known insecticidal properties.
=== Secondary plants ===
In addition, biological pest control sometimes makes use of plant defenses to reduce crop damage by herbivores. Techniques include polyculture, the planting together of two or more species such as a primary crop and a secondary plant, which may also be a crop. This can allow the secondary plant's defensive chemicals to protect the crop planted with it.
== Target pests ==
=== Fungal pests ===
Botrytis cinerea on lettuce, by Fusarium spp. and Penicillium claviforme, on grape and strawberry by Trichoderma spp., on strawberry by Cladosporium herbarum, on Chinese cabbage by Bacillus brevis, and on various other crops by various yeasts and bacteria. Sclerotinia sclerotiorum by several fungal biocontrols. Fungal pod infection of snap bean by Trichoderma hamatum if before or concurrent with infection. Cryphonectria parasitica, Gaeumannomyces graminis, Sclerotinia spp., and Ophiostoma novo-ulmi by viruses. Various powdery mildews and rusts by various Bacillus spp. and fluorescent Pseudomonads. Colletotrichum orbiculare will suppress further infection by itself if manipulated to produce plant-induced systemic resistance by infected the lowest leaf.
== Difficulties ==
Many of the most important pests are exotic, invasive species that severely impact agriculture, horticulture, forestry, and urban environments. They tend to arrive without their co-evolved
parasites, pathogens and predators, and by escaping from these, populations may soar. Importing the natural enemies of these pests may seem a logical move but this may have unintended consequences; regulations may be ineffective and there may be unanticipated effects on biodiversity, and the adoption of the techniques may prove challenging because of a lack of knowledge among farmers and growers.
=== Side effects ===
Biological control can affect biodiversity through predation, parasitism, pathogenicity, competition, or other attacks on non-target species. An introduced control does not always target only the intended pest species; it can also target native species. In Hawaii during the 1940s parasitic wasps were introduced to control a lepidopteran pest and the wasps are still found there today. This may have a negative impact on the native ecosystem; however, host range and impacts need to be studied before declaring their impact on the environment.
Vertebrate animals tend to be generalist feeders, and seldom make good biological control agents; many of the classic cases of "biocontrol gone awry" involve vertebrates. For example, the cane toad (Rhinella marina) was intentionally introduced to Australia to control the greyback cane beetle (Dermolepida albohirtum), and other pests of sugar cane. 102 toads were obtained from Hawaii and bred in captivity to increase their numbers until they were released into the sugar cane fields of the tropic north in 1935. It was later discovered that the toads could not jump very high and so were unable to eat the cane beetles which stayed on the upper stalks of the cane plants. However, the toad thrived by feeding on other insects and soon spread very rapidly; it took over native amphibian habitat and brought foreign disease to native toads and frogs, dramatically reducing their populations. Also, when it is threatened or handled, the cane toad releases poison from parotoid glands on its shoulders; native Australian species such as goannas, tiger snakes, dingos and northern quolls that attempted to eat the toad were harmed or killed. However, there has been some recent evidence that native predators are adapting, both physiologically and through changing their behaviour, so in the long run, their populations may recover.
Rhinocyllus conicus, a seed-feeding weevil, was introduced to North America to control exotic musk thistle (Carduus nutans) and Canadian thistle (Cirsium arvense). However, the weevil also attacks native thistles, harming such species as the endemic Platte thistle (Cirsium neomexicanum) by selecting larger plants (which reduced the gene pool), reducing seed production and ultimately threatening the species' survival. Similarly, the weevil Larinus planus was also used to try to control the Canadian thistle, but it damaged other thistles as well. This included one species classified as threatened.
The small Asian mongoose (Herpestus javanicus) was introduced to Hawaii in order to control the rat population. However, the mongoose was diurnal, and the rats emerged at night; the mongoose, therefore, preyed on the endemic birds of Hawaii, especially their eggs, more often than it ate the rats, and now both rats and mongooses threaten the birds. This introduction was undertaken without understanding the consequences of such an action. No regulations existed at the time, and more careful evaluation should prevent such releases now.
The sturdy and prolific eastern mosquitofish (Gambusia holbrooki) is a native of the southeastern United States and was introduced around the world in the 1930s and '40s to feed on mosquito larvae and thus combat malaria. However, it has thrived at the expense of local species, causing a decline of endemic fish and frogs through competition for food resources, as well as through eating their eggs and larvae. In Australia, control of the mosquitofish is the subject of discussion; in 1989 researchers A. H. Arthington and L. L. Lloyd stated that "biological population control is well beyond present capabilities".
=== Grower education ===
A potential obstacle to the adoption of biological pest control measures is that growers may prefer to stay with the familiar use of pesticides. However, pesticides have undesired effects, including the development of resistance among pests, and the destruction of natural enemies; these may in turn enable outbreaks of pests of other species than the ones originally targeted, and on crops at a distance from those treated with pesticides. One method of increasing grower adoption of biocontrol methods involves letting them learn by doing, for example showing them simple field experiments, enabling them to observe the live predation of pests, or demonstrations of parasitised pests. In the Philippines, early-season sprays against leaf folder caterpillars were common practice, but growers were asked to follow a 'rule of thumb' of not spraying against leaf folders for the first 30 days after transplanting; participation in this resulted in a reduction of insecticide use by 1/3 and a change in grower perception of insecticide use.
== Related techniques ==
Related to biological pest control is the technique of introducing sterile individuals into the native population of some organism. This technique is widely practised with insects: a large number of males sterilized by radiation are released into the environment, which proceed to compete with the native males for females. Those females that copulate with the sterile males will lay infertile eggs, resulting in a decrease in the size of the population. Over time, with repeated introductions of sterile males, this could result in a significant decrease in the size of the organism's population. A similar technique has recently been applied to weeds using irradiated pollen, resulting in deformed seeds that do not sprout.
== See also ==
== References ==
K. Esser and J.W. Bennett, ed. (2002). XI Agricultural Applications. The Mycota - A Comprehensive Treatise on Fungi as Experimental Systems for Basic and Applied Research. Berlin, Heidelberg: Springer Berlin Heidelberg. p. VII-388. ISBN 978-3-662-03059-2. OCLC 851379901. ISBN 978-3-642-07650-3
Chapter 6, Elad, Yigal; Freeman, Stanley. "Biological Control of Fungal Plant Pathogens". .
== Further reading ==
=== General ===
Wiedenmann, R. (2000). Introduction to Biological Control Archived 2011-08-10 at the Wayback Machine. Midwest Institute for Biological Control, Illinois.
Cowie, R. H. (2001). "Can snails ever be effective and safe biocontrol agents?" (PDF). International Journal of Pest Management. 47 (1): 23–40. CiteSeerX 10.1.1.694.2798. doi:10.1080/09670870150215577. S2CID 51510769. Archived from the original (PDF) on 2010-10-11. Retrieved 2010-04-07.
Cook, R. James (September 1993). "Making Greater Use of Introduced Microorganisms for Biological Control of Plant Pathogens". Annual Review of Phytopathology. 31 (1): 53–80. Bibcode:1993AnRvP..31...53C. doi:10.1146/annurev.py.31.090193.000413. PMID 18643761.
U.S. Congress, Office of Technology Assessment (1995). "Biologically based technologies for pest control" (PDF). Ota-Env-636.
Felix Wäckers; Paul van Rijn & Jan Bruin (2005). Plant-Provided Food for Carnivorous Insects – a protective mutualism and its applications. Cambridge University Press, 2005. ISBN 978-0-521-81941-1.
=== Effects on native biodiversity ===
Pereira, M. J.; et al. (1998). "Conservation of natural vegetation in Azores Islands". Bol. Mus. Munic. Funchal. 5: 299–305.
Weeden, C. R.; Shelton, A. M.; Hoffman, M. P. Biological Control: A Guide to Natural Enemies in North America.
Cane toad: a case study. 2003.
Humphrey, J. and Hyatt. 2004. CSIRO Australian Animal Health Laboratory. Biological Control of the Cane Toad Bufo marinus in Australia
Cory, J.; Myers, J. (2000). "Direct and indirect ecological effects of biological control". Trends in Ecology & Evolution. 15 (4): 137–139. Bibcode:2000TEcoE..15..137C. doi:10.1016/s0169-5347(99)01807-8.
Johnson, M. 2000. Nature and Scope of Biological Control. Biological Control of Pests.
=== Economic effects ===
Griffiths, G. J. K. (2007). "Efficacy and economics of shelter habitats for conservation". Biological Control. 45: 200–209. doi:10.1016/j.biocontrol.2007.09.002.
Collier, T.; Steenwyka, R. (2003). "A critical evaluation of augmentative biological control". Economics of Augmentation. 31 (2): 245–256. doi:10.1016/j.biocontrol.2004.05.001.
== External links ==
Association of Natural Biocontrol Producers
International Organization for Biological Control | Wikipedia/Biological_pest_control |
Electronic pest control is the name given to any of several types of electrically powered devices designed to repel or eliminate pests, usually rodents or insects. Since these devices are not regulated under the Federal Insecticide, Fungicide, and Rodenticide Act in the United States, the EPA does not require the same kind of efficacy testing that it does for chemical pesticides.
== Types of devices ==
=== Ultrasonic ===
Ultrasonic devices operate through emitting short wavelength, high frequency sound waves that are too high in pitch to be heard by the human ear (generally accepted to be frequencies greater than 20,000 Hz). Humans are usually unable to hear sounds higher than 20 kHz due to physiological limitations of the cochlea, though there is considerable variation between individuals, especially at such high frequencies. Some animals, such as bats, dogs, and rodents, can hear well into the ultrasonic range. Some insects, such as grasshoppers and locusts, can detect frequencies from 50,000 Hz to 100,000 Hz, and lacewings and moths can detect ultrasound as high as 240,000 Hz produced by insect-hunting bats. Contrary to popular belief, birds cannot hear ultrasonic sound. Some smartphone applications attempt to use this technology to produce high frequency sounds to repel mosquitoes and other insects, but the claims of effectiveness of these applications and of ultrasonic control of pest creatures in general has been questioned. The ultrasonic repeller has several inconvenient side effects in addition to its questionable effectiveness.
=== Radio wave pest control ===
The concept of radio wave (RW) or radio frequency (RF) to control the behavior of living organisms has shown promise. According to Drs. Juming Tang and Shaojin Wang at Washington State University (WSU) with colleagues at the University of California-Davis and USDA's Agricultural Research Service in Parlier, California, since RF energy generates heat through agitation of bound water molecules, it generates heat through ionic conduction and agitation of free water molecules in insects. As a result, more thermal energy is converted in insects.
RF treatments control insect pests without negatively affecting food stuffs and storage locations. RF treatments may serve as a non-chemical alternative to chemical fumigants for post-harvest pest control in commodities (such as almonds, pecans, pistachios, lentils, peas, and soybeans), reducing the long-term impact on the environment, human health, and competitiveness of agricultural industries.
== Ultrasound studies ==
In 2003, the Federal Trade Commission required Global Instruments, the maker of the Pest-A-Cator/Riddex series of electromagnetic pest control devices, to discontinue any claims for their efficacy until they are backed by credible scientific evidence. This ban continues to be in effect.
In 2007 a Cochrane report reviewed by the Infectious Diseases Group determined that there was no evidence based on 10 field studies, in which ultrasonic repellent devices had been put to the test to suggest that they had any repellent effect on mosquitoes, and therefore no evidence to support their promotion. They advised discontinuing further randomized controlled trials due to field studies showing no promise in the effort to combat malaria.
=== Effects on animals ===
==== Effects on mosquitoes ====
Bart Knols, an entomologist who chairs the advisory board of the Dutch Malaria Foundation and edits the website Malaria World, states there is "no scientific evidence whatsoever" that ultrasound repels mosquitoes.
In 2005, the British consumer magazine Holiday reported the results of its test of a range of mosquito deterrents. The magazine's editor Lorna Cowan described the four appliances that used a buzzer as "a shocking waste of money" which "should be removed from sale". One, the Lovebug, a ladybird-shaped gadget designed to be clipped onto a baby's cot or child's pushchair - was singled out as a particular cause for concern, because of the likelihood that parents would trust it to keep mosquitoes away, and their children would be hurt as a result. (The Lovebug is still readily available in Europe, though it was withdrawn from the US market after the Federal Trade Commission reprimanded the manufacturer Prince Lionheart.)
==== Effects on rodents ====
Based on a review of tests of six commercial products, a report made at the University of Lincoln, Nebraska in 1995 concluded that all the devices, when evaluated at a range of frequencies and decibel levels, were insufficient in repelling rodents. The EPA pursued legal action against purveyors of the products, and none were subsequently marketed as a result of fines against the manufacturers.
== Safety ==
Professor Tim Leighton at the Institute of Sound and Vibration Research, University of Southampton, U.K. produced an 83-page paper entitled "What is Ultrasound?" (2007), in which he expressed concern about the growth in commercial products which exploit the discomforting effects of in-air ultrasound (to pests for whom it is within their audible frequency range, or to humans for whom it is not, but who can experience unpleasant subjective effects and, potentially, shifts in the hearing threshold). Leighton claims that commercial products are often advertised with cited levels which cannot be critically accepted due to lack of accepted measurement standards for ultrasound in air, and little understanding of the mechanism by which they may represent a hazard. However, there has not yet been sufficient research to confirm or deny a link between inaudible ultrasound and hearing problems in humans.
The UK's independent Advisory Group on Non-ionising Radiation (AGNIR) produced a 180-page report on the health effects of human exposure to ultrasound and infrasound in 2010. The UK Health Protection Agency (HPA) published their report, which recommended an exposure limit for the general public to airborne ultrasound sound pressure levels (SPL) of 70 dB (at 20 kHz), and 100 dB (at 25 kHz and above).
== See also ==
Bug zapper
Fly-killing device
Shark repellent
== References ==
== Further reading ==
"News Release". Federal Trade Commission. 2001.
"Consent Agreement". Federal Trade Commission. July 2003.
"Press Release Radio Waves May Offer a New, Environmentally Safe Pest Control Method". USDA. 2008. Archived from the original on 2015-02-24. | Wikipedia/Electronic_pest_control |
A field trial is a competitive event for gun dogs. Field trials are conducted for pointing dogs and setters, retrievers and spaniels, with each assessing the different types various working traits. In the United States, field trials are also conducted for basset hounds, beagles, and dachshunds.
== Pointer and setter trials ==
Pointer and setter trials are trials for both pointing dogs and setters. During pointer and setter trials the dogs are run in a brace (pair of dogs run together) with two judges observing, the dogs are worked into the wind on live gamebirds, they are required to quarter their assigned beat, finding and pointing any game in the beat. Once on the point the dog must remain staunch until the judge indicates then move in and flush the bird, once the bird is flushed a shot is fired and dog must drop to the ground. Dogs are judged for their ability to find game, their style and staunchness on point, their backing of the other dog, their quartering ability and their pace, eliminating faults include flushing the game early, chasing the game, running out of control or giving tongue (barking).
In the United States, dog handlers, judges and observers at American Kennel Club run pointer and setter trials often follow on horseback. Handlers, judges and observers at United Kennel Club trails are all on foot.
The first pointer and setter field trial was conducted in Bedfordshire in 1865.
=== HPR trials ===
HPR trials are trials for hunt, point, retrieve or "versatile" pointer breeds, in these trials the dog is expected to find and point game as in a pointer and setter trial, but after the game is shot they are also expected to retrieve the shot game. HPR trials are usually conducted on varying terrain to test the dogs in different environments, and they usually include at least one retrieve from water.
== Spaniel trials ==
Spaniel trials are designed to replicate the rough shoot that is typically undertaken by spaniels, where the spaniel quarters the ground in front of its handler flushing game and afterwards retrieving it. Usually two dogs are trialled simultaneously with a judge walking in line approximately 40 yards (37 m) apart judging each dog, the dogs are expected to work independently with the judges watching the dog's manner whilst quartering, courage in cover and game finding ability. It is desirable for both winged and ground game to be available during spaniel trials, once the game is shot the judge gives approval and the spaniel is expected to retrieve the game to hand. Once all of the dogs have run the course, if the judges cannot agree on a winner a runoff is conducted where three or four dogs are run simultaneously so the judges can make a determination.
The first spaniel field trial was conducted in Britain in 1899.
== Retriever trials ==
Retriever trials are designed to replicate the work of a retriever; whereas working retrievers used by sportsmen often hunt for game and retrieve, retriever trials only focus on the conduct of the retrieve. In the United Kingdom retriever trails are conducted in a similar manner to driven shoots, where retrievers are used to collect shot game either whilst walking in line or waiting at the pegs. Usually six dogs are trialled together in a line with three judges each judging a pair of dogs but alternating the dogs down the line so every dog is observed by each judge. Dogs are judged on their style, marking, ability to take directions and retrieving to hand, no dog is permitted to retrieve game without the judge's consent, when not retrieving dogs are expected to remain quietly by their handlers side watching the other dogs work.
In the United States dogs are usually trialled individually and they are assessed equally retrieving from land and from water, with both marked retrieves and blind retrieves. Marked retrieves are where the dog observes the fall of the bird, blind retrieves are when the dog is sent to retrieve an unobserved bird by command.
Andy Bear was a three-time State Champion (1991, 1992, 1996).
== Basset, Beagle and Dachshund field trials ==
In the United States trials of Basset Hounds, Beagles and Dachshunds are also conducted, also called field trials the different breeds of hound compete whilst tracking a rabbit or a hare.
=== Basset trials ===
Sponsored by the American Kennel Club, Basset trials are conducted in either braces (pairs of hounds), small packs of seven hounds or large packs of 25 hounds, tracking a live rabbit or hare. There is also a gundog brace competition where a brace of Bassets are cast to locate a rabbit which is then shot at with a blank cartridge.
=== Beagle trials ===
Beagle trials sponsored by the American Kennel Club are run in the same brace, small pack, large pack and gundog brace events as Basset trials. United Kennel Club sponsored Beagle trials are conducted in two forms; in the first four beagles and their handlers each try to out-perform each other in locating game, in the second five hounds are worked together following a scent trail with the judge comparaing their individual performances.
=== Dachshund trials ===
Sponsored by the American Kennel Club, Dachshund trials are conducted in braces in the same manner as Basset or Beagle brace trials.
== Field and hunt tests ==
Field tests and hunt tests are non-competitive activities designed to test a gundog's natural hunting abilities in a field environment without the added pressure of competition. Unlike in field trials where dogs compete against each other, in hunt tests dogs compete to pass the requirements of the tests. In the United Kingdom they are called field tests and are most frequently run by gun clubs or local field sports organisations. In the United States they are called hunt tests and are more formally organised, being run by both the American Kennel Club and United Kennel Club, with separate tests for pointing dogs, retrievers, and spaniels.
== References ==
=== Citations ===
=== Bibliography ===
Douglas, James (2003). The complete gundog training manual. Shrewsbury: Swan Hill Press. ISBN 978-1-904057-05-5.
Hudson, David (1995). The shooting man's dog: a complete guide to gundogs. Shrewsbury: Swan Hill Press. ISBN 1-85310-560-0.
Morgan, Diane (2009). The encyclopedia of dog sports and activities: a field guide to 36 fun activities for you and your dog. Neptune City: T.F.H Publications. ISBN 978-0-7938-1275-2.
Moxon, P. R. A. (1974). Gundogs: training and field trials (10th revised ed.). London: Popular Dogs Publishing Ltd. ISBN 0-09-121670-2.
== External links ==
Field Trial Rules and Standard Procedure for Pointing Breeds (PDF). New York: American Kennel Club. December 2018.
Field Trial Rules and Standard Procedure for Retrievers (PDF). New York: American Kennel Club. November 2017.
Field Trial Rules and Standard Procedure for Spaniels (PDF). New York: American Kennel Club. August 2017. | Wikipedia/Field_trial |
Integrated pest management (IPM), also known as integrated pest control (IPC) integrates both chemical and non-chemical practices for economic control of pests. The UN's Food and Agriculture Organization defines IPM as "the careful consideration of all available pest control techniques and subsequent integration of appropriate measures that discourage the development of pest populations and keep pesticides and other interventions to levels that are economically justified and reduce or minimize risks to human health and the environment. IPM emphasizes the growth of a healthy crop with the least possible disruption to agro-ecosystems and encourages natural pest control mechanisms." Entomologists and ecologists have urged the adoption of IPM pest control since the 1970s. IPM is a safer pest control framework than reliance on the use of chemical pesticides, mitigating risks such as: insecticide-induced resurgence, pesticide resistance and (especially food) crop residues.
== History ==
Shortly after World War II, when synthetic insecticides were introduced, entomologists in California developed the concept of "supervised insect control". Around the same time, entomologists in the US Cotton Belt were advocating a similar approach. Under this scheme, insect control was "supervised" by qualified entomologists and insecticide applications were based on conclusions reached from periodic monitoring of pest and natural-enemy populations. This was viewed as an alternative to calendar-based programs. Supervised control was based on knowledge of the ecology and analysis of projected trends in pest and natural-enemy populations.
Supervised control formed much of the conceptual basis for the "integrated control" that University of California entomologists articulated in the 1950s. Integrated control sought to identify the best mix of chemical and biological controls for a given insect pest. Chemical insecticides were to be used in the manner least disruptive to biological control. The term "integrated" was thus synonymous with "compatible." Chemical controls were to be applied only after regular monitoring indicated that a pest population had reached a level that required treatment (the economic threshold) to prevent the population from reaching a level at which economic losses would exceed the cost of the control measures (the economic injury level).
IPM extended the concept of integrated control to all classes of pests and was expanded to include all tactics. Controls such as pesticides were to be applied as in integrated control, but these now had to be compatible with tactics for all classes of pests. Other tactics, such as host-plant resistance and cultural manipulations, became part of the IPM framework. IPM combined entomologists, plant pathologists, nematologists and weed scientists.
In the United States, IPM was formulated into national policy in February 1972 as directed by President Richard Nixon. In 1979, President Jimmy Carter established an interagency IPM Coordinating Committee to ensure development and implementation of IPM practices.
Perry Adkisson and Ray F. Smith received the 1997 World Food Prize for encouraging the use of IPM.
== Applications ==
IPM is used in agriculture, horticulture, forestry, human habitations, preventive conservation of cultural property and general pest control, including structural pest management, turf pest management and ornamental pest management. IPM practices help to prevent and slow the development of resistance, known as resistance management.
== Principles ==
An American IPM system is designed around six basic components:
Acceptable pest levels—The emphasis is on control, not eradication. IPM holds that wiping out an entire pest population is often impossible, and the attempt can be expensive and unsafe. IPM programmes first work to establish acceptable pest levels, called action thresholds, and apply controls if those thresholds are crossed. These thresholds are pest and site specific, meaning that it may be acceptable at one site to have a weed such as white clover, but not at another site. Allowing a pest population to survive at a reasonable threshold reduces selection pressure. This lowers the rate at which a pest develops resistance to a control, because if almost all pests are killed then those that have resistance will provide the genetic basis of the future population. Retaining a significant number of unresistant specimens dilutes the prevalence of any resistant genes that appear. Similarly, the repeated use of a single class of controls will create pest populations that are more resistant to that class, whereas alternating among classes helps prevent this.
Preventive cultural practices—Selecting varieties best for local growing conditions and maintaining healthy crops is the first line of defense. Plant quarantine and 'cultural techniques' such as crop sanitation are next, e.g., removal of diseased plants, and cleaning pruning shears to prevent spread of infections. Beneficial fungi and bacteria are added to the potting media of horticultural crops vulnerable to root diseases, greatly reducing the need for fungicides.
Monitoring—Regular observation is critically important. Observation is broken into inspection and identification. Visual inspection, insect and spore traps, and other methods are used to monitor pest levels. Record-keeping is essential, as is a thorough knowledge of target pest behavior and reproductive cycles. Since insects are cold-blooded, their physical development is dependent on area temperatures. Many insects have had their development cycles modeled in terms of degree-days. The degree days of an environment determines the optimal time for a specific insect outbreak. Plant pathogens follow similar patterns of response to weather and season. Automated systems based on AI have been developed to identify and monitor flies using e-trapping devices.
Mechanical controls—Should a pest reach an unacceptable level, mechanical methods are the first options. They include simple hand-picking, barriers, traps, vacuuming and tillage to disrupt breeding.
Biological controls—Natural biological processes and materials can provide control, with acceptable environmental impact, and often at lower cost. The main approach is to promote beneficial insects that eat or parasitize target pests. Biological insecticides, derived from naturally occurring microorganisms (e.g.—Bt, entomopathogenic fungi and entomopathogenic nematodes), also fall in this category. Further 'biology-based' or 'ecological' techniques are under evaluation.
Responsible use—Synthetic pesticides are used as required and often only at specific times in a pest's life cycle. Many newer pesticides are derived from plants or naturally occurring substances (e.g.—nicotine, pyrethrum and insect juvenile hormone analogues), but the toxophore or active component may be altered to provide increased biological activity or stability. Applications of pesticides must reach their intended targets. Matching the application technique to the crop, the pest, and the pesticide is critical, for example, the use of low-volume spray equipment can considerably reduce overall pesticide use and operational costs.
Although originally developed for agricultural pest management, IPM programmes now encompass diseases, weeds and other pests that interfere with management objectives for sites such as residential and commercial structures, lawn and turf areas, and home and community gardens. Predictive models have proved to be suitable tools supporting the implementation of IPM programmes.
== Process ==
IPM is the selection and use of pest control actions that will ensure favourable economic condition, ecological and social consequences and is applicable to most agricultural, public health and amenity pest management situations. The IPM process starts with monitoring, which includes inspection and identification, followed by the establishment of economic injury levels. The economic injury levels set the economic threshold level. Economic Injury level is the pest population level at which crop damage exceeds the cost of treatment of pest. This can also be an action threshold level for determining an unacceptable level that is not tied to economic injury. Action thresholds are more common in structural pest management and economic injury levels in classic agricultural pest management. An example of an action threshold is one fly in a hospital operating room is not acceptable, but one fly in a pet kennel would be acceptable. Once a threshold has been crossed by the pest population action steps need to be taken to reduce and control the pest. Integrated pest management employs a variety of actions including cultural controls such as physical barriers, biological controls such as adding and conserving natural predators and enemies of the pest, and finally chemical controls or pesticides. Reliance on knowledge, experience, observation and integration of multiple techniques makes IPM appropriate for organic farming (excluding synthetic pesticides). These may or may not include materials listed on the Organic Materials Review Institute (OMRI) Although the pesticides and particularly insecticides used in organic farming and organic gardening are generally safer than synthetic pesticides, they are not always more safe or environmentally friendly than synthetic pesticides and can cause harm. For conventional farms IPM can reduce human and environmental exposure to hazardous chemicals, and potentially lower overall costs.
Risk assessment usually includes four issues: 1) characterization of biological control agents, 2) health risks, 3) environmental risks and 4) efficacy.
Mistaken identification of a pest may result in ineffective actions. E.g., plant damage due to over-watering could be mistaken for fungal infection, since many fungal and viral infections arise under moist conditions.
Monitoring begins immediately, before the pest's activity becomes significant. Monitoring of agricultural pests includes tracking soil/planting media fertility and water quality. Overall plant health and resistance to pests is greatly influenced by pH, alkalinity, of dissolved mineral and oxygen reduction potential. Many diseases are waterborne, spread directly by irrigation water and indirectly by splashing.
Once the pest is known, knowledge of its lifecycle provides the optimal intervention points. For example, weeds reproducing from last year's seed can be prevented with mulches and pre-emergent herbicide.
Pest-tolerant crops such as soybeans may not warrant interventions unless the pests are numerous or rapidly increasing. Intervention is warranted if the expected cost of damage by the pest is more than the cost of control. Health hazards may require intervention that is not warranted by economic considerations.
Specific sites may also have varying requirements. E.g., white clover may be acceptable on the sides of a tee box on a golf course, but unacceptable in the fairway where it could confuse the field of play.
Possible interventions include mechanical/physical, cultural, biological and chemical. Mechanical/physical controls include picking pests off plants, or using netting or other material to exclude pests such as birds from grapes or rodents from structures. Cultural controls include keeping an area free of conducive conditions by removing waste or diseased plants, flooding, sanding, and the use of disease-resistant crop varieties. Biological controls are numerous. They include: conservation of natural predators or augmentation of natural predators, sterile insect technique (SIT).
Augmentation, inoculative release and inundative release are different methods of biological control that affect the target pest in different ways. Augmentative control includes the periodic introduction of predators. With inundative release, predators are collected, mass-reared and periodically released in large numbers into the pest area. This is used for an immediate reduction in host populations, generally for annual crops, but is not suitable for long run use. With inoculative release a limited number of beneficial organisms are introduced at the start of the growing season. This strategy offers long term control as the organism's progeny affect pest populations throughout the season and is common in orchards. With seasonal inoculative release the beneficials are collected, mass-reared and released seasonally to maintain the beneficial population. This is commonly used in greenhouses. In America and other western countries, inundative releases are predominant, while Asia and the eastern Europe more commonly use inoculation and occasional introductions.
The sterile insect technique (SIT) is an area-wide IPM program that introduces sterile male pests into the pest population to trick females into (unsuccessful) breeding encounters, providing a form of birth control and reducing reproduction rates. The biological controls mentioned above only appropriate in extreme cases, because in the introduction of new species, or supplementation of naturally occurring species can have detrimental ecosystem effects. Biological controls can be used to stop invasive species or pests, but they can become an introduction path for new pests.
Chemical controls include horticultural oils or the application of insecticides and herbicides. A green pest management IPM program uses pesticides derived from plants, such as botanicals, or other naturally occurring materials.
Pesticides can be classified by their modes of action. Rotating among materials with diverse modes of action minimizes pest resistance.
Evaluation is the process of assessing whether the intervention was effective, whether it produced unacceptable side effects, whether to continue, revise or abandon the program.
== Southeast Asia ==
The Green Revolution of the 1960s and '70s introduced sturdier plants that could support the heavier grain loads resulting from intensive fertilizer use. Pesticide imports by 11 Southeast Asian countries grew nearly sevenfold in value between 1990 and 2010, according to FAO statistics, with disastrous results. Rice farmers become accustomed to spraying soon after planting, triggered by signs of the leaf folder moth, which appears early in the growing season. It causes only superficial damage and doesn't reduce yields. In 1986, Indonesia banned 57 pesticides and completely stopped subsidizing their use. Progress was reversed in the 2000s, when growing production capacity, particularly in China, reduced prices. Rice production in Asia more than doubled. But it left farmers believing more is better—whether it's seed, fertilizer, or pesticides.
The brown planthopper, Nilaparvata lugens, the farmers' main target, has become increasingly resistant. Since 2008, outbreaks have devastated rice harvests throughout Asia, but not in the Mekong Delta. Reduced spraying allowed natural predators to neutralize planthoppers in Vietnam. In 2010 and 2011, massive planthopper outbreaks hit 400,000 hectares of Thai rice fields, causing losses of about $64 million. The Thai government is now pushing the "no spray in the first 40 days" approach.
By contrast early spraying kills frogs, spiders, wasps and dragonflies that prey on the later-arriving and dangerous planthopper and produced resistant strains. Planthoppers now require pesticide doses 500 times greater than originally. Overuse indiscriminately kills beneficial insects and decimates bird and amphibian populations. Pesticides are suspected of harming human health and became a common means for rural Asians to commit suicide.
In 2001, 950 Vietnamese farmers tried IPM. In one plot, each farmer grew rice using their usual amounts of seed and fertilizer, applying pesticide as they chose. In a nearby plot, less seed and fertilizer were used and no pesticides were applied for 40 days after planting. Yields from the experimental plots were as good or better and costs were lower, generating 8% to 10% more net income. The experiment led to the "three reductions, three gains" campaign, claiming that cutting the use of seed, fertilizer and pesticide would boost yield, quality and income. Posters, leaflets, TV commercials and a 2004 radio soap opera that featured a rice farmer who gradually accepted the changes. It didn't hurt that a 2006 planthopper outbreak hit farmers using insecticides harder than those who didn't. Mekong Delta farmers cut insecticide spraying from five times per crop cycle to zero to one.
The Plant Protection Center and the International Rice Research Institute (IRRI) have been encouraging farmers to grow flowers, okra, and beans on rice paddy banks, instead of stripping vegetation, as was typical. The plants attract bees and wasps that eat planthopper eggs, while the vegetables diversify farm incomes.
Agriculture companies offer bundles of pesticides with seeds and fertilizer, with incentives for volume purchases. A proposed law in Vietnam requires licensing pesticide dealers and government approval of advertisements to prevent exaggerated claims. Insecticides that target other pests, such as Scirpophaga incertulas (stem borer), the larvae of moth species that feed on rice plants allegedly yield gains of 21% with proper use.
== See also ==
== References ==
== Further reading ==
Steve H. Dreistadt (2004). Pests of Landscape Trees and Shrubs: An Integrated Pest Management Guide. UCANR Publications. ISBN 978-1-879906-61-7. photos, reference tables, diagrams.
Bennett, Gary W.; Owens, John M.; Corrigan, Robert M. (2010). Truman's Scientific Guide to Pest Management Operations. Purdue University. ISBN 978-0-9793986-1-2.
Jahn, GC, PG Cox., E Rubia-Sanchez, and M Cohen 2001. The quest for connections: developing a research agenda for integrated pest and nutrient management. pp. 413–430, In S. Peng and B. Hardy [eds.] "Rice Research for Food Security and Poverty Alleviation." Proceedings of the International Rice Research Conference, 31 March – 3 April 2000, Los Baños, Philippines. Los Baños (Philippines): International Rice Research Institute. 692 p.
Jahn, GC, B. Khiev, C Pol, N. Chhorn and V Preap 2001. Sustainable pest management for rice in Cambodia. In P. Cox and R Chhay [eds.] "The Impact of Agricultural Research for Development in Southeast Asia" Proceedings of an International Conference held at the Cambodian Agricultural Research and Development Institute, Phnom Penh, Cambodia, 24-26 Oct. 2000, Phnom Penh (Cambodia): CARDI.
Jahn, GC; Litsinger, JA; Chen, Y; Barrion, A (8 January 2007). "Integrated Pest Management of Rice: Ecological Concepts". In Opender Koul; Gerrit W. Cuperus (eds.). Ecologically Based Integrated Pest Management. CABI. pp. 315–366. ISBN 978-1-84593-163-6.
Kogan, M. (1998). "Integrated Pest Management: Historical Perspectives and Contemporary Developments". Annual Review of Entomology. 43: 243–270. doi:10.1146/annurev.ento.43.1.243. PMID 9444752.
Nonveiller, Guido 1984. Catalogue commenté et illustré des insectes du Cameroun d'intérêt agricole : (apparitions, répartition, importance) / University of Belgrade/Institut pour la protection des plantes
Robert F. Norris; Edward P. Caswell-Chen; Marcos Kogan (2003). Concepts in integrated pest management. Prentice Hall PTR. ISBN 978-0-13-087016-2.
Hassanali, A.; Herren, H.; Khan, Z. R.; Pickett, J. A.; Woodcock, C. M. (2008). "Integrated pest management: the push-pull approach for controlling insect pests and weeds of cereals, and its potential for other agricultural systems including animal husbandry". Philosophical Transactions of the Royal Society B: Biological Sciences. 363 (1491): 611–21. doi:10.1098/rstb.2007.2173. PMC 2610173. PMID 17652071.
Victor Arnold Dyck; Jorge Hendrichs; A. S. Robinson (23 February 2006). Sterile Insect Technique: Principles and Practice in Area-Wide Integrated Pest Management. Springer. ISBN 978-1-4020-4051-1.
Regnault-Roger, Catherine; Philogene, Bernard JR (2008) Past and Current Prospects for the use of Botanicals and Plant allelochemicals in Integrated Pest Management. Pharm. Bio. 46(1–2): 41–52
Acosta, EW (2006) The History of Integrated Pest Management (IPM). Biocontrol Reference Center.
Surendra K Dara, The New Integrated Pest Management Paradigm for the Modern Age, Journal of Integrated Pest Management, Volume 1, Issue 1, 2019, 12, The New Integrated Pest Management Paradigm for the Modern Age
== External links ==
Introducing to Integrated Pest Management via EPA | Wikipedia/Integrated_pest_management |
The drugstore beetle (Stegobium paniceum), also known as the bread beetle, biscuit beetle, and misnamed as the biscuit weevil (despite not being a weevil), is a small brown beetle that infests a wide variety of dried plant products, where it is among the most common non-weevils. It is the only living member of the genus Stegobium. It belongs to the family Ptinidae, which also includes the deathwatch beetle, furniture beetle and cigarette beetle. A notable characteristic of this species is the symbiotic relationship the beetles have with a yeast-like fungus which is transmitted from female to larvae through the oviduct.
The drugstore beetle is distributed worldwide with higher prevalence in warmer climates. It is commonly confused with the cigarette beetle, as they have a similar size and coloring. Adults possess antennae ending in 3-segmented clubs, while cigarette beetles have serrated (saw-like) antennae. Their bodies are lined with grooves running longitudinally along the elytra, whereas the cigarette beetle is smooth.
== Description ==
Adult drugstore beetles are between 2.5 and 3.5 millimetres (3⁄32 and 1⁄8 in) long and have a reddish-brown colour with a cylindrical body. Larvae are habitually curled. The pupa is proportionally more slender than that of the cigarette beetle.
Both males and females appear nearly identical except that males have a sexually dimorphic slot-like structure on the tarsal claws which can only be observed under a microscope. During the pupal stage, males and females can be differentiated as the female genital papillae are bulging outwards and divergent, while the male genital papillae are not protruding and aren’t as pronounced. As adults carry their genitals within their body, main way to distinguish sexes is during the pupal stage.
== Food resources ==
Drugstore beetles primarily feed and cause damage during the larval stage. The drugstore beetle attacks a wide variety of food sources including pharmaceutical products and medicinal plants, earning its name. This species is known for feeding on both food and non-food materials. The beetle eats bread, grain, coffee beans, powdered milk, sweets like cookies and chocolates, spices and herbs, dried fruit, seeds, and more. They also consume museum specimens, wool, hair, leather, books, upholstery, and manuscripts. Adults gnaw through packaging forming large holes in the material, leading to their deterioration, contamination, and loss of structural integrity.
== Life history ==
The life cycle of this transitions from the egg, to 4-6 larval instars, the construction of a cocoon for the pupa, and finally, the adult stage. The female can lay up to 75 eggs, depositing them in or near sources of food. Approximately 80% of her eggs end up being fertile. The egg stage lasts around 7–20 days at a temperature between 20 °C and 27.5 °C. The larvae then form a cocoon of silk and food material which they use to pupate. The pupa stays in the cocoon for varying amounts of time before the adult emerges. Between temperatures 20 °C and 27.5 °C, the pupal stage typically lasts from 5–12 days. Temperature and relative humidity play an important role in the growth and development of drugstore beetles, with the optimal range being between 15 °C and 35 °C, and an ideal temperature of 30 °C. Studies have found that increasing the relative humidity or temperature shortened the incubation period for these eggs and the pupal period. At peak conditions, it takes the eggs around 40 days to develop into adults. At the end of this cycle, adults live for about 85 days at 17.5 °C. The specific length of each stage depends on the temperature and food sources available to the beetles.
== Taxonomy and evolution ==
The drugstore beetle was originally described by Carl Linnaeus in 1758 as part of his Systema Naturae under the name Dermestes paniceus. It was assigned to the newly created genus Stegobium by Victor Motschulsky in 1860. The drugstore beetle is the only living species in the genus Stegobium. The oldest known member of the genus is Stegobium raritanensis from the Late Cretaceous (Turonian ~94-90 million years ago) aged New Jersey amber.
== Genetics ==
As a stored product pest, the evolutionary history of the drugstore beetle suggests that it evolved from a wood-feeding ancestor. Studies found that the beetle has 8 autosomal chromosomes and 1 sex chromosome forming a diploid set of 18 chromosomes. The sex determination system for Stegobium paniceum is based on XX-X0 as they lack the Y chromosome. The genome size of this species is estimated to be around 238 to 345 Mb which is significantly smaller than the median genome size of 760 Mb for the Coleoptera order.
== Mating ==
Male and female S. paniceum use sex pheromones to attract a mate. Female drugstore beetles utilize stegobinone, a volatile compound, to elicit a pheromonal response that communicates their presence and availability to males. This compound makes it much easier for the drugstore beetle to search for mates, indicates their willingness to mate, and facilitates the mating process by exciting and attracting males. They produce copious amounts of sex pheromones, reaching as much as 50 to 200 ng, allowing the females to maintain the signal for greater distances. It was found that male response to females peaked 5 to 12 days after becoming an adult. For females, their pheromone levels increased after 1 day, levelled off after 5, and lasted at least 14 days. The pheromone is also specific to this species, ensuring the propagation of the drugstore beetle's genes.
The proper orientation of the male and female during the mating process follows two experimentally determined phases called pre-mounting and post-mounting. The first phase involves the female proactively directing pre-mounting behaviors such as mate finding and courtship. The latter component involves the male detecting tactile cues by coming into contact with the female’s dorsal setae, which are sensory hairs located on her back. The male uses physical touch to obtain information regarding the female’s condition and her capacity to mate, which allows him to better engage in mating behaviors. The tarsal claw slots are secondary sex features of males that play a major role in mating behavior, especially in species that don’t engage in parental care. The male drugstore beetle uses the claw slots found at the end of their legs to trap the setae on the elytra or forewing of the female. The hairs on the female beetle gets inserted and trapped into the claw slots of the males. This behavior is supported by evidence that when the male dismounts from the female, there is a time lag caused by the male trying to remove its claws from the female. This interaction improves the positioning of the male during mating, preventing him from falling off of the female prematurely, thereby prolonging the duration of mating and enhancing the overall mating process.
== Mutualism with fungi ==
Stegobium paniceum possess large cells with symbionts located in the mycetome and lumen of the intestine. Mycetomes, an organ part of the digestive system, has four lobes in drugstore beetle larvae. As the beetle develops into an adult, six tubular appendages appear from each lobe. Two of the six appendages may exist to remove waste products produced by the symbionts. They also serve to provide nitrogenous waste products to the yeast to promote their growth. The larvae lack symbionts immediately after hatching until they take in the yeast cells orally, infecting the mycetocytes of the midgut mycetome organ. The yeast continue to accumulate throughout the pupal stage. The symbiotic yeast cells found in this species are elongated with a bud attached to one end. The cells were named S. anobii and were classified under the genus Saccharomyces temporarily, but this taxonomic categorization needs further study. The size of the yeast cells ranges from 1.5 to 3.5 micrometers in width and 3 to 6 micrometers in length.
The beetles obtain sterols, necessary for their growth, from their diet as well as from the yeast-like fungi they harbor. The main function of the yeast is to provide their host with B-complex vitamins. Multiple theories exist to explain how the drugstore beetle obtains the vitamins from the yeast. The prevailing theory is that as the larvae develops, the yeast cells leave the mycetomes, allowing the host to obtain the essential vitamins by digesting the yeast cells. Another theory claims that the vitamins enter the host by diffusing from the yeast cells to the cytoplasm of the mycetome cells. Experiments discovered that when the yeast cells were eliminated, no larval growth occurred, indicating that the vitamins are essential for host survival. Drugstore beetles rely on the symbiotic relationship they have with the yeast cells housed within their bodies to survive. While rearing their young, females use their oviducts to place the yeast cells on their eggs which are then consumed by larvae after they hatch. The B vitamins that the yeast produce are essential for the survival of the larvae, making it possible for them to exist in areas with food of poorer nutritional value. This symbiotic relationship increases the chance of survival for the larvae even in environments with scarce resources. As the beetle's lifespan increases, the yeast also live for longer. The yeast cells are able to propagate themselves using the beetles, spreading through the beetle's offspring. The drugstore beetle act as a source of protection for the yeast as well. Both groups benefit greatly from their coexistence in this symbiotic relationship.
== Pest control ==
The oldest records of the modern drugstore beetle as a pest are known from the Bronze Age of Akrotiri, Santorini, Greece around 1500 BC where it was found associated with stored pulses.
=== Source of infestation ===
The most effective method of ridding a home of this beetle is to try to discover the source of the infestation. Drugstore beetles often enter a home in bulk items like bird seed, grass seed, or dry pet food, where several generations of beetles can develop unnoticed until some of the adults eventually leave to infest new locations. Telltale signs of infested items are shot-like holes puncturing the outside packaging of food items and pockmarking solid items like crackers and pasta, as well as loose powder at the bottom of storage bags. While adult beetles do not feed, they are adept at chewing holes.
Once inside the home, the adult beetles will lay their eggs on a variety of foods including whole grains, processed grains and vegetative material. Food sources which can become infested include grains, flour, bread, rice, seeds, beans, pasta, cereals, bird seed, grass seed, potpourri, spices, teas, and tobacco. While they are highly adept at chewing out of cardboard, foil, and plastic film to escape the package in which they have undergone metamorphosis to adults, they are somewhat less likely to eat into a sealed, airtight foil or plastic bag. Ideally, all open packages should be discarded in an infested home; however, it is also effective to freeze items if the entire contents can be brought below −20 °C (−4 °F).
Food storage areas like pantries and cabinets need to be vacuumed thoroughly, including the crevices between floor boards, the corners of cabinets, and areas where mice may have hoarded things like dry dog food. A bird nest within a home can also provide a haven for drugstore beetles, and a professional may need to be consulted to address this. Lowering home humidity levels can be helpful as well. While the use of chemical insecticides may be undesirable in food storage areas, food grade diatomaceous earth can be useful sprinkled in corners or even mixed into bird seed (diatomaceous earth is edible, but inhaling it should be avoided).
Another way of controlling the population rate could be by exposing the beetle to higher temperatures (43–55 °C), over longer periods of time.
=== Efficacy of essential oils ===
The cons of insecticides, increasing resistance to compounds, and high costs were incentives that drove researchers to discover alternate means of pursuing pest control. In the search for decent alternatives, scientists have found that carbon dioxide gas (CO2) and essential oils from plants could be used to safely regulate Drugstore Beetle numbers. This transition away from synthetic insecticides to plant based insecticides was meant to resolve some of the health concerns associated with synthetic compounds. Studies were conducted to investigate the usefulness of an essential oil from Z. bungeanum Maxim on Drugstore Beetle larvae and adults. Results showed that beetles that were given higher doses of these oils had higher rates of mortality. The benefit of using essential oils is that they exhibit low mammalian toxicity which makes it a promising alternative to synthetic insecticides. Z. bungeanum Maxim was shown to have high repellent activity which points to its promise as an effective means of pest control.
Drugstore Beetles are a pest that severely impacts Chinese medicinal materials. The essential oil from Z. bungeanum Maxim provides a safer alternative for pest control. It has the capacity to prolong the time it takes for larvae to develop and can even keep adults from laying eggs successfully, effectively controlling pest numbers. Both adults and larvae were impacted by the oils and any nuances in their responses was attributed to differences in morphology and behavioral response. The essential oil can be used as a natural pest control agent with healthier and safer implications compared to other means of pest management.
== Economic impact ==
A pest of many dried plant products, the drugstore beetle negatively impacts stored materials and leads to economic loss. Fumigants like phosphine were previously used to remove this pest, but after repeated usage, the fumigants posed a risk to health. Many medicinal plants of China which are used for various treatments are damaged by this pest, greatly impacting the economy. Thus, there is great motive for finding other mechanisms of combatting this species. Sex pheromones play a significant role in mate selection which suggests that this beetle has a developed olfactory system, allowing semiochemical strategies to be used to provide a safe way to control this pest. S. paniceum relies on semiochemicals to act as signals that help them locate food and oviposition and mating sites. Chemicals released by Chinese medicinal plant materials (CMPMs) attracts large numbers of these beetles, leading to an infestation. The behavior of drugstore beetles can be manipulated by utilizing volatile compounds similar to those produced by the CMPMs to target their olfactory system, but further research is needed to study these compounds.
The economic consequences of drugstore beetles are significant and diverse, affecting several businesses and individuals worldwide. These persistent pests, categorized as stored product beetles, have a remarkable ability to infest and damage a wide range of stored goods, including grains, cereals, spices, pharmaceuticals, and more. Their presence in stored products not only contaminates them with insect fragments, exoskeletons, and fecal matter but also renders them unfit for human consumption, leading to significant financial losses for businesses and households alike. The damage inflicted by drugstore beetles often necessitates the disposal of affected goods, resulting in wasted inventory and revenue loss.
Additionally, the presence of pests in food processing facilities, warehouses, and retail outlets can damage their reputation, delay the flow of goods, and attract attention from regulatory authorities, therefore worsening the economic impact. Effective pest management strategies, including regular inspection, proper storage practices, and sanitation efforts, are essential to mitigate the economic impact of drugstore beetles. By addressing infestations promptly and implementing proactive control measures, businesses and households can minimize financial losses and safeguard stored commodities from these persistent pests.
== Treatment ==
The drugstore beetle commonly infests stored products, posing a problem to many homes. There are many ways to counter their rapid growth. Once the source of the infestation is located, any disposable items populated with beetles should be wrapped in plastic and discarded. Because the beetles lay their eggs on or near food items, it’s important to thoroughly inspect food containers for them. The drugstore beetle prefers warmer temperatures so placing them in a freezer for either 16 days at −2 °C or 7 days at −25 °C will kill them at any stage in their life cycle. Alternatively, the beetles can also be heated at extremely high temperatures of 88 °C for an hour or 48 °C for 16 to 24 hours in an oven. Regular check-up and maintenance is required to prevent reinfestation. This means cleaning up any spilled items quickly and storing food in airtight glass, plastic, or metal containers. The last resort is utilizing insecticides or insect growth regulators, but these extreme measures are typically not necessary.
== References ==
== External links ==
Cornell University Insect Diagnostic Lab Factsheets | Wikipedia/Drugstore_beetle |
Population control is the practice of artificially maintaining the size of any population. It simply refers to the act of limiting the size of an animal population so that it remains manageable, as opposed to the act of protecting a species from excessive rates of extinction, which is referred to as conservation biology.
While many abiotic and biotic factors influence population control, humans are notably influential against animal populations. Whether humans need to hunt animals for food, exterminate a pest, or reduce competition for resources, managing populations involves providing nourishment, or neutering to prevent reproduction, culling individuals or the use of pesticides. Population control plays an important role in wildlife populations. Based on the species being dealt with, there are numerous ways populations of the wild are controlled. Wildlife contraception is the act of preventing reproduction in the wild, which subsequently decreases populations. An example of this includes the maintenance of deer populations with the use of vaccines. Other methods to maintain populations include lethal trapping, live trapping, egg/roost site manipulation, live-ammunition shooting, and chemical euthanization. Lethal trapping, egg/roost site manipulation, live-ammunition shooting, and chemical euthanization are methods used to eliminate animal populations and prevent reproduction, whereas live trapping captures species to remove them from a specific area.
== Factors influencing population control ==
Population control can be influenced by a variety of factors. Humans can greatly influence the size of animal populations they directly interact with. It is, for example, relatively common (and sometimes even a legal requirement) to spay or neuter dogs. Spaying – removing the ovaries and uterus of a female animal – medical term = ovariohysterectomy. Neutering - removing the testes of a male animal – medical term = orchiectomy. Various humans activities (e.g. hunting, farming, fishing, industrialization, and urbanization) all impact various animal populations.
Population control may involve culling, translocation, or manipulation of the reproductive capability. The growth of a population may be limited by environmental factors such as food supply or predation. The main biotic factors that affect population growth include:
Food – both the quantity and the quality of food are important. The population growth and decline of species depends on the amount of their food availability. The more available food, the more the population grows to meet it. The less nutritious food, the less fertile a species of reproductive age becomes. Snails, for example, cannot reproduce successfully in an environment low in calcium, no matter how much food there is because they need this mineral for shell growth.
Predators – as a prey population becomes larger, it becomes easier for predators to find prey. If the number of predators suddenly falls, the prey species might increase in number extremely quickly.
Competitors – other organisms may require the same resources from the environment, and so reduce the growth of a population. For instance, all plants compete for light. Competition for territory and for mates can drastically reduce the growth of individual organisms.
Parasites – These may cause disease, and slow down the growth and reproductive rate of organisms within a population.
Important abiotic factors affecting population growth include:
Temperature – Higher temperatures speed up Enzyme catalyzed reactions and increase growth.
Oxygen availability – affects the rate of energy production by respiration.
Light availability – for photosynthesis. light may also control breeding cycles in animals and plants.
Toxins and pollutants – tissue growth can be reduced by the presence of, for example, sulphur dioxide, and reproductive success may be affected by pollutants such as estrogen like substances.
Direct human impacts are not the only ways humans can control animal populations. Often times, humans are indirectly controlling animal populations, in other words, the humans are not aware that their actions are controlling animal populations. For example, new infrastructure and roads can lead to animals being displaced from their natural habitat. Their new habitats that they are forced to move to may not provide the same necessities to them that they require for survival. This will result in a decreasing population as a result of human actions.
== Methods for active population control ==
Animal euthanasia is often used as a final resort to controlling animal populations. In Tangipahoa Parish, Louisiana, the parish performed mass euthanasia on the entire animal shelter population, including 54 cats and 118 dogs that were put to death due to a widespread disease outbreak that spread among the animals.
Neutering is another option available to control animal populations. The annual Spay Day USA event was established by the Doris Day Animal League to promote the neutering of pets, especially those in animal shelters, so that the population remains controllable.
=== Wildlife population control ===
Wildlife contraception is used to regulate populations of animals in the wild and halt reproduction. For example, vaccines are currently being used in deer populations. GonaCon, which was developed by the US Department of Agriculture, encourages the production of antibodies in the sex drive hormones. Specifically, it is said to remove the oestrous cycles from the females, which initially attracts the males; without the oestrous cycles, males are not interested in mating. Another type of vaccine that is being used in deer is called porcine zona pellucida (PZP). PZP works by blocking sperm with antibodies on the deer's egg surface.
When preventing reproduction fails to control populations, methods such as lethal trapping, live trapping, egg/roost site manipulation, live-ammunition shooting, and chemical euthanization are used to maintain populations.
Lethal trapping is a method used to kill animals. This type of method is usually monitored in order to ensure no ethical or public concerns arise. While this tactic is most commonly used on small animals, populations of larger animals such as beavers and foxes are also controlled with this type of method.
Live trapping is a method used to capture a variety of animals. From small animals to large animals, this type of population control method uses barrel traps, restraining snares, and leg-hold devices. Just like the lethal trapping method, this tactic also needs to be regularly monitored to ensure no ethical concerns arise, as well as reduce animal distress. Specifically, this type of population control method is popular with capturing birds.
Egg/roost site manipulation is used on birds to prevent them from nesting in prohibited areas. Water spray is popular in urban and agricultural areas as it uses sprinklers to emit surfactants. The surfactants then control bird populations by killing and preventing future birds from nesting.
Live-ammunition shooting uses firearms to eliminate animals such as birds and bears. Because this type of population control method is restricted in many parts of the world, it is only to be used when other control methods have failed.
Chemical euthanization refers to the use of chemicals to cause an easy or painless death and is divided into three categories: acute toxins, anticoagulants and decalcifiers, and fumigants. Acute toxins only require a single dose to kill animals, whereas anticoagulants and decalcifiers require numerous doses over time. Fumigants are used to suffocate animals underground. While this type of population control method poses ethical concerns, the World Society for the Protection of Animals (WSPA) believes it is necessary when human health or the safety of other animals are at risk. To ensure this control method is humane, WSPA states that it must be painless, achieve rapid unconsciousness followed by death, minimize animal fear and distress, and be reliable and irreversible.
Population control also plays a significant role in managing and controlling invasive species so that they are eliminated before becoming abundant and causing any ecological harm.
== Examples ==
Several efforts have been made to control the population of ticks, which act as vectors of a number of diseases and therefore pose a risk to humans. Efforts are also continuously being made to control wildlife populations near airports. Specifically, control measures have been approved for bald eagles and deer.
== See also ==
Hunting – Searching, pursuing, and killing wild animals
Malthusianism – Idea about population growth and food supply
Overpopulation – When a population of a species exceeds the carrying capacity of its environment
Trap–neuter–return – Strategy for controlling feral animal populations
Trapping – Use of a device to remotely catch an animal
Wildlife management – Management and control of wildlife populations
== References ==
== Further reading ==
Senar, Juan C.; Montalvo, Tomás; Pascual, Jordi; Peracho, Victor (February 2017). "Reducing the availability of food to control feral pigeons: changes in population size and composition". Pest Management Science. 73 (2): 313–317. doi:10.1002/ps.4272. PMID 26947574. | Wikipedia/Population_control |
A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.
== Mechanism ==
Phosphorylation involves the transfer of phosphate groups from ATP to the enzyme, the energy for which comes from hydrolysing ATP into ADP or AMP. However, dephosphorylation releases phosphates into solution as free ions, because attaching them back to ATP would require energy input.
Cysteine-dependent phosphatases (CDPs) catalyse the hydrolysis of a phosphoester bond via a phospho-cysteine intermediate.
The free cysteine nucleophile forms a bond with the phosphorus atom of the phosphate moiety, and the P-O bond linking the phosphate group to the tyrosine is protonated, either by a suitably positioned acidic amino acid residue (Asp in the diagram below) or a water molecule. The phospho-cysteine intermediate is then hydrolysed by another water molecule, thus regenerating the active site for another dephosphorylation reaction.
Metallo-phosphatases (e.g. PP2C) co-ordinate 2 catalytically essential metal ions within their active site. There is currently some confusion of the identity of these metal ions, as successive attempts to identify them yield different answers. There is currently evidence that these metals could be magnesium, manganese, iron, zinc, or any combination thereof. It is thought that a hydroxyl ion bridging the two metal ions takes part in nucleophilic attack on the phosphorus ion.
== Sub-types ==
Phosphatases can be subdivided based upon their substrate specificity.
=== Serine/threonine PP (PPM/PPP) families ===
Protein Ser/Thr phosphatases were originally classified using biochemical assays as either, type 1 (PP1) or type 2 (PP2), and were further subdivided based on metal-ion requirement (PP2A, no metal ion; PP2B, Ca2+ stimulated; PP2C, Mg2+ dependent) (Moorhead et al., 2007). The protein Ser/Thr phosphatases PP1, PP2A and PP2B of the PPP family, together with PP2C of the PPM family, account for the majority of Ser/Thr PP activity in vivo (Barford et al., 1998). In the brain, they are present in different subcellular compartments in neuronal and glial cells, and contribute to different neuronal functions.
=== PPM ===
The PPM family, which includes PP2C and pyruvate dehydrogenase phosphatase, are enzymes with Mn2+/Mg2+ metal ions that are resistant to classic inhibitors and toxins of the PPP family. Unlike most PPPs, PP2C exists in only one subunit but, like PTPs, it displays a wide variety of structural domains that confer unique functions. In addition, PP2C does not seem to be evolutionarily related to the major family of Ser/Thr PPs and has no sequence homology to ancient PPP enzymes. The current assumption is that PPMs evolved separately from PPPs but converged during evolutionary development.
=== Class I: Cys-based PTPs ===
Class I PTPs constitute the largest family. They contain the well-known classical receptor (a) and non-receptor PTPs (b), which are strictly tyrosine-specific, and the DSPs (c) which target Ser/Thr as well as Tyr and are the most diverse in terms of substrate specificity.
=== Class III: Cys-based PTPs ===
The third class of PTPs contains three cell cycle regulators, CDC25A, CDC25B and CDC25C, which dephosphorylate CDKs at their N-terminal, a reaction required to drive progression of the cell cycle. They are themselves regulated by phosphorylation and are degraded in response to DNA damage to prevent chromosomal abnormalities.
=== Class IV: Asp-based DSPs ===
The haloacid dehalogenase (HAD) superfamily is a further PP group that uses Asp as a nucleophile and was recently shown to have dual-specificity. These PPs can target both Ser and Tyr, but are thought to have greater specificity towards Tyr. A subfamily of HADs, the Eyes Absent Family (Eya), are also transcription factors and can therefore regulate their own phosphorylation and that of transcriptional cofactor/s, and contribute to the control of gene transcription. The combination of these two functions in Eya reveals a greater complexity of transcriptional gene control than previously thought . A further member of this class is the RNA polymerase II C-terminal domain phosphatase. While this family remains poorly understood, it is known to play important roles in development and nuclear morphology.
== Alternative Structural Classification ==
Many phosphatases are promiscuous with respect to substrate type, or can evolve quickly to change substrate. An alternative structural classification notes that 20 distinct protein folds have phosphatase activity, and 10 of these contain protein phosphatases.
The CC1 fold is the most common, and includes tyrosine-specific (PTP), dual-specific (DSP) and even lipid-specific (PTEN) families.
The major serine/threonine-specific folds are PPM (PP2C) and PPPL (PPP).
The only known histidine phosphatases is in the PHP fold.
Other folds encode phosphatases that act on various combination of pSer, pThr, pTyr, and non-protein substrates (CC2, CC3, HAD, HP, AP, RTR1).
== Physiological relevance ==
Phosphatases act in opposition to kinases/phosphorylases, which add phosphate groups to proteins. The addition of a phosphate group may activate or de-activate an enzyme (e.g., kinase signalling pathways) or enable a protein-protein interaction to occur (e.g., SH2 domains ); therefore phosphatases are integral to many signal transduction pathways. Phosphate addition and removal do not necessarily correspond to enzyme activation or inhibition, and that several enzymes have separate phosphorylation sites for activating or inhibiting functional regulation. CDK, for example, can be either activated or deactivated depending on the specific amino acid residue being phosphorylated. Phosphates are important in signal transduction because they regulate the proteins to which they are attached. To reverse the regulatory effect, the phosphate is removed. This occurs on its own by hydrolysis, or is mediated by protein phosphatases.
Protein phosphorylation plays a crucial role in biological functions and controls nearly every cellular process, including metabolism, gene transcription and translation, cell-cycle progression, cytoskeletal rearrangement, protein-protein interactions, protein stability, cell movement, and apoptosis. These processes depend on the highly regulated and opposing actions of PKs and PPs, through changes in the phosphorylation of key proteins. Histone phosphorylation, along with methylation, ubiquitination, sumoylation and acetylation, also regulates access to DNA through chromatin reorganisation.
One of the major switches for neuronal activity is the activation of PKs and PPs by elevated intracellular calcium. The degree of activation of the various isoforms of PKs and PPs is controlled by their individual sensitivities to calcium. Furthermore, a wide range of specific inhibitors and targeting partners such as scaffolding, anchoring, and adaptor proteins also contribute to the control of PKs and PPs and recruit them into signalling complexes in neuronal cells. Such signalling complexes typically act to bring PKs and PPs in close proximity with target substrates and signalling molecules as well as enhance their selectivity by restricting accessibility to these substrate proteins. Phosphorylation events, therefore, are controlled not only by the balanced activity of PKs and PPs but also by their restricted localisation. Regulatory subunits and domains serve to restrict specific proteins to particular subcellular compartments and to modulate protein specificity. These regulators are essential for maintaining the coordinated action of signalling cascades, which in neuronal cells include short-term (synaptic) and long-term (nuclear) signalling. These functions are, in part, controlled by allosteric modification by secondary messengers and reversible protein phosphorylation.
It is thought that around 30% of known PPs are present in all tissues, with the rest showing some level of tissue restriction. While protein phosphorylation is a cell-wide regulatory mechanism, recent quantitative proteomics studies have shown that phosphorylation preferentially targets nuclear proteins. Many PPs that regulate nuclear events, are often enriched or exclusively present in the nucleus. In neuronal cells, PPs are present in multiple cellular compartments and play a critical role at both pre- and post-synapses, in the cytoplasm and in the nucleus where they regulate gene expression.
Phosphoprotein phosphatase is activated by the hormone insulin, which indicates that there is a high concentration of glucose in the blood. The enzyme then acts to dephosphorylate other enzymes, such as phosphorylase kinase, glycogen phosphorylase, and glycogen synthase. This leads to phosphorylase kinase and glycogen phosphorylase's becoming inactive, while glycogen synthase is activated. As a result, glycogen synthesis is increased and glycogenolysis is decreased, and the net effect is for energy to enter and be stored inside the cell.
== Learning and memory ==
In the adult brain, PPs are essential for synaptic functions and are involved in the negative regulation of higher-order brain functions such as learning and memory. Dysregulation of their activity has been linked to several disorders including cognitive ageing and neurodegeneration, as well as cancer, diabetes and obesity.
== Examples ==
Human genes that encode proteins with phosphoprotein phosphatase activity include:
=== Protein serine/threonine phosphatase ===
PPP1CA, PPP1CB, PPP1CC, PPP2CA, PPP2CB, PPP3CA, PPP3CB, PPP3CC, PPP4C
PPP5C, PPP6C
=== Protein tyrosine phosphatase ===
CDC14s: CDC14A, CDC14B, CDC14C, CDKN3
Phosphatase and tensin homologs: PTEN
slingshot: SSH1, SSH2, SSH3
=== Dual-specificity phosphatase ===
DUSP1, DUSP2, DUSP3, DUSP4, DUSP5, DUSP6, DUSP7, DUSP8, DUSP9
DUSP10, DUSP11, DUSP12, DUSP13A, DUSP13B, DUSP14, DUSP15, DUSP16, DUSP18, DUSP19
DUSP21, DUSP22, DUSP23, DUSP26, DUSP27, DUSP28
=== Ungrouped ===
CTDP1
CTDSP1, CTDSP2, CTDSPL
DULLARD
EPM2A
ILKAP
MDSP
PGAM5
PHLPP1, PHLPP2
PPEF1, PPEF2
PPM1A, PPM1B, PPM1D, PPM1E, PPM1F, PPM1G, PPM1H, PPM1J, PPM1K, PPM1L, PPM1M, PPM1N
PPTC7
PTPMT1
SSU72
UBLCP1
== References == | Wikipedia/Protein_phosphatase |
Inborn errors of carbohydrate metabolism are inborn errors of metabolism that affect the catabolism and anabolism of carbohydrates.
An example is lactose intolerance.
Carbohydrates account for a major portion of the human diet. These carbohydrates are composed of three principal monosaccharides: glucose, fructose and galactose; in addition glycogen is the storage form of carbohydrates in humans. The failure to effectively use these molecules accounts for the majority of the inborn errors of human carbohydrates metabolism.
== By Carbohydrate ==
=== Glycogen and Glucose ===
Glycogen storage diseases are deficiencies of enzymes or transport proteins which impair glycogen synthesis, glycogen degradation or glycolysis. The two organs most commonly affected are the liver and the skeletal muscle. Glycogen storage diseases that affect the liver typically cause hepatomegaly and hypoglycemia; those that affect skeletal muscle cause exercise intolerance, progressive weakness and cramping.
Glucose-6-phosphate isomerase deficiency affects step 2 of glycolysis. Triosephosphate isomerase deficiency affects step 5 of glycolysis. Phosphoglycerate kinase deficiency affects step 7 of glycolysis. Pyruvate kinase deficiency affects the 10th and last step of glycolysis.
Glucose-6-phosphate dehydrogenase deficiency affects the degradation of glucose in the pentose phosphate pathway, which is especially important in red blood cells.
For further information on inborn errors of glucose metabolism and inborn errors of glycogen metabolism see below.
=== Lactose ===
Lactose is a disaccharide sugar composed of galactose and glucose that is found in milk. Lactose can not be absorbed by the intestine and needs to be split in the small intestine into galactose and glucose by the enzyme called lactase; unabsorbed lactose can cause abdominal pain, bloating, diarrhea, gas, and nausea.
In most mammals, production of lactase diminishes after infants are weaned from maternal milk. However, 5% to 90% of the human population possess an advantageous autosomal mutation in which lactase production persists after infancy. The geographic distribution of lactase persistence is concordant with areas of high milk intake. Lactase non-persistence is common in tropical and subtropical countries. Individuals with lactase non-persistency may experience nausea, bloating and diarrhea after ingesting dairy.
==== Galactose ====
Galactosemia, the inability to metabolize galactose in liver cells, is the most common monogenic disorder of carbohydrate metabolism, affecting 1 in every 55,000 newborns. When galactose in the body is not broken down, it accumulates in tissues. The most common signs are failure to thrive, hepatic insufficiency, cataracts and developmental delay. Long term disabilities include poor growth, mental retardation, and ovarian failure in females.
Galactosemia is caused by mutations in the gene that makes the enzyme galactose-1-phosphate uridylyltransferase. Approximately 70% of galactosemia-causing alleles have a single missense mutation in exon 6. A milder form of galactosemia, called Galactokinase deficiency, is caused a lack of the enzyme uridine diphosphate galactose-4-epimerase which breaks down a byproduct of galactose. This type of is associated with cataracts, but does not cause growth failure, mental retardation, or hepatic disease. Dietary reduction of galactose is also the treatment but not as severe as in patients with classical galactosemia. This deficiency can be systemic or limited to red blood cells and leukocytes.
Screening is performed by measuring GAL-1-P urydil transferase activity. Early identification affords prompt treatment, which consists largely of eliminating dietary galactose.
=== Fructose ===
Fructose malabsorption is a digestive disorder in which absorption of fructose is impaired by deficient fructose carriers in the small intestine's enterocytes.
Three autosomal recessive disorders impair fructose metabolism in liver cells. The most common is caused by mutations in the gene encoding hepatic fructokinase, an enzyme that catalyzes the first step in the metabolism of dietary fructose. Inactivation of the hepatic fructokinase results in asymptomatic fructosuria.
Hereditary fructose intolerance (HFI) results in poor feeding, failure to thrive, chronic liver disease and chronic kidney disease, and death. HFI is caused by a deficiency of fructose 1,6-biphosphate aldolase in the liver, kidney cortex and small intestine. Infants and adults are asymptomatic unless they ingest fructose or sucrose.
Deficiency of hepatic fructose 1,6-biphosphate (FBPase) causes impaired gluconeogenesis, hypoglycemia and severe metabolic acidemia. If patients are adequately supported beyond childhood, growth and development appear to be normal.
Essential fructosuria is a clinically benign condition characterized by the incomplete metabolism of fructose in the liver, leading to its excretion in urine.
== By affected system ==
=== Glucose metabolism ===
==== Glycolysis ====
The metabolic pathway glycolysis is used by cells to break down carbohydrates like glucose (and various other simple sugars) in order to extract energy from them. During glycolysis ATP, NADH (both an energy transport form used inside cells) as well as pyruvate are produced.
Glycolysis is taking place in the cytosol where, under anaerobic conditions, pyruvate is converted to lactate. Under aerobic conditions, the pyruvate is transported from the cytosol to the mitochondrion, where further energy can be extracted through the citric acid cycle (CAC)
The liver can also create glucose (gluconeogenesis, see below); during times of low carbohydrate supply from the digestive system, the liver creates glucose and supplies it to other organs. Most enzymes of glycolysis also participate in gluconeogenesis, as it is mostly the reverse metabolic pathway of glycolysis; a deficiency of these liver enzymes will therefore impact both glycolysis and gluconeogenesis. (Note: gluconeogenesis is taking place only in the liver and not in other cells like e.g. muscle cells.)
===== Related to glycolysis =====
The pyruvate created by glycolysis (in the cytosol) is transported (together with a proton) to the mitochondrion for further energy extraction.
Under anaerobic conditions (without the use of oxygen) most if not all of the pyruvate is converted into lactate (furthermore producing NAD+ at the same time).
Under aerobic conditions (with the use of oxygen) only part of the pyruvate is converted to lactate; the pyruvate not converted feeds the citric acid cycle (CAC); both via pyruvate dehydrogenase (PDC, with Acetyl-CoA as intermediate) and via pyruvate decarboxylation - this will create further ATP and NADH for the cell's use.
The pentose phosphate pathway (HMP Shunt) is connected to the glycolysis pathway, and can convert substrates to and from the glycolysis pathway. It generates NADPH and pentoses (5-carbon sugars) as well as ribose 5-phosphate, a precursor for the synthesis of nucleotides. While the pentose phosphate pathway does involve oxidation of glucose, its primary role is anabolic rather than catabolic. The pathway is especially important in red blood cells (erythrocytes).
Transport proteins move substrates through cellular membranes. A glucose transporter (GLUT) protein is needed to assist glucose into (and in the liver and kidneys, also out of) the cell. De Vivo disease (GLUT1 deficiency) is a deficiency of GLUT1, which is needed to transport glucose across the blood-brain barrier. Fanconi-Bickel syndrome (GLUT2 deficiency, formally known as GSD-XI) is a deficiency of GLUT2, which is needed for the transport of glucose between liver and blood.
Mitochondrial pyruvate carrier deficiency (MPYCD) is a metabolic disorder, in which the transport of pyruvate from the cytosol to the mitochondria is affected (gene SLC54A1/BRP44L/MPC1); the deficiency is characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation. A similar disease is also seen in mutations of gene SLC54A2/BRP44/MPC2.
The gene SLC16A1/MCT1 is responsible for transporting lactate across membranes. Mutations in the monocarboxylate transporter 1 (MCT1) gene have been associated with three diseases: hyperinsulinemic hypoglycemia, familial 7 (HHF7); monocarboxylate transporter 1 deficiency (MCTD1); and erythrocyte lactate transporter defect (formerly, myopathy due to lactate transport defect).
(See also bioenergetic systems.)
==== Gluconeogenesis ====
=== Glycogen metabolism ===
==== Glycogenesis ====
Glycogenesis is the metabolic pathway in which glycogen is created. Glycogen, which consists of branched long chains made out of the simple sugar glucose, is an energy storage form for carbohydrates in many human cells; this is most important in liver, muscle and certain brain cells.
The monosaccharide glucose-6-phosphate (G-6-P) is typically the input substance for glycogenesis. G-6-P is most commonly created from glucose by the action of the enzymes glucokinase (see glycolysis step 1) or hexokinase.
Through the action of several enzymes glycogen is built up:
G-6-P is converted into glucose-1-phosphate (G-1-P) by the action of phosphoglucomutase (PGM), passing through the obligatory intermediate glucose-1,6-bisphosphate.
G-1-P is converted into UDP-glucose by the action of the enzyme UDP-glucose pyrophosphorylase (UGP).
The enzyme glycogenin (GYG) is needed to create initial short glycogen chains, which are lengthened and branched by the other enzymes of glycogenesis.
Once eight glucose have been added to the glycogen chain, then glycogen synthase (GYS) can bind to the growing glycogen chain and add UDP-glucose to lengthen the glucogen chain.
Branches are made by glycogen branching enzyme (GBE), which transfers the end of the chain onto an earlier part, forming branches; these grow further grow by addition of more units.
On an alternative metabolic pathway the simple sugar galactose (Gal, which is typically derived from lactose) is converted by the enzyme galactokinase (GALK) to galactose-1-phosphate (Gal-1-P), which in turn is converted by the enzyme galactose-1-phosphate uridylyltransferase (GALT) to glucose-1-phosphate (G-1-P), which can also serve as input for glycogenesis – this bypasses the first step of glycogenesis (the enzyme phosphoglucomutase PGM).
Errors in glycogenesis can have different consequences on a cellular level:
Too little glycogen is produced, e.g. in GSD 0
The glycogen is badly formed and inaccessible, typically accumulating in the affected cells (e.g. polyglucosan bodies).
Depending on the affected cells and the extent of the deficiency, a wide range of symptoms and severities are the result.
==== Glycogenolysis ====
To access the energy stored as glycogen, cells use the metabolic pathway glycogenolysis (glycogen breakdown); this produces the simple sugar glucose-6-phosphate (G-6-P), from which cells can extract energy or build other substances (e.g. riboses).
G-6-P (which is also produced from glucose) acts as an input substance for:
Glycolysis (see above)
The Pentose phosphate pathway (PPP)
(See also bioenergetic systems.)
An alternative to glycolysis is the Pentose phosphate pathway (PPP): Depending on cellular conditions the PPP can produce NADPH (another energy transport form in the cell) or synthesize riboses (important for substances based on ribose like e.g. RNA) - the PPP is for example important in red blood cells.
If glycogenolysis is taking place in the liver, G-6-P can be converted to glucose by the enzyme glucose 6-phosphatase (G6Pase); the glucose produced in the liver is then released to the bloodstream for use in other organs. Muscle cells in contrast do not have the enzyme glucose 6-phosphatase, so they cannot share their glycogen stores with the rest of the body.
In addition to glycogen breakdown with the glycogen debranching enzyme and the glycogen phosphorylase enzyme, cells also use the enzyme acid alpha-glucosidase in lysosomes to degrade glycogen.
A deficiency of an involved enzyme results in:
Accumulation of glycogen in the cells
Lack of cellular energy negatively affects the involved organs
Myophosphorylase (muscle glycogen phosphorylase) comes in two forms: form 'a' is phosphorylated by phosphorylase kinase, form 'b' is not phosphorylated. Form 'a' is de-phosphorylated into form 'b' by the enzyme phosphoprotein phosphatase, which is activated by elevated insulin.
Both forms 'a' and 'b' of myophosphorylase have two conformational states: active (R or relaxed) and inactive (T or tense). When either form 'a' or 'b' are in the active state, then the enzyme converts glycogen into glucose-1-phosphate.
Myophosphorylase-b is allosterically activated by elevated AMP within the cell, and allosterically inactivated by elevated ATP and/or glucose-6-phosphate. Myophosphorylase-a is active, unless allosterically inactivated by elevated glucose within the cell. In this way, myophosphorylase-a is the more active of the two forms as it will continue to convert glycogen into glucose-1-phosphate even with high levels of glycogen-6-phosphate and ATP. (See Glycogen phosphorylase§Regulation).
===== Related to glycogenolysis =====
Mutations in the PRKAG2 gene have been traced to fatal congenital nonlysosomal cardiac glycogenosis; PRKAG2 is a noncatalytic gamma subunit of AMP-activated protein kinase (AMPK), which affects the release of G-1-P by phosphorylase kinase during nonlysosomal glycogenolysis.
== See also ==
Glycogen Storage Disease
Metabolic Myopathies
Exercise intolerance § low ATP reservoir
Myogenic hyperuricemia
Purine nucleotide cycle § pathology (low ATP reservoir, ADP>ATP, ↑AMP)
Tachycardia § sinus (inappropriate rapid heart rate response to exercise)
IST § differential diagnoses
Second Wind (exercise phenomenon)
== References ==
== External links ==
Media related to Disorders of carbohydrate metabolism at Wikimedia Commons | Wikipedia/Inborn_errors_of_carbohydrate_metabolism |
A glycogen storage disease (GSD, also glycogenosis and dextrinosis) is a metabolic disorder caused by a deficiency of an enzyme or transport protein affecting glycogen synthesis, glycogen breakdown, or glucose breakdown, typically in muscles and/or liver cells.
GSD has two classes of cause: genetic and environmental. Genetic GSD is caused by any inborn error of carbohydrate metabolism (genetically defective enzymes or transport proteins) involved in these processes. In livestock, environmental GSD is caused by intoxication with the alkaloid castanospermine.
However, not every inborn error of carbohydrate metabolism has been assigned a GSD number, even if it is known to affect the muscles or liver. For example, phosphoglycerate kinase deficiency (gene PGK1) has a myopathic form.
Also, Fanconi-Bickel syndrome (gene SLC2A2) and Danon disease (gene LAMP2) were declassed as GSDs due to being defects of transport proteins rather than enzymes; however, GSD-1 subtypes b, c, and d are due to defects of transport proteins (genes SLC37A4, SLC17A3) yet are still considered GSDs.
Phosphoglucomutase deficiency (gene PGM1) was declassed as a GSD due to it also affecting the formation of N-glycans; however, as it affects both glycogenolysis and glycosylation, it has been suggested that it should re-designated as GSD-XIV.
(See inborn errors of carbohydrate metabolism for a full list of inherited diseases that affect glycogen synthesis, glycogen breakdown, or glucose breakdown.)
== Types ==
Some GSDs have different forms, e.g. infantile, juvenile, adult (late-onset).
Some GSDs have different subtypes, e.g. GSD1a / GSD1b, GSD9A1 / GSD9A2 / GSD9B / GSD9C / GSD9D.
GSD type 0: Although glycogen synthase deficiency does not result in storage of extra glycogen in the liver, it is classified with the GSDs as type 0 because it is another defect of glycogen storage and can cause similar problems.
GSD type VIII (GSD 8): In the past, liver phosphorylase-b kinase deficiency was considered a distinct condition, however it has been classified with GSD type VI and GSD IXa1; it has been described as X-linked recessive inherited. GSD IX has become the dominant classification for this disease, grouped with the other isoenzymes of phosphorylase-b kinase deficiency.
GSD type XI (GSD 11): Fanconi-Bickel syndrome (GLUT2 deficiency), hepatorenal glycogenosis with renal Fanconi syndrome, no longer considered a glycogen storage disease, but a defect of glucose transport. The designation of GSD type XI (GSD 11) has been repurposed for muscle lactate dehydrogenase deficiency (LDHA).
GSD type XIV (GSD 14): No longer classed as a GSD, but as a congenital disorder of glycosylation type 1T (CDG1T), affects the phosphoglucomutase enzyme (gene PGM1). Phosphoglucomutase 1 deficiency is both a glycogenosis and a congenital disorder of glycosylation. Individuals with the disease have both a glycolytic block as muscle glycogen cannot be broken down, as well as abnormal serum transferrin (loss of complete N-glycans). As it affects glycogenolysis, it has been suggested that it should re-designated as GSD-XIV.
Lafora disease is considered a complex neurodegenerative disease and also a glycogen metabolism disorder.
Polyglucosan storage myopathies are associated with defective glycogen metabolism
(Not McArdle disease, same gene but different symptoms) Myophosphorylase-a activity impaired: Autosomal dominant mutation on PYGM gene. AMP-independent myophosphorylase activity impaired, whereas the AMP-dependent activity was preserved. No exercise intolerance. Adult-onset muscle weakness. Accumulation of the intermediate filament desmin in the myofibers of the patients. Myophosphorylase comes in two forms: form 'a' is phosphorylated by phosphorylase kinase, form 'b' is not phosphorylated. Both forms have two conformational states: active (R or relaxed) and inactive (T or tense). When either form 'a' or 'b' are in the active state, then the enzyme converts glycogen into glucose-1-phosphate. Myophosphorylase-b is allosterically activated by AMP being in larger concentration than ATP and/or glucose-6-phosphate. (See Glycogen phosphorylase§Regulation).
Unknown glycogenosis related to dystrophy gene deletion: patient has a previously undescribed myopathy associated with both Becker muscular dystrophy and a glycogen storage disorder of unknown aetiology.
== Diagnosis ==
Methods to diagnose glycogen storage diseases include history and physical examination for associated symptoms, blood tests for associated metabolic disturbances, and genetic testing for suspected mutations. It may also include a non-ischemic forearm test, exercise stress test, or 12-minute walk test (12MWT). Advancements in genetic testing are slowly diminishing the need for biopsy; however, in the event of a VUS and inconclusive exercise tests, a biopsy would then be necessary to confirm diagnosis.
=== Differential diagnosis ===
==== Muscle ====
Glycogen storage diseases that involve skeletal muscle typically have exercise-induced (dynamic) symptoms, such as premature muscle fatigue, rather than fixed weakness (static) symptoms. Differential diagnoses for glycogen storage diseases that involve fixed muscle weakness, particularly of the proximal muscles, would be an inflammatory myopathy or a limb-girdle muscular dystrophy.
For those with exercise intolerance and/or proximal muscle weakness, the endocrinopathies should be considered. The timing of the symptoms of exercise intolerance, such as muscle fatigue and cramping, is important in order to help distinguish it from other metabolic myopathies such as fatty acid metabolism disorders.
Problems originating within the circulatory system, rather than the muscle itself, can produce exercise-induced muscle fatigue, pain and cramping that alleviates with rest, resulting from inadequate blood flow (ischemia) to the muscles. Ischemia that often produces symptoms in the leg muscles includes intermittent claudication, popliteal artery entrapment syndrome, and chronic venous insufficiency.
Diseases disrupting the neuromuscular junction can cause abnormal muscle fatigue, such as myasthenia gravis, an autoimmune disease. Similar, are Lambert–Eaton myasthenic syndrome (autoimmune) and the congenital myasthenic syndromes (genetic).
Diseases can disrupt glycogen metabolism secondary to the primary disease. Abnormal thyroid function—hypo- and hyperthyroidism—can manifest as myopathy with symptoms of exercise-induced muscle fatigue, cramping, muscle pain and may include proximal weakness or muscle hypertrophy (particularly of the calves). Hypothyroidism up-regulates glycogen synthesis and down-regulates glycogenolysis and glycolysis; conversely, hyperthyroidism does the reverse, up-regulating glycogenolysis and glycolysis while down-regulating glycogen synthesis.
Prolonged hypo- and hyperthyroid myopathy leads to atrophy of type II (fast-twitch/glycolytic) muscle fibres, and a predominance of type I (slow-twitch/oxidative) muscle fibres. Muscle biopsy shows abnormal muscle glycogen: high accumulation in hypothyroidism and low accumulation in hyperthyroidism. Hypothyroid myopathy includes Kocher-Debre-Semelaigne syndrome (childhood-onset), Hoffman syndrome (adult-onset), myasthenic syndrome, and atrophic form.
In patients with increased growth hormone, muscle biopsy includes, among other features, excess glycogen deposition.
EPG5-related Vici syndrome is a multisystem disorder, a congenital disorder of autophagy, with muscle biopsy showing excess glycogen accumulation, among other myopathic features.
It is interesting to note, in comparison to hypothyroid myopathy, that McArdle disease (GSD-V), which is by far the most commonly diagnosed of the muscle GSDs and therefore the most studied, has as its second highest comorbidity endocrine disease (chiefly hypothyroidism) and that some patients with McArdle disease also have hypertrophy of the calf muscles. Late-onset Pompe disease (GSD-II) also has calf hypertrophy and hypothyroidism as comorbidities.
Poor diet and malabsorption diseases (such as celiac disease) may lead to malnutrition of essential vitamins necessary for glycogen metabolism within the muscle cells. Malnutrition typically presents with systemic symptoms, but in rare instances can be limited to myopathy. Vitamin D deficiency myopathy (also known as osteomalic myopathy due to the interplay between vitamin D and calcium) results in muscle weakness, predominantly of the proximal muscles; with muscle biopsy showing abnormal glycogen accumulation, atrophy of type II (fast-twitch/glycolytic) muscle fibres, and diminished calcium uptake by the sarcoplasmic reticulum (needed for muscle contraction). Although Vitamin D deficiency myopathy typically includes muscle atrophy, rarely calf muscle hypertrophy has been reported.
Exercise-induced, electrically silent, muscle cramping and stiffness (transient muscle contractures or "pseudomyotonia") are seen not only in GSD types V, VII, IXd, X, XI, XII, and XIII, but also in Brody disease, Rippling muscle disease types 1 and 2, and CAV3-related hyperCKemia (Elevated serum creatine phosphokinase). Unlike the other myopathies, in Brody disease the muscle cramping is painless. Like GSD types II, III, and V, a pseudoathletic appearance of muscle hypertrophy is also seen in some with Brody disease and Rippling muscle disease.
Erythrocyte lactate transporter defect (formerly Lactate transporter defect, myopathy due to) also includes exercise-induced, electrically silent, painful muscle cramping and transient contractures; as well as exercise-induced muscle fatigue. EMG and muscle biopsy is normal however, as the defect is not in the muscle but in the red blood cells that should clear lactate buildup from exercising muscles.
Although most muscular dystrophies have fixed muscle weakness rather than exercise-induced muscle fatigue and/or cramping, there are a few exceptions. Limb–girdle muscular dystrophy autosomal recessive 23 (LGMD R23) has calf hypertrophy and exercise-induced cramping. Myofibrillar myopathy 10 (MFM10) has exercise-induced muscle fatigue, cramping and stiffness, with hypertrophic neck and shoulder girdle muscles. LGMD R28 has calf hypertrophy and exercise-induced muscle fatigue and pain. LGMD R8 has calf pseudohypertrophy and exercise-induced weakness (fatigue) and pain. LGMD R15 (a.k.a MDDGC3) has muscle hypertrophy, proximal muscle weakness, and muscle fatigue.
DMD-related myopathies of Duchenne and Becker muscular dystrophy are known for fixed muscle weakness and pseudohypertrophic calf muscles, but they also have secondary muscular mitochondrial impairment causing low ATP production; as well as decreasing type II (fast-twitch/glycolytic) muscle fibres, producing a predominance of type I (slow-twitch/oxidative) muscle fibres. DMD-related childhood-onset milder phenotypes present with exercise-induced muscle cramping, stiffness, pain, fatigue, and elevated CK. Becker muscular dystrophy has adult-onset exercise-induced muscle cramping, pain, and elevated CK.
Tubular aggregate myopathy (TAM) types 1 and 2 has exercise-induced muscle pain, fatigue, stiffness, with proximal muscle weakness and calf muscle pseudohypertrophy. TAM1 has cramping at rest, while TAM2 has cramping during exercise. Stormorken syndrome includes the symptoms of TAM, but is a more severe presentation including short stature and other abnormalities. Satoyoshi syndrome has exercise-induced painful muscle cramps, muscle hypertrophy, and short stature. Dimethylglycine dehydrogenase deficiency has muscle fatigue, elevated CK, and fishy body odour. Myopathy with myalgia, increased serum creatine kinase, with or without episodic rhabdomyolysis (MMCKR) has exercise-induced muscle cramps, pain, and fatigue; with some exhibiting proximal muscle weakness.
==== Liver ====
(help wikipedia by contributing to this subsection)
Glycogenosis-like phenotype of congenital hyperinsulinism due to HNF4A mutation or MODY1 (maturity-onset diabetes of the young, type 1). This phenotype of MODY1 has macrosomia and infantile-onset hyperinsulinemic hypoglycemia, physiological 3-OH butyrate, increased triglyceride serum levels, increased level of glycogen in liver and erythrocytes, increased liver transaminases, transient hepatomegaly, renal Fanconi syndrome, and later develop liver cirrhosis, decreased succinate-dependent respiration (mitochondrial dysfunction), rickets, nephrocalcinosis, chronic kidney disease, and diabetes.
== Treatment ==
Treatment is dependent on the type of glycogen storage disease. Von Gierke disease (GSD-I) is typically treated with frequent small meals of carbohydrates and cornstarch, called modified cornstarch therapy, to prevent low blood sugar, while other treatments may include allopurinol and human granulocyte colony stimulating factor.
Cori/Forbes disease (GSD-III) treatment may use modified cornstarch therapy, a high protein diet with a preference to complex carbohydrates. However, unlike GSD-I, gluconeogenesis is functional, so simple sugars (sucrose, fructose, and lactose) are not prohibited.
A ketogenic diet has demonstrated beneficial for McArdle disease (GSD-V) as ketones readily convert to acetyl CoA for oxidative phosphorylation, whereas free fatty acids take a few minutes to convert into acetyl CoA.
For phosphoglucomutase deficiency (formerly GSD-XIV), D-galactose supplements and exercise training has shown favourable improvement of signs and symptoms. In terms of exercise training, some patients with phosphoglucomutase deficiency also experience "second wind."
For McArdle disease (GSD-V), regular aerobic exercise utilizing "second wind" to enable the muscles to become aerobically conditioned, as well as anaerobic exercise (strength training) that follows the activity adaptations so as not to cause muscle injury, helps to improve exercise intolerance symptoms and maintain overall health. Studies have shown that regular low-moderate aerobic exercise increases peak power output, increases peak oxygen uptake (V̇O2peak), lowers heart rate, and lowers serum CK in individuals with McArdle disease.
Regardless of whether the patient experiences symptoms of muscle pain, muscle fatigue, or cramping, the phenomenon of second wind having been achieved is demonstrable by the sign of an increased heart rate dropping while maintaining the same speed on the treadmill. Inactive patients experienced second wind, demonstrated through relief of typical symptoms and the sign of an increased heart rate dropping, while performing low-moderate aerobic exercise (walking or brisk walking).
Conversely, patients that were regularly active did not experience the typical symptoms during low-moderate aerobic exercise (walking or brisk walking), but still demonstrated second wind by the sign of an increased heart rate dropping. For the regularly active patients, it took more strenuous exercise (very brisk walking/jogging or bicycling) for them to experience both the typical symptoms and relief thereof, along with the sign of an increased heart rate dropping, demonstrating second wind.
In young children (<10 years old) with McArdle disease (GSD-V), it may be more difficult to detect the second wind phenomenon. They may show a normal heart rate, with normal or above normal peak cardio-respiratory capacity (V̇O2max). That said, patients with McArdle disease typically experience symptoms of exercise intolerance before the age of 10 years, with the median symptomatic age of 3 years.
Tarui disease (GSD-VII) patients do not experience the "second wind" phenomenon; instead are said to be "out-of-wind." However, they can achieve sub-maximal benefit from lipid metabolism of free fatty acids during aerobic activity following a warm-up.
== Epidemiology ==
Overall, according to a study in British Columbia, approximately 2.3 children per 100,000 births (1 in 43,000) have some form of glycogen storage disease. In the United States, they are estimated to occur in 1 per 20,000–25,000 births. Dutch incidence rate is estimated to be 1 per 40,000 births.
While a Mexican incidence showed 6.78:1000 male newborns.
Within the category of muscle glycogenoses (muscle GSDs), McArdle disease (GSD-V) is by far the most commonly diagnosed.
== See also ==
Metabolic myopathies
Inborn errors of carbohydrate metabolism
== References ==
== External links ==
AGSD. - Association for Glycogen Storage Disease. A US-based non-profit, parent and patient oriented support group dedicated to promoting the best interest of all the different types of glycogen storage disease.
AGSD-UK - Association for Glycogen Storage Disease (UK). A UK-based charity which helps individuals and families affected by Glycogen Storage Disease by putting people in contact, providing information and support, publishing a magazine and holding conferences, workshops, courses and family events.
IamGSD - International Association for Muscle Glycogen Storage Disease. A non-profit, patient-led international group encouraging efforts by research and medical professionals, national support groups and individual patients worldwide.
IPA - International Pompe Association. (Pompe Disease is also known as GSD-II). A non-profit, federation of Pompe disease patient's groups world-wide. It seeks to coordinate activities and share experience and knowledge between different groups.
EUROMAC - EUROMAC is a European registry of patients affected by McArdle Disease and other rare neuromuscular glycogenoses.
CoRDS - Coordination of Rare Diseases at Sanford (CoRDS) is a centralized international patient registry for all rare diseases. They work with patient advocacy groups, including IamGSD, individuals and researchers.
CORD - Canadian Organization for Rare Disorders (CORD) is a Canadian national network for organizations representing all those with rare disorders. CORD provides a strong common voice to advocate for health policy and a healthcare system that works for those with rare disorders.
NORD - National Organization for Rare Disorders (NORD) is an American national non-profit patient advocacy organization that is dedicated to individuals with rare diseases and the organizations that serve them.
EURODIS - Rare Diseases Europe (EURODIS) is a unique, non-profit alliance of over 700 rare disease patient organizations across Europe that work together to improve the lives of the 30 million people living with a rare disease in Europe. | Wikipedia/Glycogen_storage_disease |
A nanoparticle–biomolecule conjugate is a nanoparticle with biomolecules attached to its surface. Nanoparticles are minuscule particles, typically measured in nanometers (nm), that are used in nanobiotechnology to explore the functions of biomolecules. Properties of the ultrafine particles are characterized by the components on their surfaces more so than larger structures, such as cells, due to large surface area-to-volume ratios. Large surface area-to-volume-ratios of nanoparticles optimize the potential for interactions with biomolecules.
== Characterization ==
Major characteristics of nanoparticles include volume, structure, and visual properties that make them valuable in nanobiotechnology. Depending on specific properties of size, structure, and luminescence, nanoparticles can be used for different applications. Imaging techniques are used to identify such properties and give more information about the tested sample. Techniques used to characterize nanoparticles are also useful in studying how nanoparticles interact with biomolecules, such as amino acids or DNA, and include magnetic resonance imaging (MRI), denoted by the solubility of the nanoparticles in water and fluorescent. MRI can be applied in the medical field to visualize structures; atomic force microscopy (AFM) that gives a topographic view of the sample on a substrate; transmission electron microscopy (TEM) that gives a top view, but with a different technique then that of atomic force microscopy; Raman spectroscopy or surface enhanced Raman spectroscopy (SERS) gives information about wavelengths and energy in the sample. ultraviolet-visible spectroscopy (UV-Vis) measures the wavelengths where light is absorbed; X-ray diffraction (XRD) generally gives an idea of the chemical composition of the sample. To quantify protein attachment to nanoparticles, assays such as the Bicinchoninic Acid (BCA) assay and Bradford assay are employed, providing a measure of the average protein labelling per nanoparticle.
== Chemistry ==
=== Physical ===
Nanomolecules can be created from virtually any element, but the majority produced in today's industry use carbon as the basis upon which the molecules are built around. Carbon can bond with nearly any element, allowing many possibilities when it comes to creating a specific molecule. Scientists can create thousands upon thousands of individual nanomolecules from a simple carbon basis. Some of the most famous nanomolecules currently in existence are solely carbon; these include carbon nanotubes and buckminsterfullerenes. In contrast with nanomolecules, the chemical components of nanoparticles usually consist of metals, such as iron, gold, silver, and platinum.
Interactions between nanoparticles and molecules change depending on the nanoparticle's core. Nanoparticle properties depend not only on the composition of the core material, but also on varying thicknesses of material used. Magnetic properties are particularly useful in molecule manipulation, and thus metals are often used as core material. Metals contain inherent magnetic properties that allow for manipulation of molecular assembly. As nanoparticles interact with molecules via ligand properties, molecular assembly can be controlled by external magnetic fields interacting with magnetic properties in the nanoparticles.
Significant problems with producing nanoparticles initially arise once these nanoparticles are generated in solution. Without the use of a stabilizing agent, nanoparticles tend to stick together once the stirring is stopped. In order to counteract this, a certain collidial stabilizer is generally added. These stabilizers bind to the nanoparticles in a way that prevents other particles from bonding with them. Some effective stabilizers found so far include citrate, cellulose, and sodium borohydride.
=== Application chemistry ===
Nanoparticles are desirable in today's industry for their high surface area-to-volume ratio in comparison with larger particles of the same elements. Because chemical reactions occur at a rate directly proportional to the available surface area of reactant compounds, nanoparticles can generate reactions at a much faster rate than larger particles of equal mass. Nanoparticles therefore are among the most efficient means of producing reactions and are inherently valuable in the chemical industry. The same property makes them valuable in interactions with molecules.
== Applications with biomolecules and biological processes ==
Nanoparticles have the potential to greatly influence biological processes. The potency of a nanoparticle increases as its surface area-to-volume-ratio does. Attachments of ligands to the surface of nanoparticles allow them to interact with biomolecules.
=== Identification of biomolecules ===
Nanoparticles are valuable tools in identification of biomolecules, through the use of bio-tagging or labeling. Attachments of ligands or molecular coatings to the surface of a nanoparticle facilitate nanoparticle-molecule interaction, and make them biocompatible. Conjugation can be achieved through intermolecular attractions between the nanoparticle and biomolecule such as covalent bonding, chemisorption, and noncovalent interactions.
To enhance visualization, nanoparticles can also be made to fluoresce by controlling the size and shape of a nanoparticle probe. Fluorescence increases luminescence by increasing the range of wavelengths the emitted light can reach, allowing for biomarkers with a variety of colors. This technique is used to track the efficacy of protein transfer both in vivo and in vitro in terms of genetic alternations.
=== Biological process control ===
Biological processes can be controlled through transcription regulation, gene regulation, and enzyme inhibition processes that can be regulated using nanoparticles. Nanoparticles can play a part in gene regulation through ionic bonding between positively charged cationic ligands on the surfaces of nanoparticles and negatively charged anionic nucleic acids present in DNA. In an experiment, a nanoparticle-DNA complex inhibited transcription by T7 RNA polymerase, signifying strong bonding in the complex. A high affinity of the nanoparticle-DNA complex indicates strong bonding and a favorable use of nanoparticles.
Attaching ionic ligands to nanoparticles allows control over enzyme activity. An example of enzyme inhibition is given by binding of a-chymotrypsin (ChT), an enzyme with a largely cationic active site. When a-chymotrypsin is incubated with anionic (negatively charged) nanoparticles, ChT activity is inhibited as anionic nanoparticles bind to the active site. Enzyme activity can be restored by the addition of cationic surfactants. Alkyl surfactants form a bilayer around ChT, whereas thiol and alcohol surfactants alter the surface of ChT such that interactions with nanoparticles are interrupted. Though formation of a protein-nanoparticle complex can inhibit enzyme activity, studies show that it can also stabilize protein structure, and significantly protect the protein from denaturization. Experimental and theoretical analyses have also shown that nanoparticles may suppress unfavorable lateral interactions among the adsorbed proteins, thereby leading to significant enhancements in their stability under denaturing conditions. Attachments of ligands to segments of nanoparticles selected for functionalization of metallic properties can be used to generate a magnetic nanowire, which generates a magnetic field that allows for the manipulation of cellular assemblies.
=== Genetic alteration ===
Nanoparticles can also be used in conjunction with DNA to perform genetic alterations. These are frequently monitored through the use of fluorescent materials, allowing scientists to judge if these tagged proteins have successfully been transmitted—for example green fluorescent protein, or GFP. Nanoparticles are significantly less cytotoxic than currently used organic methods, providing a more efficient method of monitoring genetic alternations. They also do not degrade or bleach with time, as organic dyes do. Suspensions of nanoparticles with the same size and shapes (mono-dispersed) with functional groups attached to their surfaces can also electrostatically bind to DNA, protecting them from several types of degradation. Because the fluorescence of these nanoparticles does not degrade, cellular localization can be tracked without the use of additional tagging, with GFPs or other methods. The 'unpacking' of the DNA can be detected in live cells using luminescence resonance energy transfer (LRET) technology.
=== Medical implications ===
Small molecules in vivo have a short retention time, but the use of larger nanoparticles does not. These nanoparticles can be used to avoid immune response, which aids in the treatment of chronic diseases. It has been investigated as a potential cancer therapy and also has the potential to affect the understanding of genetic disorders. Nanoparticles also have the potential to aid in site-specific drug delivery by improving the amount of unmodified drug that is circulated within the system, which also decreases the necessary dosage frequency. The targeted nature of nanoparticles also means that non-targeted organs are much less likely to experience side effects of drugs intended for other areas.
=== Studying cell interactions ===
Cellular interactions occur at a microscopic level and cannot be easily observed even with the advanced microscopes available today. Due to difficulties observing reactions at the molecular level, indirect methods are used which greatly limits the scope of the understanding that can be gained by studying these processes essential to life. Advances in the material industry has evolved a new field known as nanobiotechnology, that uses nanoparticles to study interactions at the biomolecular level.
One area of research featuring nanobiotechnology is the extracellular matrices of cells (ECM). The ECM is primarily composed of interwoven fibers of collagen and elastin that have diameters ranging from 10 to 300 nm. In addition to holding the cell in place, the ECM has a variety of other functions including providing a point of attachment for the ECM of other cells and transmembrane receptors that are essential for life. Until recently it has been nearly impossible to study the physical forces that help cells maintain their functionality, but nanobiotechnology has given us the ability to learn more about these interactions. Using the unique properties of nanoparticles, it is possible to control how the nanoparticles adhere to certain patterns present in the ECM, and as a result can understand how changes in the ECM's shape can affect cell functionality.
Using nanobiotechnology to study the ECM allows scientists to investigate the binding interactions that occur between the ECM and its supporting environment. Investigators were able to study these interactions by utilizing tools such as optical tweezers, which have the ability to trap nano-scale objects with focused light. The tweezers can affect the binding of a substrate to the ECM by attempting to draw the substrate away from it. The light emitted from the tweezers was used to restrain ECM-coated microbeads, and the changes in the force exerted by the ECM onto the substrate were studied by modulating the effect of the optical tweezers. Experiments showed that the force exerted by the ECM on the substrate positively correlated with the force of the tweezers, which led to the subsequent discovery that the ECM and the transmembrane proteins are able to sense external forces, and can adapt to overcome these forces.
=== Nanotechnology crossing the blood–brain barrier ===
The blood–brain barrier (BBB) is composed of a system of capillaries that has an especially dense lining of endothelial cells which protects the central nervous system (CNS) against the diffusion of foreign substances into the cerebrospinal fluid. These harmful objects include microscopic bacteria, large hydrophobic molecules, certain hormones and neurotransmitters, and low-lipid-soluble molecules. The BBB prevents these harmful particles from entering the brain via tight junctions between endothelial cells and metabolic barriers. The thoroughness with which the BBB does its job makes it difficult to treat diseases of the brain such as cancer, Alzheimer's, and autism, because it is very difficult to transport drugs across the BBB. Currently, in order to deliver therapeutic molecules into the brain, doctors must use highly invasive techniques such as drilling directly into the brain, or sabotaging the integrity of the BBB through biochemical means. Due to their small size and large surface area, nanoparticles offer a promising solution for neurotherapeutics.
Nanotechnology is helpful in delivering drugs and other molecules across the blood–brain barrier (BBB). Nanoparticles allow drugs, or other foreign molecules, to efficiently cross the BBB by camouflaging themselves and tricking the brain into providing them with the ability to cross the BBB in a process called the Trojan Horse Method. Using nanotechnology is advantageous because only the engineered complex is necessary whereas in ordinary applications the active compound must carry out the reaction. This allows for maximum efficacy of the active drug. Also, the use of nanoparticles results in the attraction of proteins to the surfaces of cells, giving cell membranes a biological identity. They also use endogenous active transport where transferrin, an iron binding protein, is linked to rod-shaped semiconductor nanocrystals, in order to move across the BBB into the brain. This discovery is a promising development towards designing an efficient nanoparticle-based drug delivery system.
== See also ==
Nanomedicine
Nanobiotechnology
Nanotechnology in fiction
Heart nanotechnology
== References == | Wikipedia/Nanoparticle–biomolecule_conjugate |
A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic.
Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.
== Mechanism ==
In order to enter cells, pathogens, such as circulating viral particles or extracellular bacteria, use molecules on their surfaces to interact with the cell surface receptors of their target cell which allows them to enter the cell and start their replication cycle. Neutralizing antibodies can inhibit infectivity by binding to the pathogen and blocking the molecules needed for cell entry. This can be due to the antibodies statically interfering with the pathogens, or toxins attaching to host cell receptors. In case of a viral infection, NAbs can bind to glycoproteins of enveloped viruses or capsid proteins of non-enveloped viruses.
Furthermore, neutralizing antibodies can act by preventing particles from undergoing structural changes often needed for successful cell entry. For example, neutralizing antibodies can prevent conformational changes of viral proteins that mediate the membrane fusion needed for entry into the host cell. In some cases, the virus is unable to infect even after the antibody dissociates. The pathogen-antibody complex is eventually taken up and degraded by macrophages.
Neutralizing antibodies are also important in neutralizing the toxic effects of bacterial toxins. An example of a neutralizing antibody is diphtheria antitoxin, which can neutralize the biological effects of diphtheria toxin. Neutralizing antibodies are not effective against extracellular bacteria, as the binding of antibodies does not prevent bacteria from replicating. Here, the immune system uses other functions of antibodies, like opsonisation and complement activation, to kill the bacteria.
=== Difference between neutralizing antibodies and binding antibodies ===
Not all antibodies that bind to a pathogenic particle are neutralizing. Non-neutralizing antibodies, or binding antibodies, bind specifically to the pathogen, but do not interfere with their infectivity. That might be because they do not bind to the right region. Non-neutralizing antibodies can be important to flag the particle for immune cells, signaling that it has been targeted, after which the particle is processed and consequently destroyed by recruited immune cells. Neutralizing antibodies on the other hand can neutralize the biological effects of the antigen without a need for immune cells.
In some cases, non-neutralizing antibodies, or an insufficient amount of neutralizing antibodies binding to viral particles, can be utilized by some species of virus to facilitate uptake into their host cells. This mechanism is known as antibody-dependent enhancement. It has been observed for Dengue virus and Zika virus.
== Production ==
Antibodies are produced and secreted by B cells.
When B cells are produced in the bone marrow, the genes that encode the antibodies undergo random genetic recombination (V(D)J recombination), which results in every mature B cell producing antibodies that differ in their amino acid sequence in the antigen-binding region. Therefore, every B cell produces antibodies that bind specifically to different antigens. A strong diversity in the antibody repertoire allows the immune system to recognize a plethora of pathogens which can come in all different forms and sizes. During an infection only antibodies that bind to the pathogenic antigen with high affinity are produced. This is achieved by clonal selection of a single B cell clone: B cells are recruited to the site of infection by sensing interferons that are released by the infected cells as part of the innate immune response. B cells display B-cell receptors on their cell surface, which is just the antibody anchored to the cell membrane. When the B-cell receptor binds to its cognate antigen with high affinity, an intracellular signalling cascade is triggered. In addition to binding to an antigen, B cells need to be stimulated by cytokines produced by T helper cells as part of the cellular response of the immune system against the pathogen. Once a B cell is fully activated, it rapidly proliferates and differentiates into plasma cells. Plasma cells then secrete the antigen-specific antibody in large quantities.
After a first encounter of the antigen by vaccination or natural infection, immunological memory allows for a more rapid production of neutralizing antibodies following the next exposure to the virus.
== Virus evasion of neutralizing antibodies ==
Viruses use a variety of mechanisms to evade neutralizing antibodies. Viral genomes mutate at a high rate. Mutations that allow viruses to evade a neutralizing antibody will be selected for, and hence prevail. Conversely, antibodies also simultaneously evolve by affinity maturation during the course of an immune response, thereby improving recognition of viral particles. Conserved parts of viral proteins that play a central role in viral function are less likely to evolve over time, and therefore are more vulnerable to antibody binding. However, viruses have evolved certain mechanisms to hinder steric access of an antibody to these regions, making binding difficult. Viruses with a low density of surface structural proteins are more difficult for antibodies to bind to. Some viral glycoproteins are heavily glycosylated by N- and O- linked glycans, creating a so-called glycan shield, which may decrease antibody binding affinity and facilitate evasion of neutralizing antibodies. HIV-1, the cause of human AIDS, uses both of these mechanisms.
== Medical uses of neutralizing antibodies ==
Neutralizing antibodies are used for passive immunisation, and can be used for patients even if they do not have a healthy immune system.
In the early 20th century, infected patients were injected with antiserum, which is the blood serum of a previously infected and recovered patient containing polyclonal antibodies against the infectious agent. This showed that antibodies could be used as an effective treatment for viral infections and toxins. Antiserum is a very crude therapy, because antibodies in the plasma are not purified or standardized and the blood plasma could be rejected by the donor. As it relies on the donation from recovered patients it cannot be easily scaled up. However, serum therapy is today still used as the first line of defence during an outbreak as it can relatively quickly obtained. Serum therapy was shown to reduce mortality in patients during the 2009 swine flu pandemic and the Western African Ebola virus epidemic. It is also being tested as possible treatment for COVID-19. Immunoglobulin therapy, which uses a mixture of antibodies obtained from healthy people, is given to immunodeficient or immunosuppressed patients to fight off infections.
For a more specific and robust treatment, purified polyclonal or monoclonal antibodies (mAb) can be used. Polyclonal antibodies are collection of antibodies that target the same pathogen but bind to different epitopes. Polyclonal antibodies are obtained from human donors or animals that have been exposed to the antigen. The antigen injected into the animal donors can be designed in such a way to preferably produce neutralizing antibodies. Polyclonal antibodies have been used as treatment for cytomegalovirus (CMV), hepatitis b virus (HBV), rabies virus, measles virus, and respiratory syncytial virus (RSV). Diphtheria antitoxin contains polyclonal antibodies against the diphtheria toxin. By treating with antibodies binding multiple epitopes, the treatment is still effective even if the virus mutates and one of the epitopes changes in structure. However, because of the nature of the production, treatment with polyclonal antibodies has batch to batch variation and low antibody titers. Monoclonal antibodies, on the other hand, all bind the same epitope with high specificity. They can be produced with the Hybridoma technology, which allows the production of mAbs in large quantities. mAbs against infections stop working when virus mutates the epitope that is targeted by the mAbs or multiple strain are circulating. Example of drugs that use monoclonal antibodies include ZMapp against Ebola and Palivizumab against RSV. Many mABs against other infections are in clinical trials.
Neutralizing antibodies also play a role in active immunisation by vaccination. By understanding the binding sites and structure of neutralizing antibodies in a natural immune response a vaccine can be rationally designed such that it stimulates the immune system to produce neutralizing antibodies and not binding antibodies.
Introducing a weakened form of a virus through vaccination allows for the production of neutralizing antibodies by B cells. After a second exposure, the neutralizing antibody response is more rapid due to the existence of memory B cells that produce antibodies specific to the virus.
An effective vaccine induces the production of antibodies that are able to neutralize the majority of variants of a virus, although virus mutation resulting in antibody evasion may require vaccines to be updated in response.
Some viruses evolve faster than others, which can require the need for vaccines to be updated in response. A well known example is the vaccine for the influenza virus, which must be updated annually to account for the recent circulating strains of the virus.
Neutralizing antibodies may also assist the treatment of multiple sclerosis. Although this type of antibody has the ability to fight retroviral infections, in some cases it attacks pharmaceuticals administered to the body which would otherwise treat multiple sclerosis. Recombinant protein drugs, especially those derived from animals, are commonly targeted by neutralizing antibodies. A few examples are Rebif, Betaseron and Avonex.
=== Methods for detection and quantification of neutralizing antibodies ===
Neutralization assays are capable of being performed and measured in different ways, including the use of techniques such as plaque reduction (which compares counts of virus plaques in control wells with those in inoculated cultures), microneutralization (which is performed in microtiter plates filled with small amounts of sera), and colorimetric assays (which depend on biomarkers indicating metabolic inhibition of the virus).
== Broadly neutralizing antibodies ==
Most of the neutralizing antibodies produced by the immune system are very specific for a single virus strain due to affinity maturation by B cells. Some pathogens with high genetic variability, such as HIV, constantly change their surface structure such that neutralizing antibodies with high specificity to the old strain can no longer bind to the new virus strain. This immune evasion strategy prevents the immune system from developing immunological memory against the pathogen. Broadly neutralizing antibodies (bNAbs), on the other hand, have the special ability to bind and neutralize multiple strains of a virus species.
bNAbs have been initially found in HIV patients. However, they are quite rare: an in situ screening study showed that only 1% of all patients develop bNAbs against HIV. bNABs can neutralize a wide range of virus strains by binding to conserved regions of the virus surface proteins that are unable to mutate because they are functionally essential for the virus replication. Most binding sites of bNAbs against HIV are on HIV's exposed surface antigen, the envelope (Env) protein (a trimer composed of gp120 and gp41 subunits). These site include the CD4 binding site or the gp41-gp120 interface. Los Alamos National Laboratory's HIV Databases is a comprehensive resource that has a wealth of information about HIV sequences, bNAbs, and more.
Additionally, bNAbs have been found for other viruses including influenza, hepatitis C, dengue and West Nile virus.
=== Research ===
Preliminary research is conducted to identify and test bNAbs against HIV-1. bNAbs are used in research to rationally design vaccines to stimulate production of bNAbs and immunity against viruses. No antigen that triggers bNAb production in animal models or humans is known.
Bispecific antibodies (bsAb) against HIV-1 are also currently being studied. One example of such an antibody binds bind both HIV-1 Env and the CD4 receptor and this seems to allow it to have enhanced ability to neutralise HIV-1 as well as an enhanced neutralisation breadth .
== See also ==
Blocking antibody
Humoral immunity
== References == | Wikipedia/Broadly_neutralizing_antibody |
Strategies for engineered negligible senescence (SENS) is a range of proposed regenerative medical therapies, either planned or currently in development, for the periodic repair of all age-related damage to human tissue. These therapies have the ultimate aim of maintaining a state of negligible senescence in patients and postponing age-associated disease. SENS was first defined by British biogerontologist Aubrey de Grey. Many mainstream scientists believe that it is a fringe theory. De Grey later highlighted similarities and differences of SENS to subsequent categorization systems of the biology of aging, such as the highly influential Hallmarks of Aging published in 2013.
While some biogerontologists support the SENS program, others contend that the ultimate goals of de Grey's programme are too speculative given the current state of technology. The 31-member Research Advisory Board of de Grey's SENS Research Foundation have signed an endorsement of the plausibility of the SENS approach.
== Framework ==
The term "negligible senescence" was first used in the early 1990s by professor Caleb Finch to describe organisms such as lobsters and hydras, which do not show symptoms of aging. The term "engineered negligible senescence" first appeared in print in Aubrey de Grey's 1999 book The Mitochondrial Free Radical Theory of Aging. De Grey defined SENS as a "goal-directed rather than curiosity-driven" approach to the science of aging, and "an effort to expand regenerative medicine into the territory of aging".
The ultimate objective of SENS is the eventual elimination of age-related diseases and infirmity by repeatedly reducing the state of senescence in the organism. The SENS project consists in implementing a series of periodic medical interventions designed to repair, prevent or render irrelevant all the types of molecular and cellular damage that cause age-related pathology and degeneration, in order to avoid debilitation and death from age-related causes.
=== Strategies ===
As described by SENS, the following table details major ailments and the program's proposed preventative strategies:
== Scientific reception ==
While some fields mentioned as branches of SENS are supported by the medical research community, e.g., stem cell research, anti-Alzheimers research and oncogenomics, the SENS programme as a whole has been a highly controversial proposal. Many of its critics argued in 2005 that the SENS agenda was fanciful and that the complicated biomedical phenomena involved in aging contain too many unknowns for SENS to be fully implementable in the foreseeable future.
Cancer may deserve special attention as an aging-associated disease, but the SENS claim that nuclear DNA damage only matters for aging because of cancer has been challenged in other literature, as well as by material studying the DNA damage theory of aging. More recently, biogerontologist Marios Kyriazis has criticised the clinical applicability of SENS by claiming that such therapies, even if developed in the laboratory, would be practically unusable by the general public. De Grey responded to one such criticism.
=== 2005 EMBO Reports statement ===
In November 2005, 28 biogerontologists published a statement of criticism in EMBO Reports, "Science fact and the SENS agenda: what can we reasonably expect from ageing research?," arguing "each one of the specific proposals that comprise the SENS agenda is, at our present stage of ignorance, exceptionally optimistic," and that some of the specific proposals "will take decades of hard work [to be medically integrated], if [they] ever prove to be useful." The researchers argue that while there is "a rationale for thinking that we might eventually learn how to postpone human illnesses to an important degree," increased basic research, rather than the goal-directed approach of SENS, is currently the scientifically appropriate goal.
== Technology Review contest ==
In February 2005, the MIT Technology Review published an article by Sherwin Nuland, a Clinical Professor of Surgery at Yale University and the author of How We Die, that drew a skeptical portrait of SENS, at the time de Grey was a computer associate in the Flybase Facility of the Department of Genetics at the University of Cambridge. While Nuland praised de Grey's intellect and rhetoric, he criticized the SENS framework both for oversimplifying "enormously complex biological problems" and for promising relatively near-at-hand solutions to those unsolved problems.
During June 2005, David Gobel, CEO and co-founder of the Methuselah Foundation with de Grey, offered Technology Review $20,000 to fund a prize competition to publicly clarify the viability of the SENS approach. In July 2005, Jason Pontin announced a $20,000 prize, funded 50/50 by Methuselah Foundation and MIT Technology Review. The contest was open to any molecular biologist, with a record of publication in biogerontology, who could prove that the alleged benefits of SENS were "so wrong that it is unworthy of learned debate." Technology Review received five submissions to its challenge. In March 2006, Technology Review announced that it had chosen a panel of judges for the Challenge: Rodney Brooks, Anita Goel, Nathan Myhrvold, Vikram Sheel Kumar, and Craig Venter. Three of the five submissions met the terms of the prize competition. They were published by Technology Review on June 9, 2006. On July 11, 2006, Technology Review published the results of the SENS Challenge.
In the end, no one won the $20,000 prize. The judges felt that no submission met the criterion of the challenge and discredited SENS, although they unanimously agreed that one submission, by Preston Estep and his colleagues, was the most eloquent. Craig Venter succinctly expressed the prevailing opinion: "Estep et al. ... have not demonstrated that SENS is unworthy of discussion, but the proponents of SENS have not made a compelling case for it." Summarizing the judges' deliberations, Pontin wrote in 2006 that SENS is "highly speculative" and that many of its proposals could not be reproduced with current scientific technology. Myhrvold described SENS as belonging to a kind of "antechamber of science" where they wait until technology and scientific knowledge advance to the point where it can be tested. Estep and his coauthors challenged the result of the contest by saying both that the judges had ruled "outside their area of expertise" and had failed to consider de Grey's frequent misrepresentations of the scientific literature.
== SENS Research Foundation ==
The SENS Research Foundation is a non-profit organization co-founded by Michael Kope, Aubrey de Grey, Jeff Hall, Sarah Marr and Kevin Perrott, which is based in California, United States. Its activities include SENS-based research programs and public relations work for the acceptance of and interest in related research.
== See also ==
== References ==
== Further reading ==
Fishman, Jennifer R.; Settersten, Richard A. Jr.; Flatt, Michael A. (February 2010). "In the vanguard of biomedicine? The curious and contradictory case of anti-ageing medicine". Sociology of Health & Illness. 32 (2): 197–210. doi:10.1111/j.1467-9566.2009.01212.x. PMC 3414193. PMID 20003037.
Isaacson, Betsy (5 March 2015). "Silicon Valley Is Trying to Make Humans Immortal—and Finding Some Success". Newsweek. Retrieved 28 April 2021.
Mykytyn, Courtney Everts (February 2010). "A history of the future: The emergence of contemporary anti-ageing medicine". Sociology of Health & Illness. 32 (2): 181–196. doi:10.1111/j.1467-9566.2009.01217.x. PMID 20149152.
Olshansky, S. Jay; Carnes, Bruce A. (2013). "Science Fact versus SENS Foreseeable". Gerontology. 59 (2): 190–192. doi:10.1159/000342959. PMID 23037994. S2CID 207588602. | Wikipedia/Strategies_for_engineered_negligible_senescence |
Precision BioSciences, Inc. is a publicly traded American clinical stage gene editing company headquartered in Durham, North Carolina. Founded in 2006, Precision is focused on developing both in vivo and ex vivo gene editing therapies using its proprietary "ARCUS" genome editing platform.
== History ==
Derek Jantz and Jeff Smith met as postdoctoral fellows at Duke University, and in March 2006, they founded Precision BioSciences along with Matt Kane, a student at the Duke Fuqua School of Business at the time. The company went through two rounds of early funding: a Series A round led by venBio to fund development of the genome editing platform, and Series B financing to fund product development efforts. The company completed its initial public offering in 2019, and trades under the Nasdaq ticker DTIL.
Precision entered into a partnership with Eli Lilly in November 2020 to use ARCUS editing for up to six in vivo targets connected to genetic disorders, beginning with Duchenne muscular dystrophy. In September 2021, Precision announced two more collaborations, with UK biotechnology company Tiziana Life Sciences to explore using foralumab to aid chimeric antigen receptor (CAR) T cell therapy, and with Philadelphia-based iECURE to advance candidates into clinical trials and investigate how ARCUS can help treat liver diseases. Michael Amoroso, the former CEO of cell and gene therapy developer Abeona Therapeutics, succeeded Matt Kane as President and CEO in October 2021. That December, Precision announced its entry into an agreement with a syndicate of investors led by ACCELR8 to spin off its subsidiary, Elo Life Systems, and create an independent company focused on food and agriculture business.
== ARCUS genome editing ==
Precision BioSciences' proprietary technology is the ARCUS platform and ARCUS nucleases. ARCUS nucleases are based on a naturally occurring genome editing enzyme, I-CreI, a homing endonuclease that evolved in the algae Chlamydomonas reinhardtii to make highly specific cuts and DNA insertions in cellular DNA. The nuclease is able to deactivate itself once gene edits are made, which minimizes potential off-targeting. An ARCUS nuclease is also much smaller in size than CRISPR spCas9. It can use either adeno-associated virus (AAV) vectors or lipid nanoparticles (LNPs) for delivery to specific tissues and cells. Precision has used ARCUS nucleases to develop multiple ex vivo allogeneic, "off-the-shelf" CAR T cell immunotherapies in early-stage clinical trials. The company also uses ARCUS for in vivo gene editing programs, some of which are in preclinical development as of May 2022.
Similar to I-CreI, ARCUS nucleases generate a unique cleavage site in DNA that is characterized by four-base-pair, 3' overhangs. ARCUS nucleases can perform a range of complex edits, including gene insertion, gene excision, and gene repair. ARCUS nucleases are able to enact all editing operations in one step, which enables efficient multiplexing of edits.
Precision has demonstrated some additional applications of the ARCUS platform, including treating ornithine transcarbamylase deficiency in newborn nonhuman primates and in the use of a LNP to treat chronic Hepatitis B. The company is also pursuing PBGENE-PCSK9, a candidate to treat familial hypercholesterolemia, and PBGENE-PH1, a candidate to treat primary hyperoxaluria type 1.
== Clinical trials ==
Precision is in the process of developing multiple candidates targeting non-Hodgkin lymphoma, acute lymphoblastic leukemia (ALL), and multiple myeloma. The company's lead candidate targeting CD19, PBCAR0191, received orphan drug designation from the U.S. Food and Drug Administration for the treatment of ALL and mantle cell lymphoma, an aggressive subtype of non-Hodgkin lymphoma, as well as fast track designation for the treatment of B-cell ALL. PBCAR0191 began its Phase 1/2a clinical trial of adult subjects in March 2019. In June 2022, Precision reported a 100% response rate, a 73% complete response rate, and a 50% durable response rate, and the company sought to increase enrollment in the study.
Precision is also developing PBCAR19B as an anti-CD19 stealth cell candidate that employs a single gene edit to knock down beta-2 microglobulin, for which a Phase 1 study began in June 2021. The company is also conducting a Phase 1/2a clinical trial evaluating PBCAR269A, its investigational allogeneic B-cell maturation antigen-targeted CAR T cell therapy, for the treatment of multiple myleloma. PBCAR269A began its Phase 1 trials in April 2020, and as of July 2022 had moved onto recruitment for its Phase 1/2a study, which features PBCAR269A in combination with nirogacestat, a gamma secretase inhibitor. In 2020, the FDA granted fast track designation to PBCAR269A for the treatment of relapsed or refractory multiple myeloma, having previously provided orphan drug designation.
== References ==
== External links ==
Official website
Business data for Precision BioSciences, Inc.: | Wikipedia/Precision_Biosciences |
Programmed cell death protein 1 (PD-1), (CD279 cluster of differentiation 279). PD-1 is a protein encoded in humans by the PDCD1 gene. PD-1 is a cell surface receptor on T cells and B cells that has a role in regulating the immune system's response to the cells of the human body by down-regulating the immune system and promoting self-tolerance by suppressing T cell inflammatory activity. This prevents autoimmune diseases, but it can also prevent the immune system from killing cancer cells.
PD-1 is an immune checkpoint and guards against autoimmunity through two mechanisms. First, it promotes apoptosis (programmed cell death) of antigen-specific T-cells in lymph nodes. Second, it reduces apoptosis in regulatory T cells (anti-inflammatory, suppressive T cells).
PD-1 inhibitors, a new class of drugs that block PD-1, activate the immune system to attack tumors and are used to treat certain types of cancer.
PD-1 is a cell surface receptor that belongs to the immunoglobulin superfamily and is expressed on T cells and pro-B cells. PD-1 binds two ligands, PD-L1 and PD-L2.
== Discovery ==
In a screen for genes involved in apoptosis, Yasumasa Ishida, Tasuku Honjo and colleagues at Kyoto University in 1992 discovered and named PD-1. In 1999, the same group demonstrated that mice where PD-1 was knocked down were prone to autoimmune disease and hence concluded that PD-1 was a negative regulator of immune responses.
== Structure ==
PD-1 is a type I membrane protein of 288 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators. The protein's structure includes an extracellular IgV domain followed by a transmembrane region and an intracellular tail. The intracellular tail contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T-cell receptor TCR signals. This is consistent with binding of SHP-1 and SHP-2 phosphatases to the cytoplasmic tail of PD-1 upon ligand binding. In addition, PD-1 ligation up-regulates E3 ubiquitin ligases CBL-b and c-CBL that trigger T cell receptor down-modulation. PD-1 is expressed on the surface of activated T cells, B cells, and macrophages, suggesting that compared to CTLA-4, PD-1 more broadly negatively regulates immune responses.
== Ligands ==
PD-1 has two ligands, PD-L1 and PD-L2, which are members of the B7 family. PD-L1 protein is upregulated on macrophages and dendritic cells (DC) in response to LPS and GM-CSF treatment, and on T cells and B cells upon TCR and B cell receptor signaling, whereas in resting mice, PD-L1 mRNA can be detected in the heart, lung, thymus, spleen, and kidney. PD-L1 is expressed on almost all murine tumor cell lines, including PA1 myeloma, P815 mastocytoma, and B16 melanoma upon treatment with IFN-γ. PD-L2 expression is more restricted and is expressed mainly by DCs and a few tumor lines.
== Function ==
Several lines of evidence suggest that PD-1 and its ligands negatively regulate immune responses. PD-1 knockout mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy on the C57BL/6 and BALB/c backgrounds, respectively. In vitro, treatment of anti-CD3 stimulated T cells with PD-L1-Ig results in reduced T cell proliferation and IFN-γ secretion. IFN-γ is a key pro-inflammatory cytokine that promotes T cell inflammatory activity. Reduced T cell proliferation was also correlated with attenuated IL-2 secretion and together, these data suggest that PD-1 negatively regulates T cell responses.
Experiments using PD-L1 transfected DCs and PD-1 expressing transgenic (Tg) CD4+ and CD8+ T cells suggest that CD8+ T cells are more susceptible to inhibition by PD-L1, although this could be dependent on the strength of TCR signaling. Consistent with a role in negatively regulating CD8+ T cell responses, using an LCMV viral vector model of chronic infection, Rafi Ahmed's group showed that the PD-1-PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus specific CD8+ T cells, which can be reversed by blocking the PD-1-PD-L1 interaction.
Expression of PD-L1 on tumor cells inhibits anti-tumor activity through engagement of PD-1 on effector T cells. Expression of PD-L1 on tumors is correlated with reduced survival in esophageal, pancreatic and other types of cancers, highlighting this pathway as a target for immunotherapy. Triggering PD-1, expressed on monocytes and up-regulated upon monocytes activation, by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.
In mice, expression of this gene is induced in the thymus when anti-CD3 antibodies are injected and large numbers of thymocytes undergo apoptosis. Mice deficient for this gene bred on a BALB/c background developed dilated cardiomyopathy and died from congestive heart failure. These studies suggest that this gene product may also be important in T cell function and contribute to the prevention of autoimmune diseases.
Overexpression of PD1 on CD8+ T cells is one of the indicators of T-cell exhaustion (e.g. in chronic infection or cancer).
== Clinical significance ==
=== Cancer ===
PD-L1, the ligand for PD1, is highly expressed in several cancers and hence the role of PD1 in cancer immune evasion is well established. Monoclonal antibodies targeting PD-1 that boost the immune system are being developed for the treatment of cancer. Many tumor cells express PD-L1, an immunosuppressive PD-1 ligand; inhibition of the interaction between PD-1 and PD-L1 can enhance T-cell responses in vitro and mediate preclinical antitumor activity. This is known as immune checkpoint blockade.
Combination therapy using both anti-PD1 along with anti-CTLA4 therapeutics have emerged as important tumor treatments within the field of checkpoint inhibition.
A combination of PD1 and CTLA4 antibodies has been shown to be more effective than either antibody alone in the treatment of a variety of cancers. The effects of the two antibodies do not appear to be redundant. Anti-CTLA4 treatment leads to an enhanced antigen specific T cell dependent immune reaction while anti-PD-1 appears to reactivate CD8+ T cells ability to lyse cancer cells.
In clinical trials, combination therapy has been shown to be effective in reducing tumor size in patients that are unresponsive to single co-inhibitory blockade, despite increasing levels of toxicity due to anti-CTLA4 treatment. A combination of PD1 and CTLA4 induced up to a ten-fold higher number of CD8+ T cells that are actively infiltrating the tumor tissue. The authors hypothesized that the higher levels of CD8+ T cell infiltration was due to anti-CTLA-4 inhibited the conversion of CD4 T cells to T regulator cells and further reduced T regulatory suppression with anti-PD-1. This combination promoted a more robust inflammatory response to the tumor that reduced the size of the cancer. Most recently, the FDA has approved a combination therapy with both anti-CTLA4 (ipilimumab) and anti-PD1 (nivolumab) in October 2015.
The molecular factors and receptors necessary making a tumor receptive to anti-PD1 treatment remains unknown. PD-L1 expression on the surface on cancer cells plays a significant role. PD-L1 positive tumors were twice as likely to respond to combination treatment. However patients with PD-L1 negative tumors also have limited response to anti-PD1, demonstrating that PD-L1 expression is not an absolute determinant of the effectiveness of therapy.
Higher mutational burden in the tumor is correlated with a greater effect of the anti-PD-1 treatment. In clinical trials, patients who benefited from anti-PD1 treatment had cancers, such as melanoma, bladder cancer, and gastric cancer, that had a median higher average number of mutations than the patients who did not respond to the therapy. However, the correlation between higher tumor burden and the clinical effectiveness of PD-1 immune blockade is still uncertain.
The 2018 Nobel Prize for Medicine was awarded to James P Allison and Tasuku Honjo "for their discovery of cancer therapy by inhibition of negative immune regulation".
=== Anti-PD-1 therapeutics ===
A number of cancer immunotherapy agents that target the PD-1 receptor have been developed.
One such anti-PD-1 antibody drug, nivolumab, (Opdivo - Bristol Myers Squibb), produced complete or partial responses in non-small-cell lung cancer, melanoma, and renal-cell cancer, in a clinical trial with a total of 296 patients. Colon and pancreatic cancer did not have a response. Nivolumab (Opdivo, Bristol-Myers Squibb) was approved in Japan in July 2014 and by the US FDA in December 2014 to treat metastatic melanoma.
Pembrolizumab (Keytruda, MK-3475, Merck), which also targets PD-1 receptors, was approved by the FDA in Sept 2014 to treat metastatic melanoma. Pembrolizumab has been made accessible to advanced melanoma patients in the UK via UK Early Access to Medicines Scheme (EAMS) in March 2015. It is being used in clinical trials in the US for lung cancer, lymphoma, and mesothelioma. It has had measured success, with little side effects. It is up to the manufacturer of the drug to submit application to the FDA for approval for use in these diseases. On October 2, 2015, Pembrolizumab was approved by FDA for advanced (metastatic) non-small cell lung cancer (NSCLC) patients whose disease has progressed after other treatments.
Toripalimab is a humanized IgG4 monoclonal antibody against PD-1 which was approved in China in 2018 and in the United States in 2023.
Drugs in early stage development targeting PD-1 receptors (checkpoint inhibitors) include pidilizumab (CT-011, Cure Tech) and BMS-936559 (Bristol Myers Squibb). Both atezolizumab (MPDL3280A, Roche) and avelumab (Merck KGaA, Darmstadt, Germany and Pfizer) target the similar PD-L1 receptor.
== Animal studies ==
=== HIV ===
Drugs targeting PD-1 in combination with other negative immune checkpoint receptors, such as (TIGIT), may augment immune responses and/or facilitate HIV eradication. T lymphocytes exhibit elevated expression of PD-1 in cases of chronic HIV infection. Heightened presence of the PD-1 receptors corresponds to exhaustion of the HIV specific CD8+ cytotoxic and CD4+ helper T cell populations that are vital in combating the virus. Immune blockade of PD-1 resulted in restoration of T cell inflammatory phenotype necessary to combat the progression of disease.
=== Alzheimer's disease ===
Blocking of PD-1 leads to a reduction in cerebral amyloid-β plaques and improves cognitive performance in mice. Immune blockade of PD-1 evoked an IFN-γ dependent immune response that recruited monocyte-derived macrophages to the brain that were then capable of clearing the amyloid-β plaques from the tissue. Repeated administrations with anti-PD-1 were found to be necessary to maintain the therapeutic effects of the treatment. Amyloid fibrils are immunosuppressive and this finding has been separately confirmed by examining the effects of the fibrils in neuroinflammatory diseases. PD-1 counteracts the effects of the fibrils by boosting immune activity and triggering an immune pathway that allows for brain repair.
== References ==
== Further reading ==
== External links ==
PDCD1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Overview of all the structural information available in the PDB for UniProt: Q15116 (Programmed cell death protein 1) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
What I Talk about When I Talk about the Discovery of PD-1 (Yasumasa Ishida)
PD-1_Project PD-1 project - Honjo Lab
PD-1プロジェクト(in Japanese) - Honjo Lab | Wikipedia/Programmed_cell_death_protein_1 |
Genome editing, or genome engineering, or gene editing, is a type of genetic engineering in which DNA is inserted, deleted, modified or replaced in the genome of a living organism. Unlike early genetic engineering techniques that randomly insert genetic material into a host genome, genome editing targets the insertions to site-specific locations. The basic mechanism involved in genetic manipulations through programmable nucleases is the recognition of target genomic loci and binding of effector DNA-binding domain (DBD), double-strand breaks (DSBs) in target DNA by the restriction endonucleases (FokI and Cas), and the repair of DSBs through homology-directed recombination (HDR) or non-homologous end joining (NHEJ).
== History ==
Genome editing was pioneered in the 1990s, before the advent of the common current nuclease-based gene-editing platforms, but its use was limited by low efficiencies of editing. Genome editing with engineered nucleases, i.e. all three major classes of these enzymes—zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and engineered meganucleases—were selected by Nature Methods as the 2011 Method of the Year. The CRISPR-Cas system was selected by Science as 2015 Breakthrough of the Year.
As of 2015, four families of engineered nucleases were used: meganucleases, zinc finger nucleases (ZFNs), transcription activator-like effector-based nucleases (TALEN), and the clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) system. Nine genome editors were available as of 2017.
In 2018, the common methods for such editing used engineered nucleases, or "molecular scissors". These nucleases create site-specific double-strand breaks (DSBs) at desired locations in the genome. The induced double-strand breaks are repaired through nonhomologous end-joining (NHEJ) or homologous recombination (HR), resulting in targeted mutations ('edits').
In May 2019, lawyers in China reported, in light of the purported creation by Chinese scientist He Jiankui of the first gene-edited humans (see Lulu and Nana controversy), the drafting of regulations that anyone manipulating the human genome by gene-editing techniques, like CRISPR, would be held responsible for any related adverse consequences. A cautionary perspective on the possible blind spots and risks of CRISPR and related biotechnologies has been recently discussed, focusing on the stochastic nature of cellular control processes.
The University of Edinburgh Roslin Institute engineered pigs resistant to a virus that causes porcine reproductive and respiratory syndrome, which costs US and European pig farmers $2.6 billion annually.
In February 2020, a US trial safely showed CRISPR gene editing on 3 cancer patients. In 2020 Sicilian Rouge High GABA, a tomato that makes more of an amino acid said to promote relaxation, was approved for sale in Japan.
In 2021, England (not the rest of the UK) planned to remove restrictions on gene-edited plants and animals, moving from European Union-compliant regulation to rules closer to those of the US and some other countries. An April 2021 European Commission report found "strong indications" that the current regulatory regime was not appropriate for gene editing. Later in 2021, researchers announced a CRISPR alternative, labelled obligate mobile element–guided activity (OMEGA) proteins including IscB, IsrB and TnpB as endonucleases found in transposons, and guided by small ωRNAs.
== Background ==
Genetic engineering, as method of introducing new genetic elements into organisms, has been around since the 1970s. One drawback of this technology has been the random nature with which the DNA is inserted into the host's genome, which can impair or alter other genes within the organism. However, several methods have been discovered that target the inserted genes to specific sites within an organism's genome. It has also enabled the editing of specific sequences within a genome, as well as reduced off-target effects. This could be used for research purposes, by targeting mutations to specific genes, and in gene therapy. By inserting a functional gene into an organism, and targeting it to replace the defective one, it could be possible to cure certain genetic diseases.
=== Gene targeting ===
==== Homologous recombination ====
Early methods to target genes to certain sites within a genome of an organism (called gene targeting) relied on homologous recombination (HR). By creating DNA constructs that contain a template that matches the targeted genome sequence, it is possible that the HR processes within the cell will insert the construct at the desired location. Using this method on embryonic stem cells led to the development of transgenic mice with targeted genes knocked out. It has also been possible to knock in genes or alter gene expression patterns. In recognition of their discovery of how homologous recombination can be used to introduce genetic modifications in mice through embryonic stem cells, Mario Capecchi, Martin Evans and Oliver Smithies were awarded the 2007 Nobel Prize for Physiology or Medicine.
==== Conditional targeting ====
If a vital gene is knocked out, it can prove lethal to the organism. In order to study the function of these genes, site specific recombinases (SSR) were used. The two most common types are the Cre-LoxP and Flp-FRT systems. Cre recombinase is an enzyme that removes DNA by homologous recombination between binding sequences known as Lox-P sites. The Flip-FRT system operates in a similar way, with the Flip recombinase recognising FRT sequences. By crossing an organism containing the recombinase sites flanking the gene of interest with an organism that express the SSR under control of tissue specific promoters, it is possible to knock out or switch on genes only in certain cells. These techniques were also used to remove marker genes from transgenic animals. Further modifications of these systems allowed researchers to induce recombination only under certain conditions, allowing genes to be knocked out or expressed at desired times or stages of development.
== Process ==
=== Double strand break repair ===
A common form of genome editing relies on the concept of DNA double stranded break (DSB) repair mechanics. There are two major pathways that repair DSB; non-homologous end joining (NHEJ) and homology directed repair (HDR). NHEJ uses a variety of enzymes to directly join the DNA ends, while the more accurate HDR uses a homologous sequence as a template for regeneration of missing DNA sequences at the break point. This can be exploited by creating a vector with the desired genetic elements within a sequence that is homologous to the flanking sequences of a DSB. This will result in the desired change being inserted at the site of the DSB. While HDR based gene editing is similar to the homologous recombination based gene targeting, the rate of recombination is increased by at least three orders of magnitude.
=== Engineered nucleases ===
The key to genome editing is creating a DSB at a specific point within the genome. Commonly used restriction enzymes are effective at cutting DNA, but generally recognize and cut at multiple sites. To overcome this challenge and create site-specific DSB, three distinct classes of nucleases have been discovered and bioengineered to date. These are the Zinc finger nucleases (ZFNs), transcription-activator like effector nucleases (TALEN), meganucleases and the clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) system.
==== Meganucleases ====
Meganucleases, discovered in the late 1980s, are enzymes in the endonuclease family which are characterized by their capacity to recognize and cut large DNA sequences (from 14 to 40 base pairs). The most widespread and best known meganucleases are the proteins in the LAGLIDADG family, which owe their name to a conserved amino acid sequence.
Meganucleases, found commonly in microbial species, have the unique property of having very long recognition sequences (>14bp) thus making them naturally very specific. However, there is virtually no chance of finding the exact meganuclease required to act on a chosen specific DNA sequence. To overcome this challenge, mutagenesis and high throughput screening methods have been used to create meganuclease variants that recognize unique sequences. Others have been able to fuse various meganucleases and create hybrid enzymes that recognize a new sequence. Yet others have attempted to alter the DNA interacting aminoacids of the meganuclease to design sequence specific meganucelases in a method named rationally designed meganuclease. Another approach involves using computer models to try to predict as accurately as possible the activity of the modified meganucleases and the specificity of the recognized nucleic sequence.
A large bank containing several tens of thousands of protein units has been created. These units can be combined to obtain chimeric meganucleases that recognize the target site, thereby providing research and development tools that meet a wide range of needs (fundamental research, health, agriculture, industry, energy, etc.) These include the industrial-scale production of two meganucleases able to cleave the human XPC gene; mutations in this gene result in Xeroderma pigmentosum, a severe monogenic disorder that predisposes the patients to skin cancer and burns whenever their skin is exposed to UV rays.
Meganucleases have the benefit of causing less toxicity in cells than methods such as Zinc finger nuclease (ZFN), likely because of more stringent DNA sequence recognition; however, the construction of sequence-specific enzymes for all possible sequences is costly and time-consuming, as one is not benefiting from combinatorial possibilities that methods such as ZFNs and TALEN-based fusions utilize.
==== Zinc finger nucleases ====
As opposed to meganucleases, the concept behind ZFNs and TALEN technology is based on a non-specific DNA cutting catalytic domain, which can then be linked to specific DNA sequence recognizing peptides such as zinc fingers and transcription activator-like effectors (TALEs). The first step to this was to find an endonuclease whose DNA recognition site and cleaving site were separate from each other, a situation that is not the most common among restriction enzymes. Once this enzyme was found, its cleaving portion could be separated which would be very non-specific as it would have no recognition ability. This portion could then be linked to sequence recognizing peptides that could lead to very high specificity.
Zinc finger motifs occur in several transcription factors. The zinc ion, found in 8% of all human proteins, plays an important role in the organization of their three-dimensional structure. In transcription factors, it is most often located at the protein-DNA interaction sites, where it stabilizes the motif. The C-terminal part of each finger is responsible for the specific recognition of the DNA sequence.
The recognized sequences are short, made up of around 3 base pairs, but by combining 6 to 8 zinc fingers whose recognition sites have been characterized, it is possible to obtain specific proteins for sequences of around 20 base pairs. It is therefore possible to control the expression of a specific gene. It has been demonstrated that this strategy can be used to promote a process of angiogenesis in animals. It is also possible to fuse a protein constructed in this way with the catalytic domain of an endonuclease in order to induce a targeted DNA break, and therefore to use these proteins as genome engineering tools.
The method generally adopted for this involves associating two DNA binding proteins – each containing 3 to 6 specifically chosen zinc fingers – with the catalytic domain of the FokI endonuclease which need to dimerize to cleave the double-strand DNA. The two proteins recognize two DNA sequences that are a few nucleotides apart. Linking the two zinc finger proteins to their respective sequences brings the two FokI domains closer together. FokI requires dimerization to have nuclease activity and this means the specificity increases dramatically as each nuclease partner would recognize a unique DNA sequence. To enhance this effect, FokI nucleases have been engineered that can only function as heterodimers.
Several approaches are used to design specific zinc finger nucleases for the chosen sequences. The most widespread involves combining zinc-finger units with known specificities (modular assembly). Various selection techniques, using bacteria, yeast or mammal cells have been developed to identify the combinations that offer the best specificity and the best cell tolerance. Although the direct genome-wide characterization of zinc finger nuclease activity has not been reported, an assay that measures the total number of double-strand DNA breaks in cells found that only one to two such breaks occur above background in cells treated with zinc finger nucleases with a 24 bp composite recognition site and obligate heterodimer FokI nuclease domains.
The heterodimer functioning nucleases would avoid the possibility of unwanted homodimer activity and thus increase specificity of the DSB. Although the nuclease portions of both ZFNs and TALEN constructs have similar properties, the difference between these engineered nucleases is in their DNA recognition peptide. ZFNs rely on Cys2-His2 zinc fingers and TALEN constructs on TALEs. Both of these DNA recognizing peptide domains have the characteristic that they are naturally found in combinations in their proteins. Cys2-His2 Zinc fingers typically happen in repeats that are 3 bp apart and are found in diverse combinations in a variety of nucleic acid interacting proteins such as transcription factors. Each finger of the Zinc finger domain is completely independent and the binding capacity of one finger is impacted by its neighbor. TALEs on the other hand are found in repeats with a one-to-one recognition ratio between the amino acids and the recognized nucleotide pairs. Because both zinc fingers and TALEs happen in repeated patterns, different combinations can be tried to create a wide variety of sequence specificities. Zinc fingers have been more established in these terms and approaches such as modular assembly (where Zinc fingers correlated with a triplet sequence are attached in a row to cover the required sequence), OPEN (low-stringency selection of peptide domains vs. triplet nucleotides followed by high-stringency selections of peptide combination vs. the final target in bacterial systems), and bacterial one-hybrid screening of zinc finger libraries among other methods have been used to make site specific nucleases.
Zinc finger nucleases are research and development tools that have already been used to modify a range of genomes, in particular by the laboratories in the Zinc Finger Consortium. The US company Sangamo BioSciences uses zinc finger nucleases to carry out research into the genetic engineering of stem cells and the modification of immune cells for therapeutic purposes. Modified T lymphocytes are currently undergoing phase I clinical trials to treat a type of brain tumor (glioblastoma) and in the fight against AIDS.
==== TALEN ====
Transcription activator-like effector nucleases (TALENs) are specific DNA-binding proteins that feature an array of 33 or 34-amino acid repeats. TALENs are artificial restriction enzymes designed by fusing the DNA cutting domain of a nuclease to TALE domains, which can be tailored to specifically recognize a unique DNA sequence. These fusion proteins serve as readily targetable "DNA scissors" for gene editing applications that enable to perform targeted genome modifications such as sequence insertion, deletion, repair and replacement in living cells. The DNA binding domains, which can be designed to bind any desired DNA sequence, comes from TAL effectors, DNA-binding proteins excreted by plant pathogenic Xanthomanos app. TAL effectors consists of repeated domains, each of which contains a highly conserved sequence of 34 amino acids, and recognize a single DNA nucleotide within the target site. The nuclease can create double strand breaks at the target site that can be repaired by error-prone non-homologous end-joining (NHEJ), resulting in gene disruptions through the introduction of small insertions or deletions. Each repeat is conserved, with the exception of the so-called repeat variable di-residues (RVDs) at amino acid positions 12 and 13. The RVDs determine the DNA sequence to which the TALE will bind. This simple one-to-one correspondence between the TALE repeats and the corresponding DNA sequence makes the process of assembling repeat arrays to recognize novel DNA sequences straightforward. These TALEs can be fused to the catalytic domain from a DNA nuclease, FokI, to generate a transcription activator-like effector nuclease (TALEN). The resultant TALEN constructs combine specificity and activity, effectively generating engineered sequence-specific nucleases that bind and cleave DNA sequences only at pre-selected sites. The TALEN target recognition system is based on an easy-to-predict code. TAL nucleases are specific to their target due in part to the length of their 30+ base pairs binding site. TALEN can be performed within a 6 base pairs range of any single nucleotide in the entire genome.
TALEN constructs are used in a similar way to designed zinc finger nucleases, and have three advantages in targeted mutagenesis: (1) DNA binding specificity is higher, (2) off-target effects are lower, and (3) construction of DNA-binding domains is easier.
==== CRISPR ====
CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats) are genetic elements that bacteria use as a kind of acquired immunity to protect against viruses. They consist of short sequences that originate from viral genomes and have been incorporated into the bacterial genome. Cas (CRISPR associated proteins) process these sequences and cut matching viral DNA sequences. By introducing plasmids containing Cas genes and specifically constructed CRISPRs into eukaryotic cells, the eukaryotic genome can be cut at any desired position.
=== Editing by nucleobase modification (Base editing) ===
One of the earliest methods of efficiently editing nucleic acids employs nucleobase modifying enzymes directed by nucleic acid guide sequences was first described in the 1990s and has seen resurgence more recently. This method has the advantage that it does not require breaking the genomic DNA strands, and thus avoids the random insertion and deletions associated with DNA strand breakage. It is only appropriate for precise editing requiring single nucleotide changes and has found to be highly efficient for this type of editing.
=== ARCUT ===
ARCUT stands for artificial restriction DNA cutter, it is a technique developed by Komiyama. This method uses pseudo-complementary peptide nucleic acid (pcPNA), for identifying cleavage site within the chromosome. Once pcPNA specifies the site, excision is carried out by cerium (CE) and EDTA (chemical mixture), which performs the splicing function.
== Precision and efficiency of engineered nucleases ==
Meganucleases method of gene editing is the least efficient of the methods mentioned above. Due to the nature of its DNA-binding element and the cleaving element, it is limited to recognizing one potential target every 1,000 nucleotides. ZFN was developed to overcome the limitations of meganuclease. The number of possible targets ZFN can recognise was increased to one in every 140 nucleotides. However, both methods are unpredictable because of their DNA-binding elements affecting each other. As a result, high degrees of expertise and lengthy and costly validation processes are required.
TALE nucleases, being the most precise and specific method, yields a higher efficiency than the previous two methods. It achieves such efficiency because the DNA-binding element consists of an array of TALE subunits, each of them having the capability of recognizing a specific DNA nucleotide chain independently from others, resulting in a higher number of target sites with high precision. New TALE nucleases take about one week and a few hundred dollars to create, with specific expertise in molecular biology and protein engineering.
CRISPR nucleases have a slightly lower precision when compared to the TALE nucleases. This is caused by the need to have a specific nucleotide at one end in order to produce the guide RNA that CRISPR uses to repair the double-strand break it induces. It has been shown to be the quickest and cheapest method, only costing less than two hundred dollars and a few days of time. CRISPR also requires the least amount of expertise in molecular biology, as the design lays in the guide RNA instead of the proteins. One major advantage that CRISPR has over the ZFN and TALEN methods is that it can be directed to target different DNA sequences using its ~80nt CRISPR sgRNAs, while both ZFN and TALEN methods required construction and testing of the proteins created for targeting each DNA sequence.
Because off-target activity of an active nuclease would have potentially dangerous consequences at the genetic and organismal levels, the precision of meganucleases, ZFNs, CRISPR, and TALEN-based fusions has been an active area of research. While variable figures have been reported, ZFNs tend to have more cytotoxicity than TALEN methods or RNA-guided nucleases, while TALEN and RNA-guided approaches tend to have the greatest efficiency and fewer off-target effects. Based on the maximum theoretical distance between DNA binding and nuclease activity, TALEN approaches result in the greatest precision.
== Multiplex Automated Genomic Engineering (MAGE) ==
The methods for scientists and researchers wanting to study genomic diversity and all possible associated phenotypes were very slow, expensive, and inefficient. Prior to this new revolution, researchers would have to do single-gene manipulations and tweak the genome one little section at a time, observe the phenotype, and start the process over with a different single-gene manipulation. Therefore, researchers at the Wyss Institute at Harvard University designed the MAGE, a powerful technology that improves the process of in vivo genome editing. It allows for quick and efficient manipulations of a genome, all happening in a machine small enough to put on top of a small kitchen table. Those mutations combine with the variation that naturally occurs during cell mitosis creating billions of cellular mutations.
Chemically combined, synthetic single-stranded DNA (ssDNA) and a pool of oligonucleotides are introduced at targeted areas of the cell, thereby creating genetic modifications. The cyclical process involves transformation of ssDNA (by electroporation) followed by outgrowth, during which bacteriophage homologous recombination proteins mediate annealing of ssDNAs to their genomic targets. Experiments targeting selective phenotypic markers are screened and identified by plating the cells on differential medias. Each cycle ultimately takes 2.5 hours to process, with additional time required to grow isogenic cultures and characterize mutations. By iteratively introducing libraries of mutagenic ssDNAs targeting multiple sites, MAGE can generate combinatorial genetic diversity in a cell population. There can be up to 50 genome edits, from single nucleotide base pairs to whole genome or gene networks simultaneously with results in a matter of days.
MAGE experiments can be divided into three classes, characterized by varying degrees of scale and complexity: (i) many target sites, single genetic mutations; (ii) single target site, many genetic mutations; and (iii) many target sites, many genetic mutations. An example of class three was reflected in 2009, where Church and colleagues were able to program Escherichia coli to produce five times the normal amount of lycopene, an antioxidant normally found in tomato seeds and linked to anti-cancer properties. They applied MAGE to optimize the 1-deoxy-D-xylulose 5-phosphate (DXP) metabolic pathway in Escherichia coli to overproduce isoprenoid lycopene. It took them about 3 days and just over $1,000 in materials. The ease, speed, and cost efficiency in which MAGE can alter genomes can transform how industries approach the manufacturing and production of important compounds in the bioengineering, bioenergy, biomedical engineering, synthetic biology, pharmaceutical, agricultural, and chemical industries.
== Applications ==
As of 2012, efficient genome editing had been developed for a wide range of experimental systems ranging from plants to animals, often beyond clinical interest, and was becoming a standard experimental strategy in research labs. The recent generation of rat, zebrafish, maize and tobacco ZFN-mediated mutants and the improvements in TALEN-based approaches testify to the significance of the methods, and the list is expanding rapidly. Genome editing with engineered nucleases will likely contribute to many fields of life sciences from studying gene functions in plants and animals to gene therapy in humans. For instance, the field of synthetic biology which aims to engineer cells and organisms to perform novel functions, is likely to benefit from the ability of engineered nuclease to add or remove genomic elements and therefore create complex systems. In addition, gene functions can be studied using stem cells with engineered nucleases.
Listed below are some specific tasks this method can carry out:
Targeted gene mutation
Gene therapy
Creating chromosome rearrangement
Study gene function with stem cells
Transgenic animals
Endogenous gene labeling
Targeted transgene addition
=== Targeted gene modification in animals ===
The combination of recent discoveries in genetic engineering, particularly gene editing and the latest improvement in bovine reproduction technologies (e.g. in vitro embryo culture) allows for genome editing directly in fertilised oocytes using synthetic highly specific endonucleases. RNA-guided endonucleases:clustered regularly interspaced short palindromic repeats associated Cas9 (CRISPR/Cas9) are a new tool, further increasing the range of methods available. In particular CRISPR/Cas9 engineered endonucleases allows the use of multiple guide RNAs for simultaneous Knockouts (KO) in one step by cytoplasmic direct injection (CDI) on mammalian zygotes.
Furthermore, gene editing can be applied to certain types of fish in aquaculture such as Atlantic salmon. Gene editing in fish is currently experimental, but the possibilities include growth, disease resistance, sterility, controlled reproduction, and colour. Selecting for these traits can allow for a more sustainable environment and better welfare for the fish.
AquAdvantage salmon is a genetically modified Atlantic salmon developed by AquaBounty Technologies. The growth hormone-regulating gene in the Atlantic salmon is replaced with the growth hormone-regulating gene from the Pacific Chinook salmon and a promoter sequence from the ocean pout
Thanks to the parallel development of single-cell transcriptomics, genome editing and new stem cell models we are now entering a scientifically exciting period where functional genetics is no longer restricted to animal models but can be performed directly in human samples. Single-cell gene expression analysis has resolved a transcriptional road-map of human development from which key candidate genes are being identified for functional studies. Using global transcriptomics data to guide experimentation, the CRISPR based genome editing tool has made it feasible to disrupt or remove key genes in order to elucidate function in a human setting.
=== Targeted gene modification in plants ===
Genome editing using Meganuclease, ZFNs, and TALEN provides a new strategy for genetic manipulation in plants and are likely to assist in the engineering of desired plant traits by modifying endogenous genes. For instance, site-specific gene addition in major crop species can be used for 'trait stacking' whereby several desired traits are physically linked to ensure their co-segregation during the breeding processes. Progress in such cases have been recently reported in Arabidopsis thaliana and Zea mays. In Arabidopsis thaliana, using ZFN-assisted gene targeting, two herbicide-resistant genes (tobacco acetolactate synthase SuRA and SuRB) were introduced to SuR loci with as high as 2% transformed cells with mutations. In Zea mays, disruption of the target locus was achieved by ZFN-induced DSBs and the resulting NHEJ. ZFN was also used to drive herbicide-tolerance gene expression cassette (PAT) into the targeted endogenous locus IPK1 in this case. Such genome modification observed in the regenerated plants has been shown to be inheritable and was transmitted to the next generation. A potentially successful example of the application of genome editing techniques in crop improvement can be found in banana, where scientists used CRISPR/Cas9 editing to inactivate the endogenous banana streak virus in the B genome of banana (Musa spp.) to overcome a major challenge in banana breeding.
In addition, TALEN-based genome engineering has been extensively tested and optimized for use in plants. TALEN fusions have also been used by a U.S. food ingredient company, Calyxt, to improve the quality of soybean oil products and to increase the storage potential of potatoes
Several optimizations need to be made in order to improve editing plant genomes using ZFN-mediated targeting. There is a need for reliable design and subsequent test of the nucleases, the absence of toxicity of the nucleases, the appropriate choice of the plant tissue for targeting, the routes of induction of enzyme activity, the lack of off-target mutagenesis, and a reliable detection of mutated cases.
A common delivery method for CRISPR/Cas9 in plants is Agrobacterium-based transformation. T-DNA is introduced directly into the plant genome by a T4SS mechanism. Cas9 and gRNA-based expression cassettes are turned into Ti plasmids, which are transformed in Agrobacterium for plant application. To improve Cas9 delivery in live plants, viruses are being used more effective transgene delivery.
== Research ==
=== Gene therapy ===
The ideal gene therapy practice is one that replaces the defective gene with a normal allele at its natural location. This is advantageous over a virally-delivered gene, as there is no need to include the full coding sequences and regulatory sequences when only a small proportion of the gene needs to be altered, as is often the case. The expression of the partially replaced genes is also more consistent with normal cell biology than full genes that are carried by viral vectors.
The first clinical use of TALEN-based genome editing was in the treatment of CD19+ acute lymphoblastic leukemia in an 11-month old child in 2015. Modified donor T cells were engineered to attack the leukemia cells, to be resistant to Alemtuzumab, and to evade detection by the host immune system after introduction.
Extensive research has been done in cells and animals using CRISPR-Cas9 to attempt to correct genetic mutations which cause genetic diseases such as Down syndrome, spina bifida, anencephaly, and Turner and Klinefelter syndromes.
In February 2019, medical scientists working with Sangamo Therapeutics, headquartered in Richmond, California, announced the first ever "in body" human gene editing therapy to permanently alter DNA - in a patient with Hunter syndrome. Clinical trials by Sangamo involving gene editing using Zinc Finger Nuclease (ZFN) are ongoing.
=== Eradicating diseases ===
Researchers have used CRISPR-Cas9 gene drives to modify genes associated with sterility in A. gambiae, the vector for malaria. This technique has further implications in eradicating other vector borne diseases such as yellow fever, dengue, and Zika.
The CRISPR-Cas9 system can be programmed to modulate the population of any bacterial species by targeting clinical genotypes or epidemiological isolates. It can selectively enable the beneficial bacterial species over the harmful ones by eliminating pathogen, which gives it an advantage over broad-spectrum antibiotics.
Antiviral applications for therapies targeting human viruses such as HIV, herpes, and hepatitis B virus are under research. CRISPR can be used to target the virus or the host to disrupt genes encoding the virus cell-surface receptor proteins. In November 2018, He Jiankui announced that he had edited two human embryos, to attempt to disable the gene for CCR5, which codes for a receptor that HIV uses to enter cells. He said that twin girls, Lulu and Nana, had been born a few weeks earlier. He said that the girls still carried functional copies of CCR5 along with disabled CCR5 (mosaicism) and were still vulnerable to HIV. The work was widely condemned as unethical, dangerous, and premature.
In January 2019, scientists in China reported the creation of five identical cloned gene-edited monkeys, using the same cloning technique that was used with Zhong Zhong and Hua Hua – the first ever cloned monkeys - and Dolly the sheep, and the same gene-editing Crispr-Cas9 technique allegedly used by He Jiankui in creating the first ever gene-modified human babies Lulu and Nana. The monkey clones were made in order to study several medical diseases.
== Prospects and limitations ==
In the future, an important goal of research into genome editing with engineered nucleases must be the improvement of the safety and specificity of the nucleases action. For example, improving the ability to detect off-target events can improve our ability to learn about ways of preventing them. In addition, zinc-fingers used in ZFNs are seldom completely specific, and some may cause a toxic reaction. However, the toxicity has been reported to be reduced by modifications done on the cleavage domain of the ZFN.
In addition, research by Dana Carroll into modifying the genome with engineered nucleases has shown the need for better understanding of the basic recombination and repair machinery of DNA. In the future, a possible method to identify secondary targets would be to capture broken ends from cells expressing the ZFNs and to sequence the flanking DNA using high-throughput sequencing.
Because of the ease of use and cost-efficiency of CRISPR, extensive research is currently being done on it. There are now more publications on CRISPR than ZFN and TALEN despite how recent the discovery of CRISPR is. Both CRISPR and TALEN are favored to be the choices to be implemented in large-scale productions due to their precision and efficiency.
Genome editing occurs also as a natural process without artificial genetic engineering. The agents that are competent to edit genetic codes are viruses or subviral RNA-agents.
Although GEEN has higher efficiency than many other methods in reverse genetics, it is still not highly efficient; in many cases less than half of the treated populations obtain the desired changes. For example, when one is planning to use the cell's NHEJ to create a mutation, the cell's HDR systems will also be at work correcting the DSB with lower mutational rates.
Traditionally, mice have been the most common choice for researchers as a host of a disease model. CRISPR can help bridge the gap between this model and human clinical trials by creating transgenic disease models in larger animals such as pigs, dogs, and non-human primates. Using the CRISPR-Cas9 system, the programmed Cas9 protein and the sgRNA can be directly introduced into fertilized zygotes to achieve the desired gene modifications when creating transgenic models in rodents. This allows bypassing of the usual cell targeting stage in generating transgenic lines, and as a result, it reduces generation time by 90%.
One potential that CRISPR brings with its effectiveness is the application of xenotransplantation. In previous research trials, CRISPR demonstrated the ability to target and eliminate endogenous retroviruses, which reduces the risk of transmitting diseases and reduces immune barriers. Eliminating these problems improves donor organ function, which brings this application closer to a reality.
In plants, genome editing is seen as a viable solution to the conservation of biodiversity. Gene drive are a potential tool to alter the reproductive rate of invasive species, although there are significant associated risks.
=== Human enhancement ===
Many transhumanists see genome editing as a potential tool for human enhancement. Australian biologist and Professor of Genetics David Andrew Sinclair notes that "the new technologies with genome editing will allow it to be used on individuals (...) to have (...) healthier children" – designer babies. According to a September 2016 report by the Nuffield Council on Bioethics in the future it may be possible to enhance people with genes from other organisms or wholly synthetic genes to for example improve night vision and sense of smell. George Church has compiled a list of potential genetic modifications for possibly advantageous traits such as less need for sleep, cognition-related changes that protect against Alzheimer's disease, disease resistances and enhanced learning abilities along with some of the associated studies and potential negative effects.
The American National Academy of Sciences and National Academy of Medicine issued a report in February 2017 giving qualified support to human genome editing. They recommended that clinical trials for genome editing might one day be permitted once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."
== Risks ==
In the 2016 Worldwide Threat Assessment of the US Intelligence Community statement United States Director of National Intelligence, James R. Clapper, named genome editing as a potential weapon of mass destruction, stating that genome editing conducted by countries with regulatory or ethical standards "different from Western countries" probably increases the risk of the creation of harmful biological agents or products. According to the statement the broad distribution, low cost, and accelerated pace of development of this technology, its deliberate or unintentional misuse might lead to far-reaching economic and national security implications. For instance technologies such as CRISPR could be used to make "killer mosquitoes" that cause plagues that wipe out staple crops.
According to a September 2016 report by the Nuffield Council on Bioethics, the simplicity and low cost of tools to edit the genetic code will allow amateurs – or "biohackers" – to perform their own experiments, posing a potential risk from the release of genetically modified bugs. The review also found that the risks and benefits of modifying a person's genome – and having those changes pass on to future generations – are so complex that they demand urgent ethical scrutiny. Such modifications might have unintended consequences which could harm not only the child, but also their future children, as the altered gene would be in their sperm or eggs. In 2001 Australian researchers Ronald Jackson and Ian Ramshaw were criticized for publishing a paper in the Journal of Virology that explored the potential control of mice, a major pest in Australia, by infecting them with an altered mousepox virus that would cause infertility as the provided sensitive information could lead to the manufacture of biological weapons by potential bioterrorists who might use the knowledge to create vaccine resistant strains of other pox viruses, such as smallpox, that could affect humans. Furthermore, there are additional concerns about the ecological risks of releasing gene drives into wild populations.
== Nobel prize ==
In 2007, the Nobel Prize for Physiology or Medicine was awarded to Mario Capecchi, Martin Evans and Oliver Smithies "for their discoveries of principles for introducing specific gene modifications in mice by the use of embryonic stem cells."
In 2020, the Nobel Prize in Chemistry was awarded to Emmanuelle Charpentier and Jennifer Doudna for "the development of a method for genome editing".
== See also ==
CRISPR/Cpf1
Woolly mouse
RNA editing
Epigenome editing
Prime editing
Transposons as a genetic tool
Germinal choice technology
NgAgo, a ssDNA-guided Argonaute endonuclease
== References ==
"WHO launches global registry on human genome editing." PharmaBiz, 31 Aug. 2019. Gale General OneFile, Accessed 27 Apr. 2020.
== Further reading ==
Saurabh S (March 2021). "Genome Editing: Revolutionizing the Crop Improvement". Plant Molecular Biology Reporte. 39 (4): 752–772. doi:10.1007/s11105-021-01286-7. S2CID 233713026.
"Special Issue on Human Germline Editing". Bioethics. 34. 2020.
"Customized Human Genes: New Promises and Perils". Scientific American. Retrieved 2019-02-21.
Connor S (25 April 2014). "Scientific split - the human genome breakthrough dividing former colleagues". The Independent. Retrieved 2016-02-11.
"What is genome editing?". yourgenome.org. Retrieved 2025-03-25. | Wikipedia/Human_gene_editing_therapy |
The retina (from Latin rete 'net'; pl. retinae or retinas) is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.
The neural retina consists of several layers of neurons interconnected by synapses and is supported by an outer layer of pigmented epithelial cells. The primary light-sensing cells in the retina are the photoreceptor cells, which are of two types: rods and cones. Rods function mainly in dim light and provide monochromatic vision. Cones function in well-lit conditions and are responsible for the perception of colour through the use of a range of opsins, as well as high-acuity vision used for tasks such as reading. A third type of light-sensing cell, the photosensitive ganglion cell, is important for entrainment of circadian rhythms and reflexive responses such as the pupillary light reflex.
Light striking the retina initiates a cascade of chemical and electrical events that ultimately trigger nerve impulses that are sent to various visual centres of the brain through the fibres of the optic nerve. Neural signals from the rods and cones undergo processing by other neurons, whose output takes the form of action potentials in retinal ganglion cells whose axons form the optic nerve.
In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain, specifically the embryonic diencephalon; thus, the retina is considered part of the central nervous system (CNS) and is actually brain tissue. It is the only part of the CNS that can be visualized noninvasively. Like most of the brain, the retina is isolated from the vascular system by the blood–brain barrier. The retina is the part of the body with the greatest continuous energy demand.
== Structure ==
=== Inverted versus non-inverted retina ===
The vertebrate retina is inverted in the sense that the light-sensing cells are in the back of the retina, so that light has to pass through layers of neurons and capillaries before it reaches the photosensitive sections of the rods and cones. The ganglion cells, whose axons form the optic nerve, are at the front of the retina; therefore, the optic nerve must cross through the retina en route to the brain. No photoreceptors are in this region, giving rise to the blind spot. In contrast, in the cephalopod retina, the photoreceptors are in front, with processing neurons and capillaries behind them. Because of this, cephalopods do not have a blind spot.
Although the overlying neural tissue is partly transparent, and the accompanying glial cells have been shown to act as fibre-optic channels to transport photons directly to the photoreceptors, light scattering does occur. Some vertebrates, including humans, have an area of the central retina adapted for high-acuity vision. This area, termed the fovea centralis, is avascular (does not have blood vessels), and has minimal neural tissue in front of the photoreceptors, thereby minimizing light scattering.
The cephalopods have a non-inverted retina, which is comparable in resolving power to the eyes of many vertebrates. Squid eyes do not have an analog of the vertebrate retinal pigment epithelium (RPE). Although their photoreceptors contain a protein, retinochrome, that recycles retinal and replicates one of the functions of the vertebrate RPE, cephalopod photoreceptors are likely not maintained as well as in vertebrates, and that as a result, the useful lifetime of photoreceptors in invertebrates is much shorter than in vertebrates. Having easily replaced stalk eyes (some lobsters) or retinae (some spiders, such as Deinopis) rarely occurs.
The cephalopod retina does not originate as an outgrowth of the brain, as the vertebrate one does. This difference suggests that vertebrate and cephalopod eyes are not homologous, but have evolved separately. From an evolutionary perspective, a more complex structure such as the inverted retina can generally come about as a consequence of two alternate processes - an advantageous "good" compromise between competing functional limitations, or as a historical maladaptive relic of the convoluted path of organ evolution and transformation. Vision is an important adaptation in higher vertebrates.
A third view of the "inverted" vertebrate eye is that it combines two benefits - the maintenance of the photoreceptors mentioned above, and the reduction in light intensity necessary to avoid blinding the photoreceptors, which are based on the extremely sensitive eyes of the ancestors of modern hagfish (fish that live in very deep, dark water).
A recent study on the evolutionary purpose for the inverted retina structure from the APS (American Physical Society) says that "The directional of glial cells helps increase the clarity of human vision. But we also noticed something rather curious: the colours that best passed through the glial cells were green to red, which the eye needs most for daytime vision. The eye usually receives too much blue—and thus has fewer blue-sensitive cones.
Further computer simulations showed that green and red are concentrated five to ten times more by the glial cells, and into their respective cones, than blue light. Instead, excess blue light gets scattered to the surrounding rods. This optimization is such that color vision during the day is enhanced, while night-time vision suffers very little".
=== Retinal layers ===
The vertebrate retina has 10 distinct layers. From closest to farthest from the vitreous body:
Inner limiting membrane – basement membrane elaborated by Müller cells
Nerve fiber layer – axons of the ganglion cell bodies (a thin layer of Müller cell footplates exists between this layer and the inner limiting membrane)
Ganglion cell layer – contains nuclei of ganglion cells, the axons of which become the optic nerve fibres, and some displaced amacrine cells
Inner plexiform layer – contains the synapse between the bipolar cell axons and the dendrites of the ganglion and amacrine cells
Inner nuclear layer – contains the nuclei and surrounding cell bodies (perikarya) of the amacrine cells, bipolar cells, and horizontal cells
Outer plexiform layer – projections of rods and cones ending in the rod spherule and cone pedicle, respectively, these make synapses with dendrites of bipolar cells and horizontal cells. In the macular region, this is known as the fiber layer of Henle.
Outer nuclear layer – cell bodies of rods and cones
External limiting membrane – layer that separates the inner segment portions of the photoreceptors from their cell nuclei
Inner segment / outer segment layer – inner segments and outer segments of rods and cones, the outer segments contain a highly specialized light-sensing apparatus.
Retinal pigment epithelium – single layer of cuboidal epithelial cells (with extrusions not shown in diagram). This layer is closest to the choroid, and provides nourishment and supportive functions to the neural retina, The black pigment melanin in the pigment layer prevents light reflection throughout the globe of the eyeball; this is extremely important for clear vision.
These layers can be grouped into four main processing stages—photoreception; transmission to bipolar cells; transmission to ganglion cells, which also contain photoreceptors, the photosensitive ganglion cells; and transmission along the optic nerve. At each synaptic stage, horizontal and amacrine cells also are laterally connected.
The optic nerve is a central tract of many axons of ganglion cells connecting primarily to the lateral geniculate body, a visual relay station in the diencephalon (the rear of the forebrain). It also projects to the superior colliculus, the suprachiasmatic nucleus, and the nucleus of the optic tract. It passes through the other layers, creating the optic disc in primates.
Additional structures, not directly associated with vision, are found as outgrowths of the retina in some vertebrate groups. In birds, the pecten is a vascular structure of complex shape that projects from the retina into the vitreous humour; it supplies oxygen and nutrients to the eye, and may also aid in vision. Reptiles have a similar, but much simpler, structure.
In adult humans, the entire retina is about 72% of a sphere about 22 mm in diameter. The entire retina contains about 7 million cones and 75 to 150 million rods. The optic disc, a part of the retina sometimes called "the blind spot" because it lacks photoreceptors, is located at the optic papilla, where the optic-nerve fibres leave the eye. It appears as an oval white area of 3 mm2. Temporal (in the direction of the temples) to this disc is the macula, at whose centre is the fovea, a pit that is responsible for sharp central vision, but is actually less sensitive to light because of its lack of rods. Human and non-human primates possess one fovea, as opposed to certain bird species, such as hawks, that are bifoviate, and dogs and cats, that possess no fovea, but a central band known as the visual streak. Around the fovea extends the central retina for about 6 mm and then the peripheral retina. The farthest edge of the retina is defined by the ora serrata. The distance from one ora to the other (or macula), the most sensitive area along the horizontal meridian, is about 32 mm.
In section, the retina is no more than 0.5 mm thick. It has three layers of nerve cells and two of synapses, including the unique ribbon synapse. The optic nerve carries the ganglion-cell axons to the brain, and the blood vessels that supply the retina. The ganglion cells lie innermost in the eye while the photoreceptive cells lie beyond. Because of this counter-intuitive arrangement, light must first pass through and around the ganglion cells and through the thickness of the retina, (including its capillary vessels, not shown) before reaching the rods and cones. Light is absorbed by the retinal pigment epithelium or the choroid (both of which are opaque).
The white blood cells in the capillaries in front of the photoreceptors can be perceived as tiny bright moving dots when looking into blue light. This is known as the blue field entoptic phenomenon (or Scheerer's phenomenon).
Between the ganglion-cell layer and the rods and cones are two layers of neuropils, where synaptic contacts are made. The neuropil layers are the outer plexiform layer and the inner plexiform layer. In the outer neuropil layer, the rods and cones connect to the vertically running bipolar cells, and the horizontally oriented horizontal cells connect to ganglion cells.
The central retina predominantly contains cones, while the peripheral retina predominantly contains rods. In total, the retina has about seven million cones and a hundred million rods. At the centre of the macula is the foveal pit where the cones are narrow and long, and arranged in a hexagonal mosaic, the most dense, in contradistinction to the much fatter cones located more peripherally in the retina. At the foveal pit, the other retinal layers are displaced, before building up along the foveal slope until the rim of the fovea, or parafovea, is reached, which is the thickest portion of the retina. The macula has a yellow pigmentation, from screening pigments, and is known as the macula lutea. The area directly surrounding the fovea has the highest density of rods converging on single bipolar cells. Since its cones have a much lesser convergence of signals, the fovea allows for the sharpest vision the eye can attain.
Though the rod and cones are a mosaic of sorts, transmission from receptors, to bipolars, to ganglion cells is not direct. Since about 150 million receptors and only 1 million optic nerve fibres exist, convergence and thus mixing of signals must occur. Moreover, the horizontal action of the horizontal and amacrine cells can allow one area of the retina to control another (e.g. one stimulus inhibiting another). This inhibition is key to lessening the sum of messages sent to the higher regions of the brain. In some lower vertebrates (e.g. the pigeon), control of messages is "centrifugal" – that is, one layer can control another, or higher regions of the brain can drive the retinal nerve cells, but in primates, this does not occur.
==== Layers imagable with optical coherence tomography ====
Using optical coherence tomography (OCT), at least 13 layers can be identified in the retina. The layers and anatomical correlation are:
From innermost to outermost, the layers identifiable by OCT are as follows:
=== Development ===
Retinal development begins with the establishment of the eye fields mediated by the SHH and SIX3 proteins, with subsequent development of the optic vesicles regulated by the PAX6 and LHX2 proteins. The role of Pax6 in eye development was elegantly demonstrated by Walter Gehring and colleagues, who showed that ectopic expression of Pax6 can lead to eye formation on Drosophila antennae, wings, and legs. The optic vesicle gives rise to three structures: the neural retina, the retinal pigmented epithelium, and the optic stalk. The neural retina contains the retinal progenitor cells (RPCs) that give rise to the seven cell types of the retina. Differentiation begins with the retinal ganglion cells and concludes with production of the Muller glia. Although each cell type differentiates from the RPCs in a sequential order, there is considerable overlap in the timing of when individual cell types differentiate. The cues that determine a RPC daughter cell fate are coded by multiple transcription factor families including the bHLH and homeodomain factors.
In addition to guiding cell fate determination, cues exist in the retina to determine the dorsal-ventral (D-V) and nasal-temporal (N-T) axes. The D-V axis is established by a ventral to dorsal gradient of VAX2, whereas the N-T axis is coordinated by expression of the forkhead transcription factors FOXD1 and FOXG1. Additional gradients are formed within the retina. This spatial distribution may aid in proper targeting of RGC axons that function to establish the retinotopic map.
=== Blood supply ===
The retina is stratified into distinct layers, each containing specific cell types or cellular compartments that have metabolisms with different nutritional requirements. To satisfy these requirements, the ophthalmic artery bifurcates and supplies the retina via two distinct vascular networks: the choroidal network, which supplies the choroid and the outer retina, and the retinal network, which supplies the retina's inner layer.
Although the inverted retina of vertebrates appears counter-intuitive, it is necessary for the proper functioning of the retina. The photoreceptor layer must be embedded in the retinal pigment epithelium (RPE), which performs at least seven vital functions, one of the most obvious being to supply oxygen and other necessary nutrients needed for the photoreceptors to function.
==== Energy requirements ====
The energy requirements of the retina are even greater than that of the brain. This is due to the additional energy needed to continuously renew the photoreceptor outer segments, of which 10% are shed daily. Energy demands are greatest during dark adaptation when its sensitivity is most enhanced. The choroid supplies about 75% of these nutrients to the retina and the retinal vasculature only 25%.
When light strikes 11-cis-retinal (in the disks in the rods and cones), 11-cis-retinal changes to all-trans-retinal which then triggers changes in the opsins. Now, the outer segments do not regenerate the retinal back into the cis- form once it has been changed by light. Instead the retinal is pumped out to the surrounding RPE where it is regenerated and transported back into the outer segments of the photoreceptors. This recycling function of the RPE protects the photoreceptors against photo-oxidative damage and allows the photoreceptor cells to have decades-long useful lives.
==== In birds ====
The bird retina is devoid of blood vessels, perhaps to give unobscured passage of light for forming images, thus giving better resolution. It is, therefore, a considered view that the bird retina depends for nutrition and oxygen supply on a specialized organ, called the "pecten" or pecten oculi, located on the blind spot or optic disk. This organ is extremely rich in blood vessels and is thought to supply nutrition and oxygen to the bird retina by diffusion through the vitreous body. The pecten is highly rich in alkaline phosphatase activity and polarized cells in its bridge portion – both befitting its secretory role. Pecten cells are packed with dark melanin granules, which have been theorized to keep this organ warm with the absorption of stray light falling on the pecten. This is considered to enhance metabolic rate of the pecten, thereby exporting more nutritive molecules to meet the stringent energy requirements of the retina during long periods of exposure to light.
=== Biometric identification and diagnosis of disease ===
The bifurcations and other physical characteristics of the inner retinal vascular network are known to vary among individuals, and these individual variances have been used for biometric identification and for early detection of the onset of disease. The mapping of vascular bifurcations is one of the basic steps in biometric identification. Results of such analyses of retinal blood vessel structure can be evaluated against the ground truth data of vascular bifurcations of retinal fundus images that are obtained from the DRIVE dataset. In addition, the classes of vessels of the DRIVE dataset have also been identified, and an automated method for accurate extraction of these bifurcations is also available. Changes in retinal blood circulation are seen with aging and exposure to air pollution, and may indicate cardiovascular diseases such as hypertension and atherosclerosis. Determining the equivalent width of arterioles and venules near the optic disc is also a widely used technique to identify cardiovascular risks.
== Function ==
The retina translates an optical image into neural impulses starting with the patterned excitation of the colour-sensitive pigments of its rods and cones, the retina's photoreceptor cells. The excitation is processed by the neural system and various parts of the brain working in parallel to form a representation of the external environment in the brain.
The cones respond to bright light and mediate high-resolution colour vision during daylight illumination (also called photopic vision). The rod responses are saturated at daylight levels and do not contribute to pattern vision. However, rods do respond to dim light and mediate lower-resolution, monochromatic vision under very low levels of illumination (called scotopic vision). The illumination in most office settings falls between these two levels and is called mesopic vision. At mesopic light levels, both the rods and cones are actively contributing pattern information. What contribution the rod information makes to pattern vision under these circumstances is unclear.
The response of cones to various wavelengths of light is called their spectral sensitivity. In normal human vision, the spectral sensitivity of a cone falls into one of three subtypes, often called blue, green, and red, but more accurately known as short, medium, and long wavelength-sensitive cone subtypes. It is a lack of one or more of the cone subtypes that causes individuals to have deficiencies in colour vision or various kinds of colour blindness. These individuals are not blind to objects of a particular colour, but are unable to distinguish between colours that can be distinguished by people with normal vision. Humans have this trichromatic vision, while most other mammals lack cones with red sensitive pigment and therefore have poorer dichromatic colour vision. However, some animals have four spectral subtypes, e.g. the trout adds an ultraviolet subgroup to short, medium, and long subtypes that are similar to humans. Some fish are sensitive to the polarization of light as well.
In the photoreceptors, exposure to light hyperpolarizes the membrane in a series of graded shifts. The outer cell segment contains a photopigment. Inside the cell the normal levels of cyclic guanosine monophosphate (cGMP) keep the Na+ channel open, and thus in the resting state the cell is depolarised. The photon causes the retinal bound to the receptor protein to isomerise to trans-retinal. This causes the receptor to activate multiple G-proteins. This in turn causes the Ga-subunit of the protein to activate a phosphodiesterase (PDE6), which degrades cGMP, resulting in the closing of Na+ cyclic nucleotide-gated ion channels (CNGs). Thus the cell is hyperpolarised. The amount of neurotransmitter released is reduced in bright light and increases as light levels fall. The actual photopigment is bleached away in bright light and only replaced as a chemical process, so in a transition from bright light to darkness the eye can take up to thirty minutes to reach full sensitivity.
When thus excited by light, the photoceptor sends a proportional response synaptically to bipolar cells which in turn signal the retinal ganglion cells. The photoreceptors are also cross-linked by horizontal cells and amacrine cells, which modify the synaptic signal before it reaches the ganglion cells, the neural signals being intermixed and combined. Of the retina's nerve cells, only the retinal ganglion cells and few amacrine cells create action potentials.
In the retinal ganglion cells there are two types of response, depending on the receptive field of the cell. The receptive fields of retinal ganglion cells comprise a central, approximately circular area, where light has one effect on the firing of the cell, and an annular surround, where light has the opposite effect. In ON cells, an increment in light intensity in the centre of the receptive field causes the firing rate to increase. In OFF cells, it makes it decrease. In a linear model, this response profile is well described by a difference of Gaussians and is the basis for edge detection algorithms. Beyond this simple difference, ganglion cells are also differentiated by chromatic sensitivity and the type of spatial summation. Cells showing linear spatial summation are termed X cells (also called parvocellular, P, or midget ganglion cells), and those showing non-linear summation are Y cells (also called magnocellular, M, or parasol retinal ganglion cells), although the correspondence between X and Y cells (in the cat retina) and P and M cells (in the primate retina) is not as simple as it once seemed.
In the transfer of visual signals to the brain, the visual pathway, the retina is vertically divided in two, a temporal (nearer to the temple) half and a nasal (nearer to the nose) half. The axons from the nasal half cross the brain at the optic chiasma to join with axons from the temporal half of the other eye before passing into the lateral geniculate body.
Although there are more than 130 million retinal receptors, there are only approximately 1.2 million fibres (axons) in the optic nerve. So, a large amount of pre-processing is performed within the retina. The fovea produces the most accurate information. Despite occupying about 0.01% of the visual field (less than 2° of visual angle), about 10% of axons in the optic nerve are devoted to the fovea. The resolution limit of the fovea has been determined to be around 10,000 points. The information capacity is estimated at 500,000 bits per second (for more information on bits, see information theory) without colour or around 600,000 bits per second including colour.
=== Spatial encoding ===
When the retina sends neural impulses representing an image to the brain, it spatially encodes (compresses) those impulses to fit the limited capacity of the optic nerve. Compression is necessary because there are 100 times more photoreceptor cells than ganglion cells. This is done by "decorrelation", which is carried out by the "centre–surround structures", which are implemented by the bipolar and ganglion cells.
There are two types of centre–surround structures in the retina – on-centres and off-centres. On-centres have a positively weighted centre and a negatively weighted surround. Off-centres are just the opposite. Positive weighting is more commonly known as excitatory, and negative weighting as inhibitory.
These centre–surround structures are not physical apparent, in the sense that one cannot see them by staining samples of tissue and examining the retina's anatomy. The centre–surround structures are logical (i.e., mathematically abstract) in the sense that they depend on the connection strengths between bipolar and ganglion cells. It is believed that the connection strength between cells is caused by the number and types of ion channels embedded in the synapses between the bipolar and ganglion cells.
The centre–surround structures are mathematically equivalent to the edge detection algorithms used by computer programmers to extract or enhance the edges in a digital photograph. Thus, the retina performs operations on the image-representing impulses to enhance the edges of objects within its visual field. For example, in a picture of a dog, a cat and a car, it is the edges of these objects that contain the most information. In order for higher functions in the brain (or in a computer for that matter) to extract and classify objects such as a dog and a cat, the retina is the first step to separating out the various objects within the scene.
As an example, the following matrix is at the heart of a computer algorithm that implements edge detection. This matrix is the computer equivalent to the centre–surround structure. In this example, each box (element) within this matrix would be connected to one photoreceptor. The photoreceptor in the centre is the current receptor being processed. The centre photoreceptor is multiplied by the +1 weight factor. The surrounding photoreceptors are the "nearest neighbors" to the centre and are multiplied by the −1/8 value. The sum of all nine of these elements is finally calculated. This summation is repeated for every photoreceptor in the image by shifting left to the end of a row and then down to the next line.
The total sum of this matrix is zero, if all the inputs from the nine photoreceptors are of the same value. The zero result indicates the image was uniform (non-changing) within this small patch. Negative or positive sums mean the image was varying (changing) within this small patch of nine photoreceptors.
The above matrix is only an approximation to what really happens inside the retina. The differences are:
The above example is called "balanced". The term balanced means that the sum of the negative weights is equal to the sum of the positive weights so that they cancel out perfectly. Retinal ganglion cells are almost never perfectly balanced.
The table is square while the centre–surround structures in the retina are circular.
Neurons operate on spike trains traveling down nerve cell axons. Computers operate on a single floating-point number that is essentially constant from each input pixel. (The computer pixel is basically the equivalent of a biological photoreceptor.)
The retina performs all these calculations in parallel while the computer operates on each pixel one at a time. The retina performs no repeated summations and shifting as would a computer.
Finally, the horizontal and amacrine cells play a significant role in this process, but that is not represented here.
Here is an example of an input image and how edge detection would modify it.
Once the image is spatially encoded by the centre–surround structures, the signal is sent out along the optic nerve (via the axons of the ganglion cells) through the optic chiasm to the LGN (lateral geniculate nucleus). The exact function of the LGN is unknown at this time. The output of the LGN is then sent to the back of the brain. Specifically, the output of the LGN "radiates" out to the V1 primary visual cortex.
Simplified signal flow: Photoreceptors → Bipolar → Ganglion → Chiasm → LGN → V1 cortex
== Clinical significance ==
There are many inherited and acquired diseases or disorders that may affect the retina. Some of them include:
Retinitis pigmentosa is a group of genetic diseases that affect the retina and cause the loss of night vision and peripheral vision.
Macular degeneration describes a group of diseases characterized by loss of central vision because of death or impairment of the cells in the macula.
Cone-rod dystrophy (CORD) describes a number of diseases where vision loss is caused by deterioration of the cones and/or rods in the retina.
In retinal separation, the retina detaches from the back of the eyeball. Ignipuncture is an outdated treatment method. The term retinal detachment is used to describe a separation of the neurosensory retina from the retinal pigment epithelium. There are several modern treatment methods for fixing a retinal detachment: pneumatic retinopexy, scleral buckle, cryotherapy, laser photocoagulation and pars plana vitrectomy.
Both hypertension and diabetes mellitus can cause damage to the tiny blood vessels that supply the retina, leading to hypertensive retinopathy and diabetic retinopathy.
Retinoblastoma is a cancer of the retina.
Retinal diseases in dogs include retinal dysplasia, progressive retinal atrophy, and sudden acquired retinal degeneration.
Lipaemia retinalis is a white appearance of the retina, and can occur by lipid deposition in lipoprotein lipase deficiency.
Retinal Detachment. The neural retina occasionally detaches from the pigment epithelium. In some instances, the cause of such detachment is injury to the eyeball that allows fluid or blood to collect between the neural retina and the pigment epithelium. Detachment is occasionally caused by contracture of fine collagenous fibrils in the vitreous humor, which pull areas of the retina toward the interior of the globe.
Night blindness: Night blindness occurs in any person with severe vitamin A deficiency. The reason for this is that without vitamin A, the amounts of retinal and rhodopsin that can be formed are severely depressed. This condition is called night blindness because the amount of light available at night is too little to permit adequate vision in vitamin A–deficient persons.
In addition, the retina has been described as a "window" into the brain and body, given that abnormalities detected through an examination of the retina can discover both neurological and systemic diseases.
=== Diagnosis ===
A number of different instruments are available for the diagnosis of diseases and disorders affecting the retina. Ophthalmoscopy and fundus photography have long been used to examine the retina. Recently, adaptive optics has been used to image individual rods and cones in the living human retina, and a company based in Scotland has engineered technology that allows physicians to observe the complete retina without any discomfort to patients.
The electroretinogram is used to non-invasively measure the retina's electrical activity, which is affected by certain diseases. A relatively new technology, now becoming widely available, is optical coherence tomography (OCT). This non-invasive technique allows one to obtain a 3D volumetric or high resolution cross-sectional tomogram of the fine structures of the retina, with histologic quality. Retinal vessel analysis is a non-invasive method to examine the small arteries and veins in the retina which allows to draw conclusions about the morphology and the function of small vessels elsewhere in the human body. It has been established as a predictor of cardiovascular disease and seems to have, according to a study published in 2019, potential in the early detection of Alzheimer's disease.
=== Treatment ===
Treatment depends upon the nature of the disease or disorder.
==== Common treatment modalities ====
The following are commonly modalities of management for retinal disease:
Intravitreal medication, such as anti-VEGF or corticosteroid agents
Vitreoretinal surgery
Use of nutritional supplements
Modification of systemic risk factors for retinal disease
==== Uncommon treatment modalities ====
Retinal gene therapy
Gene therapy holds promise as a potential avenue to cure a wide range of retinal diseases. This involves using a non-infectious virus to shuttle a gene into a part of the retina. Recombinant adeno-associated virus (rAAV) vectors possess a number of features that render them ideally suited for retinal gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner. rAAV vectors are increasingly utilized for their ability to mediate efficient transduction of retinal pigment epithelium (RPE), photoreceptor cells and retinal ganglion cells. Each cell type can be specifically targeted by choosing the appropriate combination of AAV serotype, promoter, and intraocular injection site.
Several clinical trials have already reported positive results using rAAV to treat Leber's congenital amaurosis, showing that the therapy was both safe and effective. There were no serious adverse events, and patients in all three studies showed improvement in their visual function as measured by a number of methods. The methods used varied among the three trials, but included both functional methods such as visual acuity and functional mobility as well as objective measures that are less susceptible to bias, such as the pupil's ability to respond to light and improvements on functional MRI. Improvements were sustained over the long-term, with patients continuing to do well after more than 1.5 years.
The unique architecture of the retina and its relatively immune-privileged environment help this process. Tight junctions that form the blood retinal barrier separate the subretinal space from the blood supply, thus protecting it from microbes and most immune-mediated damage, and enhancing its potential to respond to vector-mediated therapies. The highly compartmentalized anatomy of the eye facilitates accurate delivery of therapeutic vector suspensions to specific tissues under direct visualization using microsurgical techniques. In the sheltered environment of the retina, AAV vectors are able to maintain high levels of transgene expression in the retinal pigmented epithelium (RPE), photoreceptors, or ganglion cells for long periods of time after a single treatment. In addition, the eye and the visual system can be routinely and easily monitored for visual function and retinal structural changes after injections with noninvasive advanced technology, such as visual acuities, contrast sensitivity, fundus auto-fluorescence (FAF), dark-adapted visual thresholds, vascular diameters, pupillometry, electroretinography (ERG), multifocal ERG and optical coherence tomography (OCT).
This strategy is effective against a number of retinal diseases that have been studied, including neovascular diseases that are features of age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. Since the regulation of vascularization in the mature retina involves a balance between endogenous positive growth factors, such as vascular endothelial growth factor (VEGF) and inhibitors of angiogenesis, such as pigment epithelium-derived factor (PEDF), rAAV-mediated expression of PEDF, angiostatin, and the soluble VEGF receptor sFlt-1, which are all antiangiogenic proteins, have been shown to reduce aberrant vessel formation in animal models. Since specific gene therapies cannot readily be used to treat a significant fraction of patients with retinal dystrophy, there is a major interest in developing a more generally applicable survival factor therapy. Neurotrophic factors have the ability to modulate neuronal growth during development to maintain existing cells and to allow recovery of injured neuronal populations in the eye. AAV encoding neurotrophic factors such as fibroblast growth factor (FGF) family members and GDNF either protected photoreceptors from apoptosis or slowed down cell death.
Organ transplantation
Transplantation of retinas has been attempted, but without much success. At MIT, The University of Southern California, RWTH Aachen University, and the University of New South Wales, an "artificial retina" is under development: an implant which will bypass the photoreceptors of the retina and stimulate the attached nerve cells directly, with signals from a digital camera.
== History ==
Around 300 BCE, Herophilos identified the retina from dissections of cadaver eyes. He called it the arachnoid layer, from its resemblance to a spider web, and retiform, from its resemblance to a casting net. The term arachnoid came to refer to a layer around the brain; the term retiform came to refer to the retina.
Between 1011 and 1021 CE, Ibn Al-Haytham published numerous experiments demonstrating that sight occurs from light reflecting from objects into the eye. This is consistent with intromission theory and against emission theory, the theory that sight occurs from rays emitted by the eyes. However, Ibn Al-Haytham decided that the retina could not be responsible for the beginnings of vision because the image formed on it was inverted. Instead he decided it must begin at the surface of the lens.
In 1604, Johannes Kepler worked out the optics of the eye and decided that the retina must be where sight begins. He left it up to other scientists to reconcile the inverted retinal image with our perception of the world as upright.
In 1894, Santiago Ramón y Cajal published the first major characterization of retinal neurons in Retina der Wirbelthiere (The Retina of Vertebrates).
George Wald, Haldan Keffer Hartline, and Ragnar Granit won the 1967 Nobel Prize in Physiology or Medicine for their scientific research on the retina.
A recent University of Pennsylvania study calculated that the approximate bandwidth of human retinas is 8.75 megabits per second, whereas a guinea pig's retinal transfer rate is 875 kilobits per second.
MacLaren & Pearson and colleagues at University College London and Moorfields Eye Hospital in London, in 2006, showed that photoreceptor cells could be transplanted successfully in the mouse retina if donor cells were at a critical developmental stage. Recently Ader and colleagues in Dublin showed, using the electron microscope, that transplanted photoreceptors formed synaptic connections.
In 2012, Sebastian Seung and his laboratory at MIT launched EyeWire, an online Citizen science game where players trace neurons in the retina. The goals of the EyeWire project are to identify specific cell types within the known broad classes of retinal cells, and to map the connections between neurons in the retina, which will help to determine how vision works.
== Additional images ==
== See also ==
Adeno associated virus and gene therapy of the human retina
Charles Schepens – "the father of modern retinal surgery"
Evolution of the eye
Duplex retina
Retinal scan
Retinal vein occlusion
List of xanthoma variants associated with hyperlipoproteinemia subtypes
Rhodopsin
Persistence of vision
== References ==
== Further reading ==
S. Ramón y Cajal, Histologie du Système Nerveux de l'Homme et des Vertébrés, Maloine, Paris, 1911.
Rodieck RW (1965). "Quantitative analysis of cat retinal ganglion cell response to visual stimuli". Vision Res. 5 (11): 583–601. doi:10.1016/0042-6989(65)90033-7. PMID 5862581.
Wandell, Brian A. (1995). Foundations of vision. Sunderland, Mass: Sinauer Associates. ISBN 978-0-87893-853-7.
Wässle H, Boycott BB (1991). "Functional architecture of the mammalian retina". Physiol. Rev. 71 (2): 447–480. doi:10.1152/physrev.1991.71.2.447. PMID 2006220.
Schulz HL, Goetz T, Kaschkoetoe J, Weber BH (2004). "The Retinome – Defining a reference transcriptome of the adult mammalian retina/retinal pigment epithelium". BMC Genomics (about a transcriptome for eye colour). 5 (1): 50. doi:10.1186/1471-2164-5-50. PMC 512282. PMID 15283859.
Dowling, John (2007). "Retina". Scholarpedia. 2 (12): 3487. Bibcode:2007SchpJ...2.3487D. doi:10.4249/scholarpedia.3487.
== External links ==
Histology of the Eye, edited by William Krause, Dept. Pathology and Anatomical science, University of Missouri School of Medicine
Eye, Brain, and Vision – online book – by David Hubel
Kolb, H., Fernandez, E., & Nelson, R. (2003). Webvision: The neural organization of the vertebrate retina. Salt Lake City, Utah: John Moran Eye Center, University of Utah. Retrieved 22 July 2014.
Retinal layers image. NeuroScience 2nd Ed at United States National Library of Medicine
Jeremy Nathans's Seminars: "The Vertebrate Retina: Structure, Function, and Evolution"
Retina – Cell Centered Database
Histology image: 07901loa – Histology Learning System at Boston University
MedlinePlus Encyclopedia: 002291 | Wikipedia/Retinal_disease |
The retina (from Latin rete 'net'; pl. retinae or retinas) is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.
The neural retina consists of several layers of neurons interconnected by synapses and is supported by an outer layer of pigmented epithelial cells. The primary light-sensing cells in the retina are the photoreceptor cells, which are of two types: rods and cones. Rods function mainly in dim light and provide monochromatic vision. Cones function in well-lit conditions and are responsible for the perception of colour through the use of a range of opsins, as well as high-acuity vision used for tasks such as reading. A third type of light-sensing cell, the photosensitive ganglion cell, is important for entrainment of circadian rhythms and reflexive responses such as the pupillary light reflex.
Light striking the retina initiates a cascade of chemical and electrical events that ultimately trigger nerve impulses that are sent to various visual centres of the brain through the fibres of the optic nerve. Neural signals from the rods and cones undergo processing by other neurons, whose output takes the form of action potentials in retinal ganglion cells whose axons form the optic nerve.
In vertebrate embryonic development, the retina and the optic nerve originate as outgrowths of the developing brain, specifically the embryonic diencephalon; thus, the retina is considered part of the central nervous system (CNS) and is actually brain tissue. It is the only part of the CNS that can be visualized noninvasively. Like most of the brain, the retina is isolated from the vascular system by the blood–brain barrier. The retina is the part of the body with the greatest continuous energy demand.
== Structure ==
=== Inverted versus non-inverted retina ===
The vertebrate retina is inverted in the sense that the light-sensing cells are in the back of the retina, so that light has to pass through layers of neurons and capillaries before it reaches the photosensitive sections of the rods and cones. The ganglion cells, whose axons form the optic nerve, are at the front of the retina; therefore, the optic nerve must cross through the retina en route to the brain. No photoreceptors are in this region, giving rise to the blind spot. In contrast, in the cephalopod retina, the photoreceptors are in front, with processing neurons and capillaries behind them. Because of this, cephalopods do not have a blind spot.
Although the overlying neural tissue is partly transparent, and the accompanying glial cells have been shown to act as fibre-optic channels to transport photons directly to the photoreceptors, light scattering does occur. Some vertebrates, including humans, have an area of the central retina adapted for high-acuity vision. This area, termed the fovea centralis, is avascular (does not have blood vessels), and has minimal neural tissue in front of the photoreceptors, thereby minimizing light scattering.
The cephalopods have a non-inverted retina, which is comparable in resolving power to the eyes of many vertebrates. Squid eyes do not have an analog of the vertebrate retinal pigment epithelium (RPE). Although their photoreceptors contain a protein, retinochrome, that recycles retinal and replicates one of the functions of the vertebrate RPE, cephalopod photoreceptors are likely not maintained as well as in vertebrates, and that as a result, the useful lifetime of photoreceptors in invertebrates is much shorter than in vertebrates. Having easily replaced stalk eyes (some lobsters) or retinae (some spiders, such as Deinopis) rarely occurs.
The cephalopod retina does not originate as an outgrowth of the brain, as the vertebrate one does. This difference suggests that vertebrate and cephalopod eyes are not homologous, but have evolved separately. From an evolutionary perspective, a more complex structure such as the inverted retina can generally come about as a consequence of two alternate processes - an advantageous "good" compromise between competing functional limitations, or as a historical maladaptive relic of the convoluted path of organ evolution and transformation. Vision is an important adaptation in higher vertebrates.
A third view of the "inverted" vertebrate eye is that it combines two benefits - the maintenance of the photoreceptors mentioned above, and the reduction in light intensity necessary to avoid blinding the photoreceptors, which are based on the extremely sensitive eyes of the ancestors of modern hagfish (fish that live in very deep, dark water).
A recent study on the evolutionary purpose for the inverted retina structure from the APS (American Physical Society) says that "The directional of glial cells helps increase the clarity of human vision. But we also noticed something rather curious: the colours that best passed through the glial cells were green to red, which the eye needs most for daytime vision. The eye usually receives too much blue—and thus has fewer blue-sensitive cones.
Further computer simulations showed that green and red are concentrated five to ten times more by the glial cells, and into their respective cones, than blue light. Instead, excess blue light gets scattered to the surrounding rods. This optimization is such that color vision during the day is enhanced, while night-time vision suffers very little".
=== Retinal layers ===
The vertebrate retina has 10 distinct layers. From closest to farthest from the vitreous body:
Inner limiting membrane – basement membrane elaborated by Müller cells
Nerve fiber layer – axons of the ganglion cell bodies (a thin layer of Müller cell footplates exists between this layer and the inner limiting membrane)
Ganglion cell layer – contains nuclei of ganglion cells, the axons of which become the optic nerve fibres, and some displaced amacrine cells
Inner plexiform layer – contains the synapse between the bipolar cell axons and the dendrites of the ganglion and amacrine cells
Inner nuclear layer – contains the nuclei and surrounding cell bodies (perikarya) of the amacrine cells, bipolar cells, and horizontal cells
Outer plexiform layer – projections of rods and cones ending in the rod spherule and cone pedicle, respectively, these make synapses with dendrites of bipolar cells and horizontal cells. In the macular region, this is known as the fiber layer of Henle.
Outer nuclear layer – cell bodies of rods and cones
External limiting membrane – layer that separates the inner segment portions of the photoreceptors from their cell nuclei
Inner segment / outer segment layer – inner segments and outer segments of rods and cones, the outer segments contain a highly specialized light-sensing apparatus.
Retinal pigment epithelium – single layer of cuboidal epithelial cells (with extrusions not shown in diagram). This layer is closest to the choroid, and provides nourishment and supportive functions to the neural retina, The black pigment melanin in the pigment layer prevents light reflection throughout the globe of the eyeball; this is extremely important for clear vision.
These layers can be grouped into four main processing stages—photoreception; transmission to bipolar cells; transmission to ganglion cells, which also contain photoreceptors, the photosensitive ganglion cells; and transmission along the optic nerve. At each synaptic stage, horizontal and amacrine cells also are laterally connected.
The optic nerve is a central tract of many axons of ganglion cells connecting primarily to the lateral geniculate body, a visual relay station in the diencephalon (the rear of the forebrain). It also projects to the superior colliculus, the suprachiasmatic nucleus, and the nucleus of the optic tract. It passes through the other layers, creating the optic disc in primates.
Additional structures, not directly associated with vision, are found as outgrowths of the retina in some vertebrate groups. In birds, the pecten is a vascular structure of complex shape that projects from the retina into the vitreous humour; it supplies oxygen and nutrients to the eye, and may also aid in vision. Reptiles have a similar, but much simpler, structure.
In adult humans, the entire retina is about 72% of a sphere about 22 mm in diameter. The entire retina contains about 7 million cones and 75 to 150 million rods. The optic disc, a part of the retina sometimes called "the blind spot" because it lacks photoreceptors, is located at the optic papilla, where the optic-nerve fibres leave the eye. It appears as an oval white area of 3 mm2. Temporal (in the direction of the temples) to this disc is the macula, at whose centre is the fovea, a pit that is responsible for sharp central vision, but is actually less sensitive to light because of its lack of rods. Human and non-human primates possess one fovea, as opposed to certain bird species, such as hawks, that are bifoviate, and dogs and cats, that possess no fovea, but a central band known as the visual streak. Around the fovea extends the central retina for about 6 mm and then the peripheral retina. The farthest edge of the retina is defined by the ora serrata. The distance from one ora to the other (or macula), the most sensitive area along the horizontal meridian, is about 32 mm.
In section, the retina is no more than 0.5 mm thick. It has three layers of nerve cells and two of synapses, including the unique ribbon synapse. The optic nerve carries the ganglion-cell axons to the brain, and the blood vessels that supply the retina. The ganglion cells lie innermost in the eye while the photoreceptive cells lie beyond. Because of this counter-intuitive arrangement, light must first pass through and around the ganglion cells and through the thickness of the retina, (including its capillary vessels, not shown) before reaching the rods and cones. Light is absorbed by the retinal pigment epithelium or the choroid (both of which are opaque).
The white blood cells in the capillaries in front of the photoreceptors can be perceived as tiny bright moving dots when looking into blue light. This is known as the blue field entoptic phenomenon (or Scheerer's phenomenon).
Between the ganglion-cell layer and the rods and cones are two layers of neuropils, where synaptic contacts are made. The neuropil layers are the outer plexiform layer and the inner plexiform layer. In the outer neuropil layer, the rods and cones connect to the vertically running bipolar cells, and the horizontally oriented horizontal cells connect to ganglion cells.
The central retina predominantly contains cones, while the peripheral retina predominantly contains rods. In total, the retina has about seven million cones and a hundred million rods. At the centre of the macula is the foveal pit where the cones are narrow and long, and arranged in a hexagonal mosaic, the most dense, in contradistinction to the much fatter cones located more peripherally in the retina. At the foveal pit, the other retinal layers are displaced, before building up along the foveal slope until the rim of the fovea, or parafovea, is reached, which is the thickest portion of the retina. The macula has a yellow pigmentation, from screening pigments, and is known as the macula lutea. The area directly surrounding the fovea has the highest density of rods converging on single bipolar cells. Since its cones have a much lesser convergence of signals, the fovea allows for the sharpest vision the eye can attain.
Though the rod and cones are a mosaic of sorts, transmission from receptors, to bipolars, to ganglion cells is not direct. Since about 150 million receptors and only 1 million optic nerve fibres exist, convergence and thus mixing of signals must occur. Moreover, the horizontal action of the horizontal and amacrine cells can allow one area of the retina to control another (e.g. one stimulus inhibiting another). This inhibition is key to lessening the sum of messages sent to the higher regions of the brain. In some lower vertebrates (e.g. the pigeon), control of messages is "centrifugal" – that is, one layer can control another, or higher regions of the brain can drive the retinal nerve cells, but in primates, this does not occur.
==== Layers imagable with optical coherence tomography ====
Using optical coherence tomography (OCT), at least 13 layers can be identified in the retina. The layers and anatomical correlation are:
From innermost to outermost, the layers identifiable by OCT are as follows:
=== Development ===
Retinal development begins with the establishment of the eye fields mediated by the SHH and SIX3 proteins, with subsequent development of the optic vesicles regulated by the PAX6 and LHX2 proteins. The role of Pax6 in eye development was elegantly demonstrated by Walter Gehring and colleagues, who showed that ectopic expression of Pax6 can lead to eye formation on Drosophila antennae, wings, and legs. The optic vesicle gives rise to three structures: the neural retina, the retinal pigmented epithelium, and the optic stalk. The neural retina contains the retinal progenitor cells (RPCs) that give rise to the seven cell types of the retina. Differentiation begins with the retinal ganglion cells and concludes with production of the Muller glia. Although each cell type differentiates from the RPCs in a sequential order, there is considerable overlap in the timing of when individual cell types differentiate. The cues that determine a RPC daughter cell fate are coded by multiple transcription factor families including the bHLH and homeodomain factors.
In addition to guiding cell fate determination, cues exist in the retina to determine the dorsal-ventral (D-V) and nasal-temporal (N-T) axes. The D-V axis is established by a ventral to dorsal gradient of VAX2, whereas the N-T axis is coordinated by expression of the forkhead transcription factors FOXD1 and FOXG1. Additional gradients are formed within the retina. This spatial distribution may aid in proper targeting of RGC axons that function to establish the retinotopic map.
=== Blood supply ===
The retina is stratified into distinct layers, each containing specific cell types or cellular compartments that have metabolisms with different nutritional requirements. To satisfy these requirements, the ophthalmic artery bifurcates and supplies the retina via two distinct vascular networks: the choroidal network, which supplies the choroid and the outer retina, and the retinal network, which supplies the retina's inner layer.
Although the inverted retina of vertebrates appears counter-intuitive, it is necessary for the proper functioning of the retina. The photoreceptor layer must be embedded in the retinal pigment epithelium (RPE), which performs at least seven vital functions, one of the most obvious being to supply oxygen and other necessary nutrients needed for the photoreceptors to function.
==== Energy requirements ====
The energy requirements of the retina are even greater than that of the brain. This is due to the additional energy needed to continuously renew the photoreceptor outer segments, of which 10% are shed daily. Energy demands are greatest during dark adaptation when its sensitivity is most enhanced. The choroid supplies about 75% of these nutrients to the retina and the retinal vasculature only 25%.
When light strikes 11-cis-retinal (in the disks in the rods and cones), 11-cis-retinal changes to all-trans-retinal which then triggers changes in the opsins. Now, the outer segments do not regenerate the retinal back into the cis- form once it has been changed by light. Instead the retinal is pumped out to the surrounding RPE where it is regenerated and transported back into the outer segments of the photoreceptors. This recycling function of the RPE protects the photoreceptors against photo-oxidative damage and allows the photoreceptor cells to have decades-long useful lives.
==== In birds ====
The bird retina is devoid of blood vessels, perhaps to give unobscured passage of light for forming images, thus giving better resolution. It is, therefore, a considered view that the bird retina depends for nutrition and oxygen supply on a specialized organ, called the "pecten" or pecten oculi, located on the blind spot or optic disk. This organ is extremely rich in blood vessels and is thought to supply nutrition and oxygen to the bird retina by diffusion through the vitreous body. The pecten is highly rich in alkaline phosphatase activity and polarized cells in its bridge portion – both befitting its secretory role. Pecten cells are packed with dark melanin granules, which have been theorized to keep this organ warm with the absorption of stray light falling on the pecten. This is considered to enhance metabolic rate of the pecten, thereby exporting more nutritive molecules to meet the stringent energy requirements of the retina during long periods of exposure to light.
=== Biometric identification and diagnosis of disease ===
The bifurcations and other physical characteristics of the inner retinal vascular network are known to vary among individuals, and these individual variances have been used for biometric identification and for early detection of the onset of disease. The mapping of vascular bifurcations is one of the basic steps in biometric identification. Results of such analyses of retinal blood vessel structure can be evaluated against the ground truth data of vascular bifurcations of retinal fundus images that are obtained from the DRIVE dataset. In addition, the classes of vessels of the DRIVE dataset have also been identified, and an automated method for accurate extraction of these bifurcations is also available. Changes in retinal blood circulation are seen with aging and exposure to air pollution, and may indicate cardiovascular diseases such as hypertension and atherosclerosis. Determining the equivalent width of arterioles and venules near the optic disc is also a widely used technique to identify cardiovascular risks.
== Function ==
The retina translates an optical image into neural impulses starting with the patterned excitation of the colour-sensitive pigments of its rods and cones, the retina's photoreceptor cells. The excitation is processed by the neural system and various parts of the brain working in parallel to form a representation of the external environment in the brain.
The cones respond to bright light and mediate high-resolution colour vision during daylight illumination (also called photopic vision). The rod responses are saturated at daylight levels and do not contribute to pattern vision. However, rods do respond to dim light and mediate lower-resolution, monochromatic vision under very low levels of illumination (called scotopic vision). The illumination in most office settings falls between these two levels and is called mesopic vision. At mesopic light levels, both the rods and cones are actively contributing pattern information. What contribution the rod information makes to pattern vision under these circumstances is unclear.
The response of cones to various wavelengths of light is called their spectral sensitivity. In normal human vision, the spectral sensitivity of a cone falls into one of three subtypes, often called blue, green, and red, but more accurately known as short, medium, and long wavelength-sensitive cone subtypes. It is a lack of one or more of the cone subtypes that causes individuals to have deficiencies in colour vision or various kinds of colour blindness. These individuals are not blind to objects of a particular colour, but are unable to distinguish between colours that can be distinguished by people with normal vision. Humans have this trichromatic vision, while most other mammals lack cones with red sensitive pigment and therefore have poorer dichromatic colour vision. However, some animals have four spectral subtypes, e.g. the trout adds an ultraviolet subgroup to short, medium, and long subtypes that are similar to humans. Some fish are sensitive to the polarization of light as well.
In the photoreceptors, exposure to light hyperpolarizes the membrane in a series of graded shifts. The outer cell segment contains a photopigment. Inside the cell the normal levels of cyclic guanosine monophosphate (cGMP) keep the Na+ channel open, and thus in the resting state the cell is depolarised. The photon causes the retinal bound to the receptor protein to isomerise to trans-retinal. This causes the receptor to activate multiple G-proteins. This in turn causes the Ga-subunit of the protein to activate a phosphodiesterase (PDE6), which degrades cGMP, resulting in the closing of Na+ cyclic nucleotide-gated ion channels (CNGs). Thus the cell is hyperpolarised. The amount of neurotransmitter released is reduced in bright light and increases as light levels fall. The actual photopigment is bleached away in bright light and only replaced as a chemical process, so in a transition from bright light to darkness the eye can take up to thirty minutes to reach full sensitivity.
When thus excited by light, the photoceptor sends a proportional response synaptically to bipolar cells which in turn signal the retinal ganglion cells. The photoreceptors are also cross-linked by horizontal cells and amacrine cells, which modify the synaptic signal before it reaches the ganglion cells, the neural signals being intermixed and combined. Of the retina's nerve cells, only the retinal ganglion cells and few amacrine cells create action potentials.
In the retinal ganglion cells there are two types of response, depending on the receptive field of the cell. The receptive fields of retinal ganglion cells comprise a central, approximately circular area, where light has one effect on the firing of the cell, and an annular surround, where light has the opposite effect. In ON cells, an increment in light intensity in the centre of the receptive field causes the firing rate to increase. In OFF cells, it makes it decrease. In a linear model, this response profile is well described by a difference of Gaussians and is the basis for edge detection algorithms. Beyond this simple difference, ganglion cells are also differentiated by chromatic sensitivity and the type of spatial summation. Cells showing linear spatial summation are termed X cells (also called parvocellular, P, or midget ganglion cells), and those showing non-linear summation are Y cells (also called magnocellular, M, or parasol retinal ganglion cells), although the correspondence between X and Y cells (in the cat retina) and P and M cells (in the primate retina) is not as simple as it once seemed.
In the transfer of visual signals to the brain, the visual pathway, the retina is vertically divided in two, a temporal (nearer to the temple) half and a nasal (nearer to the nose) half. The axons from the nasal half cross the brain at the optic chiasma to join with axons from the temporal half of the other eye before passing into the lateral geniculate body.
Although there are more than 130 million retinal receptors, there are only approximately 1.2 million fibres (axons) in the optic nerve. So, a large amount of pre-processing is performed within the retina. The fovea produces the most accurate information. Despite occupying about 0.01% of the visual field (less than 2° of visual angle), about 10% of axons in the optic nerve are devoted to the fovea. The resolution limit of the fovea has been determined to be around 10,000 points. The information capacity is estimated at 500,000 bits per second (for more information on bits, see information theory) without colour or around 600,000 bits per second including colour.
=== Spatial encoding ===
When the retina sends neural impulses representing an image to the brain, it spatially encodes (compresses) those impulses to fit the limited capacity of the optic nerve. Compression is necessary because there are 100 times more photoreceptor cells than ganglion cells. This is done by "decorrelation", which is carried out by the "centre–surround structures", which are implemented by the bipolar and ganglion cells.
There are two types of centre–surround structures in the retina – on-centres and off-centres. On-centres have a positively weighted centre and a negatively weighted surround. Off-centres are just the opposite. Positive weighting is more commonly known as excitatory, and negative weighting as inhibitory.
These centre–surround structures are not physical apparent, in the sense that one cannot see them by staining samples of tissue and examining the retina's anatomy. The centre–surround structures are logical (i.e., mathematically abstract) in the sense that they depend on the connection strengths between bipolar and ganglion cells. It is believed that the connection strength between cells is caused by the number and types of ion channels embedded in the synapses between the bipolar and ganglion cells.
The centre–surround structures are mathematically equivalent to the edge detection algorithms used by computer programmers to extract or enhance the edges in a digital photograph. Thus, the retina performs operations on the image-representing impulses to enhance the edges of objects within its visual field. For example, in a picture of a dog, a cat and a car, it is the edges of these objects that contain the most information. In order for higher functions in the brain (or in a computer for that matter) to extract and classify objects such as a dog and a cat, the retina is the first step to separating out the various objects within the scene.
As an example, the following matrix is at the heart of a computer algorithm that implements edge detection. This matrix is the computer equivalent to the centre–surround structure. In this example, each box (element) within this matrix would be connected to one photoreceptor. The photoreceptor in the centre is the current receptor being processed. The centre photoreceptor is multiplied by the +1 weight factor. The surrounding photoreceptors are the "nearest neighbors" to the centre and are multiplied by the −1/8 value. The sum of all nine of these elements is finally calculated. This summation is repeated for every photoreceptor in the image by shifting left to the end of a row and then down to the next line.
The total sum of this matrix is zero, if all the inputs from the nine photoreceptors are of the same value. The zero result indicates the image was uniform (non-changing) within this small patch. Negative or positive sums mean the image was varying (changing) within this small patch of nine photoreceptors.
The above matrix is only an approximation to what really happens inside the retina. The differences are:
The above example is called "balanced". The term balanced means that the sum of the negative weights is equal to the sum of the positive weights so that they cancel out perfectly. Retinal ganglion cells are almost never perfectly balanced.
The table is square while the centre–surround structures in the retina are circular.
Neurons operate on spike trains traveling down nerve cell axons. Computers operate on a single floating-point number that is essentially constant from each input pixel. (The computer pixel is basically the equivalent of a biological photoreceptor.)
The retina performs all these calculations in parallel while the computer operates on each pixel one at a time. The retina performs no repeated summations and shifting as would a computer.
Finally, the horizontal and amacrine cells play a significant role in this process, but that is not represented here.
Here is an example of an input image and how edge detection would modify it.
Once the image is spatially encoded by the centre–surround structures, the signal is sent out along the optic nerve (via the axons of the ganglion cells) through the optic chiasm to the LGN (lateral geniculate nucleus). The exact function of the LGN is unknown at this time. The output of the LGN is then sent to the back of the brain. Specifically, the output of the LGN "radiates" out to the V1 primary visual cortex.
Simplified signal flow: Photoreceptors → Bipolar → Ganglion → Chiasm → LGN → V1 cortex
== Clinical significance ==
There are many inherited and acquired diseases or disorders that may affect the retina. Some of them include:
Retinitis pigmentosa is a group of genetic diseases that affect the retina and cause the loss of night vision and peripheral vision.
Macular degeneration describes a group of diseases characterized by loss of central vision because of death or impairment of the cells in the macula.
Cone-rod dystrophy (CORD) describes a number of diseases where vision loss is caused by deterioration of the cones and/or rods in the retina.
In retinal separation, the retina detaches from the back of the eyeball. Ignipuncture is an outdated treatment method. The term retinal detachment is used to describe a separation of the neurosensory retina from the retinal pigment epithelium. There are several modern treatment methods for fixing a retinal detachment: pneumatic retinopexy, scleral buckle, cryotherapy, laser photocoagulation and pars plana vitrectomy.
Both hypertension and diabetes mellitus can cause damage to the tiny blood vessels that supply the retina, leading to hypertensive retinopathy and diabetic retinopathy.
Retinoblastoma is a cancer of the retina.
Retinal diseases in dogs include retinal dysplasia, progressive retinal atrophy, and sudden acquired retinal degeneration.
Lipaemia retinalis is a white appearance of the retina, and can occur by lipid deposition in lipoprotein lipase deficiency.
Retinal Detachment. The neural retina occasionally detaches from the pigment epithelium. In some instances, the cause of such detachment is injury to the eyeball that allows fluid or blood to collect between the neural retina and the pigment epithelium. Detachment is occasionally caused by contracture of fine collagenous fibrils in the vitreous humor, which pull areas of the retina toward the interior of the globe.
Night blindness: Night blindness occurs in any person with severe vitamin A deficiency. The reason for this is that without vitamin A, the amounts of retinal and rhodopsin that can be formed are severely depressed. This condition is called night blindness because the amount of light available at night is too little to permit adequate vision in vitamin A–deficient persons.
In addition, the retina has been described as a "window" into the brain and body, given that abnormalities detected through an examination of the retina can discover both neurological and systemic diseases.
=== Diagnosis ===
A number of different instruments are available for the diagnosis of diseases and disorders affecting the retina. Ophthalmoscopy and fundus photography have long been used to examine the retina. Recently, adaptive optics has been used to image individual rods and cones in the living human retina, and a company based in Scotland has engineered technology that allows physicians to observe the complete retina without any discomfort to patients.
The electroretinogram is used to non-invasively measure the retina's electrical activity, which is affected by certain diseases. A relatively new technology, now becoming widely available, is optical coherence tomography (OCT). This non-invasive technique allows one to obtain a 3D volumetric or high resolution cross-sectional tomogram of the fine structures of the retina, with histologic quality. Retinal vessel analysis is a non-invasive method to examine the small arteries and veins in the retina which allows to draw conclusions about the morphology and the function of small vessels elsewhere in the human body. It has been established as a predictor of cardiovascular disease and seems to have, according to a study published in 2019, potential in the early detection of Alzheimer's disease.
=== Treatment ===
Treatment depends upon the nature of the disease or disorder.
==== Common treatment modalities ====
The following are commonly modalities of management for retinal disease:
Intravitreal medication, such as anti-VEGF or corticosteroid agents
Vitreoretinal surgery
Use of nutritional supplements
Modification of systemic risk factors for retinal disease
==== Uncommon treatment modalities ====
Retinal gene therapy
Gene therapy holds promise as a potential avenue to cure a wide range of retinal diseases. This involves using a non-infectious virus to shuttle a gene into a part of the retina. Recombinant adeno-associated virus (rAAV) vectors possess a number of features that render them ideally suited for retinal gene therapy, including a lack of pathogenicity, minimal immunogenicity, and the ability to transduce postmitotic cells in a stable and efficient manner. rAAV vectors are increasingly utilized for their ability to mediate efficient transduction of retinal pigment epithelium (RPE), photoreceptor cells and retinal ganglion cells. Each cell type can be specifically targeted by choosing the appropriate combination of AAV serotype, promoter, and intraocular injection site.
Several clinical trials have already reported positive results using rAAV to treat Leber's congenital amaurosis, showing that the therapy was both safe and effective. There were no serious adverse events, and patients in all three studies showed improvement in their visual function as measured by a number of methods. The methods used varied among the three trials, but included both functional methods such as visual acuity and functional mobility as well as objective measures that are less susceptible to bias, such as the pupil's ability to respond to light and improvements on functional MRI. Improvements were sustained over the long-term, with patients continuing to do well after more than 1.5 years.
The unique architecture of the retina and its relatively immune-privileged environment help this process. Tight junctions that form the blood retinal barrier separate the subretinal space from the blood supply, thus protecting it from microbes and most immune-mediated damage, and enhancing its potential to respond to vector-mediated therapies. The highly compartmentalized anatomy of the eye facilitates accurate delivery of therapeutic vector suspensions to specific tissues under direct visualization using microsurgical techniques. In the sheltered environment of the retina, AAV vectors are able to maintain high levels of transgene expression in the retinal pigmented epithelium (RPE), photoreceptors, or ganglion cells for long periods of time after a single treatment. In addition, the eye and the visual system can be routinely and easily monitored for visual function and retinal structural changes after injections with noninvasive advanced technology, such as visual acuities, contrast sensitivity, fundus auto-fluorescence (FAF), dark-adapted visual thresholds, vascular diameters, pupillometry, electroretinography (ERG), multifocal ERG and optical coherence tomography (OCT).
This strategy is effective against a number of retinal diseases that have been studied, including neovascular diseases that are features of age-related macular degeneration, diabetic retinopathy and retinopathy of prematurity. Since the regulation of vascularization in the mature retina involves a balance between endogenous positive growth factors, such as vascular endothelial growth factor (VEGF) and inhibitors of angiogenesis, such as pigment epithelium-derived factor (PEDF), rAAV-mediated expression of PEDF, angiostatin, and the soluble VEGF receptor sFlt-1, which are all antiangiogenic proteins, have been shown to reduce aberrant vessel formation in animal models. Since specific gene therapies cannot readily be used to treat a significant fraction of patients with retinal dystrophy, there is a major interest in developing a more generally applicable survival factor therapy. Neurotrophic factors have the ability to modulate neuronal growth during development to maintain existing cells and to allow recovery of injured neuronal populations in the eye. AAV encoding neurotrophic factors such as fibroblast growth factor (FGF) family members and GDNF either protected photoreceptors from apoptosis or slowed down cell death.
Organ transplantation
Transplantation of retinas has been attempted, but without much success. At MIT, The University of Southern California, RWTH Aachen University, and the University of New South Wales, an "artificial retina" is under development: an implant which will bypass the photoreceptors of the retina and stimulate the attached nerve cells directly, with signals from a digital camera.
== History ==
Around 300 BCE, Herophilos identified the retina from dissections of cadaver eyes. He called it the arachnoid layer, from its resemblance to a spider web, and retiform, from its resemblance to a casting net. The term arachnoid came to refer to a layer around the brain; the term retiform came to refer to the retina.
Between 1011 and 1021 CE, Ibn Al-Haytham published numerous experiments demonstrating that sight occurs from light reflecting from objects into the eye. This is consistent with intromission theory and against emission theory, the theory that sight occurs from rays emitted by the eyes. However, Ibn Al-Haytham decided that the retina could not be responsible for the beginnings of vision because the image formed on it was inverted. Instead he decided it must begin at the surface of the lens.
In 1604, Johannes Kepler worked out the optics of the eye and decided that the retina must be where sight begins. He left it up to other scientists to reconcile the inverted retinal image with our perception of the world as upright.
In 1894, Santiago Ramón y Cajal published the first major characterization of retinal neurons in Retina der Wirbelthiere (The Retina of Vertebrates).
George Wald, Haldan Keffer Hartline, and Ragnar Granit won the 1967 Nobel Prize in Physiology or Medicine for their scientific research on the retina.
A recent University of Pennsylvania study calculated that the approximate bandwidth of human retinas is 8.75 megabits per second, whereas a guinea pig's retinal transfer rate is 875 kilobits per second.
MacLaren & Pearson and colleagues at University College London and Moorfields Eye Hospital in London, in 2006, showed that photoreceptor cells could be transplanted successfully in the mouse retina if donor cells were at a critical developmental stage. Recently Ader and colleagues in Dublin showed, using the electron microscope, that transplanted photoreceptors formed synaptic connections.
In 2012, Sebastian Seung and his laboratory at MIT launched EyeWire, an online Citizen science game where players trace neurons in the retina. The goals of the EyeWire project are to identify specific cell types within the known broad classes of retinal cells, and to map the connections between neurons in the retina, which will help to determine how vision works.
== Additional images ==
== See also ==
Adeno associated virus and gene therapy of the human retina
Charles Schepens – "the father of modern retinal surgery"
Evolution of the eye
Duplex retina
Retinal scan
Retinal vein occlusion
List of xanthoma variants associated with hyperlipoproteinemia subtypes
Rhodopsin
Persistence of vision
== References ==
== Further reading ==
S. Ramón y Cajal, Histologie du Système Nerveux de l'Homme et des Vertébrés, Maloine, Paris, 1911.
Rodieck RW (1965). "Quantitative analysis of cat retinal ganglion cell response to visual stimuli". Vision Res. 5 (11): 583–601. doi:10.1016/0042-6989(65)90033-7. PMID 5862581.
Wandell, Brian A. (1995). Foundations of vision. Sunderland, Mass: Sinauer Associates. ISBN 978-0-87893-853-7.
Wässle H, Boycott BB (1991). "Functional architecture of the mammalian retina". Physiol. Rev. 71 (2): 447–480. doi:10.1152/physrev.1991.71.2.447. PMID 2006220.
Schulz HL, Goetz T, Kaschkoetoe J, Weber BH (2004). "The Retinome – Defining a reference transcriptome of the adult mammalian retina/retinal pigment epithelium". BMC Genomics (about a transcriptome for eye colour). 5 (1): 50. doi:10.1186/1471-2164-5-50. PMC 512282. PMID 15283859.
Dowling, John (2007). "Retina". Scholarpedia. 2 (12): 3487. Bibcode:2007SchpJ...2.3487D. doi:10.4249/scholarpedia.3487.
== External links ==
Histology of the Eye, edited by William Krause, Dept. Pathology and Anatomical science, University of Missouri School of Medicine
Eye, Brain, and Vision – online book – by David Hubel
Kolb, H., Fernandez, E., & Nelson, R. (2003). Webvision: The neural organization of the vertebrate retina. Salt Lake City, Utah: John Moran Eye Center, University of Utah. Retrieved 22 July 2014.
Retinal layers image. NeuroScience 2nd Ed at United States National Library of Medicine
Jeremy Nathans's Seminars: "The Vertebrate Retina: Structure, Function, and Evolution"
Retina – Cell Centered Database
Histology image: 07901loa – Histology Learning System at Boston University
MedlinePlus Encyclopedia: 002291 | Wikipedia/Retinal_diseases |
Deoxyribonucleic acid ( ; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of all known organisms and many viruses. DNA and ribonucleic acid (RNA) are nucleic acids. Alongside proteins, lipids and complex carbohydrates (polysaccharides), nucleic acids are one of the four major types of macromolecules that are essential for all known forms of life.
The two DNA strands are known as polynucleotides as they are composed of simpler monomeric units called nucleotides. Each nucleotide is composed of one of four nitrogen-containing nucleobases (cytosine [C], guanine [G], adenine [A] or thymine [T]), a sugar called deoxyribose, and a phosphate group. The nucleotides are joined to one another in a chain by covalent bonds (known as the phosphodiester linkage) between the sugar of one nucleotide and the phosphate of the next, resulting in an alternating sugar-phosphate backbone. The nitrogenous bases of the two separate polynucleotide strands are bound together, according to base pairing rules (A with T and C with G), with hydrogen bonds to make double-stranded DNA. The complementary nitrogenous bases are divided into two groups, the single-ringed pyrimidines and the double-ringed purines. In DNA, the pyrimidines are thymine and cytosine; the purines are adenine and guanine.
Both strands of double-stranded DNA store the same biological information. This information is replicated when the two strands separate. A large part of DNA (more than 98% for humans) is non-coding, meaning that these sections do not serve as patterns for protein sequences. The two strands of DNA run in opposite directions to each other and are thus antiparallel. Attached to each sugar is one of four types of nucleobases (or bases). It is the sequence of these four nucleobases along the backbone that encodes genetic information. RNA strands are created using DNA strands as a template in a process called transcription, where DNA bases are exchanged for their corresponding bases except in the case of thymine (T), for which RNA substitutes uracil (U). Under the genetic code, these RNA strands specify the sequence of amino acids within proteins in a process called translation.
Within eukaryotic cells, DNA is organized into long structures called chromosomes. Before typical cell division, these chromosomes are duplicated in the process of DNA replication, providing a complete set of chromosomes for each daughter cell. Eukaryotic organisms (animals, plants, fungi and protists) store most of their DNA inside the cell nucleus as nuclear DNA, and some in the mitochondria as mitochondrial DNA or in chloroplasts as chloroplast DNA. In contrast, prokaryotes (bacteria and archaea) store their DNA only in the cytoplasm, in circular chromosomes. Within eukaryotic chromosomes, chromatin proteins, such as histones, compact and organize DNA. These compacting structures guide the interactions between DNA and other proteins, helping control which parts of the DNA are transcribed.
== Properties ==
DNA is a long polymer made from repeating units called nucleotides. The structure of DNA is dynamic along its length, being capable of coiling into tight loops and other shapes. In all species it is composed of two helical chains, bound to each other by hydrogen bonds. Both chains are coiled around the same axis, and have the same pitch of 34 ångströms (3.4 nm). The pair of chains have a radius of 10 Å (1.0 nm). According to another study, when measured in a different solution, the DNA chain measured 22–26 Å (2.2–2.6 nm) wide, and one nucleotide unit measured 3.3 Å (0.33 nm) long. The buoyant density of most DNA is 1.7g/cm3.
DNA does not usually exist as a single strand, but instead as a pair of strands that are held tightly together. These two long strands coil around each other, in the shape of a double helix. The nucleotide contains both a segment of the backbone of the molecule (which holds the chain together) and a nucleobase (which interacts with the other DNA strand in the helix). A nucleobase linked to a sugar is called a nucleoside, and a base linked to a sugar and to one or more phosphate groups is called a nucleotide. A biopolymer comprising multiple linked nucleotides (as in DNA) is called a polynucleotide.
The backbone of the DNA strand is made from alternating phosphate and sugar groups. The sugar in DNA is 2-deoxyribose, which is a pentose (five-carbon) sugar. The sugars are joined by phosphate groups that form phosphodiester bonds between the third and fifth carbon atoms of adjacent sugar rings. These are known as the 3′-end (three prime end), and 5′-end (five prime end) carbons, the prime symbol being used to distinguish these carbon atoms from those of the base to which the deoxyribose forms a glycosidic bond.
Therefore, any DNA strand normally has one end at which there is a phosphate group attached to the 5′ carbon of a ribose (the 5′ phosphoryl) and another end at which there is a free hydroxyl group attached to the 3′ carbon of a ribose (the 3′ hydroxyl). The orientation of the 3′ and 5′ carbons along the sugar-phosphate backbone confers directionality (sometimes called polarity) to each DNA strand. In a nucleic acid double helix, the direction of the nucleotides in one strand is opposite to their direction in the other strand: the strands are antiparallel. The asymmetric ends of DNA strands are said to have a directionality of five prime end (5′ ), and three prime end (3′), with the 5′ end having a terminal phosphate group and the 3′ end a terminal hydroxyl group. One major difference between DNA and RNA is the sugar, with the 2-deoxyribose in DNA being replaced by the related pentose sugar ribose in RNA.
The DNA double helix is stabilized primarily by two forces: hydrogen bonds between nucleotides and base-stacking interactions among aromatic nucleobases. The four bases found in DNA are adenine (A), cytosine (C), guanine (G) and thymine (T). These four bases are attached to the sugar-phosphate to form the complete nucleotide, as shown for adenosine monophosphate. Adenine pairs with thymine and guanine pairs with cytosine, forming A-T and G-C base pairs.
=== Nucleobase classification ===
The nucleobases are classified into two types: the purines, A and G, which are fused five- and six-membered heterocyclic compounds, and the pyrimidines, the six-membered rings C and T. A fifth pyrimidine nucleobase, uracil (U), usually takes the place of thymine in RNA and differs from thymine by lacking a methyl group on its ring. In addition to RNA and DNA, many artificial nucleic acid analogues have been created to study the properties of nucleic acids, or for use in biotechnology.
=== Non-canonical bases ===
Modified bases occur in DNA. The first of these recognized was 5-methylcytosine, which was found in the genome of Mycobacterium tuberculosis in 1925. The reason for the presence of these noncanonical bases in bacterial viruses (bacteriophages) is to avoid the restriction enzymes present in bacteria. This enzyme system acts at least in part as a molecular immune system protecting bacteria from infection by viruses. Modifications of the bases cytosine and adenine, the more common and modified DNA bases, play vital roles in the epigenetic control of gene expression in plants and animals.
A number of noncanonical bases are known to occur in DNA. Most of these are modifications of the canonical bases plus uracil.
Modified Adenine
N6-carbamoyl-methyladenine
N6-methyadenine
Modified Guanine
7-Deazaguanine
7-Methylguanine
Modified Cytosine
N4-Methylcytosine
5-Carboxylcytosine
5-Formylcytosine
5-Glycosylhydroxymethylcytosine
5-Hydroxycytosine
5-Methylcytosine
Modified Thymidine
α-Glutamythymidine
α-Putrescinylthymine
Uracil and modifications
Base J
Uracil
5-Dihydroxypentauracil
5-Hydroxymethyldeoxyuracil
Others
Deoxyarchaeosine
2,6-Diaminopurine (2-Aminoadenine)
=== Grooves ===
Twin helical strands form the DNA backbone. Another double helix may be found tracing the spaces, or grooves, between the strands. These voids are adjacent to the base pairs and may provide a binding site. As the strands are not symmetrically located with respect to each other, the grooves are unequally sized. The major groove is 22 ångströms (2.2 nm) wide, while the minor groove is 12 Å (1.2 nm) in width. Due to the larger width of the major groove, the edges of the bases are more accessible in the major groove than in the minor groove. As a result, proteins such as transcription factors that can bind to specific sequences in double-stranded DNA usually make contact with the sides of the bases exposed in the major groove. This situation varies in unusual conformations of DNA within the cell (see below), but the major and minor grooves are always named to reflect the differences in width that would be seen if the DNA was twisted back into the ordinary B form.
=== Base pairing ===
In a DNA double helix, each type of nucleobase on one strand bonds with just one type of nucleobase on the other strand. This is called complementary base pairing. Purines form hydrogen bonds to pyrimidines, with adenine bonding only to thymine in two hydrogen bonds, and cytosine bonding only to guanine in three hydrogen bonds. This arrangement of two nucleotides binding together across the double helix (from six-carbon ring to six-carbon ring) is called a Watson-Crick base pair. DNA with high GC-content is more stable than DNA with low GC-content. A Hoogsteen base pair (hydrogen bonding the 6-carbon ring to the 5-carbon ring) is a rare variation of base-pairing. As hydrogen bonds are not covalent, they can be broken and rejoined relatively easily. The two strands of DNA in a double helix can thus be pulled apart like a zipper, either by a mechanical force or high temperature. As a result of this base pair complementarity, all the information in the double-stranded sequence of a DNA helix is duplicated on each strand, which is vital in DNA replication. This reversible and specific interaction between complementary base pairs is critical for all the functions of DNA in organisms.
==== ssDNA vs. dsDNA ====
Most DNA molecules are actually two polymer strands, bound together in a helical fashion by noncovalent bonds; this double-stranded (dsDNA) structure is maintained largely by the intrastrand base stacking interactions, which are strongest for G,C stacks. The two strands can come apart—a process known as melting—to form two single-stranded DNA (ssDNA) molecules. Melting occurs at high temperatures, low salt and high pH (low pH also melts DNA, but since DNA is unstable due to acid depurination, low pH is rarely used).
The stability of the dsDNA form depends not only on the GC-content (% G,C basepairs) but also on sequence (since stacking is sequence specific) and also length (longer molecules are more stable). The stability can be measured in various ways; a common way is the melting temperature (also called Tm value), which is the temperature at which 50% of the double-strand molecules are converted to single-strand molecules; melting temperature is dependent on ionic strength and the concentration of DNA. As a result, it is both the percentage of GC base pairs and the overall length of a DNA double helix that determines the strength of the association between the two strands of DNA. Long DNA helices with a high GC-content have more strongly interacting strands, while short helices with high AT content have more weakly interacting strands. In biology, parts of the DNA double helix that need to separate easily, such as the TATAAT Pribnow box in some promoters, tend to have a high AT content, making the strands easier to pull apart.
In the laboratory, the strength of this interaction can be measured by finding the melting temperature Tm necessary to break half of the hydrogen bonds. When all the base pairs in a DNA double helix melt, the strands separate and exist in solution as two entirely independent molecules. These single-stranded DNA molecules have no single common shape, but some conformations are more stable than others.
=== Amount ===
In humans, the total female diploid nuclear genome per cell extends for 6.37 Gigabase pairs (Gbp), is 208.23 cm long and weighs 6.51 picograms (pg). Male values are 6.27 Gbp, 205.00 cm, 6.41 pg. Each DNA polymer can contain hundreds of millions of nucleotides, such as in chromosome 1. Chromosome 1 is the largest human chromosome with approximately 220 million base pairs, and would be 85 mm long if straightened.
In eukaryotes, in addition to nuclear DNA, there is also mitochondrial DNA (mtDNA) which encodes certain proteins used by the mitochondria. The mtDNA is usually relatively small in comparison to the nuclear DNA. For example, the human mitochondrial DNA forms closed circular molecules, each of which contains 16,569 DNA base pairs, with each such molecule normally containing a full set of the mitochondrial genes. Each human mitochondrion contains, on average, approximately 5 such mtDNA molecules. Each human cell contains approximately 100 mitochondria, giving a total number of mtDNA molecules per human cell of approximately 500. However, the amount of mitochondria per cell also varies by cell type, and an egg cell can contain 100,000 mitochondria, corresponding to up to 1,500,000 copies of the mitochondrial genome (constituting up to 90% of the DNA of the cell).
=== Sense and antisense ===
A DNA sequence is called a "sense" sequence if it is the same as that of a messenger RNA copy that is translated into protein. The sequence on the opposite strand is called the "antisense" sequence. Both sense and antisense sequences can exist on different parts of the same strand of DNA (i.e. both strands can contain both sense and antisense sequences). In both prokaryotes and eukaryotes, antisense RNA sequences are produced, but the functions of these RNAs are not entirely clear. One proposal is that antisense RNAs are involved in regulating gene expression through RNA-RNA base pairing.
A few DNA sequences in prokaryotes and eukaryotes, and more in plasmids and viruses, blur the distinction between sense and antisense strands by having overlapping genes. In these cases, some DNA sequences do double duty, encoding one protein when read along one strand, and a second protein when read in the opposite direction along the other strand. In bacteria, this overlap may be involved in the regulation of gene transcription, while in viruses, overlapping genes increase the amount of information that can be encoded within the small viral genome.
=== Supercoiling ===
DNA can be twisted like a rope in a process called DNA supercoiling. With DNA in its "relaxed" state, a strand usually circles the axis of the double helix once every 10.4 base pairs, but if the DNA is twisted the strands become more tightly or more loosely wound. If the DNA is twisted in the direction of the helix, this is positive supercoiling, and the bases are held more tightly together. If they are twisted in the opposite direction, this is negative supercoiling, and the bases come apart more easily. In nature, most DNA has slight negative supercoiling that is introduced by enzymes called topoisomerases. These enzymes are also needed to relieve the twisting stresses introduced into DNA strands during processes such as transcription and DNA replication.
=== Alternative DNA structures ===
DNA exists in many possible conformations that include A-DNA, B-DNA, and Z-DNA forms, although only B-DNA and Z-DNA have been directly observed in functional organisms. The conformation that DNA adopts depends on the hydration level, DNA sequence, the amount and direction of supercoiling, chemical modifications of the bases, the type and concentration of metal ions, and the presence of polyamines in solution.
The first published reports of A-DNA X-ray diffraction patterns—and also B-DNA—used analyses based on Patterson functions that provided only a limited amount of structural information for oriented fibers of DNA. An alternative analysis was proposed by Wilkins et al. in 1953 for the in vivo B-DNA X-ray diffraction-scattering patterns of highly hydrated DNA fibers in terms of squares of Bessel functions. In the same journal, James Watson and Francis Crick presented their molecular modeling analysis of the DNA X-ray diffraction patterns to suggest that the structure was a double helix.
Although the B-DNA form is most common under the conditions found in cells, it is not a well-defined conformation but a family of related DNA conformations that occur at the high hydration levels present in cells. Their corresponding X-ray diffraction and scattering patterns are characteristic of molecular paracrystals with a significant degree of disorder.
Compared to B-DNA, the A-DNA form is a wider right-handed spiral, with a shallow, wide minor groove and a narrower, deeper major groove. The A form occurs under non-physiological conditions in partly dehydrated samples of DNA, while in the cell it may be produced in hybrid pairings of DNA and RNA strands, and in enzyme-DNA complexes. Segments of DNA where the bases have been chemically modified by methylation may undergo a larger change in conformation and adopt the Z form. Here, the strands turn about the helical axis in a left-handed spiral, the opposite of the more common B form. These unusual structures can be recognized by specific Z-DNA binding proteins and may be involved in the regulation of transcription.
=== Alternative DNA chemistry ===
For many years, exobiologists have proposed the existence of a shadow biosphere, a postulated microbial biosphere of Earth that uses radically different biochemical and molecular processes than currently known life. One of the proposals was the existence of lifeforms that use arsenic instead of phosphorus in DNA. A report in 2010 of the possibility in the bacterium GFAJ-1 was announced, though the research was disputed, and evidence suggests the bacterium actively prevents the incorporation of arsenic into the DNA backbone and other biomolecules.
=== Quadruplex structures ===
At the ends of the linear chromosomes are specialized regions of DNA called telomeres. The main function of these regions is to allow the cell to replicate chromosome ends using the enzyme telomerase, as the enzymes that normally replicate DNA cannot copy the extreme 3′ ends of chromosomes. These specialized chromosome caps also help protect the DNA ends, and stop the DNA repair systems in the cell from treating them as damage to be corrected. In human cells, telomeres are usually lengths of single-stranded DNA containing several thousand repeats of a simple TTAGGG sequence.
These guanine-rich sequences may stabilize chromosome ends by forming structures of stacked sets of four-base units, rather than the usual base pairs found in other DNA molecules. Here, four guanine bases, known as a guanine tetrad, form a flat plate. These flat four-base units then stack on top of each other to form a stable G-quadruplex structure. These structures are stabilized by hydrogen bonding between the edges of the bases and chelation of a metal ion in the centre of each four-base unit. Other structures can also be formed, with the central set of four bases coming from either a single strand folded around the bases, or several different parallel strands, each contributing one base to the central structure.
In addition to these stacked structures, telomeres also form large loop structures called telomere loops, or T-loops. Here, the single-stranded DNA curls around in a long circle stabilized by telomere-binding proteins. At the very end of the T-loop, the single-stranded telomere DNA is held onto a region of double-stranded DNA by the telomere strand disrupting the double-helical DNA and base pairing to one of the two strands. This triple-stranded structure is called a displacement loop or D-loop.
=== Branched DNA ===
In DNA, fraying occurs when non-complementary regions exist at the end of an otherwise complementary double-strand of DNA. However, branched DNA can occur if a third strand of DNA is introduced and contains adjoining regions able to hybridize with the frayed regions of the pre-existing double-strand. Although the simplest example of branched DNA involves only three strands of DNA, complexes involving additional strands and multiple branches are also possible. Branched DNA can be used in nanotechnology to construct geometric shapes, see the section on uses in technology below.
=== Artificial bases ===
Several artificial nucleobases have been synthesized, and successfully incorporated in the eight-base DNA analogue named Hachimoji DNA. Dubbed S, B, P, and Z, these artificial bases are capable of bonding with each other in a predictable way (S–B and P–Z), maintain the double helix structure of DNA, and be transcribed to RNA. Their existence could be seen as an indication that there is nothing special about the four natural nucleobases that evolved on Earth. On the other hand, DNA is tightly related to RNA which does not only act as a transcript of DNA but also performs as molecular machines many tasks in cells. For this purpose it has to fold into a structure. It has been shown that to allow to create all possible structures at least four bases are required for the corresponding RNA, while a higher number is also possible but this would be against the natural principle of least effort.
=== Acidity ===
The phosphate groups of DNA give it similar acidic properties to phosphoric acid and it can be considered as a strong acid. It will be fully ionized at a normal cellular pH, releasing protons which leave behind negative charges on the phosphate groups. These negative charges protect DNA from breakdown by hydrolysis by repelling nucleophiles which could hydrolyze it.
=== Macroscopic appearance ===
Pure DNA extracted from cells forms white, stringy clumps.
== Chemical modifications and altered DNA packaging ==
=== Base modifications and DNA packaging ===
The expression of genes is influenced by how the DNA is packaged in chromosomes, in a structure called chromatin. Base modifications can be involved in packaging, with regions that have low or no gene expression usually containing high levels of methylation of cytosine bases. DNA packaging and its influence on gene expression can also occur by covalent modifications of the histone protein core around which DNA is wrapped in the chromatin structure or else by remodeling carried out by chromatin remodeling complexes (see Chromatin remodeling). There is, further, crosstalk between DNA methylation and histone modification, so they can coordinately affect chromatin and gene expression.
For one example, cytosine methylation produces 5-methylcytosine, which is important for X-inactivation of chromosomes. The average level of methylation varies between organisms—the worm Caenorhabditis elegans lacks cytosine methylation, while vertebrates have higher levels, with up to 1% of their DNA containing 5-methylcytosine. Despite the importance of 5-methylcytosine, it can deaminate to leave a thymine base, so methylated cytosines are particularly prone to mutations. Other base modifications include adenine methylation in bacteria, the presence of 5-hydroxymethylcytosine in the brain, and the glycosylation of uracil to produce the "J-base" in kinetoplastids.
=== Damage ===
DNA can be damaged by many sorts of mutagens, which change the DNA sequence. Mutagens include oxidizing agents, alkylating agents and also high-energy electromagnetic radiation such as ultraviolet light and X-rays. The type of DNA damage produced depends on the type of mutagen. For example, UV light can damage DNA by producing thymine dimers, which are cross-links between pyrimidine bases. On the other hand, oxidants such as free radicals or hydrogen peroxide produce multiple forms of damage, including base modifications, particularly of guanosine, and double-strand breaks. A typical human cell contains about 150,000 bases that have suffered oxidative damage. Of these oxidative lesions, the most dangerous are double-strand breaks, as these are difficult to repair and can produce point mutations, insertions, deletions from the DNA sequence, and chromosomal translocations. These mutations can cause cancer. Because of inherent limits in the DNA repair mechanisms, if humans lived long enough, they would all eventually develop cancer. DNA damages that are naturally occurring, due to normal cellular processes that produce reactive oxygen species, the hydrolytic activities of cellular water, etc., also occur frequently. Although most of these damages are repaired, in any cell some DNA damage may remain despite the action of repair processes. These remaining DNA damages accumulate with age in mammalian postmitotic tissues. This accumulation appears to be an important underlying cause of aging.
Many mutagens fit into the space between two adjacent base pairs, this is called intercalation. Most intercalators are aromatic and planar molecules; examples include ethidium bromide, acridines, daunomycin, and doxorubicin. For an intercalator to fit between base pairs, the bases must separate, distorting the DNA strands by unwinding of the double helix. This inhibits both transcription and DNA replication, causing toxicity and mutations. As a result, DNA intercalators may be carcinogens, and in the case of thalidomide, a teratogen. Others such as benzo[a]pyrene diol epoxide and aflatoxin form DNA adducts that induce errors in replication. Nevertheless, due to their ability to inhibit DNA transcription and replication, other similar toxins are also used in chemotherapy to inhibit rapidly growing cancer cells.
== Biological functions ==
DNA usually occurs as linear chromosomes in eukaryotes, and circular chromosomes in prokaryotes. The set of chromosomes in a cell makes up its genome; the human genome has approximately 3 billion base pairs of DNA arranged into 46 chromosomes. The information carried by DNA is held in the sequence of pieces of DNA called genes. Transmission of genetic information in genes is achieved via complementary base pairing. For example, in transcription, when a cell uses the information in a gene, the DNA sequence is copied into a complementary RNA sequence through the attraction between the DNA and the correct RNA nucleotides. Usually, this RNA copy is then used to make a matching protein sequence in a process called translation, which depends on the same interaction between RNA nucleotides. In an alternative fashion, a cell may copy its genetic information in a process called DNA replication. The details of these functions are covered in other articles; here the focus is on the interactions between DNA and other molecules that mediate the function of the genome.
=== Genes and genomes ===
Genomic DNA is tightly and orderly packed in the process called DNA condensation, to fit the small available volumes of the cell. In eukaryotes, DNA is located in the cell nucleus, with small amounts in mitochondria and chloroplasts. In prokaryotes, the DNA is held within an irregularly shaped body in the cytoplasm called the nucleoid. The genetic information in a genome is held within genes, and the complete set of this information in an organism is called its genotype. A gene is a unit of heredity and is a region of DNA that influences a particular characteristic in an organism. Genes contain an open reading frame that can be transcribed, and regulatory sequences such as promoters and enhancers, which control transcription of the open reading frame.
In many species, only a small fraction of the total sequence of the genome encodes protein. For example, only about 1.5% of the human genome consists of protein-coding exons, with over 50% of human DNA consisting of non-coding repetitive sequences. The reasons for the presence of so much noncoding DNA in eukaryotic genomes and the extraordinary differences in genome size, or C-value, among species, represent a long-standing puzzle known as the "C-value enigma". However, some DNA sequences that do not code protein may still encode functional non-coding RNA molecules, which are involved in the regulation of gene expression.
Some noncoding DNA sequences play structural roles in chromosomes. Telomeres and centromeres typically contain few genes but are important for the function and stability of chromosomes. An abundant form of noncoding DNA in humans are pseudogenes, which are copies of genes that have been disabled by mutation. These sequences are usually just molecular fossils, although they can occasionally serve as raw genetic material for the creation of new genes through the process of gene duplication and divergence.
=== Transcription and translation ===
A gene is a sequence of DNA that contains genetic information and can influence the phenotype of an organism. Within a gene, the sequence of bases along a DNA strand defines a messenger RNA sequence, which then defines one or more protein sequences. The relationship between the nucleotide sequences of genes and the amino-acid sequences of proteins is determined by the rules of translation, known collectively as the genetic code. The genetic code consists of three-letter 'words' called codons formed from a sequence of three nucleotides (e.g. ACT, CAG, TTT).
In transcription, the codons of a gene are copied into messenger RNA by RNA polymerase. This RNA copy is then decoded by a ribosome that reads the RNA sequence by base-pairing the messenger RNA to transfer RNA, which carries amino acids. Since there are 4 bases in 3-letter combinations, there are 64 possible codons (43 combinations). These encode the twenty standard amino acids, giving most amino acids more than one possible codon. There are also three 'stop' or 'nonsense' codons signifying the end of the coding region; these are the TAG, TAA, and TGA codons, (UAG, UAA, and UGA on the mRNA).
=== Replication ===
Cell division is essential for an organism to grow, but, when a cell divides, it must replicate the DNA in its genome so that the two daughter cells have the same genetic information as their parent. The double-stranded structure of DNA provides a simple mechanism for DNA replication. Here, the two strands are separated and then each strand's complementary DNA sequence is recreated by an enzyme called DNA polymerase. This enzyme makes the complementary strand by finding the correct base through complementary base pairing and bonding it onto the original strand. As DNA polymerases can only extend a DNA strand in a 5′ to 3′ direction, different mechanisms are used to copy the antiparallel strands of the double helix. In this way, the base on the old strand dictates which base appears on the new strand, and the cell ends up with a perfect copy of its DNA.
=== Extracellular nucleic acids ===
Naked extracellular DNA (eDNA), most of it released by cell death, is nearly ubiquitous in the environment. Its concentration in soil may be as high as 2 μg/L, and its concentration in natural aquatic environments may be as high at 88 μg/L. Various possible functions have been proposed for eDNA: it may be involved in horizontal gene transfer; it may provide nutrients; and it may act as a buffer to recruit or titrate ions or antibiotics. Extracellular DNA acts as a functional extracellular matrix component in the biofilms of several bacterial species. It may act as a recognition factor to regulate the attachment and dispersal of specific cell types in the biofilm; it may contribute to biofilm formation; and it may contribute to the biofilm's physical strength and resistance to biological stress.
Cell-free fetal DNA is found in the blood of the mother, and can be sequenced to determine a great deal of information about the developing fetus.
Under the name of environmental DNA eDNA has seen increased use in the natural sciences as a survey tool for ecology, monitoring the movements and presence of species in water, air, or on land, and assessing an area's biodiversity.
=== Neutrophil extracellular traps ===
Neutrophil extracellular traps (NETs) are networks of extracellular fibers, primarily composed of DNA, which allow neutrophils, a type of white blood cell, to kill extracellular pathogens while minimizing damage to the host cells.
== Interactions with proteins ==
All the functions of DNA depend on interactions with proteins. These protein interactions can be non-specific, or the protein can bind specifically to a single DNA sequence. Enzymes can also bind to DNA and of these, the polymerases that copy the DNA base sequence in transcription and DNA replication are particularly important.
=== DNA-binding proteins ===
Structural proteins that bind DNA are well-understood examples of non-specific DNA-protein interactions. Within chromosomes, DNA is held in complexes with structural proteins. These proteins organize the DNA into a compact structure called chromatin. In eukaryotes, this structure involves DNA binding to a complex of small basic proteins called histones, while in prokaryotes multiple types of proteins are involved. The histones form a disk-shaped complex called a nucleosome, which contains two complete turns of double-stranded DNA wrapped around its surface. These non-specific interactions are formed through basic residues in the histones, making ionic bonds to the acidic sugar-phosphate backbone of the DNA, and are thus largely independent of the base sequence. Chemical modifications of these basic amino acid residues include methylation, phosphorylation, and acetylation. These chemical changes alter the strength of the interaction between the DNA and the histones, making the DNA more or less accessible to transcription factors and changing the rate of transcription. Other non-specific DNA-binding proteins in chromatin include the high-mobility group proteins, which bind to bent or distorted DNA. These proteins are important in bending arrays of nucleosomes and arranging them into the larger structures that make up chromosomes.
A distinct group of DNA-binding proteins is the DNA-binding proteins that specifically bind single-stranded DNA. In humans, replication protein A is the best-understood member of this family and is used in processes where the double helix is separated, including DNA replication, recombination, and DNA repair. These binding proteins seem to stabilize single-stranded DNA and protect it from forming stem-loops or being degraded by nucleases.
In contrast, other proteins have evolved to bind to particular DNA sequences. The most intensively studied of these are the various transcription factors, which are proteins that regulate transcription. Each transcription factor binds to one particular set of DNA sequences and activates or inhibits the transcription of genes that have these sequences close to their promoters. The transcription factors do this in two ways. Firstly, they can bind the RNA polymerase responsible for transcription, either directly or through other mediator proteins; this locates the polymerase at the promoter and allows it to begin transcription. Alternatively, transcription factors can bind enzymes that modify the histones at the promoter. This changes the accessibility of the DNA template to the polymerase.
As these DNA targets can occur throughout an organism's genome, changes in the activity of one type of transcription factor can affect thousands of genes. Consequently, these proteins are often the targets of the signal transduction processes that control responses to environmental changes or cellular differentiation and development. The specificity of these transcription factors' interactions with DNA come from the proteins making multiple contacts to the edges of the DNA bases, allowing them to "read" the DNA sequence. Most of these base-interactions are made in the major groove, where the bases are most accessible.
=== DNA-modifying enzymes ===
==== Nucleases and ligases ====
Nucleases are enzymes that cut DNA strands by catalyzing the hydrolysis of the phosphodiester bonds. Nucleases that hydrolyse nucleotides from the ends of DNA strands are called exonucleases, while endonucleases cut within strands. The most frequently used nucleases in molecular biology are the restriction endonucleases, which cut DNA at specific sequences. For instance, the EcoRV enzyme shown to the left recognizes the 6-base sequence 5′-GATATC-3′ and makes a cut at the horizontal line. In nature, these enzymes protect bacteria against phage infection by digesting the phage DNA when it enters the bacterial cell, acting as part of the restriction modification system. In technology, these sequence-specific nucleases are used in molecular cloning and DNA fingerprinting.
Enzymes called DNA ligases can rejoin cut or broken DNA strands. Ligases are particularly important in lagging strand DNA replication, as they join the short segments of DNA produced at the replication fork into a complete copy of the DNA template. They are also used in DNA repair and genetic recombination.
==== Topoisomerases and helicases ====
Topoisomerases are enzymes with both nuclease and ligase activity. These proteins change the amount of supercoiling in DNA. Some of these enzymes work by cutting the DNA helix and allowing one section to rotate, thereby reducing its level of supercoiling; the enzyme then seals the DNA break. Other types of these enzymes are capable of cutting one DNA helix and then passing a second strand of DNA through this break, before rejoining the helix. Topoisomerases are required for many processes involving DNA, such as DNA replication and transcription.
Helicases are proteins that are a type of molecular motor. They use the chemical energy in nucleoside triphosphates, predominantly adenosine triphosphate (ATP), to break hydrogen bonds between bases and unwind the DNA double helix into single strands. These enzymes are essential for most processes where enzymes need to access the DNA bases.
==== Polymerases ====
Polymerases are enzymes that synthesize polynucleotide chains from nucleoside triphosphates. The sequence of their products is created based on existing polynucleotide chains—which are called templates. These enzymes function by repeatedly adding a nucleotide to the 3′ hydroxyl group at the end of the growing polynucleotide chain. As a consequence, all polymerases work in a 5′ to 3′ direction. In the active site of these enzymes, the incoming nucleoside triphosphate base-pairs to the template: this allows polymerases to accurately synthesize the complementary strand of their template. Polymerases are classified according to the type of template that they use.
In DNA replication, DNA-dependent DNA polymerases make copies of DNA polynucleotide chains. To preserve biological information, it is essential that the sequence of bases in each copy are precisely complementary to the sequence of bases in the template strand. Many DNA polymerases have a proofreading activity. Here, the polymerase recognizes the occasional mistakes in the synthesis reaction by the lack of base pairing between the mismatched nucleotides. If a mismatch is detected, a 3′ to 5′ exonuclease activity is activated and the incorrect base removed. In most organisms, DNA polymerases function in a large complex called the replisome that contains multiple accessory subunits, such as the DNA clamp or helicases.
RNA-dependent DNA polymerases are a specialized class of polymerases that copy the sequence of an RNA strand into DNA. They include reverse transcriptase, which is a viral enzyme involved in the infection of cells by retroviruses, and telomerase, which is required for the replication of telomeres. For example, HIV reverse transcriptase is an enzyme for AIDS virus replication. Telomerase is an unusual polymerase because it contains its own RNA template as part of its structure. It synthesizes telomeres at the ends of chromosomes. Telomeres prevent fusion of the ends of neighboring chromosomes and protect chromosome ends from damage.
Transcription is carried out by a DNA-dependent RNA polymerase that copies the sequence of a DNA strand into RNA. To begin transcribing a gene, the RNA polymerase binds to a sequence of DNA called a promoter and separates the DNA strands. It then copies the gene sequence into a messenger RNA transcript until it reaches a region of DNA called the terminator, where it halts and detaches from the DNA. As with human DNA-dependent DNA polymerases, RNA polymerase II, the enzyme that transcribes most of the genes in the human genome, operates as part of a large protein complex with multiple regulatory and accessory subunits.
== Genetic recombination ==
A DNA helix usually does not interact with other segments of DNA, and in human cells, the different chromosomes even occupy separate areas in the nucleus called "chromosome territories". This physical separation of different chromosomes is important for the ability of DNA to function as a stable repository for information, as one of the few times chromosomes interact is in chromosomal crossover which occurs during sexual reproduction, when genetic recombination occurs. Chromosomal crossover is when two DNA helices break, swap a section and then rejoin.
Recombination allows chromosomes to exchange genetic information and produces new combinations of genes, which increases the efficiency of natural selection and can be important in the rapid evolution of new proteins. Genetic recombination can also be involved in DNA repair, particularly in the cell's response to double-strand breaks.
The most common form of chromosomal crossover is homologous recombination, where the two chromosomes involved share very similar sequences. Non-homologous recombination can be damaging to cells, as it can produce chromosomal translocations and genetic abnormalities. The recombination reaction is catalyzed by enzymes known as recombinases, such as RAD51. The first step in recombination is a double-stranded break caused by either an endonuclease or damage to the DNA. A series of steps catalyzed in part by the recombinase then leads to joining of the two helices by at least one Holliday junction, in which a segment of a single strand in each helix is annealed to the complementary strand in the other helix. The Holliday junction is a tetrahedral junction structure that can be moved along the pair of chromosomes, swapping one strand for another. The recombination reaction is then halted by cleavage of the junction and re-ligation of the released DNA. Only strands of like polarity exchange DNA during recombination. There are two types of cleavage: east-west cleavage and north–south cleavage. The north–south cleavage nicks both strands of DNA, while the east–west cleavage has one strand of DNA intact. The formation of a Holliday junction during recombination makes it possible for genetic diversity, genes to exchange on chromosomes, and expression of wild-type viral genomes.
== Evolution ==
DNA contains the genetic information that allows all forms of life to function, grow and reproduce. However, it is unclear how long in the 4-billion-year history of life DNA has performed this function, as it has been proposed that the earliest forms of life may have used RNA as their genetic material. RNA may have acted as the central part of early cell metabolism as it can both transmit genetic information and carry out catalysis as part of ribozymes. This ancient RNA world where nucleic acid would have been used for both catalysis and genetics may have influenced the evolution of the current genetic code based on four nucleotide bases. This would occur, since the number of different bases in such an organism is a trade-off between a small number of bases increasing replication accuracy and a large number of bases increasing the catalytic efficiency of ribozymes. However, there is no direct evidence of ancient genetic systems, as recovery of DNA from most fossils is impossible because DNA survives in the environment for less than one million years, and slowly degrades into short fragments in solution. Claims for older DNA have been made, most notably a report of the isolation of a viable bacterium from a salt crystal 250 million years old, but these claims are controversial.
Building blocks of DNA (adenine, guanine, and related organic molecules) may have been formed extraterrestrially in outer space. Complex DNA and RNA organic compounds of life, including uracil, cytosine, and thymine, have also been formed in the laboratory under conditions mimicking those found in outer space, using starting chemicals, such as pyrimidine, found in meteorites. Pyrimidine, like polycyclic aromatic hydrocarbons (PAHs), the most carbon-rich chemical found in the universe, may have been formed in red giants or in interstellar cosmic dust and gas clouds.
Ancient DNA has been recovered from ancient organisms at a timescale where genome evolution can be directly observed, including from extinct organisms up to millions of years old, such as the woolly mammoth.
== Uses in technology ==
=== Genetic engineering ===
Methods have been developed to purify DNA from organisms, such as phenol-chloroform extraction, and to manipulate it in the laboratory, such as restriction digests and the polymerase chain reaction. Modern biology and biochemistry make intensive use of these techniques in recombinant DNA technology. Recombinant DNA is a man-made DNA sequence that has been assembled from other DNA sequences. They can be transformed into organisms in the form of plasmids or in the appropriate format, by using a viral vector. The genetically modified organisms produced can be used to produce products such as recombinant proteins, used in medical research, or be grown in agriculture.
=== DNA profiling ===
Forensic scientists can use DNA in blood, semen, skin, saliva or hair found at a crime scene to identify a matching DNA of an individual, such as a perpetrator. This process is formally termed DNA profiling, also called DNA fingerprinting. In DNA profiling, the lengths of variable sections of repetitive DNA, such as short tandem repeats and minisatellites, are compared between people. This method is usually an extremely reliable technique for identifying a matching DNA. However, identification can be complicated if the scene is contaminated with DNA from several people. DNA profiling was developed in 1984 by British geneticist Sir Alec Jeffreys, and first used in forensic science to convict Colin Pitchfork in the 1988 Enderby murders case.
The development of forensic science and the ability to now obtain genetic matching on minute samples of blood, skin, saliva, or hair has led to re-examining many cases. Evidence can now be uncovered that was scientifically impossible at the time of the original examination. Combined with the removal of the double jeopardy law in some places, this can allow cases to be reopened where prior trials have failed to produce sufficient evidence to convince a jury. People charged with serious crimes may be required to provide a sample of DNA for matching purposes. The most obvious defense to DNA matches obtained forensically is to claim that cross-contamination of evidence has occurred. This has resulted in meticulous strict handling procedures with new cases of serious crime.
DNA profiling is also used successfully to positively identify victims of mass casualty incidents, bodies or body parts in serious accidents, and individual victims in mass war graves, via matching to family members.
DNA profiling is also used in DNA paternity testing to determine if someone is the biological parent or grandparent of a child with the probability of parentage is typically 99.99% when the alleged parent is biologically related to the child. Normal DNA sequencing methods happen after birth, but there are new methods to test paternity while a mother is still pregnant.
=== DNA enzymes or catalytic DNA ===
Deoxyribozymes, also called DNAzymes or catalytic DNA, were first discovered in 1994. They are mostly single stranded DNA sequences isolated from a large pool of random DNA sequences through a combinatorial approach called in vitro selection or systematic evolution of ligands by exponential enrichment (SELEX). DNAzymes catalyze variety of chemical reactions including RNA-DNA cleavage, RNA-DNA ligation, amino acids phosphorylation-dephosphorylation, carbon-carbon bond formation, etc. DNAzymes can enhance catalytic rate of chemical reactions up to 100,000,000,000-fold over the uncatalyzed reaction. The most extensively studied class of DNAzymes is RNA-cleaving types which have been used to detect different metal ions and designing therapeutic agents. Several metal-specific DNAzymes have been reported including the GR-5 DNAzyme (lead-specific), the CA1-3 DNAzymes (copper-specific), the 39E DNAzyme (uranyl-specific) and the NaA43 DNAzyme (sodium-specific). The NaA43 DNAzyme, which is reported to be more than 10,000-fold selective for sodium over other metal ions, was used to make a real-time sodium sensor in cells.
=== Bioinformatics ===
Bioinformatics involves the development of techniques to store, data mine, search and manipulate biological data, including DNA nucleic acid sequence data. These have led to widely applied advances in computer science, especially string searching algorithms, machine learning, and database theory. String searching or matching algorithms, which find an occurrence of a sequence of letters inside a larger sequence of letters, were developed to search for specific sequences of nucleotides. The DNA sequence may be aligned with other DNA sequences to identify homologous sequences and locate the specific mutations that make them distinct. These techniques, especially multiple sequence alignment, are used in studying phylogenetic relationships and protein function. Data sets representing entire genomes' worth of DNA sequences, such as those produced by the Human Genome Project, are difficult to use without the annotations that identify the locations of genes and regulatory elements on each chromosome. Regions of DNA sequence that have the characteristic patterns associated with protein- or RNA-coding genes can be identified by gene finding algorithms, which allow researchers to predict the presence of particular gene products and their possible functions in an organism even before they have been isolated experimentally. Entire genomes may also be compared, which can shed light on the evolutionary history of particular organism and permit the examination of complex evolutionary events.
=== DNA nanotechnology ===
DNA nanotechnology uses the unique molecular recognition properties of DNA and other nucleic acids to create self-assembling branched DNA complexes with useful properties. DNA is thus used as a structural material rather than as a carrier of biological information. This has led to the creation of two-dimensional periodic lattices (both tile-based and using the DNA origami method) and three-dimensional structures in the shapes of polyhedra. Nanomechanical devices and algorithmic self-assembly have also been demonstrated, and these DNA structures have been used to template the arrangement of other molecules such as gold nanoparticles and streptavidin proteins. DNA and other nucleic acids are the basis of aptamers, synthetic oligonucleotide ligands for specific target molecules used in a range of biotechnology and biomedical applications.
=== History and anthropology ===
Because DNA collects mutations over time, which are then inherited, it contains historical information, and, by comparing DNA sequences, geneticists can infer the evolutionary history of organisms, their phylogeny. This field of phylogenetics is a powerful tool in evolutionary biology. If DNA sequences within a species are compared, population geneticists can learn the history of particular populations. This can be used in studies ranging from ecological genetics to anthropology.
=== Information storage ===
DNA as a storage device for information has enormous potential since it has much higher storage density compared to electronic devices. However, high costs, slow read and write times (memory latency), and insufficient reliability has prevented its practical use.
== History ==
DNA was first isolated by the Swiss physician Friedrich Miescher who, in 1869, discovered a microscopic substance in the pus of discarded surgical bandages. As it resided in the nuclei of cells, he called it "nuclein". In 1878, Albrecht Kossel isolated the non-protein component of "nuclein", nucleic acid, and later isolated its five primary nucleobases.
In 1909, Phoebus Levene identified the base, sugar, and phosphate nucleotide unit of RNA (then named "yeast nucleic acid"). In 1929, Levene identified deoxyribose sugar in "thymus nucleic acid" (DNA). Levene suggested that DNA consisted of a string of four nucleotide units linked together through the phosphate groups ("tetranucleotide hypothesis"). Levene thought the chain was short and the bases repeated in a fixed order. In 1927, Nikolai Koltsov proposed that inherited traits would be inherited via a "giant hereditary molecule" made up of "two mirror strands that would replicate in a semi-conservative fashion using each strand as a template". In 1928, Frederick Griffith in his experiment discovered that traits of the "smooth" form of Pneumococcus could be transferred to the "rough" form of the same bacteria by mixing killed "smooth" bacteria with the live "rough" form. This system provided the first clear suggestion that DNA carries genetic information.
In 1933, while studying virgin sea urchin eggs, Jean Brachet suggested that DNA is found in the cell nucleus and that RNA is present exclusively in the cytoplasm. At the time, "yeast nucleic acid" (RNA) was thought to occur only in plants, while "thymus nucleic acid" (DNA) only in animals. The latter was thought to be a tetramer, with the function of buffering cellular pH.
In 1937, William Astbury produced the first X-ray diffraction patterns that showed that DNA had a regular structure.
In 1943, Oswald Avery, along with co-workers Colin MacLeod and Maclyn McCarty, identified DNA as the transforming principle, supporting Griffith's suggestion (Avery–MacLeod–McCarty experiment). Erwin Chargaff developed and published observations now known as Chargaff's rules, stating that in DNA from any species of any organism, the amount of guanine should be equal to cytosine and the amount of adenine should be equal to thymine.
Late in 1951, Francis Crick started working with James Watson at the Cavendish Laboratory within the University of Cambridge. DNA's role in heredity was confirmed in 1952 when Alfred Hershey and Martha Chase in the Hershey–Chase experiment showed that DNA is the genetic material of the enterobacteria phage T2.
In May 1952, Raymond Gosling, a graduate student working under the supervision of Rosalind Franklin, took an X-ray diffraction image, labeled as "Photo 51", at high hydration levels of DNA. This photo was given to Watson and Crick by Maurice Wilkins and was critical to their obtaining the correct structure of DNA. Franklin told Crick and Watson that the backbones had to be on the outside. Before then, Linus Pauling, and Watson and Crick, had erroneous models with the chains inside and the bases pointing outwards. Franklin's identification of the space group for DNA crystals revealed to Crick that the two DNA strands were antiparallel. In February 1953, Linus Pauling and Robert Corey proposed a model for nucleic acids containing three intertwined chains, with the phosphates near the axis, and the bases on the outside. Watson and Crick completed their model, which is now accepted as the first correct model of the double helix of DNA. On 28 February 1953 Crick interrupted patrons' lunchtime at The Eagle pub in Cambridge, England to announce that he and Watson had "discovered the secret of life".
The 25 April 1953 issue of the journal Nature published a series of five articles giving the Watson and Crick double-helix structure DNA and evidence supporting it. The structure was reported in a letter titled "MOLECULAR STRUCTURE OF NUCLEIC ACIDS A Structure for Deoxyribose Nucleic Acid", in which they said, "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material." This letter was followed by a letter from Franklin and Gosling, which was the first publication of their own X-ray diffraction data and of their original analysis method. Then followed a letter by Wilkins and two of his colleagues, which contained an analysis of in vivo B-DNA X-ray patterns, and which supported the presence in vivo of the Watson and Crick structure.
In April 2023, scientists, based on new evidence, concluded that Rosalind Franklin was a contributor and "equal player" in the discovery process of DNA, rather than otherwise, as may have been presented subsequently after the time of the discovery.
In 1962, after Franklin's death, Watson, Crick, and Wilkins jointly received the Nobel Prize in Physiology or Medicine. Nobel Prizes are awarded only to living recipients. A debate continues about who should receive credit for the discovery.
In an influential presentation in 1957, Crick laid out the central dogma of molecular biology, which foretold the relationship between DNA, RNA, and proteins, and articulated the "adaptor hypothesis". Final confirmation of the replication mechanism that was implied by the double-helical structure followed in 1958 through the Meselson–Stahl experiment. Further work by Crick and co-workers showed that the genetic code was based on non-overlapping triplets of bases, called codons, allowing Har Gobind Khorana, Robert W. Holley, and Marshall Warren Nirenberg to decipher the genetic code. These findings represent the birth of molecular biology.
In 1986, DNA analysis was first used in a criminal investigation when police in the UK requested Alec Jeffreys of the University of Leicester to prove or disprove the involvement in a particular case of a suspect who claimed innocence in the matter. Although the suspect had already confessed to committing a recent rape-murder, he was denying any involvement in a similar crime committed three years earlier. Yet the details of the two cases were so alike that the police concluded both crimes had been committed by the same person. However, all charges against the suspect were dropped when Jeffreys' DNA testing exonerated the suspect — from both the earlier murder and the one to which he'd confessed. Further such DNA profiling led to positive identification of another suspect who, in 1988, was found guilty of both rape-murders.
== See also ==
== References ==
== Further reading ==
== External links ==
DNA binding site prediction on protein
DNA the Double Helix Game From the official Nobel Prize web site
DNA under electron microscope
Dolan DNA Learning Center
Double Helix: 50 years of DNA, Nature
Proteopedia DNA
Proteopedia Forms_of_DNA
ENCODE threads explorer ENCODE home page at Nature
Double Helix 1953–2003 National Centre for Biotechnology Education
Genetic Education Modules for Teachers – DNA from the Beginning Study Guide
PDB Molecule of the Month DNA
"Clue to chemistry of heredity found". The New York Times, June 1953. First American newspaper coverage of the discovery of the DNA structure
DNA from the Beginning Another DNA Learning Center site on DNA, genes, and heredity from Mendel to the human genome project.
The Register of Francis Crick Personal Papers 1938 – 2007 at Mandeville Special Collections Library, University of California, San Diego
Seven-page, handwritten letter that Crick sent to his 12-year-old son Michael in 1953 describing the structure of DNA. See Crick's medal goes under the hammer, Nature, 5 April 2013. | Wikipedia/Naked_DNA |
The Collingridge dilemma is a methodological quandary in which efforts to influence or control the further development of technology face a double-bind problem:
An information problem: impacts cannot be easily predicted until the technology is extensively developed and widely used.
A power problem: control or change is difficult when the technology has become entrenched.
The idea was coined by David Collingridge at the University of Aston Technology Policy Unit in his 1980 book The Social Control of Technology. The dilemma is a basic point of reference in technology assessment debates.
== Background ==
In "This Explains Everything," edited by John Brockman, technology critic Evgeny Morozov explains Collingridge's idea by quoting Collingridge himself: "When change is easy, the need for it cannot be foreseen; when the need for change is apparent, change has become expensive, difficult, and time-consuming."
In "The Pacing Problem, the Collingridge Dilemma & Technological Determinism" by Adam Thierer, a senior research fellow at the Mercatus Center at George Mason University, the Collingridge dilemma is related to the "pacing problem" in technology regulation. The "pacing problem" refers to the notion that technological innovation is increasingly outpacing the ability of laws and regulations to keep up, first explained in Larry Downes' 2009 book The Laws of Disruption, in which he states that "technology changes exponentially, but social, economic, and legal systems change incrementally". In Thierer's essay, he tries to correlate these two concepts by saying that "the 'Collingridge dilemma' is simply a restatement of the pacing problem but with greater stress on the social drivers behind the pacing problem and an implicit solution to 'the problem' in the form of preemptive control of new technologies while they are still young and more manageable."
One solution to Collingridge dilemma is the "Precautionary Principle." Adam Thierer defines it as the belief that new innovations should not be embraced "until their developers can prove that they will not cause any harm to individuals, groups, specific entities, cultural norms, or various existing laws, norms, or traditions". If they fail to do so, this innovation should be "prohibited, curtailed, modified, junked, or ignored". This definition has been criticized by Kevin Kelly who believe such a principle is ill-defined and is biased against anything new because it drastically elevates the threshold for anything innovative. According to the American philosopher Max More, the Precautionary Principle "is very good for one thing — stopping technological progress...not because it leads in bad directions, but because it leads in no direction at all." But the 1992 Rio Declaration on Environment and Development defines the precautionary principle as ""Where there are threats of serious or irreversible damage, lack of full scientific certainty shall not be used as a reason for postponing cost-effective measures to prevent environmental degradation." So rather than conceived as imposing no change until proof of safety is produced, this definition of the precautionary principle is meant to legitimate protective measures, attempting to avoid the desire of a technology's advocates to delay legislation until irrefutable evidence of harm can be produced.
Collingridge's solution was not exactly the precautionary principle but rather the application of "Intelligent Trial and Error," a process by which decision making power remains decentralized, changes are manageable, technologies and infrastructures are designed to be flexible, and the overall process is oriented towards learning quickly while keeping the potential costs as low as possible. Collingridge advocated ensuring that innovation occurs more incrementally so as to better match the pace of human learning and avoiding technologies whose design was antithetical to an Intelligent Trial and Error process.
== Current context ==
The Collingridge Dilemma applies well to a world where Artificial Intelligence and Cloud are gaining ground and developers are consuming new technology at a rapid pace. Governing AI, Cloud or other similar exponential technology without slowing the pace of development of the technology is a big challenge, governments and organizations now face.
== References == | Wikipedia/Collingridge_dilemma |
Differential technological development is a strategy of technology governance aiming to decrease risks from emerging technologies by influencing the sequence in which they are developed. Using this strategy, societies would strive to delay the development of harmful technologies and their applications while accelerating the development of beneficial technologies, especially those that offer protection against harmful technologies.
== History of the idea ==
Differential technological development was initially proposed by philosopher Nick Bostrom in 2002 and he applied the idea to the governance of artificial intelligence in his 2014 book Superintelligence: Paths, Dangers, Strategies. The strategy was also endorsed by philosopher Toby Ord in his 2020 book The Precipice: Existential Risk and the Future of Humanity, who writes that "While it may be too difficult to prevent the development of a risky technology, we may be able to reduce existential risk by speeding up the development of protective technologies relative to dangerous ones."
== Informal discussion ==
Paul Christiano believes that while accelerating technological progress appears to be one of the best ways to improve human welfare in the next few decades, a faster rate of growth cannot be equally important for the far future because growth must eventually saturate due to physical limits. Hence, from the perspective of the far future, differential technological development appears more crucial.
Inspired by Bostrom's proposal, Luke Muehlhauser and Anna Salamon suggested a more general project of "differential intellectual progress", in which society advances its wisdom, philosophical sophistication, and understanding of risks faster than its technological power. Brian Tomasik has expanded on this notion.
== See also ==
Existential risk
== References == | Wikipedia/Differential_technological_development |
Apolipoprotein E (Apo-E) is a protein involved in the metabolism of fats in the body of mammals. A subtype is implicated in Alzheimer's disease and cardiovascular diseases. It is encoded in humans by the gene APOE.
Apo-E belongs to a family of fat-binding proteins called apolipoproteins. In the circulation, it is present as part of several classes of lipoprotein particles, including chylomicron remnants, VLDL, IDL, and some HDL. Apo-E interacts significantly with the low-density lipoprotein receptor (LDLR), which is essential for the normal processing (catabolism) of triglyceride-rich lipoproteins. In peripheral tissues, Apo-E is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. In the central nervous system, Apo-E is mainly produced by astrocytes and transports cholesterol to neurons via Apo-E receptors, which are members of the low density lipoprotein receptor gene family. Apo-E is the principal cholesterol carrier in the brain. Apo-E qualifies as a checkpoint inhibitor of the classical complement pathway by complex formation with activated C1q.
== Evolution ==
Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them. It is believed that APOE arose via gene duplications of APOC1 before the fish–tetrapod split ca. 400 million years ago. Proteins similar in function have been found in choanoflagellates, suggesting that they are a very old class of proteins predating the dawn of all living animals.
The three major human alleles (E4, E3, E2) arose after the primate–human split around 7.5 million years ago. These alleles are the by-product of non-synonymous mutations which led to changes in functionality. The first allele to emerge was E4. After the primate–human split, there were four amino acid changes in the human lineage, three of which had no effect on protein function (V174L, A18T, A135V). The fourth substitution (T61R) traded a threonine for an arginine altering the protein's functionality. This substitution occurred somewhere in the 6 million year gap between the primate–human split and the Denisovan–human split, since exactly the same substitutions were found in Denisovan APOE.
About 220,000 years ago, a cysteine to arginine substitution took place at amino acid 112 (Cys112Arg) of the APOE4 gene, and this resulted in the E3 allele. Finally, 80,000 years ago, another arginine to cysteine substitution at amino acid 158 (Arg158Cys) of the APOE3 gene created the E2 allele.
== Structure ==
=== Gene ===
The gene, APOE, is mapped to chromosome 19 in a cluster with the apolipoprotein C1 (APOC1) gene and the apolipoprotein C2 (APOC2) gene. The APOE gene consists of four exons and three introns, totaling 3597 base pairs. APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol, fatty acid, and glucose homeostasis) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with retinoid X receptors. In melanocytic cells APOE gene expression may be regulated by MITF.
=== Protein ===
Apoe-E is 299 amino acids long and contains multiple amphipathic α-helices. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein. The N-terminal region (residues 1–167) forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. Meanwhile, the C-terminal domain (residues 206–299) contains three α-helices which form a large exposed hydrophobic surface and interact with those in the N-terminal helix bundle domain through hydrogen bonds and salt-bridges. The C-terminal region also contains a low density lipoprotein receptor (LDLR)-binding site.
=== Polymorphisms ===
APOE is polymorphic, with three major alleles (epsilon 2, epsilon 3, and epsilon 4): APOE-ε2 (cys112, cys158), APOE-ε3 (cys112, arg158), and APOE-ε4 (arg112, arg158). Although these allelic forms differ from each other by only one or two amino acids at positions 112 and 158, these differences alter APOE structure and function.
There are several low-frequency polymorphisms of APOE. APOE5 comes in two subtypes E5f and E5s, based on migration rates. APOE5 E5f and APOE7 combined were found in 2.8% of Japanese males. APOE7 is a mutation of APOE3 with two lysine residues replacing glutamic acid residues at positions 244 and 245.
Much remains to be learned about the APOE isoforms, including the interaction of other protective genes. Indeed, the apolipoprotein ε4 isoform is more protective against cognitive decline than other isoforms in some cases, so caution is advised before making determinant statements about the influence of APOE polymorphisms on cognition, development of Alzheimer's disease, cardiovascular disease, telomere shortening, etc. Many of the studies cited that purport these adverse outcomes are from single studies that have not been replicated and the research is based on unchecked assumptions about this isoform. As of 2007, there was no evidence that APOE polymorphisms influence cognition in younger age groups (other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups), nor that the APOE4 isoform places individuals at increased risk for any infectious disease.
However, the association between the APOE4 allele and Alzheimer's disease has been shown to be weaker in minority groups differently compared to their Caucasian counterparts. Hispanics/Latinos and African Americans who were homozygous for the APOE4 allele had 2.2 and 5.7 times the odds, respectively of developing Alzheimer's disease. The homozygous APOE4 allele has an even stronger effect in East Asian populations, with Japanese populations have 33 times the odds compared to the heterozygous population. Caucasians who were homozygous for the allele had 12.5 times the odds.
== Function ==
As a component of the lipoprotein lipid transport system, APOE facilitates the transport of lipids, fat-soluble vitamins, and cholesterol via the blood. It interacts with the LDL receptor to facilitate endocytosis of VLDL remnants. It is synthesized principally in the liver, but has also been found in other tissues such as the brain, kidneys, and spleen. APOE synthesized in the liver associates with HDL which can then distribute it to newly formed VLDL or chylomicron particles to facilitate their eventual uptake by the liver.
In the nervous system, non-neuronal cell types, most notably astroglia and microglia, are the primary producers of APOE, while neurons preferentially express the receptors for APOE. There are seven currently identified mammalian receptors for APOE which belong to the evolutionarily conserved LDLR family.
APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. Defects in APOE result in familial dysbetalipoproteinemia aka type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron, VLDL and LDL. More recently, it has been studied for its role in several biological processes not directly related to lipoprotein transport, including Alzheimer's disease (AD), immunoregulation, and cognition. Though the exact mechanisms remain to be elucidated, isoform 4 of APOE, encoded by an APOE allele, has been associated with increased calcium ion levels and apoptosis following mechanical injury.
In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation (by CD1) to natural killer T cell as well as modulation of inflammation and oxidation. APOE is produced by macrophages and APOE secretion has been shown to be restricted to classical monocytes in PBMC, and the secretion of APOE by monocytes is down regulated by inflammatory cytokines and upregulated by TGF-beta.
== Clinical significance ==
=== Alzheimer's disease ===
As of 2012, the E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD) in a variety of ethnic groups. However, the E4 variant does not correlate with risk in every population. Nigerian people have the highest observed frequency of the APOE4 allele in world populations, but AD is rare among them. This may be due to their low cholesterol levels. Caucasian and Japanese carriers of two E4 alleles have between 10 and 30 times the risk of developing AD by 75 years of age, as compared to those not carrying any E4 alleles. This may be caused by an interaction with amyloid. Alzheimer's disease is characterized by build-ups of aggregates of the peptide beta-amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. The isoform APOE-ε4 is not as effective as the others at promoting these reactions, resulting in increased vulnerability to AD in individuals with that gene variation.
Recently, the amyloid hypothesis of Alzheimer's disease has been questioned, and an article in Science claimed that "Just as removing smoke does not extinguish a fire, reducing amyloid plaques may not affect the course of Alzheimer's disease." The role that the E4 variant carries can still be fully explained even in the absence of a valid amyloid hypothesis given the fact that reelin signaling emerges to be one of the key processes involved in Alzheimer's disease and the E4 variant is shown to interact with ApoER2, one of the neuronal reelin receptors, thereby obstructing reelin signaling.
Although 40–65% of AD patients have at least one copy of the ε4 allele, APOE4 is not a determinant of the disease. At least one-third of patients with AD are APOE4 negative and some APOE4 homozygotes never develop the disease. Yet those with two ε4 alleles have up to 20 times the risk of developing AD. There is also evidence that the APOE2 allele may serve a protective role in AD. Thus, the genotype most at risk for Alzheimer's disease and at an earlier age is APOE4,4. Using genotype APOE3,3 as a benchmark (with the persons who have this genotype regarded as having a risk level of 1.0) and for white populations only, individuals with genotype APOE4,4 have an odds ratio of 14.9 of developing Alzheimer's disease. Individuals with the APOE3,4 genotype face an odds ratio of 3.2, and people with a copy of the 2 allele and the 4 allele (APOE2,4), have an odds ratio of 2.6. Persons with one copy each of the 2 allele and the 3 allele (APOE2,3) have an odds ratio of 0.6. Persons with two copies of the 2 allele (APOE2,2) also have an odds ratio of 0.6.
While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer's, a 2002 study concluded, that in persons with any combination of APOE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD. Projecting from their data, some researchers have suggested that lowering serum cholesterol levels may reduce a person's risk for Alzheimer's disease, even if they have two ApoE4 alleles, thus reducing the risk from nine or ten times the odds of getting AD down to just two times the odds.
Women are more likely to develop AD than men across most ages and APOE genotypes. Premorbid women with the ε4 allele have significantly more neurological dysfunction than men.
APOE-ε4 increases the risk not only for AD but also for dementia in pure alpha-synucleinopathies. The influence of APOE-ε4 on hippocampal atrophy was suggested to be more predominant early in the course of AD at milder stages prior to more widespread neurodegeneration.
With the approval of the first disease-modifying therapies for Alzheimer's disease based on monoclonal antibodies against amyloid-beta, which delay disease progression, APOE genotyping has also become important in assessing a patient’s risk of side effects under therapy. In November 2024, the Committee for Medicinal Products for Human Use of the European Medicines Agency following a re-examination procedure, adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Leqembi, intended for the treatment of early Alzheimer's disease in apolipoprotein E ε4 (ApoE ε4) non-carriers or heterozygotes. The applicant for this medicinal product is Eisai GmbH.
=== Atherosclerosis ===
Knockout mice that lack the apolipoprotein-E gene (APOE−/−) develop extreme hypercholesterolemia when fed a high-fat diet.
=== Malaria ===
APOE−/− knockout mice show marked attenuation of cerebral malaria and increased survival, as well as decreased sequestration of parasites and T cells within the brain, likely due to protection of the blood–brain barrier. Human studies have shown that the APOE2 polymorphism correlates with earlier infection, and APOE3/4 polymorphisms increase likelihood of severe malaria.
=== Lyme disease ===
Borrelia burgdorferi, the causative agent of Lyme disease, is a host-adapted pathogen that acquires environmental cholesterol to form glycolipids for use in cell membrane maintenance. In one experiment in 2015, mice engineered with apoE deficiency were infected with Borrelia spirochetes. The knockout mice suffered from an increased spirochete burden in joints, as well as inflamed ankles, when compared with wild-type mice. This study suggests that apoE deficiency (and potentially other hyperlipidemias) may be a risk factor in the pathogenicity of Lyme disease.
== Interactions ==
=== Interactive pathway map ===
Click on genes, proteins and metabolites below to link to respective articles.
== References ==
== Further reading ==
== External links ==
Apolipoproteins+E at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Human APOE genome location and APOE gene details page in the UCSC Genome Browser.
Overview of all the structural information available in the PDB for UniProt: P02649 (Apolipoprotein E) at the PDBe-KB. | Wikipedia/Apolipoprotein_E |
Peripheral artery disease (PAD) is a vascular disorder that causes abnormal narrowing of arteries other than those that supply the heart or brain. PAD can happen in any blood vessel, but it is more common in the legs than the arms.
When narrowing occurs in the heart, it is called coronary artery disease (CAD), and in the brain, it is called cerebrovascular disease. Peripheral artery disease most commonly affects the legs, but other arteries may also be involved, such as those of the arms, neck, or kidneys.
Peripheral artery disease (PAD) is a form of peripheral vascular disease. Vascular refers to the arteries and veins within the body. PAD differs from peripheral veinous disease. PAD means the arteries are narrowed or blocked—the vessels that carry oxygen-rich blood as it moves from the heart to other parts of the body. Peripheral veinous disease, on the other hand, refers to problems with veins—the vessels that bring the blood back to the heart.
The classic symptom is leg pain when walking, which resolves with rest and is known as intermittent claudication. Other symptoms include skin ulcers, bluish skin, cold skin, or abnormal nail and hair growth in the affected leg. Complications may include an infection or tissue death, which may require amputation; coronary artery disease; or stroke. Up to 50% of people with PAD do not have symptoms.
The greatest risk factor for PAD is cigarette smoking. Other risk factors include diabetes, high blood pressure, kidney problems, and high blood cholesterol. PAD is primarily caused by the buildup of fatty plaque in the arteries, which is called atherosclerosis, especially in individuals over 40 years old. Other mechanisms include artery spasm, blood clots, trauma, fibromuscular dysplasia, and vasculitis. PAD is typically diagnosed by finding an ankle-brachial index (ABI) less than 0.90, which is the systolic blood pressure at the ankle divided by the systolic blood pressure of the arm. Duplex ultrasonography and angiography may also be used. Angiography is more accurate and allows for treatment at the same time; however, it is associated with greater risks.
It is unclear if screening for peripheral artery disease in people without symptoms is useful, as it has not been properly studied. For those with intermittent claudication from PAD, stopping smoking and supervised exercise therapy may improve outcomes. Medications, including statins, ACE inhibitors, and cilostazol, may also help. Aspirin, which helps with thinning the blood and thus improving blood flow, does not appear to help those with mild disease but is usually recommended for those with more significant disease due to the increased risk of heart attacks. Anticoagulants (blood thinners) such as warfarin show no definitive scientific evidence of benefit in PAD. Surgical procedures used to treat PAD include bypass grafting, angioplasty, and atherectomy.
In 2015, about 155 million people had PAD worldwide. It becomes more common with age. In the developed world, it affects about 5.3% of 45- to 50-year-olds and 18.6% of 85- to 90-year-olds. In the developing world, it affects 4.6% of people between the ages of 45 and 50 and 15% of people between the ages of 85 and 90. PAD in the developed world is equally common among men and women, though in the developing world, women are more commonly affected. In 2015, PAD resulted in about 52,500 deaths, which is an increase from the 16,000 deaths in 1990.
== Signs and symptoms ==
The signs and symptoms of peripheral artery disease are based on the affected body part. About 66% of patients affected by PAD either do not have symptoms or have atypical symptoms. The most common presenting symptom is intermittent claudication (IC), which typically refers to lower extremity skeletal muscle pain that occurs during exercise. IC presents when there is insufficient oxygen delivery to meet the metabolic requirements of the skeletal muscles. IC is a common manifestation of peripheral arterial disease (PAD). The pain is usually located in the calf muscles of the affected leg and is relieved by rest. This occurs because during exercise, the muscles require more oxygen. Normally, the arteries would be able to increase the amount of blood flow and therefore increase the amount of oxygen going to the exercised muscle. However, in PAD, the artery cannot respond appropriately to the increased muscular demand for oxygen. Therefore, the muscles are deprived of oxygen, leading to muscle pain that subsides with rest.
Other symptoms may include:
Pain, aches, and/or cramps in the buttocks, hip, or thigh
Muscle atrophy (muscle loss) of the affected limb
Hair loss of the affected limb
Skin that is smooth, shiny, or cool to the touch in the affected area
Decreased or absent pulse in the feet
Cold and/or numbness in the toes
Sores/ulcers on the affected limb that do not heal
In individuals with severe PAD, complications may arise, including critical limb ischemia and gangrene. Critical limb ischemia occurs when the obstruction of blood flow in the artery is compromised to the point where the blood cannot maintain oxygenation of the tissue at rest. This can lead to pain at rest, a feeling of coldness, or numbness in the affected foot and toes. Other complications of severe PAD include lower limb tissue loss (amputation), arterial insufficiency ulcers, erectile dysfunction, and gangrene. People with diabetes are affected by gangrene of the feet at a rate that is 30 times higher than the unaffected population. Many of these severe complications, such as those leading to amputation, are irreversible.
== Causes ==
=== Risk factors ===
Factors contributing to an increased risk of PAD are the same as those for atherosclerosis. These include age, sex, and ethnicity. PAD is twice as common in males as in females. In terms of ethnicity, PAD is more common in people of color compared to the white population in a 2:1 ratio. The factors with the greatest risk associations are hyperlipidemia, hypertension, diabetes mellitus, chronic kidney disease, and smoking. Presenting three of these factors or more increases the risk of developing PAD tenfold.
Smoking – Tobacco use in any form is the single greatest risk factor for peripheral artery disease internationally. Smokers have up to a 10-fold increase in the risk of PAD in a dose-response relationship. Exposure to second-hand smoke has also been shown to promote changes in the lining of blood vessels (endothelium), which can lead to atherosclerosis. Smokers are 2–3 times more likely to have lower extremity PAD than coronary artery disease. Greater than 80%–90% of patients with lower extremity peripheral arterial disease are current or former smokers. The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked.
High blood sugar – Diabetes mellitus is shown to increase the risk of PAD by 2–4 fold. It does this by causing endothelial and smooth-muscle cell dysfunction in peripheral arteries. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes.
High blood cholesterol – Dyslipidemia is an unhealthy pattern of cholesterol or fat in the blood. Dyslipidemia is characterized by a high level of a protein called low-density lipoprotein (LDL cholesterol), low levels of high-density lipoprotein (HDL cholesterol), elevation of total cholesterol, and/or high triglyceride levels. This abnormality in blood cholesterol levels has been correlated with accelerated peripheral artery disease. Management of dyslipidemia by diet, exercise, and/or medication is associated with a major reduction in rates of heart attack and stroke.
High blood pressure – Hypertension or elevated blood pressure can increase a person's risk of developing PAD. Similarly to PAD, there is a known association between high blood pressure and heart attacks, strokes, and abdominal aortic aneurysms. High blood pressure increases the risk of intermittent claudication, the most common symptom of PAD, by 2.5- to 4-fold in men and women, respectively.
Other risk factors that are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, and lipoprotein A. Individuals with increased levels of homocysteine in their blood have a 2-fold risk of developing peripheral artery disease. While there are genetic factors leading to risk factors for peripheral artery disease, including diabetes and high blood pressure, there have been no specific genes or gene mutations directly associated with the development of peripheral artery disease.
=== High risk populations ===
Peripheral arterial disease is more common in these populations:
All people who have leg symptoms with exertion (suggestive of claudication) or ischemic rest pain
All people aged 65 years and over, regardless of risk factor status
All people between 50 and 69 who have a cardiovascular risk factor (particularly diabetes or smoking)
Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)
Individuals with an abnormal lower extremity pulse examination
Those with known atherosclerotic coronary, carotid, or renal artery disease
All people with a Framingham risk score of 10%–20%
All people who have previously experienced chest pain
== Etiology and pathophysiology ==
Peripheral arterial disease is considered to be a set of chronic or acute syndromes, generally derived from the presence of occlusive arterial disease, which causes inadequate blood flow to the limbs.
As previously mentioned, the most common etiology of peripheral artery disease, especially in patients over 40 years old, is atherosclerosis. Atherosclerosis is a narrowing of the arteries caused by lipid or fat buildup and calcium deposition in the wall of the affected arteries.
The pathophysiology of atherosclerosis involves complex interactions between cholesterol and vascular cells. In the early stages of PAD, the arteries compensate for plaque buildup by dilating to preserve flow through the vessel. Eventually, the artery cannot dilate further, and the atherosclerotic plaque narrows the arterial flow lumen.
When there is an imbalance between the needs of the peripheral tissues and the blood supply, the affected person is faced with ischemia.
From the pathophysiologic point of view, a restriction of blood supply (ischemia) to the lower limbs can be classified as either functional or critical. Functional ischemia occurs when the blood flow is normal at rest but insufficient during exercise, presenting clinically as intermittent claudication. Critical ischemia is produced when the reduction in blood flow results in a perfusion deficit at rest and is defined by the presence of pain at rest or trophic lesions in the legs. In this situation, precise diagnosis is fundamental, as there is a clear risk of limb loss if adequate blood flow is not re-established, either by surgery or endovascular therapy. Differentiating between the two concepts is important to establish the therapeutic indication and the prognosis in patients with PAD.
Other causes include vasculitis and in situ thrombosis related to hypercoagulable states. Additional mechanisms of peripheral artery disease include arterial spasm and fibromuscular dysplasia. The cause and pathophysiology of arterial spasm are not fully understood, but it is hypothesized that they can occur secondary to trauma. The symptoms of claudication ensue when the artery spasms, or clamps down on itself, creating an obstruction. Like atherosclerosis, this leads to decreased blood flow to the tissue downstream of the obstruction. Thrombosis, or the formation of a blood clot, usually occurs due to stasis or trauma.
== Diagnosis ==
Diagnosing or identifying peripheral artery disease requires a history of symptoms and a physical exam, followed by confirmatory testing. These tests could include CT scans (Computed Tomographic Angiography), MRA scans (Magnetic Resonance Angiography), or ultrasounds for imaging. A physician will examine an individual for specific exam findings if symptoms are consistent with peripheral artery disease. Abnormal physical exam findings can lead a healthcare provider to consider the diagnosis. However, to confirm a diagnosis, confirmatory testing is required.
These findings are associated with peripheral artery disease:
Decreased or absent pulses
Muscle atrophy or wasting
Noticeable blueness of the affected limb
Decreased temperature (coolness) in the affected limb when compared to the other
Thickened nails
Smooth or shiny skin and hair loss
Buerger's test can check for pallor when the affected limb is in an elevated position. The limb is then moved from an elevated to a sitting position and checked for redness, which is called reactive hyperemia. Buerger's test is an assessment of arterial sufficiency, which is the ability of the artery to supply oxygenated blood to the tissue that it goes to.
Nonhealing lower extremity wound
If peripheral artery disease is suspected, the initial study is the ankle–brachial index (ABI). The ABI is a simple, non-invasive test that measures the ratio of systolic blood pressure in the ankle to the systolic blood pressure in the upper arm. This is based on the idea that if blood pressure readings in the ankle are lower than those in the arm, a blockage in the arteries that provide blood from the heart to the ankle is suspected. An ABI range of 0.90 to 1.40 is considered normal. A person is considered to have PAD when the ABI is ≤ 0.90. However, PAD can be further graded as mild to moderate if the ABI is between 0.41 and 0.90, and severe if the ABI is less than 0.40. These categories can provide insight into the disease course. Furthermore, ABI values of 0.91 to 0.99 are considered borderline, and values >1.40 indicate noncompressible arteries. If an ABI >1.40 is calculated, this could indicate vessel wall stiffness caused by calcification, which can occur in people with uncontrolled diabetes. Abnormally high ABIs (>1.40) are usually considered false negatives, and thus, such results merit further investigation and higher-level studies. Individuals with noncompressible arteries have an increased risk of cardiovascular mortality within two years.
Individuals with suspected PAD with normal ABIs can undergo exercise testing for ABI. A baseline ABI is obtained before exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (for a maximum of 5 minutes), after which the ankle pressure is again measured. A decrease in ABI of 15%–20% would be diagnostic of PAD.
If ABIs are abnormal, the next step is generally a lower limb Doppler ultrasound to look at the site of obstruction and the extent of atherosclerosis. Other imaging can be performed by angiography, where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radio-dense contrast agent, an X-ray is taken. Any blood flow-limiting blockage found in the X-ray can be identified and treated by procedures including atherectomy, angioplasty, or stenting. Contrast angiography is the most readily available and widely used imaging technique. Modern computerized tomography (CT) scanners provide direct imaging of the arterial system. Studies have shown the sensitivity and specificity of CT in identifying lesions with >50% stenosis to be 95% and 96%, respectively. As such, CT may be considered as an alternative to invasive angiography. An important distinction between the two is that, unlike invasive angiography, assessment of the arterial system with CT does not allow for vascular intervention.
Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution, three-dimensional imaging of the entire abdomen, pelvis, and lower extremities in one sitting.
=== Classification ===
The two most commonly used methods to classify peripheral artery disease are the Fontaine and Rutherford classification systems. The Fontaine stages were introduced by René Fontaine in 1954 to define the severity of chronic limb ischemia:
Stage I: asymptomatic
Stage IIa: intermittent claudication after walking a distance of more than 200 meters
Stage IIb: intermittent claudication after walking a distance of less than 200 meters
Stage III: rest pain
Stage IV: ulcers or gangrene of the limb
The Rutherford classification was created by the Society for Vascular Surgery and the International Society of Cardiovascular Surgery, introduced in 1986 and revised in 1997 (and known as the Rutherford classification after the lead author, Robert B. Rutherford). This classification system consists of four grades and seven categories (categories 0–6):
Grade 0, Category 0: asymptomatic
Grade I, Category 1: mild claudication
Grade I, Category 2: moderate claudication
Grade I, Category 3: severe claudication
Grade II, Category 4: rest pain
Grade III, Category 5: minor tissue loss; ischemic ulceration not exceeding ulcer of the digits of the foot
Grade IV, Category 6: major tissue loss; severe ischemic ulcers or frank gangrene
Moderate to severe PAD, classified by Fontaine's stages III to IV or Rutherford's categories 4 to 5, presents a limb threat (risk of limb loss) in the form of critical limb ischemia.
Recently, the Society for Vascular Surgery came out with a classification system based on "wound, ischemia and foot infection" (WIfI). This classification system, published in 2013, was created to account for the demographic changes that have occurred over the past forty years, including the increased incidence of high blood sugar and evolving techniques and abilities for revascularization. This system was created on the basis that ischemia and angiographic disease patterns are not the sole determinants of amputation risk. The WIfI classification system is broken up into two parts: wounds and ischemia. Wounds are graded 0 through 3 based on the presence of ulceration, gangrene, and ischemia.
Grade 0: no ulcer, no gangrene
Grade 1: small, shallow ulcer; no gangrene
Grade 2: deep ulcer with exposed tendon or bone, gangrene limited to toes
Grade 3: extensive, full-thickness ulcer; gangrene extending to the forefoot or midfoot
Ischemia is graded 0 through 3 based on ABI, ankle systolic pressure, and toe pressure.
Grade 0: ABI ≥0.80, ankle systolic pressure ≥100 mm Hg, toe pressure ≥60 mm Hg
Grade 1: arterial brachial index 0.6 to 0.79, ankle systolic pressure 70 to 100 mm Hg, toe pressure 40 to 59 mm Hg
Grade 2: ABI 0.4–0.59, ankle systolic pressure 50 to 70 mm Hg, toe pressure 30 to 39 mm Hg
Grade 3: ABI ≤0.39, ankle systolic pressure <50 mm Hg, toe pressure <30 mm Hg
The TASC (and TASC II) classification suggests PAD treatment is based on the severity of the disease seen on an angiogram.
=== Screening ===
It is unclear if screening for disease in the general population is useful, as it has not been extensively studied. This includes screening with the ankle-brachial index (ABI), although a systematic review of the literature did not support the use of routine ABI screening in asymptomatic patients.
Testing for coronary artery disease or carotid artery disease is of unclear benefit. While PAD is a risk factor for abdominal aortic aneurysms (AAA), there is no data on screening individuals with asymptomatic PAD for abdominal aortic aneurysms. For people with symptomatic PAD, screening by ultrasound for AAA is not unreasonable.
=== Wearable devices and remote patient monitoring ===
A 2022 review found that a variety of wearable medical devices measuring different parameters (such as body temperature) were being combined with remote patient monitoring of PAD patients, to improve health outcomes.
Some studies propose the development of devices measuring oxygen continuously during exercise. This is because resting perfusion and metabolic activity are extremely low and differences between non-patients and PAD patients are barely measurable. As such, testing of vascular function and energetics requires a physiological challenge. Pulse oximeters can be inconvenient to wear during exercise and only give oxygen values at discrete time points, nor is there sufficient evidence to support any use in identifying PAD. Some publications and studies therefore discuss the use of wearable sensors measuring oxygen levels continuously in PAD patients, such as through transcutaneous means. However, because transcutaneous measurements are affected by movement (such as during exercise) and body temperature, the use of oxygen sensors that are inserted subcutaneously as opposed to transcutaneously may most effectively help monitor a PAD patient's progress and direct therapy decisions. To date, one oxygen sensing system has been approved for use in Europe to measure tissue perfusion in all PAD patients.
== Treatment ==
Depending on the severity of the disease, these steps can be taken, according to these guidelines:
=== Lifestyle ===
Stopping smoking (cigarettes promote PAD and are a risk factor for cardiovascular disease)
Regular exercise for those with claudication helps open up alternative small vessels (collateral flow), and the limitation in walking often improves. Treadmill exercise (35 to 50 minutes, three or four times per week) has been reviewed as another treatment with several positive outcomes, including a reduction in cardiovascular events and improved quality of life. Supervised exercise programs increase pain-free walking time and the maximum walking distance in people with PAD.
=== Medication ===
Management of diabetes
Management of hypertension
Management of high cholesterol, and antiplatelet drugs such as aspirin and clopidogrel. Statins reduce clot formation and cholesterol levels, respectively, and can help with disease progression and address the other cardiovascular risks that the affected person is likely to have.
According to guidelines, taking aspirin or clopidogrel is recommended to reduce AMI ("heart attack"), stroke, and other causes of vascular death in people with symptomatic peripheral artery disease. It is recommended that aspirin and clopidogrel be taken alone and not in conjunction with one another (i.e., not as dual antiplatelet therapy). The recommended daily dosage of aspirin for treating PAD is between 75 and 325 mg, while the recommended daily dosage for clopidogrel is 75 mg. The effectiveness of both aspirin and clopidogrel to reduce the risk of cardiovascular ischemic events in people with symptomatic PAD is not well established. Research also suggests that low-dose rivaroxaban plus aspirin is effective as a new anti-thrombotic regimen for PAD.
Cilostazol can improve symptoms in some people. Pentoxifylline is of unclear benefit. Cilostazol may improve walking distance for people who experience claudication due to peripheral artery disease, but no strong evidence suggests that it improves the quality of life, decreases mortality, or decreases the risk of cardiovascular events.
Treatment with other drugs or vitamins is unsupported by clinical evidence, "but trials evaluating the effect of folate and vitamin B12 on hyperhomocysteinemia, a putative vascular risk factor, are near completion".
=== Revascularization ===
After a trial of the best medical treatment outlined above, if symptoms persist, patients may be referred to a vascular or endovascular surgeon. The benefit of revascularization is thought to correspond to the severity of ischemia and the presence of other risk factors for limb loss, such as wound and infection severity.
Angioplasty (or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but may not have sustained benefits. Patency rates following angioplasty are highest for iliac arteries and decrease with arteries towards the toes. Other criteria that affect the outcome following revascularization are the length of the lesion and the number of lesions. There do not appear to be any long-term advantages or sustained benefits to placing a stent following angioplasty in order to hold the narrowing of the subsartorial artery open.
Atherectomy, in which the plaque is scraped off the inside of the vessel wall (albeit with no better results than angioplasty).
Vascular bypass grafting can be performed to circumvent a diseased area of the arterial vasculature. The great saphenous vein is used as a conduit if available, although artificial (Gore-Tex or PTFE) material is often used for long grafts when adequate venous conduit is unavailable.
When gangrene has set in, amputation may be required to prevent infected tissues from causing sepsis, a life-threatening illness.
Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism.
shockwave intravascular lithotripsy, a minimally invasive method that uses ultrasound waves to break up plaque within the artery without the need for penetration. The method was first approved by the US Food and Drug Administration in February 2021, and has been used as a complement to more widely-used methods of atherectomy.
=== Guidelines ===
A guideline from the American College of Cardiology and American Heart Association for the diagnosis and treatment of lower extremity, renal, mesenteric, and abdominal aortic PAD was compiled in 2013, combining the 2005 and 2011 guidelines. For chronic limb-threatening ischemia, the ACCF/AHA guidelines recommend balloon angioplasty only for people with a life expectancy of 2 years or less or those who do not have an autogenous vein available. For those with a life expectancy greater than 2 years or who have an autogenous vein, bypass surgery is recommended.
== Prognosis ==
Individuals with PAD have an "exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology". Prognosis is correlated with the severity of the PAD as measured by an ABI. Large-vessel PAD increases mortality from cardiovascular disease significantly. PAD carries a greater than "20% risk of a coronary event in 10 years".
The risk is low that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication. Of patients with intermittent claudication, only "7% will undergo lower-extremity bypass surgery, 4% major amputations, and 16% worsening claudication", but stroke and heart attack events are elevated, and the "5-year mortality rate is estimated to be 30% (versus 10% in controls)".
== Epidemiology ==
The prevalence of PAD in the general population is 3–7%, affecting up to 20% of those over 70; 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularization or amputation. Peripheral artery disease affects one in three diabetics over the age of 50. In the US, it affects 12–20 percent of Americans age 65 and older. Around 10 million Americans have PAD. Despite its prevalence and implications for cardiovascular risk, there are still low levels of awareness of risk factors and symptoms, with 26% of the population in the US reported to have knowledge of PAD.
In 2000, among people aged 40 years and older in the United States, rates of PAD were 4.3%. Rates were 14.5% for people aged 70 years or over. Within age groups, rates were generally higher for women than men. Non-Hispanic blacks had a rate of 7.9% compared to 4.4% in Non-Hispanic whites and 3.0% (1.4%–4.6%) in Mexican Americans.
The incidence of symptomatic PAD increases with age, from about 0.3% per year for men aged 40–55 years to about 1% per year for men aged over 75 years. The prevalence of PAD varies considerably depending on how PAD is defined and the age of the population being studied. People diagnosed with PAD have a greater risk of a MACE (Major Adverse Cardiac Event) and stroke. Their risk of developing a reinfarction, stroke, or transient ischemic attack within one year following a heart attack increases to 22.9%, compared to 11.4% for those without PAD.
The Diabetes Control and Complications Trial and the UK Prospective Diabetes Study trials in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. Pathologic changes occurring in small vessels may be more sensitive to chronically elevated glucose levels than atherosclerosis occurring in larger arteries.
== Research ==
Research is being done on therapies to prevent the progression of PAD. In those who have developed critically poor blood flow to the legs, the benefit of autotransplantation of autologous mononuclear cells is unclear.
Only one randomized controlled trial has been conducted comparing vascular bypass to angioplasty for the treatment of severe PAD. The trial found no difference in amputation-free survival between vascular bypass and angioplasty at the planned clinical endpoint, but the trial has been criticized as being underpowered, limiting endovascular options, and comparing inappropriate endpoints. As of 2017, two randomized clinical trials are being conducted to better understand the optimal revascularization technique for severe PAD and critical limb ischemia (CLI), the BEST-CLI (Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia) Trial and the BASIL-2 (Bypass Versus Angioplasty in Severe Ischaemia of the Leg – 2 )Trial.
In 2011, pCMV-vegf165 was registered in Russia as the first-in-class gene therapy drug for the treatment of PAD, including the advanced stage of critical limb ischemia.
== References ==
== External links ==
"Peripheral Arterial Disease" at the National Heart, Lung and Blood Institute
Peripheral Arterial Disease (P.A.D.) at the American College of Foot and Ankle Surgeons
Gerhard-Herman MD, Gornik HL, Barrett C, Barshes NR, Corriere MA, Drachman DE, et al. (March 2017). "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines". Circulation. 135 (12): e686 – e725. doi:10.1161/CIR.0000000000000470. PMC 5479414. PMID 27840332. | Wikipedia/Peripheral_artery_disease |
Gene therapy is being studied for some forms of epilepsy. It relies on viral or non-viral vectors to deliver DNA or RNA to target brain areas where seizures arise, in order to prevent the development of epilepsy or to reduce the frequency and/or severity of seizures. Gene therapy has delivered promising results in early stage clinical trials for other neurological disorders such as Parkinson's disease, raising the hope that it will become a treatment for intractable epilepsy.
== Overview ==
Epilepsy refers to a group of chronic neurological disorders that are characterized by seizures, affecting over 50 million people, or 0.4–1% of the global population. There is a basic understanding of the pathophysiology of epilepsy, especially of forms characterized by the onset of seizures from a specific area of the brain (partial-onset epilepsy). Although most patients respond to medication, approximately 20%–30% do not improve with or fail to tolerate antiepileptic drugs. For such patients, surgery to remove the epileptogenic zone can be offered in a small minority, but is not feasible if the seizures arise from brain areas that are essential for language, vision, movement or other functions. As a result, many people with epilepsy are left without any treatment options to consider, and thus there is a strong need for the development of innovative methods for treating epilepsy.
Through the use of viral vector gene transfer, with the purpose of delivering DNA or RNA to the epileptogenic zone, several neuropeptides, ion channels and neurotransmitter receptors have shown potential as transgenes for epilepsy treatment. Among vectors are adenovirus and adeno-associated virus vectors (AAV), which have the properties of high and efficient transduction, ease of production in high volumes, a wide range of hosts, and extended gene expression. Lentiviral vectors have also shown promise.
== Clinical research ==
Among challenges to clinical translation of gene therapy are possible immune responses to the viral vectors and transgenes and the possibility of insertional mutagenesis, which can be detrimental to patient safety. Scaling up from the volume needed for animal trials to that needed for effective human transfection is an area of difficulty, although it has been overcome in other diseases. With its size of less than 20 nm, AAV in part addresses these problems, allowing for its passage through the extracellular space, leading to widespread transfection. Although lentivectors can integrate in the genome of the host this may not represent a risk for treatment of neurological diseases because adult neurons do not divide and so are less prone to insertional mutagenesis
== Viral approaches in preclinical development ==
In finding a method for treating epilepsy, the pathophysiology of epilepsy is considered. As the seizures that characterize epilepsy typically result from excessive and synchronous discharges of excitatory neurons, the logical goal for gene therapy treatment is to reduce excitation or enhance inhibition. Out of the viral approaches, neuropeptide transgenes being researched are somatostatin, galanin, and neuropeptide Y (NPY). However, adenosine and gamma-aminobutyric acid (GABA) and GABA receptors are gaining more momentum as well. Other transgenes being studied are potassium channels and tools for on-demand suppression of excitability (optogenetics and chemogenetics).
=== Adenosine ===
Adenosine is an inhibitory nucleoside that doubles up as a neuromodulator, aiding in the modulation of brain function. It has anti-inflammatory properties, in addition to neuroprotective and anti-epileptic properties. The most prevalent theory is that upon brain injury there is an increased expression of the adenosine kinase (ADK). The increase in adenosine kinase results in an increased metabolic rate for adenosine nucleosides. Due to the decrease in these nucleosides that possess anti-epileptic properties and the overexpression of the ADK, seizures are triggered, potentially resulting in the development of epileptogenesis. Studies have shown that ADK overexpression results from astrogliosis following a brain injury, which can lead to the development of epileptogenesis. While ADK overexpression leads to increased susceptibility to seizures, the effects can be counteracted and moderated by adenosine. Based on the properties afforded by adenosine in preventing seizures, in addition to its FDA approval in the treatment of other ailments such as tachycardia and chronic pain, adenosine is an ideal target for the development of anti-epileptic gene therapies.
=== Galanin ===
Galanin, found primarily within the central nervous system (limbic system, piriform cortex, and amygdala), plays a role in the reduction of long term potentiation (LTP), regulating consumption habits, as well as inhibiting seizure activity. Introduced back in the 1990s by Mazarati et al., galanin has been shown to have neuroprotective and inhibitory properties. Through the use of mice that are deficient in GalR1 receptors, a picrotoxin-kindled model was utilized to show that galanin plays a role in modulating and preventing hilar cell loss as well as decreasing the duration of induced seizures. Conducted studies confirm these findings of preventing hilar hair cell loss, decreasing the number and duration of induced seizures, increasing the stimulation threshold required to induce seizures, and suppressing the release of glutamate that would increase susceptibility to seizure activity. Galanin expression can be utilized to significantly moderate and reduce seizure activity and limit seizure cell death.
=== Neuropeptide Y ===
Neuropeptide Y (NPY), which is found in the autonomic nervous system, helps modulate the hypothalamus, and therefore, consumption habits. Experiments have been conducted to determine the effect of NPY on animal models before and after induced seizures. To evaluate the effect prior to seizures, one study inserted vectors 8 weeks prior to kindling, showing an increase in seizure threshold. In order to evaluate the effects after epileptogenesis was present, the vectors were injected into the hippocampus of rats after seizures were induced. This resulted in a reduction of seizure activity. These studies established that NPY increased the seizure threshold in rats, arrested disease progression, and reduced seizure duration. After examining the effects of NPY on behavioral and physiological responses, it was discovered that it had no effect on LTP, learning, or memory. A protocol for NPY gene transfer is being reviewed by the FDA.
=== Somatostatin ===
Somatostatin is a neuropeptide and neuromodulator that plays a role in the regulation of hormones as well as aids in sleep and motor activity. It is primarily found in interneurons that modulates the firing rates of pyramidal cells primarily at a local level. They feed-forward inhibit pyramidal cells. In a series of studies where somatostatin was expressed in a rodent kindling model, it was concluded that somatostatin resulted in a decreased average duration for seizures, increasing its potential as an anti-seizure drug. The theory in utilizing somatostatin is that if pyramidal cells are eliminated, then the feed forward, otherwise known as inhibition, is lost. Somatostatin containing interneurons carry the neurotransmitter GABA, which primarily hyperpolarizes the cells, which is where the feed forward theory is derived from. The hope of gene therapy is that by overexpressing somatostatin in specific cells, and increasing the GABAergic tone, it is possible to restore balance between inhibition and excitation.
=== Potassium channels ===
Kv1.1 is a voltage-gated potassium channel encoded by the KCNA1 gene. It is widely expressed in the brain and peripheral nerves, and plays a role in controlling the excitability of neurons and the amount of neurotransmitter released from axon terminals. Successful gene therapy using lentiviral delivery of KCNA1 has been reported in a rodent model of focal motor cortex epilepsy. The treatment was well tolerated, with no detectable effect on sensorimotor coordination. Gene therapy with a modified potassium channel delivered using either a non-integrating lentivector that avoids the risk of insertional mutagenesis or an AAV has also been shown to be effective in other models of epilepsy.
=== Optogenetics ===
A potential obstacle to clinical translation of gene therapy is that viral vector-mediated manipulation of the genetic make-up of neurons is irreversible. An alternative approach is to use tools for on-demand suppression of neuronal and circuit excitability. The first such approach was to use optogenetics. Several laboratories have shown that the inhibitory light-sensitive protein Halorhodopsin can suppress seizure-like discharges in vitro as well as epileptic activity in vivo. A draw-back of optogenetics is that light needs to be delivered to the area of the brain expressing the opsin. This can be achieved with laser-coupled fiber-optics or light-emitting diodes, but these are invasive.
=== Chemogenetics ===
An alternative approach for on-demand control of circuit excitability that does not require light delivery to the brain is to use chemogenetics. This relies on expressing a mutated receptor in the seizure focus, which does not respond to endogenous neurotransmitters but can be activated by an exogenous drug. G-protein coupled receptors mutated in this way are called Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). Success in treating epilepsy has been reported using the inhibitory DREADD hM4D(Gi), which is derived from the M4 muscarinic receptor. AAV-mediated expression of hM4D(Gi) in a rodent model of focal epilepsy on its own had no effect, but when activated by the drug clozapine N-oxide it suppressed seizures. The treatment had no detectable side effects and is, in principle, suited for clinical translation. Olanzapine has been identified as a full and potent activator of hM4D(Gi). A 'closed-loop' variant of chemogenetics to stop seizures, which avoids the need for an exogenous ligand, relies on a glutamate-gated chloride channel which inhibits neurons whenever the extracellular concentration of the excitatory neurotransmitter glutamate rises.
=== CRISPR ===
A mouse model of Dravet syndrome has been treated using a variant of CRISPR that relies on a guide RNA and a dead Cas9 (dCas9) protein to recruit transcriptional activators to the promoter region of the sodium channel gene Scn1a in interneurons.
== Non-viral approaches ==
Magnetofection is done through the use of super paramagnetic iron oxide nanoparticles coated with polyethylenimine. Iron oxide nanoparticles are ideal for biomedical applications in the body due to their biodegradable, cationic, non-toxic, and FDA-approved nature. Under gene transfer conditions, the receptors of interest are coated with the nanoparticles. The receptors will then home in and travel to the target of interest. Once the particle docks, the DNA is delivered to the cell via pinocytosis or endocytosis. Upon delivery, the temperature is increased ever so slightly, lysing the iron oxide nanoparticle and releasing the DNA. Overall, the technique is useful for combatting slow vector accumulation and low vector concentration at target areas. The technique is also customizable to the physical and biochemical properties of the receptors by modifying the characteristics of the iron oxide nanoparticles.
== Future implications ==
The use of gene therapy in treating neurological disorders such as epilepsy has presented itself as an increasingly viable area of ongoing research with the primary targets being somatostatin, galanin, neuropeptide y, potassium channels, optogenetics and chemogenetics for epilepsy. As the field of gene therapy continues to grow and show promising results for the treatment of epilepsy among other diseases, additional research needs to be done in ensuring patient safety, developing alternative methods for DNA delivery, and finding feasible methods for scaling up delivery volumes.
== References == | Wikipedia/Gene_therapy_for_epilepsy |
The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endpoints. Drug approval typically requires clinical trials with endpoints that demonstrate a clinical benefit, such as increased survival for cancer patients. Drugs with accelerated approval can initially be tested in clinical trials that use a surrogate endpoint, or something that is thought to predict clinical benefit. Surrogate endpoints typically require less time, and in the case of a cancer patient, it is much faster to measure a reduction in tumor size, for example, than overall patient survival.
Drugs approved under the FDA Accelerated Approval Program still need to be tested in clinical trials using endpoints that demonstrate clinical benefit, and those trials are known as phase 4 confirmatory trials. If the drug later proves unable to demonstrate clinical benefit to patients, the FDA may withdraw approval. A study published in 2023, following a similar study focused on oncology in 2022, suggested that the Accelerated Approval Program was having the intended impact of shortening the timeline to either traditional approval or withdrawal of applications in cases where confirmatory trials had begun before the start of the Accelerated Approval process; further, there appeared to be no impact on the ratio of approval to withdrawal whether accelerated or traditional pathway was used.
== Controversies ==
In 2022 Congress investigated the accelerated passage and approval of the Alzheimers drug Aduhelm, manufactured by Biogen and being marketed at $56,000 per patient a year. Although the FDA usually follows an advisory committee's recommendation, the investigation found that the FDA decided to consider it under the accelerated approval pathway even though none of the 11 members of the committee recommended Aduhelm approval. They found that the FDA inappropriately collaborated with the maker when it granted accelerated approval and that it was released in June 2021 despite concerns raised by experts about the inconsistency of the drug's clinical data. The FDA also gave the drug a broad label, allowing it to be used on all Alzheimer's patients regardless of severity, even though it had only been tested on people with early Alzheimer's and mild symptoms. According to the report, Biogen knew its $56,000 launch price
was "unjustifiably high," but company executives wanted to "make history" and "establish Aduhelm as one of the top pharmaceutical launches of all time."
== See also ==
Fast track (FDA)
Orphan drug
== References ==
== External links ==
Henninger, Daniel (2002). "Drug Lag". In David R. Henderson (ed.). Concise Encyclopedia of Economics (1st ed.). Library of Economics and Liberty. OCLC 317650570, 50016270, 163149563 | Wikipedia/Accelerated_approval_(FDA) |
Coronary artery disease (CAD), also called coronary heart disease (CHD), or ischemic heart disease (IHD), is a type of heart disease involving the reduction of blood flow to the cardiac muscle due to a build-up of atheromatous plaque in the arteries of the heart. It is the most common of the cardiovascular diseases. CAD can cause stable angina, unstable angina, myocardial ischemia, and myocardial infarction.
A common symptom is angina, which is chest pain or discomfort that may travel into the shoulder, arm, back, neck, or jaw. Occasionally it may feel like heartburn. In stable angina, symptoms occur with exercise or emotional stress, last less than a few minutes, and improve with rest. Shortness of breath may also occur and sometimes no symptoms are present. In many cases, the first sign is a heart attack. Other complications include heart failure or an abnormal heartbeat.
Risk factors include high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, depression, and excessive alcohol consumption. A number of tests may help with diagnosis including electrocardiogram, cardiac stress testing, coronary computed tomographic angiography, biomarkers (high-sensitivity cardiac troponins) and coronary angiogram, among others.
Ways to reduce CAD risk include eating a healthy diet, regularly exercising, maintaining a healthy weight, and not smoking. Medications for diabetes, high cholesterol, or high blood pressure are sometimes used. There is limited evidence for screening people who are at low risk and do not have symptoms. Treatment involves the same measures as prevention. Additional medications such as antiplatelets (including aspirin), beta blockers, or nitroglycerin may be recommended. Procedures such as percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG) may be used in severe disease. In those with stable CAD it is unclear if PCI or CABG in addition to the other treatments improves life expectancy or decreases heart attack risk.
In 2015, CAD affected 110 million people and resulted in 8.9 million deaths. It makes up 15.6% of all deaths, making it the most common cause of death globally. The risk of death from CAD for a given age decreased between 1980 and 2010, especially in developed countries. The number of cases of CAD for a given age also decreased between 1990 and 2010. In the United States in 2010, about 20% of those over 65 had CAD, while it was present in 7% of those 45 to 64, and 1.3% of those 18 to 45; rates were higher among males than females of a given age.
== Signs and symptoms ==
The most common symptom is chest pain or discomfort that occurs regularly with activity, after eating, or at other predictable times; this phenomenon is termed stable angina and is associated with narrowing of the arteries of the heart. Angina also includes chest tightness, heaviness, pressure, numbness, fullness, or squeezing. Angina that changes in intensity, character, or frequency is termed unstable. Unstable angina may precede myocardial infarction. In adults who go to the emergency department with an unclear cause of pain, about 30% have pain due to coronary artery disease. Angina, shortness of breath, sweating, nausea or vomiting, and lightheadedness are signs of a heart attack or myocardial infarction, and immediate emergency medical services are crucial.
With advanced disease, the narrowing of coronary arteries reduces the supply of oxygen-rich blood flowing to the heart, which becomes more pronounced during strenuous activities during which the heart beats faster and has an increased oxygen demand. For some, this causes severe symptoms, while others experience no symptoms at all.
=== Symptoms in females ===
Symptoms in females can differ from those in males, and the most common symptom reported by females of all races is shortness of breath. Other symptoms more commonly reported by females than males are extreme fatigue, sleep disturbances, indigestion, and anxiety. However, some females experience irregular heartbeat, dizziness, sweating, and nausea. Burning, pain, or pressure in the chest or upper abdomen that can travel to the arm or jaw can also be experienced in females, but females less commonly report it than males. Generally, females experience symptoms 10 years later than males. Females are less likely to recognize symptoms and seek treatment.
== Risk factors ==
Coronary artery disease is characterized by heart problems that result from atherosclerosis. Atherosclerosis is a type of arteriosclerosis which is the "chronic inflammation of the arteries which causes them to harden and accumulate cholesterol plaques (atheromatous plaques) on the artery walls". CAD has several well-determined risk factors contributing to atherosclerosis. These risk factors for CAD include "smoking, diabetes, high blood pressure (hypertension), abnormal (high) amounts of cholesterol and other fat in the blood (dyslipidemia), type 2 diabetes and being overweight or obese (having excess body fat)" due to lack of exercise and a poor diet. Some other risk factors include high blood pressure, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet, depression, family history, psychological stress and excessive alcohol. About half of cases are linked to genetics. Apart from these classical risk factors, several unconventional risk factors have also been studied including high serum fibrinogen, high c-reactive protein (CRP), chronic inflammatory conditions, hypovitaminosis D, high lipoprotein A levels, serum homocysteine etc. Smoking and obesity are associated with about 36% and 20% of cases, respectively. Smoking just one cigarette per day about doubles the risk of CAD. Lack of exercise has been linked to 7–12% of cases. Exposure to the herbicide Agent Orange may increase risk. Rheumatologic diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, and psoriatic arthritis are independent risk factors as well.
Job stress appears to play a minor role accounting for about 3% of cases. In one study, females who were free of stress from work life saw an increase in the diameter of their blood vessels, leading to decreased progression of atherosclerosis. In contrast, females who had high levels of work-related stress experienced a decrease in the diameter of their blood vessels and significantly increased disease progression.
=== Air pollution ===
Air pollution, both indoor and outdoor, is responsible for roughly 28% of deaths from CAD. This varies by region: In highly developed areas, this is approximately 10%, whereas in Southern, East and West Africa, and South Asia, approximately 40% of deaths from CAD can be attributed to unhealthy air. In particular, fine particle pollution (PM2.5), which comes mostly from the burning of fossil fuels, is a key risk factor for CAD.
=== Blood fats ===
The consumption of different types of fats including trans fat (trans unsaturated), and saturated fat, in a diet "influences the level of cholesterol that is present in the bloodstream". Unsaturated fats originate from plant sources (such as oils). There are two types of unsaturated fats, cis and trans isomers. Cis unsaturated fats are bent in molecular structure and trans are linear. Saturated fats originate from animal sources (such as animal fats) and are also molecularly linear in structure. The linear configurations of unsaturated trans and saturated fats allow them to easily accumulate and stack at the arterial walls when consumed in high amounts (and other positive measures towards physical health are not met).
Fats and cholesterol are insoluble in blood and thus are amalgamated with proteins to form lipoproteins for transport. Low-density lipoproteins (LDL) transport cholesterol from the liver to the rest of the body and raise blood cholesterol levels. The consumption of "saturated fats increases LDL levels within the body, thus raising blood cholesterol levels".
High-density lipoproteins (HDL) are considered 'good' lipoproteins as they search for excess cholesterol in the body and transport it back to the liver for disposal. Trans fats also "increase LDL levels whilst decreasing HDL levels within the body, significantly raising blood cholesterol levels".
High levels of cholesterol in the bloodstream lead to atherosclerosis. With increased levels of LDL in the bloodstream, "LDL particles will form deposits and accumulate within the arterial walls, which will lead to the development of plaques, restricting blood flow". The resultant reduction in the heart's blood supply due to atherosclerosis in coronary arteries "causes shortness of breath, angina pectoris (chest pains that are usually relieved by rest), and potentially fatal heart attacks (myocardial infarctions)".
=== Genetics ===
The heritability of coronary artery disease has been estimated between 40% and 60%. Genome-wide association studies have identified over 160 genetic susceptibility loci for coronary artery disease.
=== Transcriptome ===
Several RNA Transcripts associated with CAD - FoxP1, ICOSLG, IKZF4/Eos, SMYD3, TRIM28, and TCF3/E2A are likely markers of regulatory T cells (Tregs), consistent with known reductions in Tregs in CAD.
The RNA changes are mostly related to ciliary and endocytic transcripts, which in the circulating immune system would be related to the immune synapse. One of the most differentially expressed genes, fibromodulin (FMOD), which is increased 2.8-fold in CAD, is found mainly in connective tissue and is a modulator of the TGF-beta signaling pathway. However, not all RNA changes may be related to the immune synapse. For example, Nebulette, the most down-regulated transcript (2.4-fold), is found in cardiac muscle; it is a 'cytolinker' that connects actin and desmin to facilitate cytoskeletal function and vesicular movement. The endocytic pathway is further modulated by changes in tubulin, a key microtubule protein, and fidgetin, a tubulin-severing enzyme that is a marker for cardiovascular risk identified by genome-wide association study. Protein recycling would be modulated by changes in the proteasomal regulator SIAH3, and the ubiquitin ligase MARCHF10. On the ciliary aspect of the immune synapse, several of the modulated transcripts are related to ciliary length and function. Stereocilin is a partner to mesothelin, a related super-helical protein, whose transcript is also modulated in CAD. DCDC2, a double-cortin protein, modulates ciliary length. In the signaling pathways of the immune synapse, numerous transcripts are directly related to T-cell function and the control of differentiation. Butyrophilin is a co-regulator for T cell activation. Fibromodulin modulates the TGF-beta signaling pathway, a primary determinant of Tre differentiation. Further impact on the TGF-beta pathway is reflected in concurrent changes in the BMP receptor 1B RNA (BMPR1B), because the bone morphogenic proteins are members of the TGF-beta superfamily, and likewise impact Treg differentiation. Several of the transcripts (TMEM98, NRCAM, SFRP5, SHISA2) are elements of the Wnt signaling pathway, which is a major determinant of Treg differentiation.
=== Other ===
Endometriosis in females under the age of 40.
Depression and hostility appear to be risks.
The number of categories of adverse childhood experiences (psychological, physical, or sexual abuse; violence against mother; or living with household members who used substances, mentally ill, suicidal, or incarcerated) showed a graded correlation with the presence of adult diseases including coronary artery (ischemic heart) disease.
Hemostatic factors: High levels of fibrinogen and coagulation factor VII are associated with an increased risk of CAD.
Low hemoglobin.
In the Asian population, the b fibrinogen gene G-455A polymorphism was associated with the risk of CAD.
Patient-specific vessel ageing or remodelling determines endothelial cell behaviour and thus disease growth and progression. Such 'hemodynamic markers' are patient-specific risk surrogates.
HIV is a known risk factor for developing atherosclerosis and coronary artery disease.
== Pathophysiology ==
Limitation of blood flow to the heart causes ischemia (cell starvation secondary to a lack of oxygen) of the heart's muscle cells. The heart's muscle cells may die from lack of oxygen and this is called a myocardial infarction (commonly referred to as a heart attack). It leads to damage, death, and eventual scarring of the heart muscle without regrowth of heart muscle cells. Chronic high-grade narrowing of the coronary arteries can induce transient ischemia which leads to the induction of a ventricular arrhythmia, which may terminate into a dangerous heart rhythm known as ventricular fibrillation, which often leads to death.
Typically, coronary artery disease occurs when part of the smooth, elastic lining inside a coronary artery (the arteries that supply blood to the heart muscle) develops atherosclerosis. With atherosclerosis, the artery's lining becomes hardened, stiffened, and accumulates deposits of calcium, fatty lipids, and abnormal inflammatory cells – to form a plaque. Calcium phosphate (hydroxyapatite) deposits in the muscular layer of the blood vessels appear to play a significant role in stiffening the arteries and inducing the early phase of coronary arteriosclerosis. This can be seen in a so-called metastatic mechanism of calciphylaxis as it occurs in chronic kidney disease and hemodialysis. Although these people have kidney dysfunction, almost fifty percent of them die due to coronary artery disease. Plaques can be thought of as large "pimples" that protrude into the channel of an artery, causing partial obstruction to blood flow. People with coronary artery disease might have just one or two plaques or might have dozens distributed throughout their coronary arteries. A more severe form is chronic total occlusion (CTO) when a coronary artery is completely obstructed for more than 3 months.
Microvascular angina is a type of angina pectoris in which chest pain and chest discomfort occur without signs of blockages in the larger coronary arteries of their hearts when an angiogram (coronary angiogram) is being performed.
The exact cause of microvascular angina is unknown. Explanations include microvascular dysfunction or epicardial atherosclerosis. For reasons that are not well understood, females are more likely than males to have it; however, hormones and other risk factors unique to females may play a role.
== Diagnosis ==
The diagnosis of CAD depends largely on the nature of the symptoms and imaging. The first investigation when CAD is suspected is an electrocardiogram (ECG/EKG), both for stable angina and acute coronary syndrome. An X-ray of the chest, blood tests and resting echocardiography may be performed.
For stable symptomatic patients, several non-invasive tests can diagnose CAD depending on pre-assessment of the risk profile. Noninvasive imaging options include; Computed tomography angiography (CTA) (anatomical imaging, best test in patients with low-risk profile to "rule out" the disease), positron emission tomography (PET), single-photon emission computed tomography (SPECT)/nuclear stress test/myocardial scintigraphy and stress echocardiography (the three latter can be summarized as functional noninvasive methods and are typically better to "rule in"). Exercise ECG or stress test is inferior to non-invasive imaging methods due to the risk of false negative and false positive test results. The use of non-invasive imaging is not recommended on individuals who are exhibiting no symptoms and are otherwise at low risk for developing coronary disease. Invasive testing with coronary angiography (ICA) can be used when non-invasive testing is inconclusive or show a high event risk.
The diagnosis of microvascular angina (previously known as cardiac syndrome X – the rare coronary artery disease that is more common in females, as mentioned, is a diagnosis of exclusion. Therefore, usually, the same tests are used as in any person suspected of having coronary artery disease:
Intravascular ultrasound
Magnetic resonance imaging (MRI)
=== Stable angina ===
Stable angina is the most common manifestation of ischemic heart disease, and is associated with reduced quality of life and increased mortality. It is caused by epicardial coronary stenosis which results in reduced blood flow and oxygen supply to the myocardium.
Stable angina is short-term chest pain during physical exertion caused by an imbalance between myocardial oxygen supply and metabolic oxygen demand. Various forms of cardiac stress tests may be used to induce both symptoms and detect changes by way of electrocardiography (using an ECG), echocardiography (using ultrasound of the heart) or scintigraphy (using uptake of radionuclide by the heart muscle). If part of the heart seems to receive an insufficient blood supply, coronary angiography may be used to identify stenosis of the coronary arteries and suitability for angioplasty or bypass surgery.
In minor to moderate cases, nitroglycerine may be used to alleviate acute symptoms of stable angina or may be used immediately before exertion to prevent the onset of angina. Sublingual nitroglycerine is most commonly used to provide rapid relief for acute angina attacks and as a complement to anti-anginal treatments in patients with refractory and recurrent angina. When nitroglycerine enters the bloodstream, it forms free radical nitric oxide, or NO, which activates guanylate cyclase and in turn stimulates the release of cyclic GMP. This molecular signaling stimulates smooth muscle relaxation, resulting in vasodilation and consequently improved blood flow to heart regions affected by atherosclerotic plaque.
Stable coronary artery disease (SCAD) is also often called stable ischemic heart disease (SIHD). A 2015 monograph explains that "Regardless of the nomenclature, stable angina is the chief manifestation of SIHD or SCAD." There are U.S. and European clinical practice guidelines for SIHD/SCAD. In patients with non-severe asymptomatic aortic valve stenosis and no overt coronary artery disease, the increased troponin T (above 14 pg/mL) was found associated with an increased 5-year event rate of ischemic cardiac events (myocardial infarction, percutaneous coronary intervention, or coronary artery bypass surgery).
=== Acute coronary syndrome ===
Diagnosis of acute coronary syndrome generally takes place in the emergency department, where ECGs may be performed sequentially to identify "evolving changes" (indicating ongoing damage to the heart muscle). Diagnosis is clear-cut if ECGs show elevation of the "ST segment", which in the context of severe typical chest pain is strongly indicative of an acute myocardial infarction (MI); this is termed a STEMI (ST-elevation MI) and is treated as an emergency with either urgent coronary angiography and percutaneous coronary intervention (angioplasty with or without stent insertion) or with thrombolysis ("clot buster" medication), whichever is available. In the absence of ST-segment elevation, heart damage is detected by cardiac markers (blood tests that identify heart muscle damage). If there is evidence of damage (infarction), the chest pain is attributed to a "non-ST elevation MI" (NSTEMI). If there is no evidence of damage, the term "unstable angina" is used. This process usually necessitates hospital admission and close observation on a coronary care unit for possible complications (such as cardiac arrhythmias – irregularities in the heart rate). Depending on the risk assessment, stress testing or angiography may be used to identify and treat coronary artery disease in patients who have had an NSTEMI or unstable angina.
=== Risk assessment ===
There are various risk assessment systems for determining the risk of coronary artery disease, with various emphasis on the different variables above. A notable example is Framingham Score, used in the Framingham Heart Study. It is mainly based on age, gender, diabetes, total cholesterol, HDL cholesterol, tobacco smoking, and systolic blood pressure. When predicting risk in younger adults (18–39 years old), the Framingham Risk Score remains below 10–12% for all deciles of baseline-predicted risk.
Polygenic score is another way of risk assessment. In one study the relative risk of incident coronary events was 91% higher among participants at high genetic risk than among those at low genetic risk.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Prevention involves adequate physical exercise, decreasing obesity, treating high blood pressure, eating a healthy diet, decreasing cholesterol levels, and stopping smoking. Medications and exercise are roughly equally effective. High levels of physical activity reduce the risk of coronary artery disease by about 25%. Life's Essential 8 are the key measures for improving and maintaining cardiovascular health, as defined by the American Heart Association. AHA added sleep as a factor influencing heart health in 2022.
Most guidelines recommend combining these preventive strategies. A 2015 Cochrane Review found some evidence that counseling and education to bring about behavioral change might help in high-risk groups. However, there was insufficient evidence to show an effect on mortality or actual cardiovascular events.
In diabetes mellitus, there is little evidence that very tight blood sugar control improves cardiac risk although improved sugar control appears to decrease other problems such as kidney failure and blindness.
A 2024 study published in The Lancet Diabetes & Endocrinology found that the oral glucose tolerance test (OGTT) is more effective than hemoglobin A1c (HbA1c) for detecting dysglycemia in patients with coronary artery disease. The study highlighted that 2-hour post-load glucose levels of at least 9 mmol/L were strong predictors of cardiovascular outcomes, while HbA1c levels of at least 5.9% were also significant but not independently associated when combined with OGTT results.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death. Vegetarians have a lower risk of heart disease, possibly due to their greater consumption of fruits and vegetables. Evidence also suggests that the Mediterranean diet and a high fiber diet lower the risk.
The consumption of trans fat (commonly found in hydrogenated products such as margarine) has been shown to cause a precursor to atherosclerosis and increase the risk of coronary artery disease.
Evidence does not support a beneficial role for omega-3 fatty acid supplementation in preventing cardiovascular disease (including myocardial infarction and sudden cardiac death).
=== Secondary prevention ===
Secondary prevention is preventing further sequelae of already established disease. Effective lifestyle changes include:
Weight control
Smoking cessation
Avoiding the consumption of trans fats (in partially hydrogenated oils)
Decreasing psychosocial stress
Exercise
Aerobic exercise, like walking, jogging, or swimming, can reduce the risk of mortality from coronary artery disease. Aerobic exercise can help decrease blood pressure and the amount of blood cholesterol (LDL) over time. It also increases HDL cholesterol.
Although exercise is beneficial, it is unclear whether doctors should spend time counseling patients to exercise. The U.S. Preventive Services Task Force found "insufficient evidence" to recommend that doctors counsel patients on exercise but "it did not review the evidence for the effectiveness of physical activity to reduce chronic disease, morbidity, and mortality", only the effectiveness of counseling itself. The American Heart Association, based on a non-systematic review, recommends that doctors counsel patients on exercise.
Psychological symptoms are common in people with CHD. Many psychological treatments may be offered following cardiac events. There is no evidence that they change mortality, the risk of revascularization procedures, or the rate of non-fatal myocardial infarction.
Antibiotics for secondary prevention of coronary heart disease
Early studies suggested that antibiotics might help patients with coronary disease to reduce the risk of heart attacks and strokes. However, a 2021 Cochrane meta-analysis found that antibiotics given for secondary prevention of coronary heart disease are harmful to people with increased mortality and occurrence of stroke. So, antibiotic use is not currently supported for preventing secondary coronary heart disease.
=== Neuropsychological assessment ===
A thorough systematic review found that indeed there is a link between a CHD condition and brain dysfunction in females. Consequently, since research is showing that cardiovascular diseases, like CHD, can play a role as a precursor for dementia, like Alzheimer's disease, individuals with CHD should have a neuropsychological assessment.
== Treatment ==
There are a number of treatment options for coronary artery disease:
Lifestyle changes
Medical treatment – commonly prescribed drugs (e.g., cholesterol lowering medications, beta-blockers, nitroglycerin, calcium channel blockers, etc.);
Coronary interventions as angioplasty and coronary stent;
Coronary artery bypass grafting (CABG)
=== Medications ===
Statins, which reduce cholesterol, reduce the risk of coronary artery disease
Nitroglycerin
Calcium channel blockers and/or beta-blockers
Antiplatelet drugs such as aspirin
It is recommended that blood pressure typically be reduced to less than 140/90 mmHg. The diastolic blood pressure should not be below 60 mmHg. Beta-blockers are recommended first line for this use.
==== Aspirin ====
In those with no previous history of heart disease, aspirin decreases the risk of a myocardial infarction but does not change the overall risk of death. Aspirin therapy to prevent heart disease is thus recommended only in adults who are at increased risk for cardiovascular events, which may include postmenopausal females, males above 40, and younger people with risk factors for coronary heart disease, including high blood pressure, a family history of heart disease, or diabetes. The benefits outweigh the harms most favorably in people at high risk for a cardiovascular event, where high risk is defined as at least a 3% chance over five years, but others with lower risk may still find the potential benefits worth the associated risks.
==== Anti-platelet therapy ====
Clopidogrel plus aspirin (dual anti-platelet therapy) reduces cardiovascular events more than aspirin alone in those with a STEMI. In others at high risk but not having an acute event, the evidence is weak. Specifically, its use does not change the risk of death in this group. In those who have had a stent, more than 12 months of clopidogrel plus aspirin does not affect the risk of death.
=== Surgery ===
Revascularization for acute coronary syndrome has a mortality benefit. Percutaneous revascularization for stable ischaemic heart disease does not appear to have benefits over medical therapy alone. In those with disease in more than one artery, coronary artery bypass grafts appear better than percutaneous coronary interventions. Newer "anaortic" or no-touch off-pump coronary artery revascularization techniques have shown reduced postoperative stroke rates comparable to percutaneous coronary intervention. Hybrid coronary revascularization has also been shown to be a safe and feasible procedure that may offer some advantages over conventional CABG though it is more expensive.
== Epidemiology ==
As of 2010, CAD was the leading cause of death globally resulting in over 7 million deaths. This increased from 5.2 million deaths from CAD worldwide in 1990. It may affect individuals at any age but becomes dramatically more common at progressively older ages, with approximately a tripling with each decade of life. Males are affected more often than females.
The World Health Organization reported that: "The world's biggest killer is ischemic heart disease, responsible for 13% of the world's total deaths. Since 2000, the largest increase in deaths has been for this disease, rising by 2.7 million to 9.1 million deaths in 2021."
It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue.
Coronary artery disease is the leading cause of death for both males and females and accounts for approximately 600,000 deaths in the United States every year. According to present trends in the United States, half of healthy 40-year-old males will develop CAD in the future, and one in three healthy 40-year-old females. It is the most common reason for death of males and females over 20 years of age in the United States.
After analysing data from 2 111 882 patients, the recent meta-analysis revealed that the incidence of coronary artery diseases in breast cancer survivors was 4.29 (95% CI 3.09–5.94) per 1000 person-years.
== Society and culture ==
=== Names ===
Other terms sometimes used for this condition are "hardening of the arteries" and "narrowing of the arteries". In Latin it is known as morbus ischaemicus cordis (MIC).
=== Support groups ===
The Infarct Combat Project (ICP) is an international nonprofit organization founded in 1998 which tries to decrease ischemic heart diseases through education and research.
=== Industry influence on research ===
In 2016 research into the internal documents of the Sugar Research Foundation, the trade association for the sugar industry in the US, had sponsored an influential literature review published in 1965 in the New England Journal of Medicine that downplayed early findings about the role of a diet heavy in sugar in the development of CAD and emphasized the role of fat; that review influenced decades of research funding and guidance on healthy eating.
== Research ==
Research efforts are focused on new angiogenic treatment modalities and various (adult) stem-cell therapies. A region on chromosome 17 was confined to families with multiple cases of myocardial infarction. Other genome-wide studies have identified a firm risk variant on chromosome 9 (9p21.3). However, these and other loci are found in intergenic segments and need further research in understanding how the phenotype is affected.
A more controversial link is that between Chlamydophila pneumoniae infection and atherosclerosis. While this intracellular organism has been demonstrated in atherosclerotic plaques, evidence is inconclusive regarding whether it can be considered a causative factor. Treatment with antibiotics in patients with proven atherosclerosis has not demonstrated a decreased risk of heart attacks or other coronary vascular diseases.
Myeloperoxidase has been proposed as a biomarker.
Plant-based nutrition has been suggested as a way to reverse coronary artery disease, but strong evidence is still lacking for claims of potential benefits.
Several immunosuppressive drugs targeting the chronic inflammation in coronary artery disease have been tested.
== See also ==
Mental stress-induced myocardial ischemia
== References ==
== External links ==
Risk Assessment of having a heart attack or dying of coronary artery disease, from the American Heart Association.
"Coronary Artery Disease". MedlinePlus. U.S. National Library of Medicine.
Norman J (7 October 2019). "Managing Diabetes with Blood Glucose Control". Endocrineweb. | Wikipedia/Coronary_artery_disease |
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases start with testing for drug safety in a few human subjects, then expand to many study participants (potentially tens of thousands) to determine if the treatment is effective. Clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays.
== Description ==
Clinical trials testing potential medical products are commonly classified into four phases. The drug development process will normally proceed through all four phases over many years. When expressed specifically, a clinical trial phase is capitalized both in name and Roman numeral, such as "Phase I" clinical trial.
If the drug successfully passes through Phases I, II, and III, it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are 'post-marketing' or 'surveillance' studies conducted to monitor safety over several years.
== Preclinical studies ==
Before clinical trials are undertaken for a candidate drug, vaccine, medical device, or diagnostic assay, the product candidate is tested extensively in preclinical studies. Such studies involve in vitro (test tube or cell culture) and in vivo (animal model) experiments using wide-ranging doses of the study agent to obtain preliminary efficacy, toxicity and pharmacokinetic information. Such tests assist the developer to decide whether a drug candidate has scientific merit for further development as an investigational new drug.
== Phase 0 ==
Phase 0 is a designation for optional exploratory trials, originally introduced by the United States Food and Drug Administration's (FDA) 2006 Guidance on Exploratory Investigational New Drug (IND) Studies, but now generally adopted as standard practice. Phase 0 trials are also known as human microdosing studies and are designed to speed up the development of promising drugs or imaging agents by establishing very early on whether the drug or agent behaves in human subjects as was expected from preclinical studies. Distinctive features of Phase 0 trials include the administration of single subtherapeutic doses of the study drug to a small number of subjects (10 to 15) to gather preliminary data on the agent's pharmacokinetics (what the body does to the drugs).
A Phase 0 study gives no data on safety or efficacy, being by definition a dose too low to cause any therapeutic effect. Drug development companies carry out Phase 0 studies to rank drug candidates to decide which has the best pharmacokinetic parameters in humans to take forward into further development. They enable go/no-go decisions to be based on relevant human models instead of relying on sometimes inconsistent animal data.
== Phase I ==
Phase I trials were formerly referred to as "first-in-man studies" but the field generally moved to the gender-neutral language phrase "first-in-humans" in the 1990s; these trials are the first stage of testing in human subjects. They are designed to test the safety, side effects, best dose, and formulation method for the drug. Phase I trials are not randomized, and thus are vulnerable to selection bias.
Normally, a small group of 20–100 healthy volunteers will be recruited. These trials are often conducted in a clinical trial clinic, where the subject can be observed by full-time staff. These clinical trial clinics are often run by contract research organization (CROs) who conduct these studies on behalf of pharmaceutical companies or other research investigators.
The subject who receives the drug is usually observed until several half-lives of the drug have passed. This phase is designed to assess the safety (pharmacovigilance), tolerability, pharmacokinetics, and pharmacodynamics of a drug. Phase I trials normally include dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer. The tested range of doses will usually be a fraction of the dose that caused harm in animal testing.
Phase I trials most often include healthy volunteers. However, there are some circumstances when clinical patients are used, such as patients who have terminal cancer or HIV and the treatment is likely to make healthy individuals ill. These studies are usually conducted in tightly controlled clinics called Central Pharmacological Units, where participants receive 24-hour medical attention and oversight. In addition to the previously mentioned unhealthy individuals, "patients who have typically already tried and failed to improve on the existing standard therapies" may also participate in Phase I trials. Volunteers are paid a variable inconvenience fee for their time spent in the volunteer center.
Before beginning a Phase I trial, the sponsor must submit an Investigational New Drug application to the FDA detailing the preliminary data on the drug gathered from cellular models and animal studies.
Phase I trials can be further divided:
=== Phase Ia ===
Single ascending dose (Phase Ia): In single ascending dose studies, small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time to confirm safety. Typically, a small number of participants, usually three, are entered sequentially at a particular dose. If they do not exhibit any adverse side effects, and the pharmacokinetic data are roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is then given a higher dose.
If unacceptable toxicity is observed in any of the three participants, an additional number of participants, usually three, are treated at the same dose. This is continued until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)). If an additional unacceptable toxicity is observed, then the dose escalation is terminated and that dose, or perhaps the previous dose, is declared to be the maximally tolerated dose. This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity. Variations of this design exist, but most are similar.
=== Phase Ib ===
Multiple ascending dose (Phase Ib): Multiple ascending dose studies investigate the pharmacokinetics and pharmacodynamics of multiple doses of the drug, looking at safety and tolerability. In these studies, a group of patients receives multiple low doses of the drug, while samples (of blood, and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
=== Food effect ===
A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.
== Phase II ==
Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect. Phase II trials are performed on larger groups (50–300 individuals) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Genetic testing is common, particularly when there is evidence of variation in metabolic rate. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.
Phase II studies are sometimes divided into Phase IIa and Phase IIb. There is no formal definition for these two sub-categories, but generally:
Phase IIa studies are usually pilot studies designed to find an optimal dose and assess safety ('dose finding' studies).
Phase IIb studies determine how well the drug works in subjects at a given dose to assess efficacy ('proof of concept' studies).
=== Trial design ===
Some Phase II trials are designed as case series, demonstrating a drug's safety and activity in a selected group of participants. Other Phase II trials are designed as randomized controlled trials, where some patients receive the drug/device and others receive placebo/standard treatment. Randomized Phase II trials have far fewer patients than randomized Phase III trials.
==== Example: cancer design ====
In the first stage, the investigator attempts to rule out drugs that have no or little biologic activity. For example, the researcher may specify that a drug must have some minimal level of activity, say, in 20% of participants. If the estimated activity level is less than 20%, the researcher chooses not to consider this drug further, at least not at that maximally tolerated dose. If the estimated activity level exceeds 20%, the researcher will add more participants to get a better estimate of the response rate. A typical study for ruling out a 20% or lower response rate enters 14 participants. If no response is observed in the first 14 participants, the drug is considered not likely to have a 20% or higher activity level. The number of additional participants added depends on the degree of precision desired, but ranges from 10 to 20. Thus, a typical cancer phase II study might include fewer than 30 people to estimate the response rate.
==== Efficacy vs effectiveness ====
When a study assesses efficacy, it is looking at whether the drug given in the specific manner described in the study is able to influence an outcome of interest (e.g. tumor size) in the chosen population (e.g. cancer patients with no other ongoing diseases). When a study is assessing effectiveness, it is determining whether a treatment will influence the disease. In an effectiveness study, it is essential that participants are treated as they would be when the treatment is prescribed in actual practice. That would mean that there should be no aspects of the study designed to increase compliance above those that would occur in routine clinical practice. The outcomes in effectiveness studies are also more generally applicable than in most efficacy studies (for example does the patient feel better, come to the hospital less or live longer in effectiveness studies as opposed to better test scores or lower cell counts in efficacy studies). There is usually less rigid control of the type of participant to be included in effectiveness studies than in efficacy studies, as the researchers are interested in whether the drug will have a broad effect in the population of patients with the disease.
=== Success rate ===
Phase II clinical programs historically have experienced the lowest success rate of the four development phases. In 2010, the percentage of Phase II trials that proceeded to Phase III was 18%, and only 31% of developmental candidates advanced from Phase II to Phase III in a study of trials over 2006–2015.
== Phase III ==
This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice. Phase III studies are randomized controlled multicenter trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current 'gold standard' treatment. Because of their size and comparatively long duration, Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic medical conditions. Phase III trials of chronic conditions or diseases often have a short follow-up period for evaluation, relative to the period of time the intervention might be used in practice. This is sometimes called the "pre-marketing phase" because it actually measures consumer response to the drug.
It is common practice that certain Phase III trials will continue while the regulatory submission is pending at the appropriate regulatory agency. This allows patients to continue to receive possibly lifesaving drugs until the drug can be obtained by purchase. Other reasons for performing trials at this stage include attempts by the sponsor at "label expansion" (to show the drug works for additional types of patients/diseases beyond the original use for which the drug was approved for marketing), to obtain additional safety data, or to support marketing claims for the drug. Studies in this phase are by some companies categorized as "Phase IIIB studies."
While not required in all cases, it is typically expected that there be at least two successful Phase III trials, demonstrating a drug's safety and efficacy, to obtain approval from the appropriate regulatory agencies such as FDA (US), or the EMA (European Union).
Once a drug has proved satisfactory after Phase III trials, the trial results are usually combined into a large document containing a comprehensive description of the methods and results of human and animal studies, manufacturing procedures, formulation details, and shelf life. This collection of information makes up the "regulatory submission" that is provided for review to the appropriate regulatory authorities in different countries. They will review the submission, and if it is acceptable, give the sponsor approval to market the drug.
Most drugs undergoing Phase III clinical trials can be marketed under FDA norms with proper recommendations and guidelines through a New Drug Application (NDA) containing all manufacturing, preclinical, and clinical data. In case of any adverse effects being reported anywhere, the drugs need to be recalled immediately from the market. While most pharmaceutical companies refrain from this practice, it is not abnormal to see many drugs undergoing Phase III clinical trials in the market.
=== Adaptive design ===
The design of individual trials may be altered during a trial – usually during Phase II or III – to accommodate interim results for the benefit of the treatment, adjust statistical analysis, or to reach early termination of an unsuccessful design, a process called an "adaptive design". Examples are the 2020 World Health Organization Solidarity trial, European Discovery trial, and UK RECOVERY Trial of hospitalized people with severe COVID-19 infection, each of which applies adaptive designs to rapidly alter trial parameters as results from the experimental therapeutic strategies emerge.
Adaptive designs within ongoing Phase II–III clinical trials on candidate therapeutics may shorten trial durations and use fewer subjects, possibly expediting decisions for early termination or success, and coordinating design changes for a specific trial across its international locations.
=== Success rate ===
For vaccines, the probability of success ranges from 7% for non-industry-sponsored candidates to 40% for industry-sponsored candidates.
A 2019 review of average success rates of clinical trials at different phases and diseases over the years 2005–15 found a success range of 5–14%. Separated by diseases studied, cancer drug trials were on average only 3% successful, whereas ophthalmology drugs and vaccines for infectious diseases were 33% successful. Trials using disease biomarkers, especially in cancer studies, were more successful than those not using biomarkers.
A 2010 review found about 50% of drug candidates either fail during the Phase III trial or are rejected by the national regulatory agency.
== Cost of trials by phases ==
In the early 21st century, a typical Phase I trial conducted at a single clinic in the United States ranged from $1.4 million for pain or anesthesia studies to $6.6 million for immunomodulation studies. Main expense drivers were operating and clinical monitoring costs of the Phase I site.
The amount of money spent on Phase II or III trials depends on numerous factors, with therapeutic area being studied and types of clinical procedures as key drivers. Phase II studies may cost as low as $7 million for cardiovascular projects, and as much as $20 million for hematology trials.
Phase III trials for dermatology may cost as low as $11 million, whereas a pain or anesthesia Phase III trial may cost as much as $53 million. An analysis of Phase III pivotal trials leading to 59 drug approvals by the US Food and Drug Administration over 2015–16 showed that the median cost was $19 million, but some trials involving thousands of subjects may cost 100 times more.
Across all trial phases, the main expenses for clinical trials were administrative staff (about 20% of the total), clinical procedures (about 19%), and clinical monitoring of the subjects (about 11%).
== Phase IV ==
A Phase IV trial is also known as a postmarketing surveillance trial or drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive (finding a new market for the drug) or other reasons (for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).
== Overall cost ==
The entire process of developing a drug from preclinical research to marketing can take approximately 12 to 18 years and often costs well over $1 billion.
== References == | Wikipedia/Phase_I_clinical_trial |
Stem-cell therapy uses stem cells to treat or prevent a disease or condition. As of 2024, the only FDA-approved therapy using stem cells is hematopoietic stem cell transplantation. This usually takes the form of a bone marrow or peripheral blood stem cell transplantation, but the cells can also be derived from umbilical cord blood. Research is underway to develop various sources for stem cells as well as to apply stem-cell treatments for neurodegenerative diseases and conditions such as diabetes and heart disease.
Stem-cell therapy has become controversial following developments such as the ability of scientists to isolate and culture embryonic stem cells, to create stem cells using somatic cell nuclear transfer, and their use of techniques to create induced pluripotent stem cells. This controversy is often related to abortion politics and human cloning. Additionally, efforts to market treatments based on transplant of stored umbilical cord blood have been controversial.
== Medical uses ==
For over 90 years, hematopoietic stem cell transplantation (HSCT) has been used to treat people with conditions such as leukemia and lymphoma; this is the only widely practiced form of stem-cell therapy. During chemotherapy, most growing cells are killed by the cytotoxic agents. These agents, however, cannot discriminate between the leukaemia or neoplastic cells, and the hematopoietic stem cells within the bone marrow. This is the side effect of conventional chemotherapy strategies that the stem-cell transplant attempts to reverse; a donor's healthy bone marrow reintroduces functional stem cells to replace the cells lost in the host's body during treatment. The transplanted cells also generate an immune response that helps to kill off the cancer cells; this process can go too far, however, leading to graft vs host disease, the most serious side effect of this treatment.
Another stem-cell therapy, called Prococvhymal, was conditionally approved in Canada in 2012 for the management of acute graft-vs-host disease in children who are unresponsive to steroids. It is an allogenic stem therapy based on mesenchymal stem cells (MSCs) derived from the bone marrow of adult donors. MSCs are purified from the marrow, cultured and packaged, with up to 10,000 doses derived from a single donor. The doses are stored frozen until needed.
The FDA has approved five hematopoietic stem-cell products derived from umbilical cord blood, for the treatment of blood and immunological diseases.
In 2014, the European Medicines Agency recommended approval of limbal stem cells for people with severe limbal stem cell deficiency due to burns in the eye.
== Research only ==
Stem cells are being studied for several reasons. The molecules and exosomes released from stem cells are also being studied in an effort to make medications. In addition to the functions of the cells themselves, paracrine soluble factors produced by stem cells, known as the stem cell secretome, have been found to be another mechanism by which stem cell-based therapies mediate their effects in degenerative, autoimmune, and inflammatory diseases.
=== Sources for human stem cells ===
Most stem cells intended for regenerative therapy are generally isolated either from the patient's bone marrow or from adipose tissue. Mesenchymal stem cells can differentiate into the cells that make up bone, cartilage, tendons, and ligaments, as well as muscle, neural and other progenitor tissues. They have been the main type of stem cells studied in the treatment of diseases affecting these tissues. The number of stem cells transplanted into damaged tissue may alter the efficacy of treatment. Accordingly, stem cells derived from bone marrow aspirates, for instance, are cultured in specialized laboratories for expansion to millions of cells. Although adipose-derived tissue also requires processing prior to use, the culturing methodology for adipose-derived stem cells is not as extensive as that for bone marrow-derived cells. While it is thought that bone-marrow-derived stem cells are preferred for bone, cartilage, ligament, and tendon repair, others believe that the less challenging collection techniques and the multi-cellular microenvironment already present in adipose-derived stem cell fractions make the latter the preferred source for autologous transplantation.
New sources of mesenchymal stem cells are being researched, including stem cells present in the skin and dermis which are of interest because of the ease at which they can be harvested with minimal risk to the animal. Hematopoietic stem cells have also been discovered to be travelling in the blood stream and possess equal differentiating ability as other mesenchymal stem cells, again with a very non-invasive harvesting technique.
There has been more recent interest in the use of extra embryonic mesenchymal stem cells. Research is underway to examine the differentiating capabilities of stem cells found in the umbilical cord, yolk sac and placenta of different animals. These stem cells are thought to have more differentiating ability than their adult counterparts, including the ability to more readily form tissues of endodermal and ectodermal origin.
==== Embryonic stem cell lines ====
As of 2010, there was widespread controversy over the use of human embryonic stem cells. This controversy primarily targets the techniques used to derive new embryonic stem cell lines, which often requires the destruction of the blastocyst. Opposition to the use of human embryonic stem cells in research is often based on philosophical, moral, or religious objections. There is other stem cell research that does not involve the destruction of a human embryo, and such research involves adult stem cells, amniotic stem cells, and induced pluripotent stem cells.
In January 2009, the US Food and Drug Administration gave clearance to Geron Corporation for the first clinical trial of an embryonic stem-cell-based therapy on humans. The trial aimed to evaluate the drug GRNOPC1, embryonic stem cell-derived oligodendrocyte progenitor cells, on people with acute spinal cord injury. The trial was discontinued in November 2011 so that the company could focus on therapies in the "current environment of capital scarcity and uncertain economic conditions". In 2013 biotechnology and regenerative medicine company BioTime (AMEX: BTX) acquired Geron's stem cell assets in a stock transaction, with the aim of restarting the clinical trial.
==== Mesenchymal stromal cells (MSCs) ====
Scientists reported 2012 that MSCs when transfused immediately within few hours post thawing may show reduced function or show decreased efficacy in treating diseases as compared to those MSCs which are in log phase of cell growth (fresh), so cryopreserved MSCs should be brought back into log phase of cell growth in in vitro culture before administration. Re-culturing of MSCs will help in recovering from the shock the cells get during freezing and thawing. Various MSC clinical trials which used cryopreserved product immediately post thaw have failed as compared to those clinical trials which used fresh MSCs.
=== In drug discovery and biomedical research ===
The ability to grow up functional adult tissues indefinitely in culture through Directed differentiation creates new opportunities for drug research. Researchers are able to grow up differentiated cell lines and then test new drugs on each cell type to examine possible interactions in vitro before performing in vivo studies. This is critical in the development of drugs for use in veterinary research because of the possibilities of species-specific interactions. The hope is that having these cell lines available for research use will reduce the need for research animals used because effects on human tissue in vitro will provide insight not normally known before the animal testing phase.
With the advent of induced pluripotent stem cells (iPSC), treatments being explored and created for the used in endangered low production animals possible. Rather than needing to harvest embryos or eggs, which are limited, the researchers can remove mesenchymal stem cells with greater ease and greatly reducing the danger to the animal due to noninvasive techniques. This allows the limited eggs to be put to use for reproductive purposes only.
=== Stem cell expansion ===
To be used for research or treatment applications, large numbers of high-quality stem cells are needed. Thus, it is necessary to develop culture systems which produce pure populations of tissue-specific stem cells in vitro without the loss of stem-cell potential. Two main approaches are taken for this purpose: two-dimensional and three-dimensional cell culture.
Cell culture in two dimensions has been routinely performed in thousands of laboratories worldwide for the past four decades. In two-dimensional platforms, cells are typically exposed to a solid, rigid flat surface on the basal side and to liquid at the apical
surface. Inhabiting such a two-dimensional rigid substrate requires a dramatic adaption for the surviving cells because they lack the extracellular matrix that is unique to each cell type which may alter cell metabolism and reduce its functionality.
Three-dimensional cell culture systems may create a biomimicking microenvironment for stem cells, resembling their native three-dimensional extracellular matrix (ECM). Advanced biomaterials have significantly contributed to three-dimensional cell culture systems in recent decades, and more unique and complex biomaterials have been proposed for improving stem-cell proliferation and controlled differentiation. Among them, nanostructured biomaterials are of particular interest because they have the advantage of a high surface-to-volume ratio, and they mimic the physical and biological features of natural ECM at the nanoscale.
=== Assumed regenerative models ===
Stem cells are thought to mediate repair via five primary mechanisms: 1) providing an anti-inflammatory effect, 2) homing to damaged tissues and recruiting other cells, such as endothelial progenitor cells, that are necessary for tissue growth, 3) supporting tissue remodeling over scar formation, 4) inhibiting apoptosis, and 5) differentiating into bone, cartilage, tendon, and ligament tissue.
To further enrich blood supply to the damaged areas, and consequently promote tissue regeneration, platelet-rich plasma could be used in conjunction with stem cell transplantation. The efficacy of some stem cell populations may also be affected by the method of delivery; for instance, to regenerate bone, stem cells are often introduced in a scaffold where they produce the minerals necessary for generation of functional bone.
Stem cells have been shown to have low immunogenicity due to the relatively low number of MHC molecules found on their surface. In addition, they have been found to secrete chemokines that alter the immune response and promote tolerance of the new tissue. This allows for allogeneic treatments to be performed without a high rejection risk.
=== Potential applications ===
==== Neurodegeneration ====
Research has been conducted on the effects of stem cells on animal models of brain degeneration, such as in Parkinson's disease, Amyotrophic lateral sclerosis, and Alzheimer's disease. Preliminary studies related to multiple sclerosis have been conducted, and a 2020 phase 2 trial found significantly improved outcomes for mesenchymal stem cell treated patients compared to those receiving a sham treatment. In January 2021 the FDA approved the first clinical trial for an investigational stem cell therapy to restore lost brain cells in people with advanced Parkinson's disease.
Healthy adult brains contain neural stem cells, which divide to maintain general stem-cell numbers, or become progenitor cells. In healthy adult laboratory animals, progenitor cells migrate within the brain and function primarily to maintain neuron populations for olfaction (the sense of smell). Pharmacological activation of endogenous neural stem cells has been reported to induce neuroprotection and behavioral recovery in adult rat models of neurological disorders.
==== Brain and spinal cord injury ====
Stroke and traumatic brain injury lead to cell death, characterized by a loss of neurons and oligodendrocytes within the brain. Clinical and animal studies have been conducted into the experimental use of stem cells in cases of spinal cord injury.
==== Frailty syndrome ====
In 2017, a small-scale study on individuals 60 years or older with aging frailty showed, after intravenous treatment with Mesenchymal stem cells (MSC) from healthy young donors, significant improvements in physical performance measures. MSC helps with the blockade of inflammation by decreasing it, causing the effects of frailty to reverse.
==== Heart ====
In 2012, stem cells were studied in people with severe heart disease. The work by Bodo-Eckehard Strauer was discredited by identifying hundreds of factual contradictions. Among several clinical trials reporting that adult stem cell therapy is safe and effective, actual evidence of benefit has been reported from only a few studies. Some preliminary clinical trials achieved only modest improvements in heart function following the use of bone marrow stem cell therapy.
Stem-cell therapy for the treatment of myocardial infarction usually makes use of autologous bone marrow stem cells, but other types of adult stem cells may be used, such as adipose-derived stem cells.
Possible mechanisms of recovery include:Generation of heart muscle cells, Stimulating growth of new blood vessels to repopulate damaged heart tissue and secretion of growth factors.
==== Blood-cell formation ====
The specificity of the human immune-cell repertoire is what allows the human body to defend itself from rapidly adapting antigens. However, the immune system is vulnerable to degradation upon the pathogenesis of disease, and because of the critical role that it plays in overall defense, its degradation is often fatal to the organism as a whole. Diseases of hematopoietic cells are diagnosed and classified via a subspecialty of pathology known as hematopathology. The specificity of the immune cells is what allows recognition of foreign antigens, causing further challenges in the treatment of immune disease. Identical matches between donor and recipient are no longer required for successful transplantation. Rather, haploidentical matches have facilitated numerous transplants, given improvements in post-transplant immunosuppressive regimens. Research using both hematopoietic adult stem cells and embryonic stem cells has provided insight into the possible mechanisms and methods of treatment for many of these ailments.
Fully mature human red blood cells may be generated ex vivo by hematopoietic stem cells (HSCs), which are precursors of red blood cells. In this process, HSCs are grown together with stromal cells, creating an environment that mimics the conditions of bone marrow, the natural site of red-blood-cell growth. Erythropoietin, a growth factor, is added, coaxing the stem cells to complete terminal differentiation into red blood cells. Further research into this technique should have potential benefits for gene therapy, blood transfusion, and topical medicine.
==== Regrowing teeth ====
In 2004, scientists at King's College London discovered a way to cultivate a complete tooth in mice and were able to grow bioengineered teeth stand-alone in the laboratory. Researchers are confident that tooth regeneration technology can be used to grow live teeth in people.
In theory, stem cells taken from the patient could be coaxed in the lab turning into a tooth bud which, when implanted in the gums, will give rise to a new tooth, and would be expected to be grown in a time over three weeks. It will fuse with the jawbone and release chemicals that encourage nerves and blood vessels to connect with it. The process is similar to what happens when humans grow their original adult teeth. Many challenges remain, however, before stem cells can be a choice for the replacement of missing teeth in the future.
==== Cochlear hair cell regrowth ====
Heller has reported success in re-growing cochlea hair cells with the use of embryonic stem cells.
In a 2019 review that looked at hearing regeneration and regenerative medicine, stem cell-derived otic progenitors have the potential to greatly improve hearing.
==== Blindness and vision impairment ====
Since 2003, researchers have successfully transplanted corneal stem cells into damaged eyes to restore vision. "Sheets of retinal cells used by the team are harvested from aborted fetuses, which some people find objectionable." When these sheets are transplanted over the damaged cornea, the stem cells stimulate renewed repair, eventually restoring vision. The latest such development was in June 2005, when researchers at the Queen Victoria Hospital of Sussex, England were able to restore the sight of forty people using the same technique. The group, led by Sheraz Daya, was able to successfully use adult stem cells obtained from the patient, a relative, or even a cadaver. Further rounds of trials are ongoing.
==== Pancreatic beta cells ====
People with Type 1 diabetes lose the function of insulin-producing beta cells within the pancreas. In a 2007 publication of experiments, scientists have been able to coax embryonic stem cells to turn into beta cells in the lab. In theory, if the beta cell is transplanted successfully, they will be able to replace malfunctioning ones in a diabetic patient. There are adverse effects of high glucose concentrations on stem cell therapy, however.
A key challenge in cell transplantation therapies for Type 1 diabetes is hypoxia and low oxygen conditions in transplant environments that can impair the function and identity of stem cell-derived beta cells.
==== Orthopedics ====
As of 2017, use of mesenchymal stem cells (MSCs) derived from adult stem cells was under preliminary research for potential orthopedic applications in bone and muscle trauma, cartilage repair, osteoarthritis, intervertebral disc surgery, rotator cuff surgery, and musculoskeletal disorders, among others. Other areas of orthopedic research for uses of MSCs include tissue engineering and regenerative medicine.
==== Wound healing ====
Stem cells can also be used to stimulate the growth of human tissues. In an adult, wounded tissue is most often replaced by scar tissue, which is characterized in the skin by disorganized collagen structure, loss of hair follicles and irregular vascular structure. In the case of wounded fetal tissue, however, wounded tissue is replaced with normal tissue through the activity of stem cells. A possible method for tissue regeneration in adults is to place adult stem cell "seeds" inside a tissue bed "soil" in a wound bed and allow the stem cells to stimulate differentiation in the tissue bed cells. This method elicits a regenerative response more similar to fetal wound-healing than adult scar tissue formation. As of 2018, researchers were still investigating different aspects of the "soil" tissue that are conducive to regeneration. Because of the general healing capabilities of stem cells, they have gained interest for the treatment of cutaneous wounds, such as in skin cancer.
==== HIV/AIDS ====
In 2013, scientists have been investigating an alternative approach to treating HIV-1/AIDS, based on the creation of a disease-resistant immune system through transplantation of autologous, gene-modified (HIV-1-resistant) hematopoietic stem and progenitor cells (GM-HSPC).
==== Stem Cell-Derived Exosomes ====
Recent research suggests that stem cell-derived exosomes could become an alternative to stem cell-based therapy to minimize the limitations associated with traditional stem cell therapy such as immunogenicity and tumorigenic risk.
== Criticisms ==
In 2013, studies of autologous bone marrow stem cells on ventricular function were found to contain "hundreds" of discrepancies. Critics report that of 48 reports, just five underlying trials seemed to be used, and that in many cases whether they were randomized or merely observational accepter-versus-rejecter, was contradictory between reports of the same trial. One pair of reports of identical baseline characteristics and final results, was presented in two publications as, respectively, a 578-patient randomized trial and as a 391-subject observational study. Other reports required (impossible) negative standard deviations in subsets of people or contained fractional subjects, negative NYHA classes. Overall, many more people were reported as having receiving stem cells in trials, than the number of stem cells processed in the hospital's laboratory during that time. A university investigation, closed in 2012 without reporting, was reopened in July 2013.
In 2014, a meta-analysis on stem cell therapy using bone-marrow stem cells for heart disease revealed discrepancies in published clinical trial reports, whereby studies with a higher number of discrepancies showed an increase in effect sizes. Another meta-analysis based on the intra-subject data of 12 randomized trials was unable to find any significant benefits of stem cell therapy on primary endpoints, such as major adverse events or increase in heart function measures, concluding there was no benefit.
2018 results of the TIME trial, which used a randomized, double-blind, placebo-controlled trial design, concluded that "bone marrow mononuclear cells administration did not improve recovery of LV function over 2 years" in people who had a myocardial infarction. Accordingly, the BOOST-2 trial conducted in 10 medical centers in Germany and Norway reported that the trial result "does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF". Furthermore, the trial also did not meet any other secondary MRI endpoints, leading to a conclusion that intracoronary bone marrow stem cell therapy does not offer a functional or clinical benefit.
In 2021, stem cell injections in the US have caused grave infections in at least 20 patients who received umbilical cord blood-derived products marketed as "stem cell treatment". In 2023, the case of a woman who was infected with Mycobacterium abscessus and sustained meningitis after stem cell treatment for multiple sclerosis at a commercial clinic in Baja California, Mexico was published.
== Veterinary medicine ==
Research conducted on horses, dogs, and cats has led to the development of stem cell treatments in veterinary medicine which can target a wide range of injuries and diseases, such as myocardial infarction, stroke, tendon and ligament damage, osteoarthritis, osteochondrosis and muscular dystrophy, both in large animals as well as in humans. While investigation of cell-based therapeutics generally reflects human medical needs, the high degree of frequency and severity of certain injuries in racehorses has put veterinary medicine at the forefront of this novel regenerative approach. Companion animals can serve as clinically relevant models that closely mimic human disease.
=== Sources of veterinarian stem cells ===
Veterinary applications of stem cell therapy as a means of tissue regeneration have been largely shaped by research that began with the use of adult-derived mesenchymal stem cells to treat animals with injuries or defects affecting bone, cartilage, ligaments and/or tendons. There are two main categories of stem cells used for treatments: allogeneic stem cells derived from a genetically different donor within the same species, and autologous mesenchymal stem cells, derived from the patient before use in various treatments. A third category, xenogenic stem cells, or stem cells derived from different species, are used primarily for research purposes, especially for human treatments.
=== Bone repair ===
Bone has a unique and well-documented natural healing process that normally is sufficient to repair fractures and other common injuries. Misaligned breaks due to severe trauma, as well as treatments like tumor resections of bone cancer, are prone to improper healing if left to the natural process alone. Scaffolds composed of natural and artificial components are seeded with mesenchymal stem cells and placed in the defect. Within four weeks of placing the scaffold, newly formed bone begins to integrate with the old bone and within 32 weeks, full union is achieved. Further studies are necessary to fully characterize the use of cell-based therapeutics for treatment of bone fractures.
Stem cells have been used to treat degenerative bone diseases in dogs. The normally recommended treatment for dogs that have Legg–Calve–Perthes disease is to remove the head of the femur after the degeneration has progressed. Recently, mesenchymal stem cells have been injected directly in to the head of the femur, with success not only in bone regeneration, but also in pain reduction.
=== Ligament and tendon repair ===
Autologous stem cell-based treatments for ligament injury, tendon injury, osteoarthritis, osteochondrosis, and sub-chondral bone cysts have been commercially available to practicing veterinarians to treat horses since 2003 in the United States and since 2006 in the United Kingdom. Autologous stem cell based treatments for tendon injury, ligament injury, and osteoarthritis in dogs have been available to veterinarians in the United States since 2005. Over 3000 privately owned horses and dogs have been treated with autologous adipose-derived stem cells. The efficacy of these treatments has been shown in double-blind clinical trials for dogs with osteoarthritis of the hip and elbow and horses with tendon damage.
Race horses are especially prone to injuries of the tendon and ligaments. Conventional therapies are very unsuccessful in returning the horse to full functioning potential. Natural healing, guided by the conventional treatments, leads to the formation of fibrous scar tissue that reduces flexibility and full joint movement. Traditional treatments prevented a large number of horses from returning to full activity and also have a high incidence of re-injury due to the stiff nature of the scarred tendon. Introduction of both bone marrow and adipose derived stem cells, along with natural mechanical stimulus promoted the regeneration of tendon tissue. The natural movement promoted the alignment of the new fibers and tendocytes with the natural alignment found in uninjured tendons. Stem cell treatment not only allowed more horses to return to full duty and also greatly reduced the re-injury rate over a three-year period.
The use of embryonic stem cells has also been applied to tendon repair. The embryonic stem cells were shown to have a better survival rate in the tendon as well as better migrating capabilities to reach all areas of damaged tendon. The overall repair quality was also higher, with better tendon architecture and collagen formed. There was also no tumor formation seen during the three-month experimental period. Long-term studies need to be carried out to examine the long-term efficacy and risks associated with the use of embryonic stem cells. Similar results have been found in small animals.
==== Joint repair ====
Osteoarthritis is the main cause of joint pain both in animals and humans. Horses and dogs are most frequently affected by arthritis. Natural cartilage regeneration is very limited. Different types of mesenchymal stem cells and other additives are still being researched to find the best type of cell and method for long-term treatment.
Adipose-derived mesenchymal cells are currently the most often used for stem cell treatment of osteoarthritis because of the non-invasive harvesting. This is a recently developed, non-invasive technique developed for easier clinical use. Dogs receiving this treatment showed greater flexibility in their joints and less pain.
=== Muscle repair ===
Stem cells have successfully been used to ameliorate healing in the heart after myocardial infarction in dogs. Adipose and bone marrow derived stem cells were removed and induced to a cardiac cell fate before being injected into the heart. The heart was found to have improved contractility and a reduction in the damaged area four weeks after the stem cells were applied.
In 2007, a trial was underway for a patch made of a porous substance onto which the stem cells are "seeded" in order to induce tissue regeneration in heart defects. Tissue was regenerated and the patch was well incorporated into the heart tissue. This is thought to be due, in part, to improved angiogenesis and reduction of inflammation. Although cardiomyocytes were produced from the mesenchymal stem cells, they did not appear to be contractile. Other treatments that induced a cardiac fate in the cells before transplanting had greater success at creating contractile heart tissue.
2018 research, such as the European nTRACK research project, aims to demonstrate that multimodal nanoparticles can structurally and functionally track stem cell in muscle regeneration therapy. The idea is to label stem cells with gold nano-particles that are fully characterised for uptake, functionality, and safety. The labelled stem cells will be injected into an injured muscle and tracked using imaging systems. However, the system still needs to be demonstrated at lab scale.
=== Nervous system repair ===
Spinal cord injuries are one of the most common traumas brought into veterinary hospitals. Spinal injuries occur in two ways after the trauma: the primary mechanical damage, and in secondary processes, like inflammation and scar formation, in the days following the trauma. These cells involved in the secondary damage response secrete factors that promote scar formation and inhibit cellular regeneration. Mesenchymal stem cells that are induced to a neural cell fate are loaded onto a porous scaffold and are then implanted at the site of injury. The cells and scaffold secrete factors that counteract those secreted by scar forming cells and promote neural regeneration. Eight weeks later, dogs treated with stem cells showed immense improvement over those treated with conventional therapies. Dogs treated with stem cells were able to occasionally support their own weight, which has not been seen in dogs undergoing conventional therapies.
In a study to evaluate the treatment of experimentally induced MS in dogs using laser activated non-expanded adipose derived stem cells. The results showed amelioration of the clinical signs over time confirmed by the resolution of the previous lesions on MRI. Positive migration of the injected cells to the site of lesion, increased remyelination detected by Myelin Basic Proteins, positive differentiation into Olig2 positive oligodendrocytes, prevented the glial scar formation and restored axonal architecture.
Treatments are also in clinical trials to repair and regenerate peripheral nerves. Peripheral nerves are more likely to be damaged, but the effects of the damage are not as widespread as seen in injuries to the spinal cord. Treatments are currently in clinical trials to repair severed nerves, with early success. Stem cells induced to a neural fate injected in to a severed nerve. Within four weeks, regeneration of previously damaged stem cells and completely formed nerve bundles were observed.
Stem cells are also in clinical phases for treatment in ophthalmology. Hematopoietic stem cells have been used to treat corneal ulcers of different origin of several horses. These ulcers were resistant to conventional treatments available, but quickly responded positively to the stem cell treatment. Stem cells were also able to restore sight in one eye of a horse with retinal detachment, allowing the horse to return to daily activities.
=== Conservation ===
Stem cells are being explored for use in conservation efforts. Spermatogonial stem cells have been harvested from a rat and placed into a mouse host and fully mature sperm were produced with the ability to produce viable offspring. Currently research is underway to find suitable hosts for the introduction of donor spermatogonial stem cells. If this becomes a viable option for conservationists, sperm can be produced from high genetic quality individuals who die before reaching sexual maturity, preserving a line that would otherwise be lost.
== Society and culture ==
=== Marketing and costs ===
In the late 1990s and early 2000s, there was an initial wave of companies and clinics offering stem cell therapy, while not substantiating health claims or having regulatory approval. By 2012, a second wave of companies and clinics had emerged, usually located in developing countries where medicine is less regulated and offering stem cell therapies on a medical tourism model. Like the first wave companies and clinics, they made similar strong, but unsubstantiated, claims, mainly by clinics in the United States, Mexico, Thailand, India, and South Africa. By 2016, research indicated that there were more than 550 stem cell clinics in the US alone selling generally unproven therapies for a wide array of medical conditions in almost every state in the country, altering the dynamic of stem cell tourism. In 2018, the FDA sent a warning letter to StemGenex Biologic Laboratories in San Diego, which marketed a service in which it took body fat from people, processed it into mixtures it said contained various forms of stem cells, and administered it back to the person by inhalation, intravenously, or infusion into their spinal cords; the company said the treatment was useful for many chronic and life-threatening conditions.
One common marketing tactic is registering on ClinicalTrials.gov, the US government database for clinical trials. Registration of a study notifies the agency but does not prove that review has taken place. Registration with the FDA similarly does not prove that approval has been granted.
Costs of stem cell therapies range widely by clinic, condition, and cell type, but most commonly range between $10,000-$20,000. Insurance does not cover stem cell injections at clinics so patients often use on-line fundraising. In 2018, the US Federal Trade Commission found health centers and an individual physician making unsubstantiated claims for stem cell therapies, and forced refunds of some $500,000. The FDA filed suit against two stem cell clinic firms around the same time, seeking permanent injunctions against their marketing and use of unapproved adipose stem cell products.
=== COVID-19-related marketing and government agency responses ===
Although according to the NIH no stem cell treatments have been approved for COVID-19, and the agency recommends against the use of MSCs for the disease, some stem cell clinics began marketing both unproven and non-FDA-approved stem cells and exosomes for COVID-19 in 2020. The FDA took prompt action by sending letters to the firms in question. The FTC also warned a stem cell firm for misleading COVID-19-related marketing.
== See also ==
== References ==
== External links ==
Media related to Stem-cell therapy at Wikimedia Commons
EuroStemCell: types of stem cells and their uses | Wikipedia/Stem-cell_therapy |
Lipoprotein lipase deficiency is a genetic disorder in which a person has a defective gene for lipoprotein lipase, which leads to very high triglycerides, which in turn causes stomach pain and deposits of fat under the skin, and which can lead to problems with the pancreas and liver, which in turn can lead to diabetes. The disorder only occurs if a child acquires the defective gene from both parents (it is autosomal recessive). It is managed by restricting fat in diet to less than 20 g/day.
== Signs and symptoms ==
The disease often presents in infancy with colicky pain, failure to thrive, and other symptoms and signs of the chylomicronemia syndrome. In women the use of estrogens or first pregnancy are also well known trigger factors for initial manifestation of LPLD. At all ages, the most common clinical manifestation is recurrent abdominal pain and acute pancreatitis. The pain may be epigastric, with radiation to the back, or it may be diffuse, with the appearance of an emergent acute abdomen. Other typical symptoms are eruptive xanthomas (in about 50% of patients), lipaemia retinalis and hepatosplenomegaly.
=== Complications ===
Patients with LPLD are at high risk of acute pancreatitis, which can be life-threatening, and can lead to chronic pancreatic insufficiency and diabetes.
== Diagnosis ==
Lab tests show massive accumulation of chylomicrons in the plasma and corresponding severe hypertriglyceridemia. Typically, the plasma in a fasting blood sample appears creamy (plasma lactescence).
Familial LPL deficiency should be considered in anyone with severe hypertriglyceridemia and the chylomicronemia syndrome. The absence of secondary causes of severe hypertriglyceridemia (like e.g. diabetes, alcohol, estrogen-, glucocorticoid-, antidepressant- or isotretinoin-therapy, certain antihypertensive agents, and paraproteinemic disorders) increases the possibility of LPL deficiency. In this instance besides LPL also other loss-of-function mutations in genes that regulate catabolism of triglyceride-rich lipoproteins (like e.g. ApoC2, ApoA5, LMF-1, GPIHBP-1 and GPD1) should also be considered
The diagnosis of familial lipoprotein lipase deficiency is finally confirmed by detection of either homozygous or compound heterozygous pathogenic gene variants in LPL with either low or absent lipoprotein lipase enzyme activity.
Lipid measurements
· Milky, lipemic plasma revealing severe hyperchylomicronemia;
· Severely elevated fasting plasma triglycerides (>2000 mg/dL);
LPL enzyme
· Low or absent LPL activity in post-heparin plasma;
· LPL mass level reduced or absent in post-heparin plasma;
Molecular genetic testing
The LPL gene is located on the short (p) arm of chromosome 8 at position 22. More than 220 mutations in the LPL gene have been found to cause familial lipoprotein lipase deficiency so far.
== Treatment ==
Treatment of LPLD has two different objectives: immediate prevention of pancreatitis attacks and long-term reduction of cardiovascular disease risk.
Olezarsen (Tryngolza) was approved for medical use in the United States in December 2024.
=== Gene therapy ===
In 2012, the European Commission approved alipogene tiparvovec (Glybera), a gene therapy for adults with familial LPLD (confirmed by genetic testing) and having severe or multiple pancreatitis attacks despite dietary fat restrictions. It is the first gene therapy to receive marketing authorization in the European Union; it was priced at about $1 million per treatment, and as of 2016, only one person had been treated with it commercially. A total of 31 people were treated with Glybera, most for free in clinical trials before it was taken off the market.
== Incidence ==
The disorder affects about 1 out of 1,000,000 people; however, epidemiological data are limited and there are regional differences due to cofounder effect (e.g. in Canada) or intermarriage.
== See also ==
Primary hyperlipoproteinemia
Familial apoprotein CII deficiency
List of cutaneous conditions
== References ==
== Further reading ==
Gaudet, D; de Wal, J; Tremblay, K; Déry, S; van Deventer, S; Freidig, A; Brisson, D; Méthot, J (June 2010). "Review of the clinical development of alipogene tiparvovec gene therapy for lipoprotein lipase deficiency". Atherosclerosis. Supplements. 11 (1): 55–60. doi:10.1016/j.atherosclerosissup.2010.03.004. PMID 20427244.
"LPL gene". NIH Genetics Home Reference. February 2015.
Hegele, RA; et al. (August 2014). "The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management". The Lancet. Diabetes & Endocrinology. 2 (8): 655–66. doi:10.1016/S2213-8587(13)70191-8. PMC 4201123. PMID 24731657.
== External links == | Wikipedia/Lipoprotein_lipase_deficiency |
Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins. It collects triglycerides from very-low-density lipoproteins (VLDL) or chylomicrons and exchanges them for cholesteryl esters from high-density lipoproteins (HDL), and vice versa. Most of the time, however, CETP does a heteroexchange, trading a triglyceride for a cholesteryl ester or a cholesteryl ester for a triglyceride.
== Genetics ==
The CETP gene is located on chromosome 16 (16q21).
== Protein fold ==
The crystal structure of CETP is that of dimer of two TUbular LIPid (TULIP) binding domains. Each domain consists of a core of 6 elements: 4 beta-sheets forming an extended superhelix; 2 flanking elements that tend to include some alpha helix. The sheets wrap around the helices to produce a cylinder 6 x 2.5 x 2.5 nm. CETP contains two of these domains that interact head-to-head via an interface made of 6 beta-sheets, 3 from each protomer. The same fold is shared by Bacterial Permeability Inducing proteins (examples: BPIFP1 BPIFP2 BPIFA3 and BPIFB4), phospholipid transfer protein (PLTP), and long-Palate Lung, and Nasal Epithelium protein (L-PLUNC). The fold is similar to intracellular SMP domains, and originated in bacteria. The crystal structure of CETP has been obtained with bound CETP inhibitors. However, this has not resolved the doubt over whether CETP function as a lipid tube or shuttle.
== Role in disease ==
Rare mutations leading to reduced function of CETP have been linked to accelerated atherosclerosis. In contrast, a polymorphism (I405V) of the CETP gene leading to lower serum levels has also been linked to exceptional longevity and to metabolic response to nutritional intervention. However, this mutation also increases the prevalence of coronary heart disease in patients with hypertriglyceridemia. The D442G mutation, which lowers CETP levels and increases HDL levels also increases coronary heart disease.
Elaidic acid, a major component of trans fat, increases CETP activity.
== Pharmacology ==
As HDL can alleviate atherosclerosis and other cardiovascular diseases, and certain disease states such as the metabolic syndrome feature low HDL, pharmacological inhibition of CETP is being studied as a method of improving HDL levels. To be specific, in a 2004 study, the small molecular agent torcetrapib was shown to increase HDL levels, alone and with a statin, and lower LDL when co-administered with a statin. Studies into cardiovascular endpoints, however, were largely disappointing. While they confirmed the change in lipid levels, most reported an increase in blood pressure, no change in atherosclerosis, and, in a trial of a combination of torcetrapib and atorvastatin, an increase in cardiovascular events and mortality.
A compound related to torcetrapib, Dalcetrapib (investigative name JTT-705/R1658), was also studied, but trials have ceased. It increases HDL levels by 30%, as compared to 60% by torcetrapib. Two CETP inhibitors were previously under development. One was Merck's MK-0859 anacetrapib, which in initial studies did not increase blood pressure. In 2017, its development was abandoned by Merck. The other was Eli Lilly's evacetrapib, which failed in Phase 3 trials.
== Interactive pathway map ==
Click on genes, proteins and metabolites below to link to respective articles.
== References ==
== Further reading ==
== External links ==
Cholesterol+ester+transfer+proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Cholesteryl_ester_transfer_protein |
Robot-assisted surgery or robotic surgery are any types of surgical procedures that are performed using robotic systems. Robotically assisted surgery was developed to try to overcome the limitations of pre-existing minimally-invasive surgical procedures and to enhance the capabilities of surgeons performing open surgery.
In the case of robotically assisted minimally-invasive surgery, instead of the surgeon directly moving the instruments, the surgeon uses one of two methods to perform dissection, hemostasis and resection, using a direct telemanipulator, or through computer control.
A telemanipulator (e.g. the da Vinci Surgical System) is a system of remotely controlled manipulators that allows the surgeon to operate real-time under stereoscopic vision from a control console separate from the operating table. The robot is docked next to the patient, and robotic arms carry out endoscopy-like maneuvers via end-effectors inserted through specially designed trocars. A surgical assistant and a scrub nurse are often still needed scrubbed at the tableside to help switch effector instruments or provide additional suction or temporary tissue retraction using endoscopic grasping instruments.
In computer-controlled systems, the surgeon uses a computer system to relay control data and direct the robotic arms and its end-effectors, though these systems can also still use telemanipulators for their input. One advantage of using the computerized method is that the surgeon does not have to be present on campus to perform the procedure, leading to the possibility for remote surgery and even AI-assisted or automated procedures.
Robotic surgery has been criticized for its expense, with the average costs in 2007 ranging from $5,607 to $45,914 per patient. This technique has not been approved for cancer surgery as of 2019 as the safety and usefulness is unclear.
== History ==
The concept of using standard hand grips to control manipulators and cameras of various sizes down to sub-miniature was described in the Robert Heinlein story 'Waldo' in August 1942, which also mentioned brain surgery.
The first robot to assist in surgery was the Arthrobot, which was developed and used for the first time in Vancouver in 1983. This robot assisted in being able to manipulate and position the patient's leg on voice command. Intimately involved were biomedical engineer James McEwen, Geof Auchinleck, a UBC engineering physics grad, and Dr. Brian Day as well as a team of engineering students. The robot was used in an orthopaedic surgical procedure on 12 March 1983, at the UBC Hospital in Vancouver. The next great step was in 1985. in brain biopsy under CT guidance with the assistance of a robotic arm—PUMA560. Over 60 arthroscopic surgical procedures were performed in the first 12 months, and a 1985. National Geographic video on industrial robots, The Robotics Revolution, featured the device. Other related robotic devices developed at the same time included a surgical scrub nurse robot, which handed operative instruments on voice command, and a medical laboratory robotic arm. A YouTube video entitled Arthrobot – the world's first surgical robot illustrates some of these in operation.
In 1985 a robot, the Unimation Puma 200, was used to orient a needle for a brain biopsy while under CT guidance during a neurological procedure. In the late 1980s, Imperial College in London developed PROBOT, which was then used to perform prostatic surgery. The advantages to this robot was its small size, accuracy and lack of fatigue for the surgeon. In the 1990s, computer-controlled surgical devices began to emerge, enabling greater precision and control in surgical procedures. One of the most significant advancements in this period was the da Vinci Surgical System, which was approved by the FDA for use in surgical procedures in 2000 (Intuitive Surgical, 2021). The da Vinci system uses robotic arms to manipulate surgical instruments, allowing surgeons to perform complex procedures with greater accuracy and control. In 1992, the ROBODOC was introduced and revolutionized orthopedic surgery by being able to assist with hip replacement surgeries. The latter was the first surgical robot that was approved by the FDA in 2008. The ROBODOC from Integrated Surgical Systems (working closely with IBM) could mill out precise fittings in the femur for hip replacement. The purpose of the ROBODOC was to replace the previous method of carving out a femur for an implant, the use of a mallet and broach/rasp.
Further development of robotic systems was carried out by SRI International and Intuitive Surgical with the introduction of the da Vinci Surgical System and Computer Motion with the AESOP and the ZEUS robotic surgical system. The first robotic surgery took place at The Ohio State University Medical Center in Columbus, Ohio under the direction of Robert E. Michler.
AESOP was a breakthrough in robotic surgery when introduced in 1994, as it was the first laparoscopic camera holder to be approved by the FDA. NASA initially funded the company that produces AESOP, Computer Motion, due to its goal to create a robotic arm that can be used in space, but this project ended up becoming a camera used in laparoscopic procedures. Voice control was then added in 1996 with the AESOP 2000 and seven degrees of freedom to mimic a human hand was added in 1998 with the AESOP 3000.
ZEUS was introduced commercially in 1998, and started the idea of telerobotics or telepresence surgery where the surgeon is at a distance from the robot on a console and operates on the patient. ZEUS was first used during a gynecological surgery in 1997 to reconnect Fallopian tubes in Cleveland Ohio, a beating heart coronary artery bypass graft in October 1999, and the Lindbergh Operation, which was a cholecystectomy performed remotely in September 2001. In 2003, ZEUS made its most prominent mark in cardiac surgery after successfully harvesting the left internal mammary arteries in 19 patients, all of which had very successful clinical outcomes.
The original telesurgery robotic system that the da Vinci was based on was developed at Stanford Research Institute International in Menlo Park with grant support from DARPA and NASA. A demonstration of an open bowel anastomosis was given to the Association of Military Surgeons of the US. Although the telesurgical robot was originally intended to facilitate remotely performed surgery in the battlefield to reduce casualties and to be used in other remote environments, it turned out to be more useful for minimally invasive on-site surgery. The patents for the early prototype were sold to Intuitive Surgical in Mountain View, California. The da Vinci senses the surgeon's hand movements and translates them electronically into scaled-down micro-movements to manipulate the tiny proprietary instruments. It also detects and filters out any tremors in the surgeon's hand movements, so that they are not duplicated robotically. The camera used in the system provides a true stereoscopic picture transmitted to a surgeon's console. Compared to the ZEUS, the da Vinci robot is attached to trocars to the surgical table, and can imitate the human wrist. In 2000, the da Vinci obtained FDA approval for general laparoscopic procedures and became the first operative surgical robot in the US. Examples of using the da Vinci system include the first robotically assisted heart bypass (performed in Germany) in May 1998, and the first performed in the United States in September 1999; and the first all-robotic-assisted kidney transplant, performed in January 2009. The da Vinci Si was released in April 2009 and initially sold for $1.75 million.
In 2005, a surgical technique was documented in canine and cadaveric models called the transoral robotic surgery (TORS) for the da Vinci robot surgical system as it was the only FDA-approved robot to perform head and neck surgery. In 2006, three patients underwent resection of the tongue using this technique. The results were more clear visualization of the cranial nerves, lingual nerves, and lingual artery, and the patients had a faster recovery to normally swallowing. In May 2006 the first artificial intelligence doctor-conducted unassisted robotic surgery was on a 34-year-old male to correct heart arrhythmia. The results were rated as better than an above-average human surgeon. The machine had a database of 10,000 similar operations, and so, in the words of its designers, was "more than qualified to operate on any patient". In August 2007, Dr. Sijo Parekattil of the Robotics Institute and Center for Urology (Winter Haven Hospital and University of Florida) performed the first robotic-assisted microsurgery procedure denervation of the spermatic cord for chronic testicular pain. In February 2008, Dr. Mohan S. Gundeti of the University of Chicago Comer Children's Hospital performed the first robotic pediatric neurogenic bladder reconstruction.
On 12 May 2008, the first image-guided MR-compatible robotic neurosurgical procedure was performed at University of Calgary by Dr. Garnette Sutherland using the NeuroArm. In June 2008, the German Aerospace Centre (DLR) presented a robotic system for minimally invasive surgery, the MiroSurge. In September 2010, the Eindhoven University of Technology announced the development of the Sofie surgical system, the first surgical robot to employ force feedback. In September 2010, the first robotic operation at the femoral vasculature was performed at the University Medical Centre Ljubljana by a team led by Borut Geršak.
In 2019 the Versius Surgical Robotic System was launched and is a rival of the Da Vinci surgical system and claims to be more flexible and versatile, having independent modular arms which are "quick and easy to set up". The small-scale design means that it is suitable for virtually any operating room and can be operated at either a standing or a sitting position.
== Uses ==
=== Ophthalmology ===
Ophthalmology is still part of the frontier for robotic-assisted surgeries. However, there are a couple of robotic systems that are capable of successfully performing surgeries.
PRECEYES Surgical System is being used for vitreoretinal surgeries. This is a single arm robot, that is tele manipulated by a surgeon. This system attaches to the head of the operating room table and provides surgeons with increased precision with the help of the intuitive motion controller. Preceyes is the only robotic instrument to be CE certified. Some other companies like Forsight Robotics, Acusurgical that raised 5.75 M€ (France), and Horizon (US) are working in this field.
The da Vinci Surgical System, though not specifically designed for ophthalmic procedures, uses telemanipulation to perform pterygium repairs and ex-vivo corneal surgeries.
=== Heart ===
Some examples of heart surgery being assisted by robotic surgery systems include:
Atrial septal defect repair – the repair of a hole between the two upper chambers of the heart,
Mitral valve repair – the repair of the valve that prevents blood from regurgitating back into the upper heart chambers during contractions of the heart,
Coronary artery bypass – rerouting of blood supply by bypassing blocked arteries that provide blood to the heart.
=== Thoracic ===
Robotic surgery has become more widespread in thoracic surgery for mediastinal pathologies, pulmonary pathologies and more recently complex esophageal surgery.
The da Vinci Xi system is used for lung and mediastinal mass resection. This minimally invasive approach as a comparable alternative to video-assisted thoracoscopic surgery (VATS) and the standard open thoracic surgery. Although VATS is the less expensive option, the robotic-assisted approach offers benefits such as 3D visualizations with seven degrees of freedom and improved dexterity while having equivalent perioperative outcomes.
=== ENT ===
The first successful robot-assisted cochlear implantation in a person took place in Bern, Switzerland in 2017. Surgical robots have been developed for use at various stages of cochlear implantation, including drilling through the mastoid bone, accessing the inner ear and inserting the electrode into the cochlea.
Advantages of robot-assisted cochlear implantation include improved accuracy, resulting in fewer mistakes during electrode insertion and better hearing outcomes for patients. The surgeon uses image-guided surgical planning to program the robot based on the patient's individual anatomy. This helps the implant team to predict where the contacts of the electrode array will be located within the cochlea, which can assist with audio processor fitting post-surgery. The surgical robots also allow surgeons to reach the inner ear in a minimally invasive way.
Challenges that still need to be addressed include safety, time, efficiency and cost.
Surgical robots have also been shown to be useful for electrode insertion with pediatric patients.
=== Gastrointestinal ===
Multiple types of procedures have been performed with either the 'Zeus' or da Vinci robot systems, including bariatric surgery and gastrectomy for cancer. Surgeons at various universities initially published case series demonstrating different techniques and the feasibility of GI surgery using the robotic devices. Specific procedures have been more fully evaluated, specifically esophageal fundoplication for the treatment of gastroesophageal reflux and Heller myotomy for the treatment of achalasia.
Robot-assisted pancreatectomies have been found to be associated with "longer operating time, lower estimated blood loss, a higher spleen-preservation rate, and shorter hospital stay[s]" than laparoscopic pancreatectomies; there was "no significant difference in transfusion, conversion to open surgery, overall complications, severe complications, pancreatic fistula, severe pancreatic fistula, ICU stay, total cost, and 30-day mortality between the two groups."
=== Gynecology ===
The first report of robotic surgery in gynecology was published in 1999 from the Cleveland Clinic. The adoption of robotic surgery has contributed to the increase in minimally invasive surgery for gynecologic disease. Gynecologic procedures may take longer with robot-assisted surgery and the rate of complications may be higher, but there are not enough high-quality studies to know at the present time. In the United States, robotic-assisted hysterectomy for benign conditions was shown to be more expensive than conventional laparoscopic hysterectomy in 2015, with no difference in overall rates of complications.
This includes the use of the da Vinci surgical system in benign gynecology and gynecologic oncology. Robotic surgery can be used to treat fibroids, abnormal periods, endometriosis, ovarian tumors, uterine prolapse, and female cancers. Using the robotic system, gynecologists can perform hysterectomies, myomectomies, and lymph node biopsies. The Hominis robotic system developed by Momentis Surgical™ is aimed to provide a robotic platform for natural orifice transluminal endoscopic surgery (NOTES) for myomectomy through the vagina.
A 2017 review of surgical removal of the uterus and cervix for early cervical cancer robotic and laparoscopic surgery resulted in similar outcomes with respect to the cancer.
=== Bone ===
Robots are used in orthopedic surgery.
ROBODOC is the first active robotic system that performs some of the surgical actions in a total hip arthroplasty (THA). It is programmed preoperatively using data from computer tomography (CT) scans. This allows for the surgeon to choose the optimal size and design for the replacement hip.
Acrobot and Rio are semi-active robotic systems that are used in THA. It consists of a drill bit that is controlled by the surgeon however the robotic system does not allow any movement outside the predetermined boundaries.
Mazor X is used in spinal surgeries to assist surgeons with placing pedicle screw instrumentation. Inaccuracy when placing a pedicle screw can result in neurovascular injury or construct failure. Mazor X functions by using templating imaging to locate itself to the target location of where the pedicle screw is needed.
=== Spine ===
Robotic devices started to be used in minimally invasive spine surgery starting in the mid-2000s. As of 2014, there were too few randomized clinical trials to judge whether robotic spine surgery is more or less safe than other approaches.
As of 2019, the application of robotics in spine surgery has mainly been limited to pedicle screw insertion for spinal fixation. In addition, the majority of studies on robot-assisted spine surgery have investigated lumbar or lumbosacral vertebrae only. Studies on use of robotics for placing screws in the cervical and thoracic vertebrae are limited.
=== Transplant surgery ===
The first fully robotic kidney transplantations were performed in the late 2000s. It may allow kidney transplantations in people who are obese who could not otherwise have the procedure. Weight loss however is the preferred initial effort.
In 2021, the team at Cedars-Sinai in Los Angeles, California completed the world's first robotic lung transplant, allowing a minimally invasive approach to the procedure.
=== General surgery ===
With regards to robotic surgery, this type of procedure is currently best suited for single-quadrant procedures, in which the operations can be performed on any one of the four quadrants of the abdomen. Cost disadvantages are applied with procedures such as a cholecystectomy and fundoplication, but are suitable opportunities for surgeons to advance their robotic surgery skills.
=== Hernia and abdominal wall surgery ===
Over the past several decades, there have been great advances in the field of abdominal wall and hernia surgery especially when it comes to robotic-assisted surgery. Unlike laparoscopic surgery, the robotic platform allows for the correction of large hernia defects with specialized techniques that would traditionally only be performed via an open approach. Compared to open surgery, robotic surgery for hernia repair can reduce pain, length of hospital stay, and improve outcomes. As the robotic instruments have 6 degrees of articulation, freedom of movement and ergonomics are greatly improved compared to laparoscopy.
The first robotic inguinal hernia repairs were done in conjunction with prostatectomies in 2007. The first ventral hernia repairs were performed robotically in 2009. Since then the field has rapidly expanded to include most types of reconstruction including anterior as well as posterior component separation.
With newer techniques such as direct access into the abdominal wall, major reconstruction of large hernias can be done without even entering the abdominal cavity. Due to its complexity, however, major reconstruction done robotically should be undertaken at advanced hernia centers such as the Columbia Hernia Center in New York City, NY, USA. The American Hernia Society and the European Hernia Society are moving towards specialty designation for hernia centers who are credentialed for complex hernia surgery, including robotic surgery.
=== Urology ===
Robotic surgery in the field of urology has become common, especially in the United States.
There is inconsistent evidence of benefits compared to standard surgery to justify the increased costs. Some have found tentative evidence of more complete removal of cancer and fewer side effects from surgery for prostatectomy.
In 2000, the first robot-assisted laparoscopic radical prostatectomy was performed.
Robotic surgery has also been utilized in radical cystectomies. A 2013 review found less complications and better short term outcomes when compared to open technique.
=== Pediatrics ===
Pediatric procedures are also benefiting from robotic surgical systems. The smaller abdominal size in pediatric patients limits the viewing field in most urology procedures. The robotic surgical systems help surgeons overcome these limitations. Robotic technology provides assistance in performing
Pyeloplasty - alternative to the conventional open dismembered pyeloplasty (Anderson-Hynes). Pyeloplasty is the most common robotic-assisted procedures in children.
Ureteral reimplantation - alternative to the open intravesical or extravesical surgery.
Ureteroureterostomy - alternative to the transperitoneal approach.
Nephrectomy and heminephrectomy - Traditionally done with laparoscopy, it is not likely that a robotic procedure offers significant advantage due to its high cost.
== Comparison to traditional methods ==
Major advances aided by surgical robots have been remote surgery, minimally invasive surgery and unmanned surgery. Due to robotic use, the surgery is done with precision, miniaturization, smaller incisions; decreased blood loss, less pain, and quicker healing time. Articulation beyond normal manipulation and three-dimensional magnification help to result in improved ergonomics. Due to these techniques, there is a reduced duration of hospital stays, blood loss, transfusions, and use of pain medication.
The existing open surgery technique has many flaws such as limited access to the surgical area, long recovery time, long hours of operation, blood loss, surgical scars, and marks.
The robot's costs range from $1 million to $2.5 million for each unit, and while its disposable supply cost is normally $1,500 per procedure, the cost of the procedure is higher. Additional surgical training is needed to operate the system. Numerous feasibility studies have been done to determine whether the purchase of such systems are worthwhile. As it stands, opinions differ dramatically. Surgeons report that, although the manufacturers of such systems provide training on this new technology, the learning phase is intensive and surgeons must perform 150 to 250 procedures to become adept in their use. During the training phase, minimally invasive operations can take up to twice as long as traditional surgery, leading to operating room tie-ups and surgical staffs keeping patients under anesthesia for longer periods. Patient surveys indicate they chose the procedure based on expectations of decreased morbidity, improved outcomes, reduced blood loss and less pain. Higher expectations may explain higher rates of dissatisfaction and regret.
Compared with other minimally invasive surgery approaches, robot-assisted surgery gives the surgeon better control over the surgical instruments and a better view of the surgical site. In addition, surgeons no longer have to stand throughout the surgery and do not get tired as quickly. Naturally occurring hand tremors are filtered out by the robot's computer software. Finally, the surgical robot can continuously be used by rotating surgery teams. Laparoscopic camera positioning is also significantly steadier with less inadvertent movements under robotic controls than compared to human assistance. The use of mixed reality to support robot-assisted surgery was developed at the Air Force Research Laboratory in 1992 through the creation of "virtual fixtures" that overlay virtual boundaries or guides that assist the human operator and has become a common method for increasing safety and precision.
There are some issues in regards to current robotic surgery usage in clinical applications. There is a lack of haptics in some robotic systems currently in clinical use, which means there is no force feedback, or touch feedback. No interaction between the instrument and the patient is felt. However, recently the Senhance robotic system by Asensus Surgical was developed with haptic feedback in order to improve the interaction between the surgeon and the tissue.
The robots can also be very large, have instrumentation limitations, and there may be issues with multi-quadrant surgery as current devices are solely used for single-quadrant application.
Critics of the system, including the American Congress of Obstetricians and Gynecologists, say there is a steep learning curve for surgeons who adopt the use of the system and that there's a lack of studies that indicate long-term results are superior to results following traditional laparoscopic surgery. Articles in the newly created Journal of Robotic Surgery tend to report on one surgeon's experience.
Complications related to robotic surgeries range from converting the surgery to open, re-operation, permanent injury, damage to viscera and nerve damage. From 2000 to 2011, out of 75 hysterectomies done with robotic surgery, 34 had permanent injury, and 49 had damage to the viscera. Prostatectomies were more prone to permanent injury, nerve damage and visceral damage as well. Very minimal surgeries in a variety of specialties had to actually be converted to open or be re-operated on, but most did sustain some kind of damage or injury. For example, out of seven coronary artery bypass grafting, one patient had to go under re-operation. It is important that complications are captured, reported and evaluated to ensure the medical community is better educated on the safety of this new technology. If something was to go wrong in a robot-assisted surgery, it is difficult to identify culpability, and the safety of the practice will influence how quickly and widespread these practices are used.
One drawback of the use of robotic surgery is the risk of mechanical failure of the system and instruments. A study from July 2005 to December 2008 was conducted to analyze the mechanical failures of the da Vinci Surgical System at a single institute. During this period, a total of 1797 robotic surgeries were performed used 4 da Vinci surgical systems. There were 43 cases (2.4%) of mechanical failure, including 24 (1.3%) cases of mechanical failure or malfunction and 19 (1.1%) cases of instrument malfunction. Additionally, one open and two laparoscopic conversions (0.17%) were performed. Therefore, the chance of mechanical failure or malfunction was found to be rare, with the rate of converting to an open or laparoscopic procedure very low.
There are also current methods of robotic surgery being marketed and advertised online. Removal of a cancerous prostate has been a popular treatment through internet marketing. Internet marketing of medical devices are more loosely regulated than pharmaceutical promotions. Many sites that claim the benefits of this type of procedure had failed to mention risks and also provided unsupported evidence. There is an issue with government and medical societies promotion a production of balanced educational material. In the US alone, many websites promotion robotic surgery fail to mention any risks associated with these types of procedures, and hospitals providing materials largely ignore risks, overestimate benefits and are strongly influenced by the manufacturer.
== Use in popular media ==
Since April 2018, medical insurance coverage was expanding in Japan, so doctors were considering promoting the procedure for cardiac surgery, as it has the advantage of reducing the burden on the patient. Japanese drama Black Pean takes on this challenge, showing both sides' point of view. Two University Hospitals are competing to be the best in the Cardiac Surgery Department. One, Tojo, has the best traditional surgeons, while the other, Teika, is all about researching and implementing the most recent technology. With this, Teika sends its technical specialist to Tojo to try to convince them to update their techniques, including the use of the Da Vinci robot (named in the drama as Darwin). Newhart Watanabe International Hospital, a pioneer in da Vinci surgery for the heart in Japan, was used as background for the drama, with Dr. Gou Watanabe providing technical support.
== See also ==
== References ==
== External links == | Wikipedia/Robot-assisted_surgery |
Retinal gene therapy holds a promise in treating different forms of non-inherited and inherited blindness.
In 2008, three independent research groups reported that patients with the rare genetic retinal disease Leber's congenital amaurosis had been successfully treated using gene therapy with adeno-associated virus (AAV). In all three studies, an AAV vector was used to deliver a functional copy of the RPE65 gene, which restored vision in children suffering from LCA. These results were widely seen as a success in the gene therapy field, and have generated excitement and momentum for AAV-mediated applications in retinal disease.
In retinal gene therapy, the most widely used vectors for ocular gene delivery are based on adeno-associated virus. The great advantage in using adeno-associated virus for the gene therapy is that it poses minimal immune responses and mediates long-term transgene expression in a variety of retinal cell types. For example, tight junctions that form the blood-retina barrier, separate subretinal space from the blood supply, providing protection from microbes and decreasing most immune-mediated damages.
There is still a lot of knowledge missing in regards of retina dystrophies. Detail characterization is needed in order to improve knowledge. To address this issue, creation of Registries is an attempt to grouped and characterize rare diseases. Registries help to localize, and measure all the phenotype of these conditions and therefore to provide easy follow-ups and provide a source of information to scientist community. Registry designs varies from region to region, however localization and characterization of the phenotype are the standard gold.
Examples of Registries are:
RetMxMap<ARVO 2009>. A Mexican and Latin-American registry created since 2009. This registry was created by Dr Adda Lízbeth Villanueva Avilés. She is a clinical-scientist gene mapping inherited retina dystrophies in Mexico and other Latin countries.
== Clinical trials ==
=== Leber's congenital amaurosis ===
Preclinical studies in mouse models of Leber's congenital amaurosis (LCA) were published in 1996 and a study in dogs published in 2001. In 2008, three groups reported results of clinical trials using adeno-associated virus for LCA. In these studies, an AAV vector encoding the RPE65 gene was delivered via a "subretinal injection", where a small amount of fluid is injected underneath the retina in a short surgical procedure. Development continued, and in December 2017 the FDA approved Voretigene neparvovec (Luxturna), an adeno-associated virus vector-based gene therapy for children and adults with biallelic RPE65 gene mutations responsible for retinal dystrophy, including Leber congenital amaurosis. People must have viable retinal cells as a prerequisite for the intraocular administration of the drug.
=== Age-related macular degeneration ===
Following the successful clinical trials in LCA, researchers have been developing similar treatments using adeno-associated virus for age-related macular degeneration (AMD). To date, efforts have focused on long-term delivery of VEGF inhibitors to treat the wet form of macular degeneration. Whereas wet AMD is treated using frequent injections of recombinant protein into the eyeball, the goal of these treatments is long-term disease management following a single administration. One such study is being conducted at the Lions Eye Institute in Australia in collaboration with Avalanche Biotechnologies, a US-based biotechnology start-up. Another early-stage study is sponsored by Genzyme Corporation.
==== Ixo-vec for Wet AMD ====
Ixoberogene soroparvovec (Ixo-vec) is an investigational intravitreal gene therapy treatment targeting wet age-related macular degeneration (AMD) that aims to reduce the treatment burden by decreasing the frequency of anti-VEGF injections. Delivered as a single intravitreal injection, Ixo-vec enables sustained release of aflibercept, an anti-VEGF protein that helps control abnormal blood vessel growth and fluid leakage, which are key in AMD progression. Results from the OPTIC and LUNA trials demonstrate Ixo-vec’s effectiveness in significantly reducing the need for regular injections over extended periods. Patients in these trials experienced a reduction in injection frequency by as much as 90%, with many remaining injection-free for extended periods. Visual acuity remained stable, and anatomical outcomes, like reductions in central subfield thickness (CST), were achieved. Mild intraocular inflammation was the most common side effect, with steroid prophylaxis proving effective in managing this issue. This treatment approach, if proven in further studies, could offer AMD patients a more convenient, long-lasting alternative to frequent anti-VEGF injections, enhancing quality of life and treatment adherence.
=== Choroideremia ===
In October 2011, the first clinical trial was announced for the treatment of choroideremia. Dr. Robert MacLaren of the University of Oxford, who lead the trial, co-developed the treatment with Dr. Miguel Seabra of the Imperial College, London. This Phase 1/2 trial used subretinal AAV to restore the REP gene in affected patients.
Initial results of the trial were reported in January 2014 as promising as all six patients had better vision.
=== Color blindness ===
Research has shown that AAV can successfully restore color vision to treat color blindness in adult monkeys. Although this treatment has not yet entered clinical trials for humans, this work was considered a breakthrough for the ability to target cone photoreceptors.
=== Macular telangiectasia type 2 ===
Revakinagene taroretcel was approved for medical use in the United States in March 2025 for the treatment of macular telangiectasia type 2.
== Mechanism ==
=== Physiological components in retinal gene therapy ===
The vertebrate neural retina composed of several layers and distinct cell types (see anatomy of the human retina). A number of these cell types are implicated in retinal diseases, including retinal ganglion cells, which degenerate in glaucoma, the rod and cone photoreceptors, which are responsive to light and degenerate in retinitis pigmentosa, macular degeneration, and other retinal diseases, and the retinal pigment epithelium (RPE), which supports the photoreceptors and is also implicated in retinitis pigmentosa and macular degeneration.
In retinal gene therapy, AAV is capable of "transducing" these various cell types by entering the cells and expressing the therapeutic DNA sequence. Since the cells of the retina are non-dividing, AAV continues to persist and provide expression of the therapeutic DNA sequence over a long time period that can last several years.
=== AAV tropism and routes of administration ===
AAV is capable of transducing multiple cell types within the retina. AAV serotype 2, the most well-studied type of AAV, is commonly administered in one of two routes: intravitreal or subretinal. Using the intravitreal route, AAV is injected in the vitreous humor of the eye. Using the subretinal route, AAV is injected underneath the retina, taking advantage of the potential space between the photoreceptors and RPE layer, in a short surgical procedure. Although this is more invasive than the intravitreal route, the fluid is absorbed by the RPE and the retina flattens in less than 14 hours without complications. Intravitreal AAV targets retinal ganglion cells and a few Muller glial cells. Subretinal AAV efficiently targets photoreceptors and RPE cells.
The reason that different routes of administration lead to different cell types being transfected (e.g., different tropism) is that the inner limiting membrane (ILM) and the various retinal layers act as physical barriers for the delivery of drugs and vectors to the deeper retinal layers. Thus overall, subretinal AAV is 5-10 times more efficient than delivery using the intravitreal route.
=== Tropism modification and novel AAV vectors ===
One important factor in gene delivery is developing altered cell tropisms to narrow or broaden rAAV-mediated gene delivery and to increase its efficiency in tissues. Specific properties like capsid conformation, cell targeting strategies can determine which cell types are affected and also the efficiency of the gene transfer process. Different kinds of modification can be undertaken. For example, modification by chemical, immunological or genetic changes that enables the AAV2 capsid to interact with specific cell surface molecules.
Initial studies with AAV in the retina have utilized AAV serotype 2. Researchers are now beginning to develop new variants of AAV, based on naturally-occurring AAV serotypes and engineered AAV variants.
Several naturally-occurring serotypes of AAV have been isolated that can transduce retinal cells. Following intravitreal injection, only AAV serotypes 2 and 8 were capable of transducing retinal ganglion cells. Occasional Muller cells were transduced by AAV serotypes 2, 8, and 9. Following subretinal injection, serotypes 2, 5, 7, and 8 efficiently transduced photoreceptors, and serotypes 1, 2, 5, 7, 8, and 9 efficiently transduce RPE cells.
One example of an engineered variant has been described that efficiently transduces Muller glia following intravitreal injection, and has been used to rescue an animal model of aggressive, autosomal-dominant retinitis pigmentosa.
=== AAV and immune privilege in the retina ===
Importantly, the retina is immune-privileged, and thus does not experience a significant inflammation or immune-response when AAV is injected. Immune response to gene therapy vectors is what has caused previous attempts at gene therapy to fail, and is considered a key advantage of gene therapy in the eye. Re-administration has been successful in large animals, indicating that no long-lasting immune response is mounted.
Data indicate that the subretinal route may be subject to a greater degree of immune privilege compared to the intravitreal route.
=== Promoter sequence ===
Expression in various retinal cell types can be determined by the promoter sequence. In order to restrict expression to a specific cell type, a tissue-specific or cell-type specific promoter can be used.
For example, in rats the murine rhodopsin gene drive the expression in AAV2, GFP reporter product was found only in rat photoreceptors, not in any other retinal cell type or in the adjacent RPE after subretinal injection. On the other hand, if ubiquitously expressed immediate-early cytomegalovirus (CMV) enhancer-promoter is expressed in a wide variety of transfected cell types. Other ubiquitous promoters such as the CBA promoter, a fusion of the chicken-actin promoter and CMV immediate-early enhancer, allows stable GFP reporter expression in both RPE and photoreceptor cells after subretinal injections.
=== Modulation of expression ===
Sometimes modulation of transgene expression may be necessary since strong constitutive expression of a therapeutic gene in retinal tissues could be deleterious for long-term retinal function. Different methods have been utilized for the expression modulation. One way is using exogenously regulatable promoter system in AAV vectors. For example, the tetracycline-inducible expression system uses a silencer/transactivator AAV2 vector and a separate inducible doxycycline-responsive coinjection. When induction occurs by oral doxycycline, this system shows tight regulation of gene expression in both photoreceptor and RPE cells.
=== Examples and animal models ===
==== Targeting RPE ====
One study that was done by Royal College of Surgeons (RCS) in rat model shows that a recessive mutation in a receptor tyrosine kinase gene, mertk results in a premature stop codon and impaired phagocytosis function by RPE cells. This mutation causes the accumulation of outer segment debris in the subretinal space, which causes photoreceptor cell death. The model organism with this disease received a subretinal injection of AAV serotype 2 carrying a mouse Mertk cDNA under the control of either the CMV or RPE65 promoters. This treatment was found to prolong photoreceptor cell survival for several months and also the number of photoreceptor was 2.5 fold higher in AAV-Mertk- treated eyes compared with controls 9 weeks after injection, also they found decreased amount of debris in the subretinal space.
The protein RPE65 is used in the retinoid cycle where the all-trans-retinol within the rod outer segment is isomerized to its 11-cis form and oxidized to 11-cis retinal before it goes back to the photoreceptor and joins with opsin molecule to form functional rhodopsin. In animal knockout model (RPE65-/-), gene transfer experiment shows that early intraocular delivery of human RPE65 vector on embryonic day 14 shows efficient transduction of retinal pigment epithelium in the RPE65-/- knockout mice and rescues visual functions. This shows successful gene therapy can be attributed to early intraocular deliver to the diseased animal.
==== Targeting of photoreceptors ====
Juvenile retinoschisis is a disease that affects the nerve tissue in the eye. This disease is an X-linked recessive degenerative disease of the central macula region, and it is caused by mutation in the RSI gene encoding the protein retinoschisin. Retinoschisin is produced in the photoreceptor and bipolar cells and it is critical in maintaining the synaptic integrity of the retina.
Specifically the AAV 5 vector containing the wild-type human RSI cDNA driven by a mouse opsin promoter showed long-term retinal functional and structural recovery. Also the retinal structural reliability improved greatly after the treatment, characterized by an increase in the outer nuclear layer thickness.
==== Retinitis pigmentosa ====
Retinitis pigmentosa is an inherited disease which leads to progressive night blindness and loss of peripheral vision as a result of photoreceptor cell death. Most people who suffer from RP are born with rod cells that are either dead or dysfunctional, so they are effectively blind at nighttime, since these are the cells responsible for vision in low levels of light. What follows often is the death of cone cells, responsible for color vision and acuity, at light levels present during the day. Loss of cones leads to full blindness as early as five years old, but may not onset until many years later. There have been multiple hypotheses about how the lack of rod cells can lead to the death of cone cells. Pinpointing a mechanism for RP is difficult because there are more than 39 genetic loci and genes correlated with this disease. In an effort to find the cause of RP, there have been different gene therapy techniques applied to address each of the hypotheses.
Different types of inheritance can attribute to this disease; autosomal recessive, autosomal dominant, X-linked type, etc. The main function of rhodopsin is initiating the phototransduction cascade. The opsin proteins are made in the photoreceptor inner segments, then transported to the outer segment, and eventually phagocytized by the RPE cells. When mutations occur in the rhodopsin the directional protein movement is affected because the mutations can affect protein folding, stability, and intracellular trafficking. One approach is introducing AAV-delivered ribozymes designed to target and destroy a mutant mRNA.
The way this system operates was shown in animal model that have a mutant rhodopsin gene. The injected AAV-ribozymes were optimized in vitro and used to cleave the mutant mRNA transcript of P23H (where most mutation occur) in vivo.
Another mutation in the rhodopsin structural protein, specifically peripherin 2 which is a membrane glycoprotein involved in the formation of photoreceptor outersegment disk, can lead to recessive RP and macular degeneration in human (19). In a mouse experiment, AAV2 carrying a wild-type peripherin 2 gene driven by a rhodopsin promoter was delivered to the mice by subretinal injection. The result showed improvement in photoreceptor structure and function which was detected by ERG (electroretinogram). The result showed improvement of photoreceptor structure and function which was detected by ERG. Also peripherin 2 was detected at the outer segment layer of the retina 2 weeks after injection and therapeutic effects were noted as soon as 3 weeks after injection. A well-defined outer segment containing both peripherin2 and rhodopsin was present 9-month after injection.
Since apoptosis can be the cause of photoreceptor death in most of the retinal dystrophies. It has been known that survival factors and antiapoptoic reagents can be an alternative treatment if the mutation is unknown for gene replacement therapy. Some scientists have experimented with treating this issue by injecting substitute trophic factors into the eye. One group of researchers injected the rod derived cone viability factor (RdCVF) protein (encoded for by the Nxnl1 (Txnl6) gene) into the eye of the most commonly occurring dominant RP mutation rat models. This treatment demonstrated success in promoting the survival of cone activity, but the treatment served even more significantly to prevent progression of the disease by increasing the actual function of the cones. Experiments were also carried out to study whether supplying AAV2 vectors with cDNA for glial cell line-derived neurotrophic factor (GDNF) can have an anti-apoptosis effect on the rod cells.
In looking at an animal model, the opsin transgene contains a truncated protein lacking the last 15 amino acids of the C terminus, which causes alteration in rhodopsin transport to the outer segment and leads to retinal degeneration. When the AAV2-CBA-GDNF vector is administered to the subretinal space, photoreceptor stabilized and rod photoreceptors increased and this was seen in the improved function of the ERG analysis. Successful experiments in animals have also been carried out using ciliary neurotrophic factor (CNTF), and CNTF is being used as a treatment in human clinical trials.
==== AAV-based treatment for retinal neovascular diseases ====
Ocular neovascularization (NV) is the abnormal formation of new capillaries from already existing blood vessels in the eye, and this is a characteristics for ocular diseases such as diabetic retinopathy (DR), retinopathy of prematurity (ROP) and (wet form) age-related macular degeneration (AMD). One of the main players in these diseases is VEGF (Vascular endothelial growth factor) which is known to induce vessel leakage and which is also known to be angiogenic. In normal tissues VEGF stimulates endothelial cell proliferation in a dose dependent manner, but such activity is lost with other angiogenic factors.
Many angiostatic factors have been shown to counteract the effect of increasing local VEGF. The naturally occurring form of soluble Flt-1 has been shown to reverse neovascularization in rats, mice, and monkeys.
Pigment epithelium-derived factor (PEDF) also acts as an inhibitor of angiogenesis. The secretion of PEDF is noticeably decreased under hypoxic conditions allowing the endothelial mitogenic activity of VEGF to dominate, suggesting that the loss of PEDF plays a central role in the development of ischemia-driven NV. One clinical finding shows that the levels of PEDF in aqueous humor of human are decreased with increasing age, indicating that the reduction may lead to the development of AMD. In animal model, an AAV with human PEDF cDNA under the control of the CMV promoter prevented choroidal and retinal NV.
The finding suggests that the AAV-mediated expression of angiostatic factors can be implemented to treat NV. This approach could be useful as an alternative to frequent injections of recombinant protein into the eye. In addition, PEDF and sFlt-1 may be able to diffuse through sclera tissue, allowing for the potential to be relatively independent of the intraocular site of administration.
== References == | Wikipedia/Gene_therapy_of_the_human_retina |
An aging-associated disease (commonly termed age-related disease, ARD) is a disease that is most often seen with increasing frequency with increasing senescence. They are essentially complications of senescence, distinguished from the aging process itself because all adult animals age (with rare exceptions) but not all adult animals experience all age-associated diseases. The term does not refer to age-specific diseases, such as the childhood diseases chicken pox and measles, only diseases of the elderly. They are also not accelerated aging diseases, all of which are genetic disorders.
Examples of aging-associated diseases are atherosclerosis and cardiovascular disease, cancer, arthritis, cataracts, osteoporosis, type 2 diabetes, hypertension and Alzheimer's disease. The incidence of all of these diseases increases exponentially with age.
Of the roughly 150,000 people who die each day across the globe, about two thirds—100,000 per day—die of age-related causes. In industrialized nations, the proportion is higher, reaching 90%.
== Patterns of differences ==
By age 3, about 30% of rats have had cancer, whereas by age 85 about 30% of humans have had cancer. Humans, dogs and rabbits get Alzheimer's disease, but rodents do not. Elderly rodents typically die of cancer or kidney disease, but not of cardiovascular disease. In humans, the relative incidence of cancer increases exponentially with age for most cancers, but levels off or may even decline by age 60–75(although colon/rectal cancer continues to increase).
People with the so-called segmental progerias are vulnerable to different sets of diseases. Those with Werner's syndrome experience osteoporosis, cataracts, and, cardiovascular disease, but not neurodegeneration or Alzheimer's disease; those with Down syndrome have type 2 diabetes and Alzheimer's disease, but not high blood pressure, osteoporosis or cataracts. In Bloom syndrome, those affected most often die of cancer.
== Research ==
Aging (senescence) increases vulnerability to age-associated diseases, whereas genetics determines vulnerability or resistance between species and individuals within species. Some age-related changes (like graying hair) are said to be unrelated to an increase in mortality. But some biogerontologists believe that the same underlying changes that cause graying hair also increase mortality in other organ systems and that understanding the incidence of age-associated disease will advance knowledge of the biology of senescence just as knowledge of childhood diseases advanced knowledge of human development.
Strategies for engineered negligible senescence (SENS) is an emerging research strategy that aims to repair "root causes" for age-related illness and degeneration, as well as develop medical procedures to periodically repair all such damage in the human body, thereby maintaining a youth-like state indefinitely. The SENS programme has identified seven types of aging-related damage, and feasible solutions have been outlined for each. Some critics argue that the SENS agenda is optimistic at best, and that the aging process is too complex and little-understood for SENS to be scientific or implementable in the foreseeable future. It has been proposed that age-related diseases are mediated by vicious cycles.
On the basis of extensive research, DNA damage has emerged a major culprit in cancer and numerous other diseases related to ageing. DNA damage can initiate the development of cancer or other aging related diseases depending on several factors. These include the type, amount, and location of the DNA damage in the body, the type of cell experiencing the damage and its stage in the cell cycle, and the specific DNA repair processes available to react to the damage.
== Types ==
=== Macular degeneration ===
Age-related macular degeneration (AMD) is a disease that affects the eyes and can lead to vision loss through break down of the central part of the retina called the macula. Degeneration can occur in one eye or both and can be classified as either wet (neovascular) or dry (atrophic). Wet AMD commonly is caused by blood vessels near the retina that lead to swelling of the macula. The cause of dry AMD is less clear, but it is thought to be partly caused by breakdown of light-sensitive cells and tissue surrounding the macula. A major risk factor for AMD is age over the age of 60.
=== Alzheimer's ===
Alzheimer's disease is classified as a "protein misfolding" disease. Aging causes mutations in protein folding, and as a result causes deposits of abnormal modified proteins to accumulate in specific areas of the brain. In Alzheimer's, deposits of Beta-amyloid and hyperphosphorylated tau protein form extracellular plaques and extracellular tangles. These deposits are shown to be neurotoxic and cause cognitive impairment due to their initiation of destructive biochemical pathways.
=== Atherosclerosis ===
Atherosclerosis is categorized as an aging disease and is brought about by vascular remodeling, the accumulation of plaque, and the loss of arterial elasticity. Over time, these processes can stiffen the vasculature. For these reasons, older age is listed as a major risk factor for atherosclerosis. Specifically, the risk of atherosclerosis increases for men above 45 years of age and women above 55 years of age.
=== Benign prostatic hyperplasia ===
Benign prostatic hyperplasia (BPH) is a noncancerous enlargement of the prostate gland due to increased growth. An enlarged prostate can result in incomplete or complete blockage of the bladder and interferes with a man's ability to urinate properly. Symptoms include overactive bladder, decreased stream of urine, hesitancy urinating, and incomplete emptying of the bladder. By age 40, 10% of men will have signs of BPH and by age 60, this percentage increases by 5 fold. Men over the age of 80 have over a 90% chance of developing BPH and almost 80% of men will develop BPH in their lifetime.
=== Cancer ===
Although it is possible for cancer to strike at any age, most patients with invasive cancer are over 65, and the most significant risk factor for developing cancer is age. According to cancer researcher Robert A. Weinberg, "If we lived long enough, sooner or later we all would get cancer." Some of the association between aging and cancer is attributed to immunosenescence, errors accumulated in DNA over a lifetime and age-related changes in the endocrine system. Aging's effect on cancer is complicated by factors such as DNA damage and inflammation promoting it and factors such as vascular aging and endocrine changes inhibiting it.
=== Parkinson's ===
Parkinson's disease, or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The disease has many complications, including anxiety, dementia, and depression. Parkinson's disease typically occurs in people over the age of 60, of whom about one percent are affected. The prevalence of Parkinson's disease dementia also increases with age, and to a lesser degree, duration of the disease. Exercise in middle age may reduce the risk of PD later in life.
=== Stroke ===
Stroke was the second most frequent cause of death worldwide in 2011, accounting for 6.2 million deaths (~11% of the total). Stroke could occur at any age, including in childhood, the risk of stroke increases exponentially from 30 years of age, and the cause varies by age. Advanced age is one of the most significant stroke risk factors. 95% of strokes occur in people age 45 and older, and two-thirds of strokes occur in those over the age of 65. A person's risk of dying if he or she does have a stroke also increases with age.
=== Endocrine diseases ===
Studies in animal models show that clearance of senescent cells improves multiple age related endocrine disorders.
==== Osteoporosis ====
Bone density declines with age. By the age of 85 years, ~70% of women and 30% of men have a osteoporosis defined as a bone density less than or equal to 2.5 standard deviations lower than young adults.
==== Metabolic syndrome ====
The metabolic syndrome is the co-occurrence of metabolic risk factors for type 2 diabetes and cardiovascular disease (abdominal obesity, hyperglycemia, dyslipidemia, and hypertension). The prevalence of the metabolic syndrome increases with age reaching close to 50% of people over 60 years old in the USA. as
== See also ==
Accelerated aging disease
Alliance for Aging Research
Gerontology
Senescence
== References ==
== External links ==
Segmental Progeria | Wikipedia/Aging-associated_diseases |
Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease (a major cause of myocardial infarction (MI)), as well as treatment for the damage that occurs to the heart after MI. After MI, the myocardium suffers from reperfusion injury which leads to death of cardiomyocytes and detrimental remodelling of the heart, consequently reducing proper cardiac function. Transfection of cardiac myocytes with human HGF reduces ischemic reperfusion injury after MI. The benefits of HGF therapy include preventing improper remodelling of the heart and ameliorating heart dysfunction post-MI.
== Human hepatocyte growth factor ==
Human hepatocyte growth factor (HGF) is an 80kD pleiotropic protein that is endogenously produced by a variety of cell types from the mesenchymal cell lineage (such as cardiomyocytes and neurons). It is produced and proteolytically cleaved to its active state in response to cellular injury or during apoptosis. HGF binds to c-met receptors found on mesenchymal cell types to produce its many different effects such as increased cellular motility, morphogenesis, proliferation and differentiation. Research has shown that HGF has potent angiogenic, anti-fibrotic, and anti-apoptotic properties. It has also been shown to act as a chemoattractant for adult mesenchymal stem cells via c-met receptor binding.
== Research and clinical trials ==
Animal research has demonstrated that administration of HGF cDNA plasmids into ischemic cardiac tissue can increase cardiac function (improved left ventricular ejection fraction and fractional shortening compared to control subjects) after induced MI or ischemia. Transfection with HGF plasmids in damaged cardiac tissue also promotes angiogenesis (increased capillary density compared to control subjects), as well as decreasing detrimental remodelling of the tissue at the site of injury (decreased fibrotic deposition). The increased production of HGF by transfected cardiomyocytes during injury has also shown to be a powerful chemo-attractant of adult mesenchymal stem cells via HGF/c-Met binding. The mitogenic and morphogenic properties of HGF induce recruited stem cells to take on cardiomyocyte phenotypes, potentially helping in the healing of ischemic tissue.
The benefits of HGF in experimental models have led to its investigation in clinical trials. A phase I clinical trial entailed injecting an adenovirus vector with the human HGF (Ad-hHGF) gene into the coronary vessels localized to ischemic tissue. Results demonstrate that it is in fact safe to administer the Ad-hHGF vector into patients with coronary artery disease in hopes of re-vascularizing damaged tissue in patients for which coronary artery bypass surgery (CABG) or percutaneous coronary intervention (PCI) are not available or possible. Despite the trial’s limitations (i.e. no assessment of left ventricular function and sample size was quite small), upon follow up assessments at 12 months, none of the patients receiving the treatment had been readmitted to hospital for MI, angina or aggravated heart failure.
== References == | Wikipedia/Human_HGF_plasmid_DNA_therapy |
Technology in science fiction is a crucial aspect of the genre.
As science fiction emerged during the era of Industrial Revolution, the increased presence of machines in everyday life and their role in shaping of the society was a major influence on the genre. It appeared as a major element of the Proto SF, represented by machines and gadgets in works of Jules Verne, George Griffith, H. G. Wells, Edward Bellamy and others. Technology has been portrayed both in positive or negative ways; in some works it is a solution to the world problems, in others, a means of its destruction. Such things as robots and space travel became commonplace in the fiction of the 19th century.
Concepts and illustrations of technology in science fiction have been a significant influence in the formation of popular culture images of future technology.
Science fiction has often affected innovation and new technology – for example many rocketry pioneers were inspired by science fiction.
At times, science fiction and fantasy overlap, and use real life or theoretical technology fused with Magic, such as in Science Fantasy, Magitek/Magi-tech/Arcanotech (Eberron setting, Final Fantasy), or Mage Punk (Shadowrun for example)
== See also ==
Emerging technologies
Hypothetical technology
Mad scientist
Technobabble
Technology forecasting
== References == | Wikipedia/Technology_in_science_fiction |
Dow AgroSciences LLC was a wholly owned subsidiary of the Dow Chemical Company specializing in not only agricultural chemicals such as pesticides, but also seeds and biotechnology solutions. The company was based in Indianapolis, Indiana, in the United States. On 31 January 2006, Dow AgroSciences announced that it had received regulatory approval for the world's first plant-cell-produced vaccine against Newcastle disease virus from USDA Center for Veterinary Biologics. Dow AgroSciences operates brand names such as Sentricon, Vikane, Mycogen®, SmartStax®, Enlist™, Pfister Seed®, PhytoGen®, Prairie Brand Seed®, Alforex Seeds®, Profume, Dairyland Seed®, and Brodbeck Seed®.
Dow AgroSciences also produces Omega-9 canola and sunflower oils.
In 2017, the Dow Chemical Company merged into DowDuPont and in April 2019, the company's parent, Dow Inc. was separated into a public company via a corporate spin-off. The Dow AgroSciences business unit remained with DowDuPont and was spun off into Corteva Inc, on June 3, 2019.
In October 2011, the U.S. Justice Department announced that a biotech specialist at Cargill had pleaded guilty to stealing information from Cargill and Dow AgroSciences. Kexue Huang, a Chinese national, was discovered to be passing information back to China from Dow for at least 3 years, from 2007 to 2010.
Dow AgroSciences unit was divested to be part of a new company Corteva.
== China ==
In 2014, Dow AgroSciences received the registration of Arylex's active ingredient (Halauxifen-methyl) from the Chinese Institute for the Control of Agrochemicals, Ministry of Agriculture (ICAMA). In the United States, Dow AgoSciences' Enlist Weed Control System was approved by the Department of Agriculture (USDA) and the Environmental Protection Agency (EPA) in 2014. Dow had submitted Enlist Corn for Chinese regulatory approval in 2011 and Enlist Soybean in 2012. As of 2017, even though 70 months have passed, approval is still being delayed by China's comparable regulatory agency, China's National Biosafety Committee (NBC). This has affected marketing, sales, and distribution of these products in the United States.
== See also ==
Sylvia M. Stoesser Lecturer in Chemistry
== References ==
== External links ==
Dow AgroSciences official website | Wikipedia/Dow_AgroSciences |
Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and patient care challenges. At their core, they represent disruptions to the intricate communication systems within the nervous system, stemming from genetic predispositions, environmental factors, infections, structural abnormalities, or degenerative processes.
The impact of neurological disorders is profound and far-reaching. Conditions like epilepsy create recurring seizures through abnormal electrical brain activity, while multiple sclerosis damages the protective myelin covering of nerve fibers, interrupting communication between the brain and body. Parkinson's disease progressively affects movement through the loss of dopamine-producing nerve cells, and strokes can cause immediate and potentially permanent neurological damage by interrupting blood flow to the brain. Diagnosing these disorders requires sophisticated medical techniques. Neuroimaging technologies like MRI and CT scans and electroencephalograms provide crucial insights into the intricate changes occurring within the nervous system. Treatment approaches are equally complex, involving multidisciplinary strategies, including medications to manage symptoms, control brain activity, or slow disease progression, coupled with neurological rehabilitation to help patients develop compensatory strategies.
Ideally, a neurological disorder is any disorder of the nervous system. Structural, biochemical or electrical abnormalities in the brain, spinal cord, or other nerves can result in a range of symptoms. Examples of symptoms include paralysis, muscle weakness, poor coordination, loss of sensation, seizures, confusion, pain, tauopathies, and altered levels of consciousness. There are many recognized neurological disorders; some are relatively common, but many are rare.
Interventions for neurological disorders include preventive measures, lifestyle changes, physiotherapy or other therapy, neurorehabilitation, pain management, medication, operations performed by neurosurgeons, or a specific diet. The World Health Organization estimated in 2006 that neurological disorders and their sequelae (direct consequences) affect as many as one billion people worldwide and identified health inequalities and social stigma/discrimination as major factors contributing to the associated disability and their impact.
== Causes ==
Although the brain and spinal cord are surrounded by tough membranes, enclosed in the bones of the skull and spinal vertebrae, and chemically isolated by the blood-brain barrier, they are very susceptible if compromised. Nerves tend to lie deep under the skin but can still become exposed to damage. Individual neurons, the neural circuits, and the nerves into which they form are susceptible to electrochemical and structural disruption. Neuroregeneration may occur in the peripheral nervous system and thus overcome or work around injuries to some extent, but it is thought to be rare in the brain and spinal cord.
The specific causes of neurological problems vary but can include genetic disorders, congenital abnormalities or disorders, infections, lifestyle, or environmental health problems such as pollution, malnutrition, brain damage, spinal cord injury, nerve injury, or gluten sensitivity (with or without intestinal damage or digestive symptoms). Metal poisoning, where metals accumulate in the human body and disrupt biological processes, has been reported to induce neurological problems, at least in the case of lead. The neurological problem may start in another body system that interacts with the nervous system. For example, cerebrovascular disease involves brain injury due to problems with the blood vessels (cardiovascular system) supplying the brain; autoimmune disorders involve damage caused by the body's own immune system; lysosomal storage diseases such as Niemann–Pick disease can lead to neurological deterioration. The National Institute for Health and Care Excellence recommends considering the evaluation of underlying coeliac disease in people with unexplained neurological symptoms, particularly peripheral neuropathy or ataxia.
In a substantial minority of cases of neurological symptoms, no neurological cause can be identified using current testing procedures, and such "idiopathic" conditions can invite different theories about what is occurring. Generally speaking, a substantial number of neurological disorders may have originated from a previous clinically not recognized viral infection. For example, it is thought that infection with the Hepatitis E virus, which is often initially asymptomatic may provoke neurological disorders, but there are many other examples as well.
Numerous examples have been described of neurological disorders that are associated with mutated DNA repair genes (for reviews see). Inadequate repair of DNA damages can lead directly to cell death and neuron depletion as well as disruptions in the pattern of epigenetic alterations required for normal neuronal function.
=== DNA damage ===
Neurons are highly oxygenated cells and as a consequence DNA damage caused by chronic exposure to endogenous reactive oxygen species is a substantial challenge for neurons. Germline mutations deficient in the repair of DNA damages cause neuronal dysfunction and are etiologically linked to many neurological disorders. For example, the neurological disorders, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are linked to DNA damage accumulation and DNA repair deficiency.
== Classification ==
Neurological disorders can be categorized according to the primary location affected, the primary type of dysfunction involved, or the primary type of cause. The broadest division is between central nervous system disorders and peripheral nervous system disorders. The Merck Manual lists brain, spinal cord disorders, and nerve disorders in the following overlapping categories:
Brain:
Brain dysfunction according to type:
Apraxia (patterns or sequences of movements)
Agnosia (identifying things or people)
Amnesia (memory)
Aphasia (language)
Dysarthria (speech)
Spinal cord disorders
Peripheral nervous system disorders (e.g., Peripheral neuropathy)
Cranial nerve disorder (e.g., trigeminal neuralgia)
Autonomic nervous system disorders (e.g., dysautonomia, multiple system atrophy)
Epilepsy
Movement disorders of the central and peripheral nervous system such as Parkinson's disease, essential tremor, amyotrophic lateral sclerosis (ALS), and Tourette syndrome
Sleep disorders (e.g., narcolepsy)
Some speech disorders (e.g., stuttering)
Headaches (e.g., migraine, cluster headache, tension headache)
Pain (e.g., complex regional pain syndrome, fibromyalgia)
Delirium
Dementia (e.g., Alzheimer's disease)
Coma and impaired consciousness, (e.g., stupor)
Stroke
Tumors of the nervous system (e.g., cancer)
Multiple sclerosis and other demyelinating diseases
Brain infections
Meningitis
Prion diseases (a type of infectious agent)
Neurological disorders in non-human animals are treated by veterinarians.
== Mental functioning ==
A neurological examination can, to some extent, assess the impact of neurological damage and disease on brain function in terms of behavior, memory, or cognition. Behavioral neurology specializes in this area. In addition, clinical neuropsychology uses neuropsychological assessment to precisely identify and track problems in mental functioning, usually after some sort of brain injury or neurological impairment.
Alternatively, a condition might first be detected through the presence of abnormalities in mental functioning, and further assessment may indicate an underlying neurological disorder. There are sometimes unclear boundaries in the distinction between disorders treated within neurology, and mental disorders treated within the other medical specialty of psychiatry, or other mental health professions such as clinical psychology. In practice, cases may present as one type, but be assessed as more appropriate to the other. Neuropsychiatry deals with mental disorders arising from specific identified diseases of the nervous system.
One area that can be contested is in cases of idiopathic neurological symptoms - conditions where the cause cannot be established. It can be decided in some cases, perhaps by exclusion of any accepted diagnosis, that higher-level brain/mental activity is causing symptoms, referred to as functional symptoms, rather than the symptoms originating in the area of the nervous system from which they may appear to originate. Cases involving these symptoms are classified as functional disorders ("functional" in this context is usually contrasted with the old term "organic disease"). For example, in functional neurologic disorder (FND), those affected present with various neurological symptoms such as functional seizures, numbness, paresthesia, and weakness, among others. Such cases may be contentiously interpreted as being "psychological" rather than "neurological." conversion disorder, If the onset functional symptoms appear to be causally linked to emotional states or responses to social stress or social contexts, it may be referred to as conversion disorder.
On the other hand, dissociation refers to partial or complete disruption of the integration of a person's conscious functioning, such that a person may feel detached from one's emotions, body and/or immediate surroundings. In extreme cases, this may be diagnosed as depersonalization-derealization disorder. There are also conditions viewed as neurological where a person appears to consciously register neurological stimuli that cannot possibly be coming from the part of the nervous system to which they would normally be attributed, such as phantom pain or synesthesia, or where limbs act without conscious direction, as in alien hand syndrome.
Conditions that are classed as mental disorders, learning disabilities, and forms of intellectual disability, are not themselves usually dealt with as neurological disorders. Biological psychiatry seeks to understand mental disorders in terms of their basis in the nervous system, however. In clinical practice, mental disorders are usually indicated by a mental state examination, or other type of structured interview or questionnaire process. At the present time, neuroimaging (brain scans) alone cannot accurately diagnose a mental disorder or tell the risk of developing one; however, it can be used to rule out other medical conditions such as a brain tumor. In research, neuroimaging and other neurological tests can show correlations between reported and observed mental difficulties and certain aspects of neural function or differences in brain structure. In general, numerous fields intersect to try to understand the basic processes involved in mental functioning, many of which are brought together in cognitive science. The distinction between neurological and mental disorders can be a matter of some debate, either in regard to specific facts about the cause of a condition or in regard to the general understanding of brain and mind.
Impacts
The consequences of neurological disorders extend beyond medical diagnosis. They profoundly affect patients' psychological well-being, social interactions, and overall life trajectory. Families and caregivers face significant challenges in supporting individuals with these conditions, often requiring extensive resources and emotional resilience (Nur & Kung, 2023). Ongoing research continues to push the boundaries of understanding. Advances in genetic research, neuroimaging, and treatment technologies offer hope for more effective interventions. Emerging fields like neuroplasticity research demonstrate the brain's remarkable ability to adapt, opening new possibilities for treatment and rehabilitation. As medical science progresses, the approach becomes increasingly personalized, recognizing the unique neurological profile of each patient and the incredible complexity of the human nervous system.
== See also ==
== References ==
== External links ==
Disorder Index of the National Institute of Neurological Disorders and Stroke | Wikipedia/Neurological_disease |
Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds (most importantly the superoxide radical due to defective phagocyte NADPH oxidase) used to kill certain ingested pathogens. This leads to the formation of granulomas in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.
This condition was first discovered in 1950 in a series of four boys from Minnesota, and in 1957 it was named "a fatal granulomatosus of childhood" in a publication describing their disease. The underlying cellular mechanism that causes chronic granulomatous disease was discovered in 1967, and research since that time has further elucidated the molecular mechanisms underlying the disease. Bernard Babior made key contributions in linking the defect of superoxide production of white blood cells, to the cause of the disease. In 1986, the X-linked form of CGD was the first disease for which positional cloning was used to identify the underlying genetic mutation.
== Symptoms and signs ==
Classically, patients with chronic granulomatous disease will have recurrent bouts of infection due to the decreased capacity of their immune system to fight off disease-causing organisms. The recurrent infections they acquire are specific and are, in decreasing order of frequency:
pneumonia
abscesses of the skin, tissues, and organs
septic arthritis
osteomyelitis
bacteremia/fungemia
superficial skin infections such as cellulitis or impetigo
Most people with CGD are diagnosed in childhood, usually, before age 5. Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur. Small groups of CGD patients may also be affected by McLeod syndrome because of the proximity of the two genes on the same X-chromosome.
=== Atypical infections ===
People with CGD are sometimes infected with organisms that usually do not cause disease in people with normal immune systems. Among the most common organisms that cause disease in CGD patients are:
Bacteria (particularly those that are catalase-positive)
Staphylococcus aureus.
Serratia marcescens.
Listeria species.
E. coli.
Klebsiella species.
Pseudomonas cepacia, a.k.a. Burkholderia cepacia.
Nocardia.
Fungi
Aspergillus species. Aspergillus has a propensity to cause infection in people with CGD and of the Aspergillus species, Aspergillus fumigatus seems to be most common in CGD.
Candida species.
Patients with CGD can usually resist infections of catalase-negative bacteria but are susceptible to catalase-positive bacteria. Catalase is an enzyme that catalyzes the breakdown of hydrogen peroxide in many organisms. In infections caused by organisms that lack catalase (catalase-negative), the host with CGD is successfully able to "borrow" hydrogen peroxide being made by the organism and use it to fight off the infection. In infections by organisms that have catalase (catalase-positive), this "borrowing mechanism" is unsuccessful because the enzyme catalase first breaks down any hydrogen peroxide that would be borrowed from the organism. Therefore in the CGD patient, hydrogen peroxide cannot be used to make oxygen radicals to fight infection, leaving the patient vulnerable to infection by catalase-positive bacteria.
== Genetics ==
Most cases of chronic granulomatous disease are transmitted as a mutation on the X chromosome and are thus called an "X-linked trait". The affected gene on the X chromosome codes for the gp91 protein p91-PHOX (91 is the weight of the protein in kDa; the gp means glycoprotein). CGD can also be transmitted in an autosomal recessive fashion (via CYBA, NCF1, NCF2 and NCF4) which affect other PHOX proteins. The type of mutation that causes both types of CGD are varied and may be deletions, frame-shift, nonsense, and missense.
A low level of NADPH, the cofactor required for superoxide synthesis, can lead to CGD. This has been reported in women who are homozygous for the genetic defect causing glucose-6-phosphate dehydrogenase deficiency (G6PD), which is characterised by reduced NADPH levels.
== Pathophysiology ==
Phagocytes (i.e. neutrophils and macrophages) require an enzyme to produce reactive oxygen species to destroy bacteria after they are ingested (phagocytosis), a process known as the respiratory burst. This enzyme is termed "phagocyte NADPH oxidase" (PHOX). This enzyme oxidizes NADPH and reduces molecular oxygen to produce superoxide anions, a reactive oxygen species. Superoxide is then disproportionated into peroxide and molecular oxygen by superoxide dismutase. Finally, peroxide is used by myeloperoxidase to oxidize chloride ions into hypochlorite (the active component of bleach), which is toxic to bacteria. Thus, NADPH oxidase is critical for phagocyte killing of bacteria through reactive oxygen species.
(Two other mechanisms are used by phagocytes to kill bacteria: nitric oxide and proteases, but the loss of ROS-mediated killing alone is sufficient to cause chronic granulomatous disease.)
Defects in one of the four essential subunits of phagocyte NADPH oxidase (PHOX) can all cause CGD of varying severity, dependent on the defect. There are over 410 known possible defects in the PHOX enzyme complex that can lead to chronic granulomatous disease.
== Diagnosis ==
When chronic granulomatous disease (CGD) is suspected, neutrophil-function testing should be carried out, and positive findings should be confirmed by genotyping. The p47phox mutation is due to a pseudogene conversion, hence it may not be detectable by standard sequencing; in these cases, an immunoblot or gene dose determination may be needed to confirm p47phox deficiency.
Infections caused by the pathogens commonly associated with CGD should prompt functional or genetic screening; neonatal or early postnatal screening of potentially affected children is essential with a family history of CGD.
Neutrophil function tests: These include nitroblue tetrazolium (NBT) reduction test, dihydrorhodamine (DHR) 123 test, direct measurement of superoxide production, cytochrome c reduction assay, and chemiluminescence. DHR test is usually preferred because it is easy to use, objective, and it is able to distinguish between X-linked and autosomal forms of CGD; furthermore, it allows to detect gp91phox carriers.
The nitroblue-tetrazolium (NBT) test is the original and most widely known test for chronic granulomatous disease. It is negative in CGD, meaning that it does not turn blue. The higher the blue score, the better the cell is at producing reactive oxygen species. This test depends upon the direct reduction of NBT to the insoluble blue compound formazan by superoxide which is produced by normal peripheral blood neutrophils stimulated in vitro; NADPH oxidase catalyzes the aforementioned reaction and NADPH is oxidized in the same reaction. This test is simple to perform and gives rapid results but only tells whether or not there is a problem with the PHOX enzymes, not how much they are affected.
Dihydrorhodamine (DHR) 123 test: In this test the respiratory burst of the neutrophils is stimulated with phorbol myristate acetate (PMA), resulting in oxidation of dihydrorhodamine 123 (nonfluorescent derivative of rhodamine) to rhodamine 123 (green fluorescent compound), which can be measured by flow cytometry. This test is abnormal in patients with chronic granulomatous disease (i.e., there is no shift in fluorescence with stimulation). Moreover, its quantitative nature allows to differentiate oxidase-positive from oxidase-negative phagocyte subpopulations in CGD carriers and identify deficiencies in gp91phox and p47phox. Modest residual production of reactive oxygen intermediates (ROI) as assessed by DHR 123 test, is associated with significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. On the other hand, in the case of complete myeloperoxidase deficiency, DHR test gives abnormal results (false positive for CGD) because the DHR signal yielded by flow cytometry depends on intact NADPH oxidase activity as well as the presence of a myeloperoxidase (MPO); however, NBT test demonstrates normal production of superoxide.
Genetic testing: Once CGD has been diagnosed based on abnormal neutrophil function tests, genetic testing should go next. As mentioned above, p47phox defect is usually difficult to identify genetically because it is caused by pseudogene conversion and may be missed in typical sequencing studies; in this case, immunoblotting or flow cytometry can show absence of protein.
Prenatal testing: It is particularly useful when a family member has already been diagnosed with CGD. This test may be performed by analysis of NADPH oxidase activity of neutrophils from fetal blood. Samples from amniotic fluid or chorionic villi provides an earlier and more reliable diagnosis for families at risk.
=== Classification ===
Chronic granulomatous disease is the name for a genetically heterogeneous group of immunodeficiencies. The core defect is a failure of phagocytic cells to kill organisms that they have engulfed because of defects in a system of enzymes that produce free radicals and other toxic small molecules. There are several types, including:
X-linked chronic granulomatous disease (CGD)
autosomal recessive cytochrome b-negative CGD
autosomal recessive cytochrome b-positive CGD type I
autosomal recessive cytochrome b-positive CGD type II
atypical granulomatous disease
== Treatment ==
Management of chronic granulomatous disease revolves around two goals: 1) diagnose the disease early so that antibiotic prophylaxis can be given to keep an infection from occurring, and 2) educate the patient about his or her condition so that prompt treatment can be given if an infection occurs.
=== Antibiotics ===
Physicians often prescribe the antibiotic trimethoprim-sulfamethoxazole to prevent bacterial infections. This drug also has the benefit of sparing the normal bacteria of the digestive tract. Fungal infection is commonly prevented with itraconazole, although a newer drug of the same type called voriconazole may be more effective. The use of this drug for this purpose is still under scientific investigation.
=== Immunomodulation ===
Interferon, in the form of interferon gamma-1b (Actimmune) is approved by the Food and Drug Administration for the prevention of infection in CGD. It has been shown to reduce infections in CGD patients by 70% and to decrease their severity. Although its exact mechanism is still not entirely understood, it has the ability to give CGD patients more immune function and therefore, greater ability to fight off infections. This therapy has been the standard treatment for CGD for several years.
=== Hematopoietic stem cell transplantation (HSCT) ===
Hematopoietic stem cell transplantation from a matched donor is curative although not without significant risk.
== Prognosis ==
There are currently no studies detailing the long term outcome of chronic granulomatous disease with modern treatment. Without treatment, children often die in the first decade of life. The increased severity of X-linked CGD results in a decreased survival rate of patients, as 20% of X-linked patients die of CGD-related causes by the age of 10, whereas 20% of autosomal recessive patients die by the age of 35.Recent experience from centers specializing in the care of patients with CGD suggests that the current mortality has fallen to under 3% and 1% respectively.
CGD was initially termed "fatal granulomatous disease of childhood" because patients rarely survived past their first decade in the time before routine use of prophylactic antimicrobial agents. The average patient now survives at least 40 years.
== Epidemiology ==
CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.
Chronic granulomatous disease affects all people of all races; however, there is limited information on prevalence outside of the United States. One survey in Sweden reported an incidence of 1 in 220,000 people, while a larger review of studies in Europe suggested a lower rate: 1 in 250,000 people.
== History ==
This condition was first described in 1954 by Janeway, who reported five cases of the disease in children. In 1957 it was further characterized as "a fatal granulomatosus of childhood". The underlying cellular mechanism that causes chronic granulomatous disease was discovered in 1967, and research since that time has further elucidated the molecular mechanisms underlying the disease. Use of antibiotic prophylaxis, surgical abscess drainage, and vaccination led to the term "fatal" being dropped from the name of the disease as children survived into adulthood.
== Research ==
Gene therapy is currently being studied as a possible treatment for chronic granulomatous disease. CGD is well-suited for gene therapy since it is caused by a mutation in single gene which only affects one body system (the hematopoietic system). Viruses have been used to deliver a normal gp91 gene to rats with a mutation in this gene, and subsequently the phagocytes in these rats were able to produce oxygen radicals.
In 2006, two human patients with X-linked chronic granulomatous disease underwent gene therapy and blood cell precursor stem cell transplantation to their bone marrow. Both patients recovered from their CGD, clearing pre-existing infections and demonstrating increased oxidase activity in their neutrophils. However, long-term complications and efficacy of this therapy were unknown.
In 2012, a 16-year-old boy with CGD was treated at the Great Ormond Street Hospital, London with an experimental gene therapy that temporarily reversed the CGD and allowed him to overcome a life-threatening lung disease.
== References ==
== External links == | Wikipedia/Chronic_granulomatous_disease |
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "breakthrough therapy" designation is not intended to imply that a drug is actually a "breakthrough" or that there is high-quality evidence of treatment efficacy for a particular condition; rather, it allows the FDA to grant priority review to drug candidates if preliminary clinical trials indicate that the therapy may offer substantial treatment advantages over existing options for patients with serious or life-threatening diseases. The FDA has other mechanisms for expediting the review and approval process for promising drugs, including fast track designation, accelerated approval, and priority review.
== Requirements ==
A breakthrough therapy designation can be assigned to a drug if "it is a drug which is intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition" and if the preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development."
Requests are reviewed by the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). CDER receives approximately 100 requests per year for breakthrough designation. Historically, about one third were approved. CBER receives 15–30 requests per year. Sponsors must apply for breakthrough status separately for each indication they intend to label the drug for.
Breakthrough designation applications are submitted as an amendment to the IND applications, usually prior to end of Phase II meeting.
== Incentives ==
Drugs that have been granted breakthrough status are given priority review. The FDA works with the sponsor of the drug application to expedite the approval process. This expedited process can include rolling reviews, smaller clinical trials, and alternative trial designs.
== Issues ==
Critics have said that the name is misleading and provides companies that obtain a breakthrough designation for a drug candidate with a marketing advantage that may be undeserved. The FDA acknowledges that the name "breakthrough therapy" may be misleading. It was never meant to imply that these drugs are actually "breakthroughs," and it does not ensure that they will provide clinical benefit, but still critics complain that they are based on preliminary evidence, including changes in surrogate markers such as laboratory measurements, that often don't reflect "meaningful clinical benefit."
The FDA guidance states: "Not all products designated as breakthrough therapies ultimately will be shown to have the substantial improvement over available therapies suggested by the preliminary clinical evidence at the time of designation. If the designation is no longer supported by subsequent data, FDA may rescind the designation."
== See also ==
List of drugs granted breakthrough therapy designation
FDA Fast Track Development Program
Priority review (FDA)
Orphan drug
== References ==
== External links ==
Media related to Breakthrough therapy at Wikimedia Commons | Wikipedia/Breakthrough_therapy |
Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.
The underlying mechanisms vary depending on the disease. It is estimated that dietary risk factors are associated with 53% of CVD deaths. Coronary artery disease, stroke, and peripheral artery disease involve atherosclerosis. This may be caused by high blood pressure, smoking, diabetes mellitus, lack of exercise, obesity, high blood cholesterol, poor diet, excessive alcohol consumption, and poor sleep, among other things. High blood pressure is estimated to account for approximately 13% of CVD deaths, while tobacco accounts for 9%, diabetes 6%, lack of exercise 6%, and obesity 5%. Rheumatic heart disease may follow untreated strep throat.
It is estimated that up to 90% of CVD may be preventable. Prevention of CVD involves improving risk factors through: healthy eating, exercise, avoidance of tobacco smoke and limiting alcohol intake. Treating risk factors, such as high blood pressure, blood lipids and diabetes is also beneficial. Treating people who have strep throat with antibiotics can decrease the risk of rheumatic heart disease. The use of aspirin in people who are otherwise healthy is of unclear benefit.
Cardiovascular diseases are the leading cause of death worldwide except Africa. Together CVD resulted in 17.9 million deaths (32.1%) in 2015, up from 12.3 million (25.8%) in 1990. Deaths, at a given age, from CVD are more common and have been increasing in much of the developing world, while rates have declined in most of the developed world since the 1970s. Coronary artery disease and stroke account for 80% of CVD deaths in males and 75% of CVD deaths in females. Most cardiovascular disease affects older adults. In the United States 11% of people between 20 and 40 have CVD, while 37% between 40 and 60, 71% of people between 60 and 80, and 85% of people over 80 have CVD. The average age of death from coronary artery disease in the developed world is around 80, while it is around 68 in the developing world. CVD is typically diagnosed seven to ten years earlier in men than in women.: 48
== Types ==
There are many cardiovascular diseases involving the blood vessels. They are known as vascular diseases.
Coronary artery disease (coronary heart disease or ischemic heart disease)
Peripheral arterial disease – a disease of blood vessels that supply blood to the arms and legs
Cerebrovascular disease – a disease of blood vessels that supply blood to the brain (includes stroke)
Renal artery stenosis
Aortic aneurysm
There are also many cardiovascular diseases that involve the heart.
Cardiomyopathy – diseases of cardiac muscle
Hypertensive heart disease – diseases of the heart secondary to high blood pressure or hypertension
Heart failure – a clinical syndrome caused by the inability of the heart to supply sufficient blood to the tissues to meet their metabolic requirements
Pulmonary heart disease – a failure at the right side of the heart with respiratory system involvement
Cardiac dysrhythmias – abnormalities of heart rhythm
Inflammatory heart diseases
Endocarditis – inflammation of the inner layer of the heart, the endocardium. The structures most commonly involved are the heart valves.
Inflammatory cardiomegaly
Myocarditis – inflammation of the myocardium, the muscular part of the heart, caused most often by viral infection and less often by bacterial infections, certain medications, toxins, and autoimmune disorders. It is characterized in part by infiltration of the heart by lymphocyte and monocyte types of white blood cells.
Eosinophilic myocarditis – inflammation of the myocardium caused by pathologically activated eosinophilic white blood cells. This disorder differs from myocarditis in its causes and treatments.
Valvular heart disease
Congenital heart disease – heart structure malformations existing at birth
Rheumatic heart disease – heart muscles and valves damage due to rheumatic fever caused by Streptococcus pyogenes a group A streptococcal infection.
== Risk factors ==
There are many risk factors for heart diseases: age, sex, tobacco use, physical inactivity, non-alcoholic fatty liver disease, excessive alcohol consumption, unhealthy diet, obesity, genetic predisposition and family history of cardiovascular disease, raised blood pressure (hypertension), raised blood sugar (diabetes mellitus), raised blood cholesterol (hyperlipidemia), undiagnosed celiac disease, psychosocial factors, poverty and low educational status, air pollution, and poor sleep. While the individual contribution of each risk factor varies between different communities or ethnic groups the overall contribution of these risk factors is very consistent. Some of these risk factors, such as age, sex or family history/genetic predisposition, are immutable; however, many important cardiovascular risk factors are modifiable by lifestyle change, social change, drug treatment (for example prevention of hypertension, hyperlipidemia, and diabetes). People with obesity are at increased risk of atherosclerosis of the coronary arteries.
=== Genetics ===
Cardiovascular disease in a person's parents increases their risk by ~3 fold, and genetics is an important risk factor for cardiovascular diseases. Genetic cardiovascular disease can occur either as
a consequence of single variant (Mendelian) or polygenic influences. There are more than 40 inherited cardiovascular disease that can be traced to a single disease-causing DNA variant, although these conditions are rare. Most common cardiovascular diseases are non-Mendelian and are thought to be due to hundreds or thousands of genetic variants (known as single nucleotide polymorphisms), each associated with a small effect.
=== Age ===
Age is the most important risk factor in developing cardiovascular or heart diseases, with approximately a tripling of risk with each decade of life. Coronary fatty streaks can begin to form in adolescence. It is estimated that 82 percent of people who die of coronary heart disease are 65 and older. Simultaneously, the risk of stroke doubles every decade after age 55.
Multiple explanations are proposed to explain why age increases the risk of cardiovascular/heart diseases. One of them relates to serum cholesterol level. In most populations, the serum total cholesterol level increases as age increases. In men, this increase levels off around age 45 to 50 years. In women, the increase continues sharply until age 60 to 65 years.
Aging is also associated with changes in the mechanical and structural properties of the vascular wall, which leads to the loss of arterial elasticity and reduced arterial compliance and may subsequently lead to coronary artery disease.
=== Sex ===
Men are at greater risk of heart disease than pre-menopausal women. Once past menopause, it has been argued that a woman's risk is similar to a man's although more recent data from the WHO and UN disputes this. If a female has diabetes, she is more likely to develop heart disease than a male with diabetes. Women who have high blood pressure and had complications in their pregnancy have three times the risk of developing cardiovascular disease compared to women with normal blood pressure who had no complications in pregnancy.
Coronary heart diseases are 2 to 5 times more common among middle-aged men than women. In a study done by the World Health Organization, sex contributes to approximately 40% of the variation in sex ratios of coronary heart disease mortality. Another study reports similar results finding that sex differences explains nearly half the risk associated with cardiovascular diseases One of the proposed explanations for sex differences in cardiovascular diseases is hormonal difference. Among women, estrogen is the predominant sex hormone. Estrogen may have protective effects on glucose metabolism and hemostatic system, and may have direct effect in improving endothelial cell function. The production of estrogen decreases after menopause, and this may change the female lipid metabolism toward a more atherogenic form by decreasing the HDL cholesterol level while increasing LDL and total cholesterol levels.
Among men and women, there are differences in body weight, height, body fat distribution, heart rate, stroke volume, and arterial compliance. In the very elderly, age-related large artery pulsatility and stiffness are more pronounced among women than men. This may be caused by the women's smaller body size and arterial dimensions which are independent of menopause.
=== Tobacco ===
Cigarettes are the major form of smoked tobacco. Risks to health from tobacco use result not only from direct consumption of tobacco, but also from exposure to second-hand smoke. Approximately 10% of cardiovascular disease is attributed to smoking; however, people who quit smoking by age 30 have almost as low a risk of death as never smokers.
=== Physical inactivity ===
Insufficient physical activity (defined as less than 5 x 30 minutes of moderate activity per week, or less than 3 x 20 minutes of vigorous activity per week) is currently the fourth leading risk factor for mortality worldwide. In 2008, 31.3% of adults aged 15 or older (28.2% men and 34.4% women) were insufficiently physically active.
The risk of ischemic heart disease and diabetes mellitus is reduced by almost a third in adults who participate in 150 minutes of moderate physical activity each week (or equivalent). In addition, physical activity assists weight loss and improves blood glucose control, blood pressure, lipid profile and insulin sensitivity. These effects may, at least in part, explain its cardiovascular benefits.
=== Diet ===
High dietary intakes of saturated fat, trans-fats and salt, and low intake of fruits, vegetables and fish are linked to cardiovascular risk, although whether all these associations indicate causes is disputed. The World Health Organization attributes approximately 1.7 million deaths worldwide to low fruit and vegetable consumption. Frequent consumption of high-energy foods, such as processed foods that are high in fats and sugars, promotes obesity and may increase cardiovascular risk. The amount of dietary salt consumed may also be an important determinant of blood pressure levels and overall cardiovascular risk. There is moderate quality evidence that reducing saturated fat intake for at least two years reduces the risk of cardiovascular disease. High trans-fat intake has adverse effects on blood lipids and circulating inflammatory markers, and elimination of trans-fat from diets has been widely advocated. In 2018 the World Health Organization estimated that trans fats were the cause of more than half a million deaths per year. There is evidence that higher consumption of sugar is associated with higher blood pressure and unfavorable blood lipids, and sugar intake also increases the risk of diabetes mellitus. High consumption of processed meats is associated with an increased risk of cardiovascular disease, possibly in part due to increased dietary salt intake.
=== Alcohol ===
The relationship between alcohol consumption and cardiovascular disease is complex, and may depend on the amount of alcohol consumed. There is a direct relationship between high levels of drinking alcohol and cardiovascular disease. Drinking at low levels without episodes of heavy drinking may be associated with a reduced risk of cardiovascular disease, but there is evidence that associations between moderate alcohol consumption and protection from stroke are non-causal. Moderate drinking is defined as one drink per day for women or two drinks a day for men. At the population level, the health risks of drinking alcohol exceed any potential benefits. Exercising regularly can provide the same benefits as potentially consuming small amounts of alcohol and is a much safer alternative. Consuming too much alcohol can cause a high blood pressure, heart failure, and cardiomyopathy. Drinking alcohol can also cause obesity, which can contribute to cardiovascular issues as well.
=== Celiac disease ===
Untreated celiac disease can cause the development of many types of cardiovascular diseases, most of which improve or resolve with a gluten-free diet and intestinal healing. However, delays in recognition and diagnosis of celiac disease can cause irreversible heart damage.
=== Sleep ===
A lack of good sleep, in amount or quality, is documented as increasing cardiovascular risk in both adults and teens. Recommendations suggest that infants typically need 12 or more hours of sleep per day, adolescents at least eight or nine hours, and adults seven or eight. About one-third of adult Americans get less than the recommended seven hours of sleep per night, and in a study of teenagers, just 2.2 percent of those studied got enough sleep, many of whom did not get good quality sleep. Studies have shown that short sleepers getting less than seven hours sleep per night have a 10 percent to 30 percent higher risk of cardiovascular disease.
Sleep disorders such as sleep-disordered breathing and insomnia, are also associated with a higher cardiometabolic risk.
An estimated 50 to 70 million Americans have insomnia, sleep apnea or other chronic sleep disorders.
In addition, sleep research displays differences in race and class. Short sleep and poor sleep tend to be more frequently reported in ethnic minorities than in whites. African-Americans report experiencing short durations of sleep five times more often than whites, possibly as a result of social and environmental factors. Black children and children living in disadvantaged neighborhoods have much higher rates of sleep apnea.
One study found that of adults who are 45 and older, subjects that fell asleep at different times each night and slept inconsistent numbers of hours each night were more likely to develop atherosclerosis. Poor sleep habits, such as too little sleep, too much sleep, or fragmented sleep, were associated with cardiovascular disease, obesity, and high blood pressure. Another study noted that participants whose sleep duration varied by more than two hours within the course of a week were 1.4 times more likely to have elevated levels of coronary artery calcium, a predictor of cardiovascular events.
=== Socioeconomic disadvantage ===
Cardiovascular disease has a greater impact on low- and middle-income countries compared to those with higher income. Although data on the social patterns of cardiovascular disease in low- and middle-income countries is limited, reports from high-income countries consistently demonstrate that low educational status or income are associated with a greater risk of cardiovascular disease. Policies that have resulted in increased socio-economic inequalities have been associated with greater subsequent socio-economic differences in cardiovascular disease implying a cause and effect relationship. Psychosocial factors, environmental exposures, health behaviours, and health-care access and quality contribute to socio-economic differentials in cardiovascular disease. The Commission on Social Determinants of Health recommended that more equal distributions of power, wealth, education, housing, environmental factors, nutrition, and health care were needed to address inequalities in cardiovascular disease and non-communicable diseases.
=== Air pollution ===
Particulate matter has been studied for its short- and long-term exposure effects on cardiovascular disease. Currently, airborne particles under 2.5 micrometers in diameter (PM2.5) are the major focus, in which gradients are used to determine CVD risk. Overall, long-term PM exposure increased rate of atherosclerosis and inflammation. In regards to short-term exposure (2 hours), every 25 μg/m3 of PM2.5 resulted in a 48% increase of CVD mortality risk. In addition, after only 5 days of exposure, a rise in systolic (2.8 mmHg) and diastolic (2.7 mmHg) blood pressure occurred for every 10.5 μg/m3 of PM2.5. Other research has implicated PM2.5 in irregular heart rhythm, reduced heart rate variability (decreased vagal tone), and most notably heart failure. PM2.5 is also linked to carotid artery thickening and increased risk of acute myocardial infarction.
=== Cardiovascular risk assessment ===
Existing cardiovascular disease or a previous cardiovascular event, such as a heart attack or stroke, is the strongest predictor of a future cardiovascular event. Age, sex, smoking, blood pressure, blood lipids and diabetes are important predictors of future cardiovascular disease in people who are not known to have cardiovascular disease. These measures, and sometimes others, may be combined into composite risk scores to estimate an individual's future risk of cardiovascular disease. Numerous risk scores exist although their respective merits are debated. Other diagnostic tests and biomarkers remain under evaluation but currently these lack clear-cut evidence to support their routine use. They include family history, coronary artery calcification score, high sensitivity C-reactive protein (hs-CRP), ankle–brachial pressure index, lipoprotein subclasses and particle concentration, lipoprotein(a), apolipoproteins A-I and B, fibrinogen, white blood cell count, homocysteine, N-terminal pro B-type natriuretic peptide (NT-proBNP), and markers of kidney function. High blood phosphorus is also linked to an increased risk.
=== Psychological stress ===
There is evidence that mental health problems, in particular depression and traumatic stress, is linked to cardiovascular diseases. Whereas mental health problems are known to be associated with risk factors for cardiovascular diseases such as smoking, poor diet, and a sedentary lifestyle, these factors alone do not explain the increased risk of cardiovascular diseases seen in depression, stress, and anxiety. Moreover, posttraumatic stress disorder is independently associated with increased risk for incident coronary heart disease, even after adjusting for depression and other covariates.
Many studies recognize depression and anxiety as two important disorders that can cause an increase in the risk of developing cardiovascular disease. Only half of the instances of cardiovascular disease are explained by factors such as age and gender that cannot be changed. The other half of instances are due to other sources, including psychological stress. Studies have shown that the prevalence of depression in patients with heart failure is higher than 20%.
Another study assessed the link between men and women who had been divorced and instance of cardiovascular disease. The study found that women who had gone through at least two divorces were just as likely to experience cardiovascular disease as a smoker or diabetic. Men, on the other hand, also had a higher risk of cardiovascular disease, however, their health improved upon remarriage while women did not.
This study also found that during a World Cup soccer event in Germany, heart attacks more than doubled during the days when the nation's team was playing. Researchers assume this link is due to the fact that stress can increase inflammation in the body, which can cause high blood pressure and low HDL cholesterol. Chronic stress can also affect sleep, exercise, and food choices.
=== Anxiety ===
Patients who suffer from generalized anxiety disorder are more likely to develop some form of cardiovascular disease. It is hypothesized that anxiety makes one more likely to develop cardiovascular disease due to the fact that it can change the body's stress response through hormonal and physiological reactions. People with anxiety often experience high blood pressure, arrhythmias, and heart attacks. The stress response caused by anxiety can increase inflammation in the body. It was also discovered that patients with anxiety had lower levels of omega-3-fatty acids which is linked to an increased risk of developing cardiovascular disease.
=== Occupational exposure ===
Little is known about the relationship between work and cardiovascular disease, but links have been established between certain toxins, extreme heat and cold, exposure to tobacco smoke, and mental health concerns such as stress and depression.
==== Non-chemical risk factors ====
A 2015 SBU-report looking at non-chemical factors found an association for those:
with mentally stressful work with a lack of control over their working situation — with an effort-reward imbalance
who experience low social support at work; who experience injustice or experience insufficient opportunities for personal development; or those who experience job insecurity
those who work night schedules; or have long working weeks
those who are exposed to noise
Specifically the risk of stroke was also increased by exposure to ionizing radiation. Hypertension develops more often in those who experience job strain and who have shift-work. Differences between women and men in risk are small, however men risk having and dying of heart attacks or stroke twice as often as women during working life.
==== Chemical risk factors ====
A 2017 SBU report found evidence that workplace exposure to silica dust, engine exhaust or welding fumes is associated with heart disease. Associations also exist for exposure to arsenic, benzopyrenes, lead, dynamite, carbon disulphide, carbon monoxide, metalworking fluids and occupational exposure to tobacco smoke. Working with the electrolytic production of aluminium or the production of paper when the sulphate pulping process is used is associated with heart disease. An association was also found between heart disease and exposure to compounds which are no longer permitted in certain work environments, such as phenoxy acids containing TCDD(dioxin) or asbestos.
Workplace exposure to silica dust or asbestos is also associated with pulmonary heart disease. There is evidence that workplace exposure to lead, carbon disulphide, phenoxyacids containing TCDD, as well as working in an environment where aluminum is being electrolytically produced, is associated with stroke.
=== Somatic mutations ===
As of 2017, evidence suggests that certain leukemia-associated mutations in blood cells may also lead to increased risk of cardiovascular disease. Several large-scale research projects looking at human genetic data have found a robust link between the presence of these mutations, a condition known as clonal hematopoiesis, and cardiovascular disease-related incidents and mortality.
=== Radiation therapy ===
Radiation treatments (RT) for cancer can increase the risk of heart disease and death, as observed in breast cancer therapy. Therapeutic radiation increases the risk of a subsequent heart attack or stroke by 1.5 to 4 times; the increase depends on the dose strength, volume, and location. Use of concomitant chemotherapy, e.g. anthracyclines, is an aggravating risk factor. The occurrence rate of RT induced cardiovascular disease is estimated between 10% and 30%.
Side-effects from radiation therapy for cardiovascular diseases have been termed radiation-induced heart disease or radiation-induced cardiovascular disease. Symptoms are dose-dependent and include cardiomyopathy, myocardial fibrosis, valvular heart disease, coronary artery disease, heart arrhythmia and peripheral artery disease. Radiation-induced fibrosis, vascular cell damage and oxidative stress can lead to these and other late side-effect symptoms.
== Pathophysiology ==
Population-based studies show that atherosclerosis, the major precursor of cardiovascular disease, begins in childhood. The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study demonstrated that intimal lesions appear in all the aortas and more than half of the right coronary arteries of youths aged 7–9 years.
Obesity and diabetes mellitus are linked to cardiovascular disease, as are a history of chronic kidney disease and hypercholesterolaemia. In fact, cardiovascular disease is the most life-threatening of the diabetic complications and diabetics are two- to four-fold more likely to die of cardiovascular-related causes than nondiabetics.
== Screening ==
Screening ECGs (either at rest or with exercise) are not recommended in those without symptoms who are at low risk. This includes those who are young without risk factors. In those at higher risk the evidence for screening with ECGs is inconclusive. Additionally echocardiography, myocardial perfusion imaging, and cardiac stress testing is not recommended in those at low risk who do not have symptoms. Some biomarkers may add to conventional cardiovascular risk factors in predicting the risk of future cardiovascular disease; however, the value of some biomarkers is questionable. Ankle-brachial index (ABI), high-sensitivity C-reactive protein (hsCRP), and coronary artery calcium, are also of unclear benefit in those without symptoms as of 2018.
The NIH recommends lipid testing in children beginning at the age of 2 if there is a family history of heart disease or lipid problems. It is hoped that early testing will improve lifestyle factors in those at risk such as diet and exercise.
Screening and selection for primary prevention interventions has traditionally been done through absolute risk using a variety of scores (ex. Framingham or Reynolds risk scores). This stratification has separated people who receive the lifestyle interventions (generally lower and intermediate risk) from the medication (higher risk). The number and variety of risk scores available for use has multiplied, but their efficacy according to a 2016 review was unclear due to lack of external validation or impact analysis. Risk stratification models often lack sensitivity for population groups and do not account for the large number of negative events among the intermediate and low risk groups. As a result, future preventative screening appears to shift toward applying prevention according to randomized trial results of each intervention rather than large-scale risk assessment.
== Prevention ==
Up to 90% of cardiovascular disease may be preventable if established risk factors are avoided. Currently practised measures to prevent cardiovascular disease include:
Maintaining a healthy diet, such as the Mediterranean diet, a vegetarian, vegan or another plant-based diet.
Replacing saturated fat with healthier choices: Clinical trials show that replacing saturated fat with polyunsaturated vegetable oil reduced CVD by 30%. Prospective observational studies show that in many populations lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD.
Decrease body fat if overweight or obese. The effect of weight loss is often difficult to distinguish from dietary change, and evidence on weight reducing diets is limited. In observational studies of people with severe obesity, weight loss following bariatric surgery is associated with a 46% reduction in cardiovascular risk.
Limit alcohol consumption to the recommended daily limits. People who moderately consume alcoholic drinks have a 25–30% lower risk of cardiovascular disease. However, people who are genetically predisposed to consume less alcohol have lower rates of cardiovascular disease suggesting that alcohol itself may not be protective. Excessive alcohol intake increases the risk of cardiovascular disease and consumption of alcohol is associated with increased risk of a cardiovascular event in the day following consumption.
Decrease non-HDL cholesterol. Statin treatment reduces cardiovascular mortality by about 31%.
Stopping smoking and avoidance of second-hand smoke. Stopping smoking reduces risk by about 35%.
At least 150 minutes (2 hours and 30 minutes) of moderate exercise per week.
Lower blood pressure, if elevated. A 10 mmHg reduction in blood pressure reduces risk by about 20%. Lowering blood pressure appears to be effective even at normal blood pressure ranges.
Not enough sleep also raises the risk of high blood pressure. Adults need about 7–9 hours of sleep. Sleep apnea is also a major risk as it causes breathing to stop briefly, which can put stress on the body which can raise the risk of heart disease.
Most guidelines recommend combining preventive strategies. There is some evidence that interventions aiming to reduce more than one cardiovascular risk factor may have beneficial effects on blood pressure, body mass index and waist circumference; however, evidence was limited and the authors were unable to draw firm conclusions on the effects on cardiovascular events and mortality.
There is additional evidence to suggest that providing people with a cardiovascular disease risk score may reduce risk factors by a small amount compared to usual care. However, there was some uncertainty as to whether providing these scores had any effect on cardiovascular disease events. It is unclear whether or not dental care in those with periodontitis affects their risk of cardiovascular disease. According to a 2021 WHO study, working 55+ hours a week raises the risk of stroke by 35% and the risk of dying from heart conditions by 17%, when compared to a 35-40 hours week.
=== Psychological prevention ===
Decrease psychosocial stress. This measure may be complicated by imprecise definitions of what constitute psychosocial interventions. Mental stress–induced myocardial ischemia is associated with an increased risk of heart problems in those with previous heart disease. Severe emotional and physical stress leads to a form of heart dysfunction known as Takotsubo syndrome in some people. Specific relaxation therapies are of unclear benefit. Decreasing psychological stress can be accomplished by receiving access to services and support, recognizing signs and symptoms of mental health disorders, awareness of family history, and understanding which mental health disorders increase the risk of cardiovascular disease. Psychosocial intervention programs have been shown to improve risk of developing cardiovascular disease in the high-risk population.
=== Diet ===
A diet high in fruits and vegetables decreases the risk of cardiovascular disease and death.
A 2021 review found that plant-based diets can provide a risk reduction for CVD if a healthy plant-based diet is consumed. Unhealthy plant-based diets do not provide benefits over diets including meat. A similar meta-analysis and systematic review also looked into dietary patterns and found "that diets lower in animal foods and unhealthy plant foods, and higher in healthy plant foods are beneficial for CVD prevention". A 2018 meta-analysis of observational studies concluded that "In most countries, a vegan diet is associated with a more favourable cardio-metabolic profile compared to an omnivorous diet."
Evidence suggests that the Mediterranean diet may improve cardiovascular outcomes. There is also evidence that a Mediterranean diet may be more effective than a low-fat diet in bringing about long-term changes to cardiovascular risk factors (e.g., lower cholesterol level and blood pressure).
The DASH diet (high in nuts, fish, fruits and vegetables, and low in sweets, red meat and fat) has been shown to reduce blood pressure, lower total and low density lipoprotein cholesterol and improve metabolic syndrome; but the long-term benefits have been questioned. A high-fiber diet is associated with lower risks of cardiovascular disease.
Worldwide, dietary guidelines recommend a reduction in saturated fat, and although the role of dietary fat in cardiovascular disease is complex and controversial there is a long-standing consensus that replacing saturated fat with unsaturated fat in the diet is sound medical advice. Total fat intake has not been found to be associated with cardiovascular risk. A 2020 systematic review found moderate quality evidence that reducing saturated fat intake for at least 2 years caused a reduction in cardiovascular events. A 2015 meta-analysis of observational studies however did not find a convincing association between saturated fat intake and cardiovascular disease. Variation in what is used as a substitute for saturated fat may explain some differences in findings. The benefit from replacement with polyunsaturated fats appears greatest, while replacement of saturated fats with carbohydrates does not appear to have a beneficial effect. A diet high in trans fatty acids is associated with higher rates of cardiovascular disease, and in 2015 the Food and Drug Administration (FDA) determined that there was 'no longer a consensus among qualified experts that partially hydrogenated oils (PHOs), which are the primary dietary source of industrially produced trans fatty acids (IP-TFA), are generally recognized as safe (GRAS) for any use in human food'. There is conflicting evidence concerning whether dietary supplements of omega-3 fatty acids (a type of polyunsaturated essential fatty acid) added to diet improve cardiovascular risk.
The benefits of recommending a low-salt diet in people with high or normal blood pressure are not clear. In those with heart failure, after one study was left out, the rest of the trials show a trend to benefit. Another review of dietary salt concluded that there is strong evidence that high dietary salt intake increases blood pressure and worsens hypertension, and that it increases the number of cardiovascular disease events; both as a result of the increased blood pressure and probably through other mechanisms. Moderate evidence was found that high salt intake increases cardiovascular mortality; and some evidence was found for an increase in overall mortality, strokes, and left ventricular hypertrophy.
==== Intermittent fasting ====
Overall, the current body of scientific evidence is uncertain on whether intermittent fasting could prevent cardiovascular disease. Intermittent fasting may help people lose more weight than regular eating patterns, but was not different from energy restriction diets.
=== Medication ===
Blood pressure medication reduces cardiovascular disease in people at risk, irrespective of age, the baseline level of cardiovascular risk, or baseline blood pressure. The commonly-used drug regimens have similar efficacy in reducing the risk of all major cardiovascular events, although there may be differences between drugs in their ability to prevent specific outcomes. Larger reductions in blood pressure produce larger reductions in risk, and most people with high blood pressure require more than one drug to achieve adequate reduction in blood pressure. Adherence to medications is often poor, and while mobile phone text messaging has been tried to improve adherence, there is insufficient evidence that it alters secondary prevention of cardiovascular disease.
Statins are effective in preventing further cardiovascular disease in people with a history of cardiovascular disease. As the event rate is higher in men than in women, the decrease in events is more easily seen in men than women. In those at risk, but without a history of cardiovascular disease (primary prevention), statins decrease the risk of death and combined fatal and non-fatal cardiovascular disease. The benefit, however, is small. A United States guideline recommends statins in those who have a 12% or greater risk of cardiovascular disease over the next ten years. Niacin, fibrates and CETP Inhibitors, while they may increase HDL cholesterol do not affect the risk of cardiovascular disease in those who are already on statins. Fibrates lower the risk of cardiovascular and coronary events, but there is no evidence to suggest that they reduce all-cause mortality.
Anti-diabetic medication may reduce cardiovascular risk in people with Type 2 diabetes, although evidence is not conclusive. A meta-analysis in 2009 including 27,049 participants and 2,370 major vascular events showed a 15% relative risk reduction in cardiovascular disease with more-intensive glucose lowering over an average follow-up period of 4.4 years, but an increased risk of major hypoglycemia.
Aspirin has been found to be of only modest benefit in those at low risk of heart disease, as the risk of serious bleeding is almost equal to the protection against cardiovascular problems. In those at very low risk, including those over the age of 70, it is not recommended. The United States Preventive Services Task Force recommends against use of aspirin for prevention in women less than 55 and men less than 45 years old; however, it is recommended for some older people.
The use of vasoactive agents for people with pulmonary hypertension with left heart disease or hypoxemic lung diseases may cause harm and unnecessary expense.
Antibiotics for secondary prevention of coronary heart disease
Antibiotics may help patients with coronary disease to reduce the risk of heart attacks and strokes. However, evidence in 2021 suggests that antibiotics for secondary prevention of coronary heart disease are harmful, with increased mortality and occurrence of stroke; the use of antibiotics is not supported for preventing secondary coronary heart disease.
=== Physical activity ===
Exercise-based cardiac rehabilitation following a heart attack reduces the risk of death from cardiovascular disease and leads to less hospitalizations. There have been few high-quality studies of the benefits of exercise training in people with increased cardiovascular risk but no history of cardiovascular disease.
A systematic review estimated that inactivity is responsible for 6% of the burden of disease from coronary heart disease worldwide. The authors estimated that 121,000 deaths from coronary heart disease could have been averted in Europe in 2008 if people had not been physically inactive. Low-quality evidence from a limited number of studies suggest that yoga has beneficial effects on blood pressure and cholesterol. Tentative evidence suggests that home-based exercise programs may be more efficient at improving exercise adherence.
=== Dietary supplements ===
While a healthy diet is beneficial, the effect of antioxidant supplementation (vitamin E, vitamin C, etc.) or vitamins has not been shown to protect against cardiovascular disease and in some cases may possibly result in harm. Mineral supplements have also not been found to be useful. Niacin, a type of vitamin B3, may be an exception with a modest decrease in the risk of cardiovascular events in those at high risk. Magnesium supplementation lowers high blood pressure in a dose-dependent manner. Magnesium therapy is recommended for people with ventricular arrhythmia associated with torsades de pointes who present with long QT syndrome, and for the treatment of people with digoxin intoxication-induced arrhythmias. There is no evidence that omega-3 fatty acid supplementation is beneficial. A 2022 review found that some dietary supplements, including micronutrients, may reduce risk factors for cardiovascular disease.
== Management ==
Cardiovascular disease is treatable with initial treatment primarily focused on diet and lifestyle interventions. Influenza may make heart attacks and strokes more likely and therefore influenza vaccination may decrease the chance of cardiovascular events and death in people with heart disease.
Proper CVD management necessitates a focus on MI and stroke cases due to their combined high mortality rate, keeping in mind the cost-effectiveness of any intervention, especially in developing countries with low or middle-income levels. Regarding MI, strategies using aspirin, atenolol, streptokinase or tissue plasminogen activator have been compared for quality-adjusted life-year (QALY) in regions of low and middle income. The costs for a single QALY for aspirin and atenolol were less than US$25, streptokinase was about $680, and t-PA was $16,000. Aspirin, ACE inhibitors, beta-blockers, and statins used together for secondary CVD prevention in the same regions showed single QALY costs of $350.
There are also surgical or procedural interventions that can save someone's life or prolong it. For heart valve problems, a person could have surgery to replace the valve. For arrhythmias, a pacemaker can be put in place to help reduce abnormal heart rhythms and for a heart attack, there are multiple options two of these are a coronary angioplasty and a coronary artery bypass surgery.
There is probably no additional benefit in terms of mortality and serious adverse events when blood pressure targets were lowered to ≤ 135/85 mmHg from ≤ 140 to 160/90 to 100 mmHg.
== Epidemiology ==
Cardiovascular diseases are the leading cause of death worldwide and in all regions except Africa. In 2008, 30% of all global death was attributed to cardiovascular diseases. Death caused by cardiovascular diseases are also higher in low- and middle-income countries as over 80% of all global deaths caused by cardiovascular diseases occurred in those countries. It is also estimated that by 2030, over 23 million people will die from cardiovascular diseases each year.
It is estimated that 60% of the world's cardiovascular disease burden will occur in the South Asian subcontinent despite only accounting for 20% of the world's population. This may be secondary to a combination of genetic predisposition and environmental factors. Organizations such as the Indian Heart Association are working with the World Heart Federation to raise awareness about this issue.
== Research ==
There is evidence that cardiovascular disease existed in pre-history, and research into cardiovascular disease dates from at least the 18th century. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis.
Recent areas of research include the link between inflammation and atherosclerosis the potential for novel therapeutic interventions, and the genetics of coronary heart disease.
== References ==
== External links ==
WHO fact sheet on cardiovascular diseases
2021 ESC Guidelines on cardiovascular disease prevention in clinical practice
Heart Disease MedicineNet Slides, photos, descriptions
Risk calculator
Interactive CV Risk Calculator | Wikipedia/Heart_disease |
Ablation (Latin: ablatio – removal) is the removal or destruction of something from an object by vaporization, chipping, erosive processes, or by other means. Examples of ablative materials are described below, including spacecraft material for ascent and atmospheric reentry, ice and snow in glaciology, biological tissues in medicine and passive fire protection materials.
== Artificial intelligence ==
In artificial intelligence (AI), especially machine learning, ablation is the removal of a component of an AI system. The term is by analogy with biology: removal of components of an organism.
== Biology ==
Biological ablation is the removal of a biological structure or functionality.
Genetic ablation is another term for gene silencing, in which gene expression is abolished through the alteration or deletion of genetic sequence information. In cell ablation, individual cells in a population or culture are destroyed or removed. Both can be used as experimental tools, as in loss-of-function experiments.
== Medicine ==
In medicine, ablation is the removal of a part of biological tissue, usually by surgery. Surface ablation of the skin (dermabrasion, also called resurfacing because it induces regeneration) can be carried out by chemicals (chemoablation), by lasers (laser ablation), by freezing (cryoablation), or by electricity (fulguration). Its purpose is to remove skin spots, aged skin, wrinkles, thus rejuvenating it. Surface ablation is also employed in otolaryngology for several kinds of surgery, such as the one for snoring. Radiofrequency ablation (RFA) is a method of removing aberrant tissue from within the body via minimally invasive procedures, it is used to cure a variety of cardiac arrhythmia such as supraventricular tachycardia, Wolff–Parkinson–White syndrome (WPW), ventricular tachycardia, and more recently as management of atrial fibrillation. The term is often used in the context of laser ablation, a process in which a laser dissolves a material's molecular bonds. For a laser to ablate tissues, the power density or fluence must be high, otherwise thermocoagulation occurs, which is simply thermal vaporization of the tissues.
Rotablation is a type of arterial cleansing that consists of inserting a tiny, diamond-tipped, drill-like device into the affected artery to remove fatty deposits or plaque. The procedure is used in the treatment of coronary heart disease to restore blood flow.
Microwave ablation (MWA) is similar to RFA but at higher frequencies of electromagnetic radiation.
High-intensity focused ultrasound (HIFU) ablation removes tissue from within the body noninvasively.
Bone marrow ablation is a process whereby the human bone marrow cells are eliminated in preparation for a bone marrow transplant. This is performed using high-intensity chemotherapy and total body irradiation. As such, it has nothing to do with the vaporization techniques described in the rest of this article.
Ablation of brain tissue is used for treating certain neurological disorders, particularly Parkinson's disease, and sometimes for psychiatric disorders as well.
Recently, some researchers reported successful results with genetic ablation. In particular, genetic ablation is potentially a much more efficient method of removing unwanted cells, such as tumor cells, because large numbers of animals lacking specific cells could be generated. Genetically ablated lines can be maintained for a prolonged period of time and shared within the research community. Researchers at Columbia University report of reconstituted caspases combined from C. elegans and humans, which maintain a high degree of target specificity. The genetic ablation techniques described could prove useful in battling cancer.
== Electro-ablation ==
Electro-ablation, is a process that removes material from a metallic workpiece to reduce surface roughness.
Electro-ablation breaks through highly resistive oxide surfaces, such as those found on titanium and other exotic metals and alloys without melting the underlying non-oxidised metal or alloy. This allows very quick surface finishing
The process is capable of providing surface finishing for a wide range of exotic and widely used metals and alloys, including: titanium, stainless steel, niobium, chromium–cobalt, Inconel, aluminium, and a range of widely available steels and alloys.
Electro-ablation is very effective at achieving high levels of surface finishing in holes, valleys and hidden or internal surfaces on metallic workpieces (parts).
The process is particularly applicable to components produced by additive manufacturing process, such as 3D-printed metals. These components tend to be produced with roughness levels well above 5–20 micron. Electro-ablation can be used to quickly reduce the surface roughness to less than 0.8 micron, allowing the post-process to be used for volume production surface finishing.
== Glaciology ==
In glaciology and meteorology, ablation—the opposite of accumulation—refers to all processes that remove snow, ice, or water from a glacier or snowfield. Ablation refers to the melting of snow or ice that runs off the glacier, evaporation, sublimation, calving, or erosive removal of snow by wind. Air temperature is typically the dominant control of ablation, with precipitation exercising secondary control. In a temperate climate during ablation season, ablation rates typically average around 2 mm/h. Where solar radiation is the dominant cause of snow ablation (e.g., if air temperatures are low under clear skies), characteristic ablation textures such as suncups and penitentes may develop on the snow surface. Ablation can refer to mass loss from the upper surface of a glacier or ocean-driven melt and calving on the face of a glacier terminus.
Ablation can refer either to the processes removing ice and snow or to the quantity of ice and snow removed.
Debris-covered glaciers have also been shown to greatly impact the ablation process. There is a thin debris layer that can be located on the top of glaciers that intensifies the ablation process below the ice. The debris-covered parts of a glacier that is experiencing ablation are sectioned into three categories which include ice cliffs, ponds, and debris. These three sections allow scientists to measure the heat digested by the debris-covered area and is calculated. The calculations are dependent on the area and net absorbed heat amounts in regards to the entire debris-covered zones. These types of calculations are done to various glaciers to understand and analyze future patterns of melting.
Moraine (glacial debris) is moved by natural processes that allow for down-slope movement of materials on the glacier body. It is noted that if the slope of a glacier is too high then the debris will continue to move along the glacier to a further location. The sizes and locations of glaciers vary around the world, so depending on the climate and physical geography the varieties of debris can differ. The size and magnitude of the debris is dependent on the area of glacier and can vary from dust-size fragments to blocks as large as a house.
There have been many experiments done to demonstrate the effect of debris on the surface of glaciers. Yoshiyuki Fujii, a professor at the National Institute of Polar Research, designed an experiment that showed ablation rate was accelerated under a thin debris layer and was retarded under a thick one as compared with that of a natural snow surface. This science is significant due to the importance of long-term availability of water resources and assess glacier response to climate change. Natural resource availability is a major drive behind research conducted in regards to the ablation process and overall study of glaciers.
== Laser ablation ==
Laser ablation is greatly affected by the nature of the material and its ability to absorb energy, therefore the wavelength of the ablation laser should have a minimum absorption depth. While these lasers can average a low power, they can offer peak intensity and fluence given by:
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Surface ablation of the cornea for several types of eye refractive surgery is now common, using an excimer laser system (LASIK and LASEK). Since the cornea does not grow back, laser is used to remodel the cornea refractive properties to correct refraction errors, such as astigmatism, myopia, and hyperopia. Laser ablation is also used to remove part of the uterine wall in women with menstruation and adenomyosis problems in a process called endometrial ablation.
Researchers have demonstrated a successful technique for ablating subsurface tumors with minimal thermal damage to surrounding healthy tissue, by using a focused laser beam from an ultra-short pulse diode laser source.
== Marine surface coatings ==
Antifouling paints and other related coatings are routinely used to prevent the buildup of microorganisms and other animals, such as barnacles for the bottom hull surfaces of recreational, commercial and military sea vessels. Ablative paints are often utilized for this purpose to prevent the dilution or deactivation of the antifouling agent. Over time, the paint will slowly decompose in the water, exposing fresh antifouling compounds on the surface. Engineering the antifouling agents and the ablation rate can produce long-lived protection from the deleterious effects of biofouling.
== Passive fire protection ==
Firestopping and fireproofing products can be ablative in nature. This can mean endothermic materials, or merely materials that are sacrificial and become "spent" over time while exposed to fire, such as silicone firestop products.
Given sufficient time under fire or heat conditions, these products char away, crumble, and disappear. The idea is to put enough of this material in the way of the fire that a level of fire-resistance rating can be maintained, as demonstrated in a fire test. Ablative materials usually have a large concentration of organic matter that is reduced by fire to ashes. In the case of silicone, organic rubber surrounds very finely divided silica dust (up to 380 m2 of combined surface area of all the dust particles per gram of this dust). When the organic rubber is exposed to fire, it burns to ash and leaves behind the silica dust with which the product started.
== Protoplanetary disk ablation ==
Protoplanetary disks are rotating circumstellar disks of dense gas and dust surrounding young, newly formed stars. Shortly after star formation, stars often have leftover surrounding material that is still gravitationally bound to them, forming primitive disks that orbit around the star's equator – not too dissimilarly from the rings of Saturn. This occurs because the decrease in the protostellar material's radius during formation increases angular momentum, which means that this remaining material gets whipped into a flattened circumstellar disk around the star. This circumstellar disk may eventually mature into what is referred to as a protoplanetary disk: a disk of gas, dust, ice and other materials from which planetary systems may form. In these disks, orbiting matter starts to accrete in the colder mid-plane of the disk from dust grains and ices sticking together. These small accretions grow from pebbles to rocks to early baby planets, called planetesimals, then protoplanets, and eventually, full planets.
As it is believed that massive stars may play a role in actively triggering star formation (by introducing gravitational instabilities amongst other factors), it is plausible that young, smaller stars with disks may be living relatively nearby to older, more massive stars. This has already been confirmed through observations to be the case in certain clusters, e.g. in the Trapezium cluster. Since massive stars tend to collapse through supernovae at the end of their lives, research is now investigating what role the shockwave of such an explosion, and the resulting supernova remnant (SNR), would play if it occurred in the line of fire of a protoplanetary disk. According to computationally modelled simulations, a SNR striking a protoplanetary disk would result in significant ablation of the disk, and this ablation would strip a significant amount of protoplanetary material from the disk – but not necessarily destroy the disk entirely. This is an important point because a disk that survives such an interaction with sufficient material leftover to form a planetary system may inherit an altered disk chemistry from the SNR, which could have effects on the planetary systems that later form.
== Spaceflight ==
In spacecraft design, ablation is used to both cool and protect mechanical parts and/or payloads that would otherwise be damaged by extremely high temperatures. Two principal applications are heat shields for spacecraft entering a planetary atmosphere from space and cooling of rocket engine nozzles. Examples include the Apollo Command Module that protected astronauts from the heat of atmospheric reentry and the Kestrel second stage rocket engine designed for exclusive use in an environment of space vacuum since no heat convection is possible.
In a basic sense, ablative material is designed so that instead of heat being transmitted into the structure of the spacecraft, only the outer surface of the material bears the majority of the heating effect. The outer surface chars and burns away – but quite slowly, only gradually exposing new fresh protective material beneath. The heat is carried away from the spacecraft by the gases generated by the ablative process, and never penetrates the surface material, so the metallic and other sensitive structures they protect, remain at a safe temperature. As the surface burns and disperses into space, the remaining solid material continues to insulate the craft from ongoing heat and superheated gases. The thickness of the ablative layer is calculated to be sufficient to survive the heat it will encounter on its mission.
There is an entire branch of spaceflight research involving the search for new fireproofing materials to achieve the best ablative performance; this function is critical to protect the spacecraft occupants and payload from otherwise excessive heat loading. The same technology is used in some passive fire protection applications, in some cases by the same vendors, who offer different versions of these fireproofing products, some for aerospace and some for structural fire protection.
== See also ==
Electrical arc flash burns
Ablative armor
== References ==
== External links ==
Chemical Peeling. American Society for Dermatological Surgery.
Lasik Laser Eye Surgery. USA Food an Drugs Administration info.
Physics of laser ablation | Wikipedia/Ablation_therapy |
Degenerative disease is the result of a continuous process based on degenerative cell changes, affecting tissues or organs, which will increasingly deteriorate over time.
In neurodegenerative diseases, cells of the central nervous system stop working or die via neurodegeneration. An example of this is Alzheimer's disease. The other two common groups of degenerative diseases are those that affect circulatory system (e.g. coronary artery disease) and neoplastic diseases (e.g. cancers).
Many degenerative diseases exist and some are related to aging. Normal bodily wear or lifestyle choices (such as exercise or eating habits) may worsen degenerative diseases, depending on the specific condition. Sometimes the main or partial cause behind such diseases is genetic. Thus some are clearly hereditary like Huntington's disease. Other causes include viruses, poisons or chemical exposures, while sometimes, the underlying cause remains unknown.
Some degenerative diseases can be cured. In those that can not, it may be possible to alleviate the symptoms.
== Examples ==
== See also ==
Life extension
Senescence
Progressive disease
List of genetic disorders
== References == | Wikipedia/Degenerative_disease |
BASF Plant Science is a subsidiary of BASF in which all plant biotechnology activities are consolidated. The company was founded in 1998 and employs approximately 700 people at 6 different locations worldwide. The headquarters of BASF Plant Science is located in Research Triangle Park (North Carolina, US) and has research sites in the US, Canada, and Europe. BASF Plant Science mainly develops genetically modified seeds at these locations.
== Company Profile ==
BASF Plant Science genetically modifies crops like maize, soy, cotton, canola, sugarcane, sugar beet, and potatoes.
These genetically modified crops are sold and distributed through biotechnology companies like Monsanto, KWS Saat, Embrapa, or CTC (Centro de Tecnologia Canavieira).
== Products ==
As of 2011, BASF Plant Science has developed three products:
Amflora, a potato developed initially for the European market, producing pure amylopectin starch for industrial use. Waxy potato starch is used in industrial procedures to make yarn stronger and paper glossier; it also makes spray concrete adhere better to walls. Due to lack of acceptance of GM crops in Europe, in 2012 BASF Plant Science decided to stop its commercialization and research activities on the European potato varieties Amflora and Fortuna. Further, it announced the relocation of the corporate headquarters from Germany to the USA.
Cultivance is an herbicide resistant soybean. It received market permission from Brazil in 2010. Marketing and sales of Cultivance are through Embrapa, a Brazilian company.
NutriDense is a higher nutritional maize plant used as a feed source for pigs, chickens, and cows.
A range of more crops are in the pipeline:
Maize, soy, canola, and cotton: The aim is higher biomass, and plants that better resist environmental factors such as drought or disease. These crops are developed on the island of Kauai in Hawaii and are distributed in cooperation with Monsanto.
Sugarcane, sugar beet: The aim is to develop plants that produce more sugar for use in food or as raw material for biofuel production.
Fortuna Potato: developed for resistance against Phytophthora infestans, a disease which is difficult to combat for European agriculturists.
Other products are being developed for the food industry for use in genetically modified foods. Examples include plants with a higher content of omega-3 fatty acids for preventing cardiovascular diseases, and plants with a higher content of astaxanthin which is used in fish farming as feed additive, and as a food supplement for humans.
== References ==
== External links ==
BASF plant biotechnology | Wikipedia/BASF_Plant_Science |
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development (a de novo mutation), or it can be inherited from two parents who are carriers of a faulty gene (autosomal recessive inheritance) or from a parent with the disorder (autosomal dominant inheritance). When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA (due to their size).
There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature. More than 600 genetic disorders are treatable. Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves.
Genetic disorders are present before birth, and some genetic disorders produce birth defects, but birth defects can also be developmental rather than hereditary. The opposite of a hereditary disease is an acquired disease. Most cancers, although they involve genetic mutations to a small proportion of cells in the body, are acquired diseases. Some cancer syndromes, however, such as BRCA mutations, are hereditary genetic disorders.
== Single-gene ==
A single-gene disorder (or monogenic disorder) is the result of a single mutated gene. Single-gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although the divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, the common form of dwarfism, achondroplasia, is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics(ones affected with achondroplasia) could be considered carriers for. Sickle cell anemia is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition. When a couple where one partner or both are affected or carriers of a single-gene disorder wish to have a child, they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder.
Most congenital metabolic disorders known as inborn errors of metabolism result from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations.
=== Autosomal dominant ===
Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.: 57 The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced penetrance, which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are Huntington's disease,: 58 neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, hereditary multiple exostoses (a highly penetrant autosomal dominant disorder), tuberous sclerosis, Von Willebrand disease, and acute intermittent porphyria. Birth defects are also called congenital anomalies.
=== Autosomal recessive ===
Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene and are referred to as genetic carriers. Each parent with a defective gene normally do not have symptoms. Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are albinism, medium-chain acyl-CoA dehydrogenase deficiency, cystic fibrosis, sickle cell disease, Tay–Sachs disease, Niemann–Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in an autosomal recessive fashion. Some autosomal recessive disorders are common because, in the past, carrying one of the faulty genes led to a slight protection against an infectious disease or toxin such as tuberculosis or malaria. Such disorders include cystic fibrosis, sickle cell disease, phenylketonuria and thalassaemia.
=== X-linked dominant ===
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets. Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such as Rett syndrome, incontinentia pigmenti type 2, and Aicardi syndrome, are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter syndrome (44+xxy) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), but his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected foetus with each pregnancy, although in cases such as incontinentia pigmenti, only female offspring are generally viable.
=== X-linked recessive ===
X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their father's Y chromosome), but his daughters will be carriers of one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseases hemophilia A, Duchenne muscular dystrophy, and Lesch–Nyhan syndrome, as well as common and less serious conditions such as male pattern baldness and red–green color blindness. X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).
=== Y-linked ===
Y-linked disorders are caused by mutations on the Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes.
Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is only possible through the circumvention of infertility by medical intervention.
=== Mitochondrial ===
This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded by mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder is Leber's hereditary optic neuropathy.
It is important to stress that the vast majority of mitochondrial diseases (particularly when symptoms develop in early life) are actually caused by a nuclear gene defect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance.
== Multifactorial disorder ==
Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person's risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Studies that aim to identify the cause of complex disorders can use several methodological approaches to determine genotype–phenotype associations. One method, the genotype-first approach, starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.
On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. This does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure).
Other such cases include:
asthma
autoimmune diseases such as multiple sclerosis
cancers
ciliopathies
cleft palate
diabetes
heart disease
hypertension
inflammatory bowel disease
intellectual disability
mood disorder
obesity
refractive error
infertility
== Chromosomal disorder ==
A chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. An example of these disorders is Trisomy 21 (the most common form of Down syndrome), in which there is an extra copy of chromosome 21 in all cells.
== Diagnosis ==
Due to the wide range of genetic disorders that are known, diagnosis is widely varied and dependent of the disorder. Most genetic disorders are diagnosed pre-birth, at birth, or during early childhood however some, such as Huntington's disease, can escape detection until the patient begins exhibiting symptoms well into adulthood.
The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history, it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or contemplate termination. Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis.
== Prognosis ==
Not all genetic disorders directly result in death; however, there are no known cures for genetic disorders. Many genetic disorders affect stages of development, such as Down syndrome, while others result in purely physical symptoms such as muscular dystrophy. Other disorders, such as Huntington's disease, show no signs until adulthood. During the active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation of quality of life and maintain patient autonomy. This includes physical therapy and pain management.
== Treatment ==
The treatment of disorder an ongoing battle, with over 1,800 gene therapy clinical trials having been completed, are ongoing, or have been approved worldwide. Despite this, most treatment options revolve around treating the symptoms of the disorders in an attempt to improve patient quality of life.
Gene therapy refers to a form of treatment where a healthy gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or slow the progression of the disease. A major obstacle has been the delivery of genes to the appropriate cell, tissue, and organ affected by the disorder. Researchers have investigated how they can introduce a gene into the potentially trillions of cells that carry the defective copy. Finding an answer to this has been a roadblock between understanding the genetic disorder and correcting the genetic disorder.
== Epidemiology ==
Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature.
== History ==
The earliest known genetic condition in a hominid was in the fossil species Paranthropus robustus, with over a third of individuals displaying amelogenesis imperfecta.
== See also ==
FINDbase (the Frequency of Inherited Disorders database)
Genetic epidemiology
List of genetic disorders
Population groups in biomedicine
Mendelian error
== References ==
== External links ==
Public Health Genomics at CDC
OMIM — Online Mendelian Inheritance in Man, a catalog of human genes and genetic disorders
Genetic and Rare Diseases Information Center (GARD) Office of Rare Diseases (ORD), National Institutes of Health (NIH)
CDC's National Center on Birth Defects and Developmental Disabilities
Genetic Disease Information from the Human Genome Project
Global Genes Project, Genetic and Rare Diseases Organization
List of Genetic Disorders - Genome.gov | Wikipedia/Hereditary_diseases |
Tay–Sachs disease is an inherited lysosomal storage disease that results in the destruction of nerve cells in the brain and spinal cord. The most common form is infantile Tay–Sachs disease, which becomes apparent around the age of three to six months of age, with the infant losing the ability to turn over, sit, or crawl. This is then followed by seizures, hearing loss, and inability to move, with death usually occurring by the age of three to five. Less commonly, the disease may occur later in childhood, adolescence, or adulthood (juvenile or late-onset). These forms tend to be less severe, but the juvenile form typically results in death by the age of 15.
Tay–Sachs disease is caused by a genetic mutation in the HEXA gene on chromosome 15, which codes a subunit of the hexosaminidase enzyme known as hexosaminidase A. It is inherited in an autosomal recessive manner. The mutation disrupts the activity of the enzyme, which results in the build-up of the molecule GM2 ganglioside within cells, leading to toxicity. Diagnosis may be supported by measuring the blood hexosaminidase A level or genetic testing. Tay–Sachs disease is a type of GM2 gangliosidosis and sphingolipidosis.
The treatment of Tay–Sachs disease is supportive in nature. This may involve multiple specialties as well as psychosocial support for the family. The disease is rare in the general population. In Ashkenazi Jews, French Canadians of southeastern Quebec, the Old Order Amish of Pennsylvania, and the Cajuns of southern Louisiana, the condition is more common. Approximately 1 in 3,600 Ashkenazi Jews at birth are affected.
The disease is named after British ophthalmologist Waren Tay, who in 1881 first described a symptomatic red spot on the retina of the eye; and American neurologist Bernard Sachs, who described in 1887 the cellular changes and noted an increased rate of disease in Ashkenazi Jews. Carriers of a single Tay–Sachs allele are typically normal. It has been hypothesized that being a carrier may confer protection from tuberculosis, explaining the persistence of the allele in certain populations. Researchers are looking at gene therapy or enzyme replacement therapy as possible treatments.
== Signs and symptoms ==
Tay–Sachs disease is typically first noticed in infants around 6 months old displaying an abnormally strong response to sudden noises or other stimuli, known as the "startle response". There may also be listlessness or muscle stiffness (hypertonia). The disease is classified into several forms, which are differentiated based on the onset age of neurological symptoms.
=== Infantile ===
Infants with Tay–Sachs disease appear to develop normally for the first six months after birth. Then, as neurons become distended with GM2 gangliosides, a relentless deterioration of mental and physical abilities begins. The child may become blind, deaf, unable to swallow, atrophied, and paralytic. Death usually occurs before the age of four.
=== Juvenile ===
Juvenile Tay–Sachs disease is rarer than other forms of Tay–Sachs and usually is initially seen in children between two and ten years old. People with Tay–Sachs disease experience cognitive and motor skill deterioration, dysarthria, dysphagia, ataxia, and spasticity. Death usually occurs between the ages of five and fifteen years.
=== Late-onset ===
A rare form of this disease, known as Adult-Onset or Late-Onset Tay–Sachs disease, usually has its first symptoms during the 30s or 40s. In contrast to the other forms, late-onset Tay–Sachs disease is usually not fatal as the effects can stop progressing. It is frequently misdiagnosed. It is characterized by unsteadiness of gait and progressive neurological deterioration. Symptoms of late-onset Tay–Sachs – which typically begin to be seen in adolescence or early adulthood – include speech and swallowing difficulties, unsteadiness of gait, spasticity, cognitive decline, and psychiatric illness, particularly a schizophrenia-like psychosis. Late-onset Tay–Sachs patients may become fully wheelchair-bound.
Until the 1970s and 1980s, when the disease's molecular genetics became known, the juvenile and adult forms of the disease were not always recognized as variants of Tay–Sachs disease. Post-infantile Tay–Sachs was often misdiagnosed as another neurological disorder, such as Friedreich's ataxia.
== Genetics ==
Tay–Sachs disease is an autosomal recessive genetic disorder, meaning that when both parents are carriers, there is a 25% risk of giving birth to an affected child with each pregnancy. The affected child would have received a mutated copy of the gene from each parent. A person with one mutated copy and one normal copy is a carrier, like the parent they received the mutant copy from. Tay–Sachs carriers are known to be more resistant to infections of mycobacteria, including tuberculosis, compared to a person with two normal copies of the gene.
Tay–Sachs results from mutations in the HEXA gene on chromosome 15, which encodes the alpha-subunit of beta-N-acetylhexosaminidase A, a lysosomal enzyme. By 2000, more than 100 different mutations had been identified in the human HEXA gene. These mutations have included single base insertions and deletions, splice phase mutations, missense mutations, and other more complex patterns. Each of these mutations alters the gene's protein product (i.e., the enzyme), sometimes severely inhibiting its function. In recent years, population studies and pedigree analysis have shown how such mutations arise and spread within small founder populations. Initial research focused on several such founder populations:
Ashkenazi Jews. A four base pair insertion in exon 11 (1278insTATC) results in an altered reading frame for the HEXA gene. This mutation is the most prevalent in the Ashkenazi Jewish population and leads to the infantile form of Tay–Sachs disease.
Cajuns. The same 1278insTATC mutation found among Ashkenazi Jews occurs in the Cajun population of southern Louisiana. Researchers have traced the ancestry of carriers from Louisiana families back to a single founder couple – not known to be Jewish – who lived in France in the 18th century.
French Canadians. Two mutations, unrelated to the Ashkenazi/Cajun mutation, are absent in France but common among certain French-Canadian communities living in southeastern Quebec and Acadians from the Province of New Brunswick. Pedigree analysis suggests that mutations were uncommon before the late 17th century.
In the 1960s and early 1970s, when the biochemical basis of Tay–Sachs disease was first becoming known, no mutations had been sequenced directly for genetic diseases. Researchers of that era did not yet know how common polymorphisms would prove to be. The "Jewish Fur Trader Hypothesis", with its implication that a single mutation must have spread from one population into another, reflected the knowledge at the time. Subsequent research, however, has proven that a large variety of different HEXA mutations can cause the disease. Because Tay–Sachs was one of the first genetic disorders for which widespread genetic screening was possible, it is one of the first genetic disorders in which the prevalence of compound heterozygosity has been demonstrated.
Compound heterozygosity ultimately explains the disease's variability, including the late-onset forms. The disease can potentially result from the inheritance of two unrelated mutations in the HEXA gene, one from each parent. Classic infantile Tay–Sachs disease results when a child has inherited mutations from both parents that completely stop the biodegradation of gangliosides. Late-onset forms occur due to the diverse mutation base – people with Tay–Sachs disease may technically be heterozygotes, with two differing HEXA mutations that both inactivate, alter, or inhibit enzyme activity. When a patient has at least one HEXA copy that still enables some hexosaminidase A activity, a later onset disease form occurs. When disease occurs because of two unrelated mutations, the patient is said to be a compound heterozygote.
Heterozygous carriers (individuals who inherit one mutant allele) show abnormal enzyme activity but manifest no disease symptoms. This phenomenon is called dominance; the biochemical reason for wild-type alleles' dominance over nonfunctional mutant alleles in inborn errors of metabolism comes from how enzymes function. Enzymes are protein catalysts for chemical reactions; as catalysts, they speed up reactions without being used up in the process, so only small enzyme quantities are required to carry out a reaction. Someone homozygous for a nonfunctional mutation in the enzyme-encoding gene has little or no enzyme activity, so will manifest the abnormal phenotype (i.e. will develop full-blown disease). A normal: mutated heterozygote (heterozygous individual, also known as a 'carrier') has at least half of the normal enzyme activity level, due to the expression of the wild-type allele. This level is normally enough to enable normal functioning and thus prevent phenotypic expression (i.e. a normal: mutated carrier will not become ill).
== Pathophysiology ==
Tay–Sachs disease is caused by insufficient activity of the enzyme hexosaminidase A. Hexosaminidase A is a vital hydrolytic enzyme, found in the lysosomes, that breaks down sphingolipids. When hexosaminidase A is no longer functioning properly, the lipids accumulate in the brain and interfere with normal biological processes. Hexosaminidase A specifically breaks down fatty acid derivatives called gangliosides; these are made and biodegraded rapidly in early life as the brain develops. Patients with and carriers of Tay–Sachs can be identified by a simple blood test that measures hexosaminidase A activity.
The hydrolysis of GM2-ganglioside requires three proteins. Two of them are subunits of hexosaminidase A; the third is a small glycolipid transport protein, the GM2 activator protein (GM2A), which acts as a substrate-specific cofactor for the enzyme. Deficiency in any one of these proteins leads to ganglioside storage, primarily in the lysosomes of neurons. Tay–Sachs disease (along with AB-variant GM2-gangliosidosis and Sandhoff disease) occurs because a mutation inherited from both parents deactivates or inhibits this process. Most Tay–Sachs mutations probably do not directly affect protein functional elements (e.g., the active site). Instead, they cause incorrect folding (disrupting function) or disable intracellular transport.
== Diagnosis ==
In patients with a clinical suspicion of Tay–Sachs disease, with any age of onset, the initial testing involves an enzyme assay to measure the activity of hexosaminidase in serum, fibroblasts, or leukocytes. Total hexosaminidase enzyme activity is decreased in individuals with Tay–Sachs as is the percentage of hexosaminidase A. After confirmation of decreased enzyme activity in an individual, confirmation by molecular analysis can be pursued. All patients with infantile-onset Tay–Sachs disease have a "cherry red" macula in the retina, easily observable by a physician using an ophthalmoscope. This red spot is a retinal area that appears red because of gangliosides in the surrounding retinal ganglion cells. The choroidal circulation is showing through "red" in this foveal region where all retinal ganglion cells are pushed aside to increase visual acuity. Thus, this cherry-red spot is the only normal part of the retina; it shows up in contrast to the rest of the retina. Microscopic analysis of the retinal neurons shows they are distended from excess ganglioside storage. Unlike other lysosomal storage diseases (e.g., Gaucher disease, Niemann–Pick disease, and Sandhoff disease), hepatosplenomegaly (liver and spleen enlargement) is not seen in Tay–Sachs.
== Prevention ==
Three main approaches have been used to prevent or reduce the incidence of Tay–Sachs:
Prenatal diagnosis. If both parents are identified as carriers, prenatal genetic testing can determine whether the fetus has inherited a defective gene copy from both parents. Chorionic villus sampling (CVS), the most common form of prenatal diagnosis, can be performed between 10 and 14 weeks of gestation. Amniocentesis is usually performed at 15–18 weeks. These procedures have risks of miscarriage of 1% or less.
Preimplantation genetic diagnosis. By retrieving the mother's eggs for in vitro fertilization, it is possible to test the embryo for the disorder before implantation. Healthy embryos are then selected and transferred into the mother's womb, while unhealthy embryos are discarded. In addition to Tay–Sachs disease, preimplantation genetic diagnosis has been used to prevent cystic fibrosis and sickle cell anemia among other genetic disorders.
Pre-marriage screening. In Orthodox Jewish circles, the organization Dor Yeshorim carries out an anonymous screening program so that carriers for Tay–Sachs and other genetic disorders can avoid marrying each other.
== Management ==
As of 2010, no treatment addressed the cause of Tay–Sachs disease or could slow its progression; people receive supportive care to ease the symptoms and extend life by reducing the chance of contracting infections. Infants are given feeding tubes when they can no longer swallow. In late-onset Tay–Sachs, medication (e.g., lithium for depression) can sometimes control psychiatric symptoms and seizures, although some medications (e.g., tricyclic antidepressants, phenothiazines, haloperidol, and risperidone) are associated with significant adverse effects.
== Outcomes ==
As of 2010, even with the best care, children with infantile Tay–Sachs disease usually die by the age of 4. Children with the juvenile form are likely to die between the ages of 5–15, while the lifespans of those with the adult form will probably not be affected.
== Epidemiology ==
Ashkenazi Jews have a high incidence of Tay–Sachs and other lipid storage diseases. In the United States, about 1 in 27 to 1 in 30 Ashkenazi Jews is a recessive carrier. The disease incidence is about 1 in every 3,500 newborns among Ashkenazi Jews. French Canadians and the Cajun community of Louisiana have an occurrence similar to the Ashkenazi Jews. Irish Americans have a 1 in 50 chance of being a carrier. In the general population, the incidence of carriers as heterozygotes is about 1 in 300. The incidence is approximately 1 in 320,000 newborns in the general population in the United States.
Three general classes of theories have been proposed to explain the high frequency of Tay–Sachs carriers in the Ashkenazi Jewish population:
Heterozygote advantage. When applied to a particular allele, this theory posits that mutation carriers have a selective advantage, perhaps in a particular environment.
Reproductive compensation. Parents who lose a child because of disease tend to "compensate" by having additional children following the loss. This phenomenon may maintain and possibly even increase the incidence of autosomal recessive disease.
Founder effect. This hypothesis states that the high incidence of the 1278insTATC chromosomes is the result of an elevated allele frequency that existed by chance in an early founder population.
Tay–Sachs disease was one of the first genetic disorders for which epidemiology was studied using molecular data. Studies of Tay–Sachs mutations using new molecular techniques such as linkage disequilibrium and coalescence analysis have brought an emerging consensus among researchers supporting the founder effect theory.
== History ==
Waren Tay and Bernard Sachs were two physicians. They described the disease's progression and provided differential diagnostic criteria to distinguish it from other neurological disorders with similar symptoms.
Both Tay and Sachs reported their first cases among Ashkenazi Jewish families. Tay reported his observations in 1881 in the first volume of the proceedings of the British Ophthalmological Society, of which he was a founding member. By 1884, he had seen three cases in a single family. Years later, Bernard Sachs, an American neurologist, reported similar findings when he reported a case of "arrested cerebral development" to other New York Neurological Society members.
Sachs, who recognized that the disease had a familial basis, proposed that the disease should be called amaurotic familial idiocy. However, its genetic basis was still poorly understood. Although Gregor Mendel had published his article on the genetics of peas in 1865, Mendel's paper was largely forgotten for more than a generation – not rediscovered by other scientists until 1899. Thus, the Mendelian model for explaining Tay–Sachs was unavailable to scientists and doctors of the time. The first edition of the Jewish Encyclopedia, published in 12 volumes between 1901 and 1906, described what was then known about the disease:
It is a curious fact that amaurotic family idiocy, a rare and fatal disease of children, occurs mostly among Jews. The largest number of cases has been observed in the United States—over thirty in number. It was at first thought that this was an exclusively Jewish disease because most of the cases at first reported were between Russian and Polish Jews, but recently there have been reported cases occurring in non-Jewish children. The chief characteristics of the disease are progressive mental and physical enfeeblement; weakness and paralysis of all the extremities; and marasmus, associated with symmetrical changes in the macula lutea. On investigation of the reported cases, they found that neither consanguinity nor syphilitic, alcoholic, or nervous antecedents in the family history are factors in the etiology of the disease. No preventive measures have as yet been discovered, and no treatment has been of benefit, all the cases having terminated fatally.
Jewish immigration to the United States peaked in the period 1880–1924, with the immigrants arriving from Russia and countries in Eastern Europe; this was also a period of nativism (hostility to immigrants) in the United States. Opponents of immigration often questioned whether immigrants from southern and eastern Europe could be assimilated into American society. Reports of Tay–Sachs disease contributed to a perception among nativists that Jews were an inferior race.
In 1969, Shintaro Okada and John S. O'Brien showed that Tay–Sachs disease was caused by an enzyme defect; they also proved that Tay–Sachs patients could be diagnosed by an assay of hexosaminidase A activity. The further development of enzyme assays demonstrated that levels of hexosaminidases A and B could be measured in patients and carriers, allowing the reliable detection of heterozygotes. During the early 1970s, researchers developed protocols for newborn testing, carrier screening, and prenatal diagnosis. By the end of 1979, researchers had identified three variant forms of GM2 gangliosidosis, including Sandhoff disease and the AB variant of GM2-gangliosidosis, accounting for false negatives in carrier testing.
== Society and culture ==
Since carrier testing for Tay–Sachs began in 1971, millions of Ashkenazi Jews have been screened as carriers. Jewish communities embraced the cause of genetic screening from the 1970s on. The success with Tay–Sachs disease has led Israel to become the first country that offers free genetic screening and counseling for all couples and opened discussions about the proper scope of genetic testing for other disorders in Israel.
Because Tay–Sachs disease was one of the first autosomal recessive genetic disorders for which there was an enzyme assay test (before polymerase chain reaction testing methods), it was intensely studied as a model for all such diseases, and researchers sought evidence of a selective process. A continuing controversy is whether heterozygotes (carriers) have or had a selective advantage. The presence of four different lysosomal storage disorders in the Ashkenazi Jewish population suggests a past selective advantage for heterozygous carriers of these conditions."
This controversy among researchers has reflected various debates among geneticists at large:
Dominance versus overdominance. In applied genetics (selective and agricultural breeding), this controversy has reflected the century-long debate over whether dominance or overdominance provides the best explanation for heterosis (hybrid vigor).
The classical/balance controversy. The classical hypothesis of genetic variability, often associated with Hermann Muller, maintains that most genes are of a normal wild type and that most individuals are homozygous for that wild type, while most selection is purifying selection that operates to eliminate deleterious alleles. The balancing hypothesis, often associated with Theodosius Dobzhansky, states that heterozygosity will be common at loci and that it frequently reflects either directional selection or balancing selection.
Selectionists versus neutralists. In theoretical population genetics, selectionists emphasize the primacy of natural selection as a determinant of evolution and variation within a population, while neutralists favor a form of Motoo Kimura's neutral theory of molecular evolution, which emphasizes the role of genetic drift.
== Research directions ==
=== Enzyme replacement therapy ===
Enzyme replacement therapy techniques have been investigated for lysosomal storage disorders, and could potentially be used to treat Tay–Sachs as well. The goal would be to replace the nonfunctional enzyme, a process similar to insulin injections for diabetes. However, in previous studies, the HEXA enzyme itself has been thought to be too large to pass through the specialized cell layer in the blood vessels that form the blood–brain barrier in humans.
Researchers have also tried directly instilling the deficient enzyme hexosaminidase A into the cerebrospinal fluid (CSF) which bathes the brain. However, intracerebral neurons seem unable to take up this physically large molecule efficiently even when it is directly by them. Therefore, this approach to treatment of Tay–Sachs disease has also been ineffective so far.
=== Jacob sheep model ===
Tay–Sachs disease exists in Jacob sheep. The biochemical mechanism for this disease in the Jacob sheep is virtually identical to that in humans, wherein diminished activity of hexosaminidase A results in increased concentrations of GM2 ganglioside in the affected animal. Sequencing of the HEXA gene cDNA of affected Jacobs sheep reveal an identical number of nucleotides and exons as in the human HEXA gene, and 86% nucleotide sequence identity. A missense mutation (G444R) was found in the HEXA cDNA of the affected sheep. This mutation is a single nucleotide change at the end of exon 11, resulting in that exon's deletion (before translation) via splicing. The Tay–Sachs model provided by the Jacob sheep is the first to offer promise as a means for gene therapy clinical trials, which may prove useful for disease treatment in humans.
=== Substrate reduction therapy ===
Other experimental methods being researched involve substrate reduction therapy, which attempts to use alternative enzymes to increase the brain's catabolism of GM2 gangliosides to a point where residual degradative activity is sufficient to prevent substrate accumulation. One experiment has demonstrated that using the enzyme sialidase allows the genetic defect to be effectively bypassed, and as a consequence, GM2 gangliosides are metabolized so that their levels become almost inconsequential. If a safe pharmacological treatment can be developed – one that increases expression of lysosomal sialidase in neurons without other toxicity – then this new form of therapy could essentially cure the disease.
Another metabolic therapy under investigation for Tay–Sachs disease uses miglustat. This drug is a reversible inhibitor of the enzyme glucosylceramide synthase, which catalyzes the first step in synthesizing glucose-based glycosphingolipids like GM2 ganglioside.
=== Increasing β-hexosaminidase A activity ===
As Tay–Sachs disease is a deficiency of β-hexosaminidase A, deterioration of affected individuals could be slowed or stopped through the use of a substance that increases its activity. However, since in infantile Tay–Sachs disease there is no β-hexosaminidase A, the treatment would be ineffective, but for people affected by Late-Onset Tay–Sachs disease, β-hexosaminidase A is present, so the treatment may be effective. The drug pyrimethamine has been shown to increase activity of β-hexosaminidase A. However, the increased levels of β-hexosaminidase A still fall far short of the desired "10% of normal HEXA", above which the phenotypic symptoms begin to disappear.
=== Cord blood transplant ===
This is a highly invasive procedure that involves destroying the patient's blood system with chemotherapy and administering cord blood. Of five people who had received the treatment as of 2008, two were still alive after five years and they still had a great deal of health problems.
Critics point to the procedure's harsh nature—and the fact that it is unapproved. Other significant issues involve the difficulty in crossing the blood–brain barrier, as well as the great expense, as each unit of cord blood costs $25,000, and adult recipients need many units.
=== Gene therapy ===
On 10 February 2022, the first-ever gene therapy was announced, it uses an adeno-associated virus (AAV) to deliver the correct instruction for the HEXA gene on brain cells which causes the disease. Only two children were part of a compassionate trial presenting improvements over the natural course of the disease and no vector-related adverse events.
== References ==
== External links ==
GeneReviews/NCBI/NIH/UW entry on hexosaminidase A deficiency, Tay–Sachs disease
NINDS Tay–Sachs Disease Information Page
Tay–Sachs disease at NLM Genetics Home Reference
Tay–Sachs on NCBI | Wikipedia/Tay–Sachs_disease |
Hematology (spelled haematology in British English) is the branch of medicine concerned with the study of the cause, prognosis, treatment, and prevention of diseases related to blood. It involves treating diseases that affect the production of blood and its components, such as blood cells, hemoglobin, blood proteins, bone marrow, platelets, blood vessels, spleen, and the mechanism of coagulation. Such diseases might include hemophilia, sickle cell anemia, blood clots (thrombus), other bleeding disorders, and blood cancers such as leukemia, multiple myeloma, and lymphoma. The laboratory analysis of blood is frequently performed by a medical technologist or medical laboratory scientist.
== Specialization ==
Physicians specialized in hematology are known as hematologists or haematologists. Their routine work mainly includes the care and treatment of patients with hematological diseases, although some may also work at the hematology laboratory viewing blood films and bone marrow slides under the microscope, interpreting various hematological test results and blood clotting test results. In some institutions, hematologists also manage the hematology laboratory. Physicians who work in hematology laboratories, and most commonly manage them, are pathologists specialized in the diagnosis of hematological diseases, referred to as hematopathologists or haematopathologists. Hematologists and hematopathologists generally work in conjunction to formulate a diagnosis and deliver the most appropriate therapy if needed. Hematology is a distinct subspecialty of internal medicine, separate from but overlapping with the subspecialty of medical oncology. Hematologists may specialize further or have special interests, for example, in:
treating bleeding disorders such as hemophilia and idiopathic thrombocytopenic purpura, with the latter of these two conditions being continuously studied by hematologists due to its unknown cause.
treating hematological malignancies such as lymphoma and leukemia (cancers)
treating hemoglobinopathies, including α-thalassemias and β-thalassemias (thalassemia syndromes) and hemoglobin S, hemoglobin C, and hemoglobin E (abnormal hemoglobins).
the science of blood transfusion and the work of a blood bank, known as transfusion medicine
bone marrow and stem cell transplantation, especially with the use of technologies to extract and isolate hematopoietic progenitor cells (HPCs).
== Training ==
Starting hematologists (in the US) complete a four-year medical degree followed by three or four more years in residency or internship programs. After completion, they further expand their knowledge by spending two or three more years learning how to experiment, diagnose, and treat blood disorders. Some exposure to hematopathology is typically included in their fellowship training. Job openings for hematologists require training in a recognized fellowship program to learn to diagnose and treat numerous blood-related benign conditions and blood cancers. Hematologists typically work across specialties to care for patients with complex illnesses, such as sickle cell disease, who require complex, multidisciplinary care, and to provide consultation on cases of disseminated intravascular coagulation, thrombosis and other conditions that can occur in hospitalized patients.
== See also ==
Hematopathology
== References == | Wikipedia/Blood_disease |
Jennifer Anne Doudna (; born February 19, 1964) is an American biochemist who has pioneered work in CRISPR gene editing, and made other fundamental contributions in biochemistry and genetics. She received the 2020 Nobel Prize in Chemistry, with Emmanuelle Charpentier, "for the development of a method for genome editing." She is the Li Ka Shing Chancellor's Chair Professor in the department of chemistry and the department of molecular and cell biology at the University of California, Berkeley. She has been an investigator with the Howard Hughes Medical Institute since 1997.
In 2012, Doudna and Emmanuelle Charpentier were the first to propose that CRISPR-Cas9 (enzymes from bacteria that control microbial immunity) could be used for programmable editing of genomes, which has been called one of the most significant discoveries in the history of biology. Since then, Doudna has been a leading figure in what is referred to as the "CRISPR revolution" for her fundamental work and leadership in developing CRISPR-mediated genome editing.
Doudna's awards and fellowships include the 2000 Alan T. Waterman Award for her research on the structure of a ribozyme, as determined by X-ray crystallography and the 2015 Breakthrough Prize in Life Sciences for CRISPR-Cas9 genome editing technology, with Charpentier. She has been a co-recipient of the Gruber Prize in Genetics (2015), the Tang Prize (2016), the Canada Gairdner International Award (2016), and the Japan Prize (2017). She was named one of the Time 100 most influential people in 2015, and in 2023 was inducted into the National Inventors Hall of Fame. In 2020, Jennifer Doudna was awarded the Nobel Prize in Chemistry alongside Emmanuelle Charpentier for the development of CRISPR-Cas9 genome editing technology, which has revolutionized molecular biology and holds immense potential for treating genetic diseases.
== Early life and education ==
Jennifer Doudna was born February 19, 1964, in Washington, D.C., as the daughter of Dorothy Jane (Williams) and Martin Kirk Doudna. Her father received his PhD in English literature from the University of Michigan, and her mother held a master's degree in education. When Doudna was seven years old, the family moved to Hawaii so her father could accept a teaching position in American literature at the University of Hawaii at Hilo. Doudna's mother earned a second master's degree in Asian history from the university and taught history at a local community college.
Growing up in Hilo, Hawaii, Doudna was fascinated by the environmental beauty of the island and its flora and fauna. Nature built her sense of curiosity and her desire to understand the underlying biological mechanisms of life. This was coupled with the atmosphere of intellectual pursuit that her parents encouraged at home. Her father enjoyed reading about science and filled the home with many books on popular science. When Doudna was in the sixth grade, he gave her a copy of James Watson's 1968 book on the discovery of the structure of DNA, The Double Helix, which was a major inspiration. Doudna also developed her interest in science and mathematics in school. Even though Doudna was told that "Women don't go into science," she knew that she wanted to be a scientist no matter what. Nothing said to her made her doubt it, Doudna said, "When someone tells me I can't do something and I know that I can, it just makes me more resolved to do it."
While she attended Hilo High School, Doudna's interest in science was nurtured by her 10th-grade chemistry teacher, Jeanette Wong, whom she has routinely cited as a significant influence in sparking her nascent scientific curiosity. A visiting lecturer on cancer cells further encouraged her pursuit of science as a career choice. She spent a summer working in the University of Hawaii at Hilo lab of noted mycologist Don Hemmes and graduated from Hilo High School in 1981.
Doudna was an undergraduate student at Pomona College in Claremont, California, where she studied biochemistry. During her freshman year, while taking a course in general chemistry, she questioned her own ability to pursue a career in science, and considered switching her major to French as a sophomore. However, her French teacher suggested she stick with science. Chemistry professors Fred Grieman and Corwin Hansch at Pomona had a major impact on her. She started her first scientific research in the lab of professor Sharon Panasenko. She earned her Bachelor of Arts degree in biochemistry in 1985. She chose Harvard Medical School for her doctoral study and earned a PhD in Biological Chemistry and Molecular Pharmacology in 1989. Her Ph.D. dissertation was on a system that increased the efficiency of a self-replicating catalytic RNA and was supervised by Jack W. Szostak.
== Career and research ==
After her PhD, she held research fellowships in molecular biology at the Massachusetts General Hospital and in genetics at Harvard Medical School. From 1991 to 1994, she was Lucille P. Markey Postdoctoral Scholar in Biomedical Science at the University of Colorado Boulder, where she worked with Thomas Cech. As of 2022, Doudna has an h-index of 141 according to Google Scholar and of 111 according to Scopus.
=== Research on ribozyme structure and function ===
Early in her scientific career, Doudna worked to uncover the structure and biological function of RNA enzymes or ribozymes. While in the Szostak lab, Doudna re-engineered the self-splicing Tetrahymena Group I catalytic intron into a true catalytic ribozyme that copied RNA templates. Her focus was on engineering ribozymes and understanding their underlying mechanisms; however, she came to realize that not being able to see the molecular mechanisms of ribozymes was a major problem. Doudna went to the lab of Thomas Cech at the University of Colorado Boulder to crystallize and determine the three-dimensional structure of a ribozyme for the first time, so ribozyme structure could be compared with that of Enzymes, the catalytic Proteins. She started this project at the Cech lab in 1991 and finished it at Yale University in 1996. Doudna joined Yale's Department of Molecular Biophysics and Biochemistry as an assistant professor in 1994.
=== X-ray diffraction-based structure of active site of a ribozyme at Yale ===
At Yale, Doudna's group was able to crystallize and solve the three-dimensional structure of the catalytic core of the Tetrahymena Group I ribozyme. They showed that a core of five magnesium ions clustered in one region of the P4-P6 domain of the ribozyme, forming a hydrophobic core around which the rest of the structure could fold. This is analogous but chemically distinct from, the way proteins typically have a core of hydrophobic amino acids. Her group has crystallized other ribozymes, including the Hepatitis Delta Virus ribozyme. This initial work to solve large RNA structures led to further structural studies on an internal ribosome entry site (IRES) and protein-RNA complexes such as the signal recognition particle.
Doudna was promoted to the position of Henry Ford II Professor of Molecular Biophysics and Biochemistry at Yale in 2000. In 2000–2001, she was Robert Burns Woodward Visiting Professor of Chemistry at Harvard University.
=== Move to Berkeley ===
In 2002, she joined her husband, Jamie Cate, at Berkeley, accepting a position as professor of biochemistry and molecular biology. Doudna also gained access to the synchrotron at Lawrence Berkeley National Laboratory for her experiments with high powered x-ray diffraction.
In 2009, she took a leave of absence from Berkeley to work at Genentech to lead discovery research. She left Genentech after two months and returned to Berkeley with the help of colleague Michael Marletta, canceling all of her obligations to study CRISPR.
As of 2023, Doudna was located at the University of California, Berkeley, where she directs the Innovative Genomics Institute, a collaboration between Berkeley and UCSF founded by Doudna to develop genome editing technology and apply it to some of society's greatest problems in human health, agriculture and climate change. Doudna holds the Li Ka Shing Chancellor's Professorship in Biomedicine and Health, and is the chair of the Chancellor's Advisor Committee on Biology. Her lab now focuses on the structure and function of CRISPR-Cas systems, developing new genome editing technology and delivery mechanisms for CRISPR therapeutics, and novel techniques for precisely editing microbiomes.
=== CRISPR-Cas9 genome editing discovery ===
Doudna was introduced to CRISPR by Jillian Banfield in 2006 who had found Doudna by way of a Google search, having typed "RNAi and UC Berkeley" into her browser, and Doudna's name came up at the top of the list. In 2012, Doudna and her colleagues made a new discovery that reduces the time and work needed to edit genomic DNA. Their discovery relies on a protein named Cas9 found in the Streptococcus bacterial "CRISPR" immune system that cooperates with guide RNA and works like scissors. The protein attacks its prey, the DNA of viruses, and slices it up, preventing it from infecting the bacterium. This system was first discovered by Yoshizumi Ishino and colleagues in 1987 and later characterized by Francisco Mojica, but Doudna and Emmanuelle Charpentier showed for the first time that they could use different RNAs to program it to cut and edit different DNAs.
As CRISPR becomes increasingly used to edit multicellular organisms, Doudna continues to be called upon to serve as a thought-leader on the ethics of changing an organism's function using CRISPR technology. Their discovery has since been further developed by many research groups for applications ranging from fundamental cell biology, plant, and animal research to treatments for diseases including sickle cell anemia, cystic fibrosis, Huntington's disease, and HIV. Doudna and several other leading biologists called for a worldwide moratorium on any clinical application of gene editing using CRISPR. Doudna supports the usage of CRISPR in somatic gene editing, gene alterations which do not get passed to the next generation, but not germline gene editing.
The CRISPR system created a new straightforward way to edit DNA and there was a rush to patent the technique. Doudna and UC Berkeley collaborators applied for a patent and so did a group at the Broad Institute affiliated with the Massachusetts Institute of Technology and Harvard. Feng Zhang at the Broad Institute had shown that CRISPR-Cas9 could edit genes in cultured human cells a few months after Doudna and Charpentier published their method. Before the UC Berkeley patent application was decided, a patent was granted to the Broad investigators and UC Berkeley filed a lawsuit against the decision. In 2017, the court decided in favor of the Broad Institute, who claimed that they had initiated the research earliest and had first applied it to human cell engineering thus supporting editing in human cells with evidence but that the UC Berkeley group had only suggested this application. UC Berkeley appealed on grounds that they had clearly discussed and spelled out how to do the application the Broad had pursued. In September 2018, the appeals court decided in favor of the Broad Institute's patent. Meanwhile, UC Berkeley and co-applicants' patent to cover the general technique was also granted. To further cloud the issue, in Europe the claim of the Broad Institute, to have initiated the research first, was disallowed. The rejection was due to a procedural flaw in the application involving a different set of personnel listed in the lawsuit and the patent application, leading to speculation that the UC Berkeley group would prevail in Europe. Doudna cofounded Caribou Biosciences, a company to commercialize CRISPR technology, in 2011. In September 2013, Doudna cofounded Editas Medicine with Zhang and others despite their legal battles, but she quit in June 2014; Charpentier then invited her to join CRISPR Therapeutics, but she declined following the "divorce"-like experience at Editas. Doudna is also a cofounder of Caribou spin-off Intellia Therapeutics and Scribe Therapeutics, which pioneered CasX, a more compact, next-generation Cas9 which can efficiently cut DNA.
In 2017, with Samuel H. Sternberg, she co-authored A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, a rare case of the first-person account of a major scientific breakthrough, aimed at the general public.
In addition to the CRISPR breakthrough, Doudna has discovered that the hepatitis C virus utilizes an unusual strategy to synthesize viral proteins. This work could lead to new drugs to stop infections without causing harm to the tissues of the body.
"I have so much optimism about what CRISPR can do to help cure unaddressed genetic diseases and improve sustainable agriculture, but I'm also concerned that the benefits of the technology might not reach those who need it most if we're not thoughtful and deliberate about how we develop the technology," Doudna said.
=== Mammoth Biosciences ===
In 2017, Doudna co-founded Mammoth Biosciences, a San Francisco-based bioengineering tech startup. Initial funding raised $23 million, with a series B round of funding in 2020 raising $45 million. The business is focused on improving access to bio sensing tests which address "challenges across healthcare, agriculture, environmental monitoring, biodefense, and more."
=== COVID-19 response ===
Beginning in March 2020, Doudna organized an effort to use CRISPR-based technologies to address the COVID-19 pandemic along with Dave Savage, Robert Tjian, Fyodor Urnov, Patrick Hsu, and other colleagues at the Innovative Genomics Institute (IGI), where they also created a testing center. This center processed over 500,000 patient samples from UC Berkeley students, staff and faculty as well as members of the surrounding community and farm workers in the Salinas area. Mammoth Biosciences announced a peer-reviewed validation of a rapid, CRISPR-based point of need COVID-19 diagnostic which is faster and less expensive than qRT-PCR based tests.
=== Other activities ===
She is also the founder and chair of the governance board of the Innovative Genomics Institute, which she co-founded in 2014. Doudna is also a faculty scientist at Lawrence Berkeley National Laboratory (LBNL), a senior investigator at the Gladstone Institutes, and an adjunct professor of cellular and molecular pharmacology at the University of California, San Francisco (UCSF). In 2025, a new supercomputer named after Doudna was announced for the National Energy Research Scientific Computing Center at LBNL, intended as the successor to the Perlmutter supercomputer.
Doudna is on the scientific advisory boards of the companies that she cofounded, such as Caribou, Intellia, Mammoth, and Scribe; as well as others such as Altos Labs, Isomorphic Labs, Johnson & Johnson, Synthego, Tempus AI, and Welch Foundation. She joined Sixth Street Partners in 2022 as their chief science advisor, to guide investment decisions related to CRISPR.
== Personal life ==
Doudna's first marriage was in 1988 to a fellow graduate student at Harvard named Tom Griffin, but his interests were more broad and less focused on research than hers and they divorced a few years later. Griffin wanted to move to Boulder, Colorado, where Doudna was also interested in working with Thomas Cech. As a postdoctoral researcher at the University of Colorado, Doudna met Jamie Cate, then a graduate student. They worked together on the project to crystallize and determine the structure of the Tetrahymena Group I intron P4-P6 catalytic region. Doudna brought Cate with her to Yale, and they married in Hawaii in 2000. Cate later became a professor at the Massachusetts Institute of Technology and Doudna followed him to Boston at Harvard, but in 2002 they both accepted faculty positions at Berkeley and moved there together; Cate preferred the less formal environment on the West Coast from his earlier experiences at the University of California, Santa Cruz and the Lawrence Berkeley National Laboratory, and Doudna liked that Berkeley is a public university. Cate is a Berkeley professor and works on gene-editing yeast to increase their cellulose fermentation for biofuel production. Doudna and Cate have a son born in 2002 who attends UC Berkeley, studying electrical engineering and computer science. They live in Berkeley.
== Awards and honors ==
Doudna was a Searle Scholar and received the 1996 Beckman Young Investigators Award. In 2000, she was awarded the Alan T. Waterman Award, the National Science Foundation's highest honor that annually recognizes an outstanding researcher under the age of 35, for her structure determination of a ribozyme. In 2001, she received the Eli Lilly Award in Biological Chemistry of the American Chemical Society.
In 2015, together with Emmanuelle Charpentier, she received the Breakthrough Prize in Life Sciences for her contributions to CRISPR/Cas9 genome editing technology. In 2016, together with Charpentier, Feng Zhang, Philippe Horvath and Rodolphe Barrangou, she received the Canada Gairdner International Award. Also in 2016, she received the Heineken Prize for Biochemistry and Biophysics. She has also been a co-recipient of the Gruber Prize in Genetics (2015), the Tang Prize (2016), the Japan Prize (2017) and the Albany Medical Center Prize (2017). In 2018, Doudna was awarded the NAS Award in Chemical Sciences, the Pearl Meister Greengard Prize from the Rockefeller University, and a Medal of Honor from the American Cancer Society. Also in 2018, she was awarded the Kavli Prize in Nanoscience (jointly with Emmanuelle Charpentier and Virginijus Šikšnys). In 2019 she received the Harvey Prize of the Technion/Israel for the year 2018 (jointly with Emmanuelle Charpentier and Feng Zhang) and the LUI Che Woo Prize in the category of Welfare Betterment. In 2020, she received the Wolf Prize in Medicine (jointly with Emmanuelle Charpentier). Also in 2020, Doudna and Charpentier were awarded the Nobel Prize in Chemistry "for the development of a method for genome editing." In 2025 she was awarded the National Medal of Technology and Innovation
She was elected to the National Academy of Sciences in 2002, the American Academy of Arts and Sciences in 2003, the National Academy of Medicine in 2010 and the National Academy of Inventors in 2014. In 2015, together with Charpentier, she became a fellow of the American Academy of Microbiology. She was elected a Foreign Member of the Royal Society (ForMemRS) in 2016. In 2017, Doudna was awarded the Golden Plate Award of the American Academy of Achievement. In 2020, she was awarded a Guggenheim Fellowship. In 2021 she received the Award for Excellence in Molecular Diagnostics from the Association for Molecular Pathology. In 2021, Pope Francis appointed Doudna, and two other women Nobel laureates Donna Strickland and Emmanuelle Charpentier, as members of the Pontifical Academy of Sciences.
She along with Charpentier was named one of the Time 100 most influential people in 2015, and she was a runner-up for Time Person of the Year in 2016 alongside other CRISPR researchers.
In 2018 and 2023, she received honorary Doctor of Science degrees from USC and Harvard, respectively.
== References ==
== Bibliography ==
Isaacson, Walter (2021). "Introduction – Into the Breach". The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race. Simon & Schuster. ISBN 978-1-9821-1585-2. Retrieved March 8, 2021.
== External links ==
Jennifer Doudna publications indexed by Google Scholar
"Jennifer Doudna (UC Berkeley / HHMI): Genome Engineering with CRISPR-Cas9". YouTube. iBiology Science Stories. March 23, 2015.
"Jennifer Doudna: CRISPR Basics". YouTube. Innovative Genomics Institute – IGI. November 4, 2017.
"Into the Future with CRISPR Technology with Jennifer Doudna". YouTube. University of California Television (UCTV). October 26, 2019.
CRISPR Scientist's Biography Explores Ethics Of Rewriting The Code Of Life. Author interview, audio and transcript. Fresh Air, NPR, March 8, 2021.
"How CRISPR lets us edit our DNA". TED talk by Jennifer Doudna on YouTube
Jennifer A. Doudna on Nobelprize.org | Wikipedia/Jennifer_Doudna |
Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule:
triacylglycerol + H2O = diacylglycerol + a carboxylate
It is also involved in promoting the cellular uptake of chylomicron remnants, cholesterol-rich lipoproteins, and free fatty acids. LPL requires ApoC-II as a cofactor.
LPL is attached to the luminal surface of endothelial cells in capillaries by the protein glycosylphosphatidylinositol HDL-binding protein 1 (GPIHBP1) and by heparan sulfated peptidoglycans. It is most widely distributed in adipose, heart, and skeletal muscle tissue, as well as in lactating mammary glands.
== Synthesis ==
In brief, LPL is secreted from heart, muscle and adipose parenchymal cells as a glycosylated homodimer, after which it is translocated through the extracellular matrix and across endothelial cells to the capillary lumen. After translation, the newly synthesized protein is glycosylated in the endoplasmic reticulum. The glycosylation sites of LPL are Asn-43, Asn-257, and Asn-359. Glucosidases then remove terminal glucose residues; it was once believed that this glucose trimming is responsible for the conformational change needed for LPL to form homodimers and become catalytically active. In the Golgi apparatus, the oligosaccharides are further altered to result in either two complex chains, or two complex and one high-mannose chain. In the final protein, carbohydrates account for about 12% of the molecular mass (55-58 kDa).
Homodimerization is required before LPL can be secreted from cells. After secretion, LPL is carried across endothelial cells and presented into the capillary lumen by the protein glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1.
== Structure ==
Crystal structures of LPL complexed with GPIHBP1 have been reported. LPL is composed of two distinct regions: the larger N-terminus domain that contains the lipolytic active site, and the smaller C-terminus domain. These two regions are attached by a peptide linker. The N-terminus domain has an α/β hydrolase fold, which is a globular structure containing a central β sheet surrounded by α helices. The C-terminus domain is a β sandwich formed by two β sheet layers, and resembles an elongated cylinder.
== Mechanism ==
The active site of LPL is composed of the conserved Ser-132, Asp-156, and His-241 triad. Other important regions of the N-terminal domain for catalysis includes an oxyanion hole (Trp-55, Leu-133), a lid region (residues 216-239), as well as a β5 loop (residues 54-64). The ApoC-II binding site is currently unknown, but it is predicted that residues on both N-and C-terminal domains are necessary for this interaction to occur. The C-terminal domain appears to confer LPL’s substrate specificity; it has a higher affinity for large triacylglyceride-rich lipoproteins than cholesterol-rich lipoproteins. The C-terminal domain is also important for binding to LDL’s receptors. Both the N-and C-terminal domains contain heparin binding sites distal to the lipid binding sites; LPL therefore serves as a bridge between the cell surface and lipoproteins. Importantly, LPL binding to the cell surface or receptors is not dependent on its catalytic activity.
The LPL non-covalent homodimer has a head-to-tail arrangement of the monomers. The Ser/Asp/His triad is in a hydrophobic groove that is blocked from solvent by the lid. Upon binding to ApoC-II and lipid in the lipoprotein, the C-terminal domain presents the lipid substrate to the lid region. The lipid interacts with both the lid region and the hydrophobic groove at the active site; this causes the lid to move, providing access to the active site. The β5 loop folds back into the protein core, bringing one of the electrophiles of the oxyanion hole into position for lipolysis. The glycerol backbone of the lipid is then able to enter the active site and is hydrolyzed.
Two molecules of ApoC-II can attach to each LPL dimer. It is estimated that up to forty LPL dimers may act simultaneously on a single lipoprotein. In regard to kinetics, it is believed that release of product into circulation is the rate-limiting step in the reaction.
== Function ==
LPL gene encodes lipoprotein lipase, which is expressed in the heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Through catalysis, VLDL is converted to IDL and then to LDL. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism.
== Regulation ==
LPL is controlled transcriptionally and posttranscriptionally. The circadian clock may be important in the control of Lpl mRNA levels in peripheral tissues.
LPL isozymes are regulated differently depending on the tissue. For example, insulin is known to activate LPL in adipocytes and its placement in the capillary endothelium. By contrast, insulin has been shown to decrease expression of muscle LPL. Muscle and myocardial LPL is instead activated by glucagon and adrenaline. This helps to explain why during fasting, LPL activity increases in muscle tissue and decreases in adipose tissue, whereas after a meal, the opposite occurs.
Consistent with this, dietary macronutrients differentially affect adipose and muscle LPL activity. After 16 days on a high-carbohydrate or a high-fat diet, LPL activity increased significantly in both tissues 6 hours after a meal of either composition, but there was a significantly greater rise in adipose tissue LPL in response to the high-carbohydrate diet compared to the high-fat diet. There was no difference between the two diets' effects on insulin sensitivity or fasting LPL activity in either tissue.
The concentration of LPL displayed on endothelial cell surface cannot be regulated by endothelial cells, as they neither synthesize nor degrade LPL. Instead, this regulation occurs by managing the flux of LPL arriving at the lipolytic site and by regulating the activity of LPL present on the endothelium. A key protein involved in controlling the activity of LPL is ANGPTL4, which serves as a local inhibitor of LPL. Induction of ANGPTL4 accounts for the inhibition of LPL activity in white adipose tissue during fasting. Growing evidence implicates ANGPTL4 in the physiological regulation of LPL activity in a variety of tissues.
An ANGPTL3-4-8 model was proposed to explain the variations of LPL activity during the fed-fast cycle. Specifically, feeding induces ANGPTL8, activating the ANGPTL8–ANGPTL3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating triglycerides available for uptake by white adipose tissue, in which LPL activity is elevated owing to diminished ANGPTL4; the reverse is true during fasting, which suppresses ANGPTL8 but induces ANGPTL4, thereby directing triglycerides to muscles. The model suggests a general framework for how triglyceride trafficking is regulated.
== Clinical significance ==
Lipoprotein lipase deficiency leads to hypertriglyceridemia (elevated levels of triglycerides in the bloodstream). In mice, overexpression of LPL has been shown to cause insulin resistance, and to promote obesity.
A high adipose tissue LPL response to a high-carbohydrate diet may predispose toward fat gain. One study reported that subjects gained more body fat over the next four years if, after following a high-carbohydrate diet and partaking of a high-carbohydrate meal, they responded with an increase in adipose tissue LPL activity per adipocyte, or a decrease in skeletal muscle LPL activity per gram of tissue.
LPL expression has been shown to be a prognostic predictor in Chronic lymphocytic leukemia. In this haematological disorder, LPL appears to provide fatty acids as an energy source to malignant cells. Thus, elevated levels of LPL mRNA or protein are considered to be indicators of poor prognosis.
== Interactions ==
Lipoprotein lipase has been shown to interact with LRP1. It is also a ligand for α2M, GP330, and VLDL receptors. LPL has been shown to be a ligand for LRP2, albeit at a lower affinity than for other receptors; however, most of the LPL-dependent VLDL degradation can be attributed to the LRP2 pathway. In each case, LPL serves as a bridge between receptor and lipoprotein.
While LPL is activated by ApoC-II, it is inhibited by ApoCIII.
== In other organisms ==
The LPL gene is highly conserved across vertebrates. Lipoprotein lipase is involved in lipid transport in the placentae of live bearing lizards (Pseudemoia entrecasteauxii).
== Interactive pathway map ==
Click on genes, proteins and metabolites below to link to respective articles.
== References ==
== Further reading ==
== External links ==
GeneReviews/NCBI/NIH/UW entry on Familial Lipoprotein Lipase Deficiency
Gene therapy for lipoprotein lipase deficiency
Lipoprotein+lipase at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Lipoprotein_lipase |
Gene therapy for color blindness is an experimental gene therapy of the human retina aiming to grant typical trichromatic color vision to individuals with congenital color blindness by introducing typical alleles for opsin genes. Animal testing for gene therapy began in 2007 with a 2009 breakthrough in squirrel monkeys suggesting an imminent gene therapy in humans. While the research into gene therapy for red-green colorblindness has lagged since then, successful human trials are ongoing for achromatopsia. Congenital color vision deficiency affects upwards of 200 million people in the world, which represents a large demand for this gene therapy.
== Color vision ==
The retina of the human eye contains photoreceptive cells called cones that allow color vision. A normal trichromat possesses three different types of cones to distinguish different colors within the visible spectrum. The three types of cones are designated L, M, and S cones, each containing an opsin sensitive to a different portion of the visible spectrum. More specifically, the L cone absorbs around 560 nm, the M cone absorbs near 530 nm, and the S cone absorbs near 420 nm. These cones transduce the absorbed light into electrical information to be relayed through other cells along the phototransduction pathway, before reaching the visual cortex in the brain.
The signals from the 3 cones are compared to each other to generate 3 opponent process channels. The channels are perceived as balances between red-green, blue-yellow and black-white.
== Color vision deficiency ==
Color vision deficiency (CVD) is the deviation of an individual's color vision from typical human trichromatic vision. Relevant to gene therapy, CVD can be classified in 2 groups.
=== Dichromacy ===
Dichromats have partial color vision. The most common form of dichromacy is red-green colorblindness. Dichromacy usually arises when one of the three opsin genes is deleted or otherwise fully nonfunctional. The effects and diagnosis depend on the missing opsin. Protanopes (very common) have no L-opsin, Deuteranopes (very common) have no M-opsin, and Tritanopes (rare) have no S-opsin. Accordingly, a missing cone means one of the opponent channels is inactive: red-green for protanopes/deuteranopes and blue-yellow for tritanopes. They therefore perceive a much reduced color space. Although dichromacy poses few critical problems in daily life, a lack of access to many occupations (where color vision may be safety-critical) is a large disadvantage.
Anomalous Trichromats are not missing an opsin gene, but rather have a mutated (or chimeric) gene. They have trichromatic vision, but with a smaller color gamut than typical color vision. Regarding gene therapy, they are equivalent to dichromats.
Blue Cone Monochromats are missing both the L- and M-opsin and therefore have no color vision. They are treated as a subset of dichromacy since a combination of gene therapies for protanopia and deuteranopia would be used.
=== Achromatopsia ===
Individuals with congenital achromatopsia tend to have typical opsin genes, but have a mutation in another gene downstream in the phototransduction pathway (e.g. GNAT2 protein) that prevents their cones (and therefore photopic vision) from functioning. Achromats rely solely on their scotopic vision. The severity of achromatopsia is much higher than dichromacy, not only in the lack of color vision, but also in co-occurring symptoms photophobia, nystagmus and poor visual acuity.
== Retinal gene therapy ==
Gene therapies aim to inject functional copies of missing or mutated genes into affected individuals by the use of viral vectors. Using a replication-defective recombinant adeno-associated virus (rAAV) as a vector, the cDNA of the affected gene can be delivered to the cones at the back of the retina typically via subretinal injection. Intravitreal injections are much less invasive, but not yet as effective as subretinal injections. Upon gaining the gene, the cone begins to express the new photopigment. The effect is ideally permanent.
== Research ==
The first retinal gene therapy to be approved by the FDA was Voretigene neparvovec in 2017, which treats Leber's congenital amaurosis, a genetic disorder that can lead to blindness. These treatments also use subretinal injections of AAV vector and are therefore foundational to research in gene therapy for color blindness.
Human L-cone photopigment have been introduced into mice. Since the mice possess only S cones and M cones, they are dichromats. M-opsin was replaced with a cDNA of L-opsin in the X chromosome of some mice. By breeding these "knock-in" transgenic mice, they generated heterozygous females with both an M cone and an L cone. These mice had improved range of color vision and have gained trichromacy, as tested by electroretinogram and behavioral tests. However, this is more difficult to apply in the form of gene therapy.
Recombinant AAV vector was to introduce the green fluorescent protein (GFP) gene in the cones of gerbils. The genetic insert was designed to only be expressed in S or M cones, and the expression of GFP in vivo was observed over time. Gene expression could stabilize if a sufficiently high dose of the viral vector is given.
In 2009, adult dichromatic squirrel monkeys were converted into trichromats using gene therapy. New world monkeys are polymorphic in their M-opsin, such that females can be trichromatic, but all males are dichromatic. Recombinant AAV vector was used to deliver a human L-opsin gene subretinally. A subset of the monkey's M-cones gained the L-opsin genes and began co-expressing the new and old photopigments. Electroretinograms demonstrated that the cones were expressing the new opsin and after 20 weeks a pseudoisochromatic color vision test demonstrated that the treated monkeys had indeed developed functional trichromatic vision.
Gene therapy was to restore some of the sight of mice with achromatopsia. The results were positive for 80% of the mice treated.
In 2010, gene therapy for a form of achromatopsia was performed in dogs. Cone function and day vision have been restored for at least 33 months in two young dogs with achromatopsia. However, this therapy was less efficient for older dogs.
In 2022, 4 young human ACHM2 and ACHM3 achromats were shown to have neurological responses (as measured with fMRI) to photopic vision that matched patterns generated by their scotopic vision after gene therapy. This inferred a photopic cone-driven system that was at least marginally functional. The methodology did not investigate novel color vision, though one respondent claimed to more easily interpret traffic lights. This may be considered the first case of a cure for colorblindness in humans.
In July 2023, a study found positive but limited improvements on congenital CNGA3 achromatopsia.
== Challenges ==
While the benefits of gene therapy to achromats typically outweigh the current risks, there are several challenges before large acceptance of gene therapy in dichromats can occur.
=== Safety ===
The procedure – namely the subretinal injection – is quite invasive, requiring several incisions and punctures in the eyeball. This poses a significant risk of infection and other complications. Subretinal injections methods promise to become less invasive with their application in other retinal gene therapies. They could also be replaced by intravitreal injections, which are significantly less invasive and can in theory be performed by a family doctor, but are less effective.
The permanence of these therapies is also in question. Mancuso et al. reported that the treated squirrel monkeys maintained 2 years of color vision after the treatment. However, if repeat injections are needed, there is also the concern of the body developing an immune reaction to the virus. If a body develops sensitivity to the viral vector, the success of the therapy could be jeopardized and/or the body may respond unfavorably. An editorial by J. Bennett points to Mancuso et al.'s use of an "unspecified postinjection corticosteroid therapy". Bennett suggests that the monkeys may have experienced inflammation due to the injection. However, the AAV virus that is commonly used for this study is non-pathogenic, and the body is less likely to develop an immune reaction.
=== Neuroplasticity ===
According to research by David H. Hubel and Torsten Wiesel, suturing shut one eye of monkeys at an early age resulted in an irreversible loss of vision in that eye, even after the suture was removed. The study concluded that the neural circuitry for vision is wired during a "critical period" in childhood, after which the visual circuitry can no longer be rewired to process new sensory input. Contrary to this finding, Mancuso et al.’s success in conferring trichromacy to adult squirrel monkeys suggests that it is possible to adapt the preexisting circuit to allow greater acuity in color vision. The researchers concluded that integrating the stimulus from the new photopigment as an adult was not analogous to vision loss following visual deprivation.
It is yet unknown how the animals that gain a new photopigment are perceiving the new color. While the article by Mancuso et al. states that the monkey has indeed gained trichromacy and gained the ability to discriminate between red and green, they claim no knowledge of how the animal internally perceives the sensation.
=== Ethics ===
As a way to introduce new genetic information to change a person's phenotype, a gene therapy for color blindness is open to the same ethical questions and criticisms as gene therapy in general. These include issues around the governance of the therapy, whether treatment should be available only to those who can afford it, and whether the availability of treatment creates a stigma for those with color blindness. Given the large number of people with color blindness, there is also the question of whether color blindness is a disorder. Furthermore, even if gene therapy succeeds in converting incomplete colorblind individuals to trichromats, the degree of satisfaction among the subjects is unknown. It is uncertain how the quality of life will improve (or worsen) after the therapy.
The gene therapy for converting dichromats to trichromats can also be used hypothetically to "upgrade" typical trichromats to tetrachromats by introducing a new opsin genes. This begs the ethics of designer babies that contain genes not available naturally in the human gene pool. In 2022, the lab of Jay Neitz engineered a novel opsin sensitive to wavelengths between the typical human S- (420 nm) and M- (530 nm) opsins, i.e. the novel opsin at 493 nm. This allowed the opsin to be clearly visible in ERGs, but could be used to create tetrachromacy.
== See also ==
Color vision
Gene therapy
Achromatopsia
Color blindness
Gene therapy of the human retina
Stem cell therapy for macular degeneration
== References == | Wikipedia/Gene_therapy_for_color_blindness |
Gene therapy in Parkinson's disease consists of the creation of new cells that produce a specific neurotransmitter (dopamine), protect the neural system, or the modification of genes that are related to the disease. Then these cells are transplanted to a patient with the disease. There are different kinds of treatments that focus on reducing the symptoms of the disease but currently there is no cure.
== Current treatments ==
Parkinson's disease (PD) is a progressive neurological disorder resulting from the death of cells in the substantia nigra that contain and produce dopamine. People with PD may develop disturbance in their motor activities. Some activities can be tremor or shaking, rigidity and slow movements (bradykinesia). Patients may eventually present certain psychiatric problems like depression and dementia. Current pharmacological intervention consist on the administration of L-dopa, a dopamine precursor. The L-dopa therapy increases dopamine production of the remaining nigral neurons. Other therapy is the deep brain electrical stimulation to modulate the overactivity of the subthalamic nucleus to the loss of dopamine signaling in the stratum. However, with this treatment, the number of substantia nigra neurons decrease so it becomes less efficient.
These treatments try to reduce the symptoms of the patient focusing on increasing the production of dopamine but they do not cure the disease. The new treatments for PD are in clinical trials and most of them are centered on gene therapy. With this, researchers expect to compensate the loss of dopamine or to protect the dopamine neurons from degeneration. The pharmacological and surgical therapies for PD focus on compensating the ganglia dysfunction caused by the degeneration of the dopaminergic neuron from substantia nigra.
== Gene therapy background ==
There are many new PD treatments in clinical trials and several of those are focusing on gene therapeutic approaches that compensate the loss of dopamine or protect the nervous system dopamine neurons from degeneration. There are some important reasons for focusing on gene therapy as a treatment for PD. First of all, currently there is no cure for this disease. Secondly, some genes have been identified which can modulate the neuron phenotype or act as neuroprotective agents. Also, the environment of the brain cannot afford repeated injections into the region where the substantia nigra meets the striatum, the nigrostriatum. Therefore, gene therapy could be a single treatment appealing, viral vectors used in the therapy are diffusible and capable to do transduction of the striatum.
== Gene therapy bases ==
The main idea of the gene therapy is to create new generations of cells that produce particular neurotransmitter (dopamine) and then transplant these cells to the patients with PD. This is because the neurons cannot proliferate nor be renewed; and replacing lost neurons it is a process that is currently going under investigation. Also, the use of embryonic dopaminergic cells cannot be used because these cells are difficult to obtain and modifications of cell can only be made on somatic cells, not germline. With the modifications of the transplanted cell, there can be a change in the expression of the genes or normalize them.
== Types of gene therapy ==
There are several types of gene therapy. There are therapies for symptomatic approaches like the production of ectopic L-dopa, the full ectopic dopamine synthesis, the ectopic L-dopa conversion or the use of glutamic acid descarboxylase (GAD). Also there are disease modifying therapies like NTN or GNDF (glial cell line-derived neurotrophic factor), the regulation of the α-synuclein and Parkin gene expression. Currently the main studies are using AAV2 as a vector platform, making it the standard vector for this disease although a lentevirus has also been used. In the different types of the gene therapy, the investigations are encoding enzymes that are necessary for dopamine synthesis, such as tyrosine hydroxylase, GTP cyclohydrolase 1 and AADC.
=== Symptomatic approaches ===
A symptomatic approach is a treatment focused on the symptoms of the patients. The first one, consists in the ectopic dopamine synthesis. Here, the production of ectopic L-dopa in the striatum is another alternative gene therapy. This therapy consists on transferring the TH and GTP cyclohydrolase 1 genes into the MSNs because the endogenous AADC activity is able to convert the L-dopa into dopamine. In an experiment in 2005, using tyrosine hydroxylase (TH) and GCH1 altogether with vectors, they could provide normal levels of L-dopa to rats. The results of this experiment showed reduced dyskinesias by 85% as well as, the reversion view of abnormal projections in the striatum using the TH-GCH1 gene transfer.
Dopamine synthesis can be fully ectopic. In this case, the enzyme AADC it is in charge of converting the levodopa to dopamine. In Parkinson disease, the loss of neurons from the nigrostriatum leads to the inability to convert levodopa to dopamine. The goal of AAV2-hAADC is to restore normal levels of AADC in the striatum so there could be more conversion of levodopa, and therefore reducing levodopa- induced dyskinesia. Using the gene therapy, in 2012, an experiment was accomplish with primates testing tyrosine hydroxylase (TH) transgene in primate astrocytes. Gene therapy was made with the transfer of a TH full-length cDNA using rat TH. The results showed behavioural improvement in the monkeys that received the plasmid, unlike the control monkey.
Another type is the ectopic L-dopa conversion in which they use a gene enzyme replacement therapy that can be used to increase the efficacy of the pharmacological L-dopa therapy by using AAV vectors. This AAV vectors have been designed to send the AADC coding sequence to the MSN (medium spiny neurons) in the striatum to be able to convert administered L-dopa into dopamine.
Other kind of gene therapy as a symptomatic approach is the use of glutamic acid decarboxylase (GAD) expression in the subthalamic nucleus. This is a gene enzyme replacement therapy that can be used to increase the efficacy of the pharmacological L-dopa therapy by using AAV vectors. This AAV vectors have been designed to send the AADC coding sequence to the MSN in the striatum to be able to convert administered L-dopa into dopamine. A phase 2 study, published in the journal Lancet Neurology Parkinson, says that a gene therapy called NLX-P101 dramatically reduces movement damage. In this study, they used glutamic acid decarboxylase (GAD). They introduced genetic material in the brain related to motor functions. The symptoms included tremor, stiffness and difficulty in movements; and were improved in half of the group in gene therapy, while in the control group, 14% improved them.
=== Disease modifying ===
There are therapies in development based in the modification of the disease. The first one is the neurotrophic factors gene delivery. In this therapy, GNDF or NTN are used to protect the system. GNDF is a factor of the TGFß superfamily, is secreted by astrocytes (glia cells that are in charge of the survival of the midbrain dopaminergic neurons) and is homologous to NTN, persephin and artemin. Preclinical studies of the nigrostriatal dopaminergic in relation to Parkinson disease system have shown that GNDF and NTN are very potential neuroprotective agents.
Another type in the disease's modification technique is the synuclein silencing. Some cases of PD were related to polymorphisms in the α-synuclein promoter and also in the multiplication of the locus that carries the α-synuclein gene. Therefore, trying to down-regulate the α-synuclein expression could impact the development of the disease. There have been explored several viral vector-based gene delivery system that interfere with α- synuclein expression, and they depend on the interference of the RNA (destabilizing the α-synuclein RNAm) and/or the block the protein translation (using short hairpin RNA or micro RNA directed against the α-synuclein RNAm sequence).
The discovery of the Parkin gene is another type of modification of PD. The Parkin gene is linked with mutations associated with autosomal recessive juvenile parkinsonism (previous state of Parkinson with the typical symptoms and pathology but with a slow progression). The mutations in the Parkin gene are responsible for the development of the autosomal recessive juvenile parkinsonism.
== New projects and investigations ==
More gene therapy trials have been conducted for PD (with the adeno-associated virus 2 gene), the objectives and strategies used on the actual researches are clear, the research tries to translate the experience obtained during the trials and try to improve the development of new technology for the gene therapy of PD.
== References == | Wikipedia/Gene_therapy_in_Parkinson's_disease |
A protein corona is a dynamic coating of biomolecules, usually proteins, around the surface of a nanoparticle that forms spontaneously in colloidal nanomaterials upon exposure to biological mediums. Protein coronas can form in many different patterns depending on their size, shape, composition, charge, and surface functional groups, and have properties that vary in different environmental factors like temperature, pH, shearing stress, immersed media composition, and exposing time. These coatings are also changeable according to the conditions of the biochemical and physiochemical surface interactions. Types of protein coronas are known to be divided into two categories: “hard” and “soft”. “Hard” coronas have higher-affinity proteins that are irreversibly bonded to the nanoparticle surface, while “soft” coronas have lower-affinity proteins on the nanoparticle surface that are reversibly bound. These reversibly-bound proteins allow for the biomolecules in “soft” protein coronas to be exchanged or detached over time for various applications. This process is governed by the intermolecular protein-nanoparticle and protein-protein interactions that exist within a solution. In "soft" protein coronas, it is common to observe an exchange of proteins at the surface; larger proteins with lower affinities will often aggregate to the surface of the nanoparticle first, and over time, smaller proteins with higher affinities will replace them, "hardening" the corona, known as the Vroman effect.
== Factors affecting formation ==
It is known that multiple physicochemical and biochemical factors influence the formation and composition of protein coronas. Many previous studies have focused on understanding these processes and how they can be utilized.
=== Protein composition and concentration ===
To determine how the protein composition and concentration affects protein coronas, one study incubated silica nanoparticles in plasma medium for 1 hr and observed the formation of the corona. They found that the proteins adsorbed easily to the silica surface and expressed themselves in different patterns depending on the amount of plasma present in the incubated medium. The experiment was run with 3%, 20%, and 80% plasma, and it was discovered that in the case of plasma, where there is a much higher concentration of lower-affinity proteins than high-affinity proteins, the lower-affinity proteins had a tendency to replace the higher-affinity proteins on the surface of the nanoparticle because of their higher abundance within the plasma. From studies like these, it is clear that a protein corona can be altered significantly, depending on the weight and affinity of the biological molecules in a particular medium.
=== Media exposure ===
Another major factor that affects protein coronas is exposure time, or the amount of time a nanoparticle coated in proteins is exposed to fluidic media. Since it is well known that instantly upon introduction of a nanoparticle to a biomolecular medium, a protein corona forms on its surface, one study exposed nanoparticles to biological fluids like human plasma and observed how the length of exposure to these mediums can affect the formation of the corona. After only 30 seconds of interaction, almost 300 proteins were detected adsorbing to the nanoparticle surface, and a majority of those molecules had low affinity (pharmacology) and a large molecular weight. After 1 minute or more of exposure, different protein corona patterns were observed, and of the proteins detected, most of them had a higher affinity and smaller molecular weight, consistent with the Vroman effect. Thus, the length of the exposure time of the nanoparticle to biological fluid can greatly alter the composition and patterns of the protein corona.
In addition to exposure time is the factor of shearing forces. In the past, researchers studied protein-nanoparticle interactions under very static conditions so that variables could be easily controlled. However, these conditions are not very representative of the conditions of the human body where nanoparticles will generally be exposed to shearing stresses and hydrodynamic fluid conditions. Thus, experiments that accounted for fluidic conditions were necessary to understand how protein coronas would endure in the human body. One study found that fluidic flow increased the biodiversity of the protein corona and altered its shape due to the shearing forces present in the environment. Because both of these factors have implications in the functionalization of protein corona nanoparticles, these observations proved the importance of studying protein coronas in the presence of fluidic conditions.
=== Temperature ===
Temperature can also greatly affect protein-nanoparticle interactions. A study performed on Cu nanoparticles showed that as the ambient temperature of the nanoparticles was increased from 15 °C, 27 °C, and 37 °C to 42 °C, the amount of protein adsorbed to the nanoparticle surface also increased. This finding was especially interesting in the effort to utilize protein coronas to treat illnesses, because in introducing these particles into the human body, they will have to exist and function at high temperatures. In feverish individuals, their altered body temperature may potentially change the biodistribution and bio-availability of the nanoparticles. Thus, it is important for researchers to account for temperature effects on protein coronas.
=== pH effects ===
The environmental pH can also affect protein corona formation. It is known that pH is an important factor to be considered when studying the properties and functionality of proteins. pH can alter protein binding affinity in protein-nanoparticle interactions, thus modifying the adsorbed protein pattern at the surface of the nanoparticle. If used for drug delivery methods, the nanoparticles will have to undergo multiple different pH changes in the cellular uptake pathway like blood (neutral pH), exposure media (pH 6.9-7.4), intracellular fluid (pH 6.8), and lysosomes (pH 4.5-5) and be able to keep its corona intact and functional. Cancer tumors especially are known to induce acidic microenvironments as well as contain certain types of proteins that are capable of modifying the protein corona around nanoparticles which can greatly alter the body’s therapeutic response to drug molecules.
=== Nanoparticle composition ===
Lastly, the composition of the nanoparticle itself can affect the protein corona formation at its surface. Differences in the hydrophilic or hydrophobic nature of the nanoparticle material can determine the amount of proteins in the corona. Usually, proteins adsorb more easily to hydrophobic materials than hydrophilic materials. As a result, hydrophobic nanoparticles are more likely to induce particle aggregation and higher opsonization in the human body, which can decrease systemic circulation time in the blood.
Additionally, to aid in formation and solubility, nanoparticles often have ligands and functional groups on their surfaces that act like “fingerprints”. Protein fingerprints refer to the ability to differentiate or identify proteins using ligands and other methods. These fingerprints allow for nanoparticles to be tailored compositionally to adsorb specific proteins to their surfaces. Nanoparticle surface roughness may also play a role in protein corona formation, since one study found that a rough nanoparticle surface can minimize repulsive interactions between the nanoparticle and parts of the binding proteins, which increases the amount of proteins adsorbed.
== Applications ==
=== Drug delivery ===
Protein coronas can be utilized for a number of different functions, the main one being drug delivery. The corona that forms when nanoparticles come in contact with biological fluid has long been investigated for its potential to deliver important drug molecules or proteins to sites of need within the human body. Nanoparticles are known to have high drug-loading efficiency as well as the ability to easily pass through biological barriers due to their nano scalability. Their composition tunability allows for their toxicity to be controlled, and they can be modified to contain diverse sets of functional groups that can perform specific activities. These qualities of nanoparticles make them ideal for drug delivery capabilities.
A major area of study within the sphere of protein corona drug delivery, is the study of the circulation time of nanoparticles in the body. In order to optimize the effectiveness of a drug, specifying the location where it is delivered and how long it stays there can be extremely useful. Often, macrophages within the blood will detect the presence of the nanoparticles and immediately work to eliminate them from the body. This is not always a good thing from the perspective of drug delivery, and thus studies were performed to prolong circulation time. It was found that when opsonins, like fibrinogen, are numerous in the protein corona, the proteins tend to induce macrophage recognition and subsequent consumption of nanoparticles. Conversely, when the corona is saturated with dysopsonins, like albumin, the macrophages show decreased recognition of the particles and thus, circulation time of the particles is greatly increased. This technique is loosely referred to as the "stealth effect". By tailoring the contents of the protein corona, the length of time a nanoparticle stays in your body can be controlled.
As mentioned previously, nanoparticles can be grown with particular functional groups on their surfaces that induce chemoselectivity. Functional biomolecules like transferrin, insulin, and folic acid are commonly used in cancer-targeting drug delivery systems. Other smaller molecules like anhydride, amine, carboxyl, and thiol can be used to direct nanoparticles to high cellular association with endothelial cells, pancreatic cells, and activated human macrophages. Certain apolipoproteins, such as Apo E, ApoA1, and ApoB-100, could potentially functionalize nanoparticles to target the nervous system.
Another more pressing problem with nanoparticle drug delivery is the tendency for nanoparticles to accumulate at the target site or in various organs, which can become toxic. It is known that the size of nanoparticles dictates their distribution within the body, meaning that nanoparticles with different sizes will tend to accumulate in certain organs. Therefore, size is a very important control factor when considering nanoparticle distribution and accumulation at target sites during drug delivery.
== References == | Wikipedia/Protein_corona |
The University of Tennessee Health Science Center (UTHSC) is a public medical school in Memphis, Tennessee. It includes the Colleges of Health Professions, Dentistry, Graduate Health Sciences, Medicine, Nursing, and Pharmacy. Since 1911, the University of Tennessee Health Science Center has educated nearly 57,000 health care professionals. As of 2010, U.S. News & World Report ranked the College of Pharmacy 17th among American pharmacy schools.
Graduate medical education programs are located in Chattanooga, Knoxville, and Nashville; family medicine centers in Jackson, Knoxville, and Memphis; dentistry clinics in Bristol, Jackson, and Union City, as well as public and continuing education programs across the state. The Health Science Center is part of the statewide, multi-campus University of Tennessee system.
The University of Tennessee Health Science Center also runs the Plough Center for Sterile Drug Delivery Systems, which celebrated its 53-year anniversary in 2016. The center educates on sterile product preparation, develops a basis for parenteral medications, and provides services to the pharmaceutical industry and individuals. Hands-on training in aseptic processing is also offered four times a year at the facility.
Areas of emphasis are the university's research efforts, which receive nearly $100 million in yearly grants from the National Institutes of Health and private foundations. The Translational Science Research Building and the Cancer Research Building house collaborative research teams for the UTHSC campus.
In its early years the school was segregated, and it desegregated in the early 1960s. The first black student, Alvin Crawford, graduated in 1964.
== Colleges and institutes ==
The University of Tennessee Health Science Center includes six colleges.
=== College of Dentistry ===
Founded in 1878, the college is the oldest dental school in the South. It has more than 7,600 alumni. An estimated 75 percent of practicing dentists in Tennessee are alumni of the UTHSC College of Dentistry. Since Arkansas does not have a dentistry graduate program, several practicing dentists in Arkansas are also UTHSC graduates.
The college offers a full range of advanced training in prosthodontics, oral surgery, endodontics, periodontics, orthodontics, and pediatric dentistry, and a two-year program in dental hygiene.
=== College of Graduate Health Sciences ===
Founded in 1928, the college offers programs in advanced graduate degrees in programs including biomedical engineering and imaging, dental science (master's only), epidemiology (master's only), health outcomes and policy research, biomedical sciences (master's only), integrated program in biomedical sciences (PhD), nursing, pharmaceutical sciences, pharmacology (master's), and speech and hearing science.
=== College of Health Professions ===
Founded in 1972, the college has more than 9,000 alumni. It offers programs of study in audiology and speech pathology on the Knoxville campus and clinical laboratory sciences, health informatics and information management (online program), occupational therapy, and physical therapy on the Memphis campus. The college offers traditional, online, and distance learning.
=== College of Medicine ===
With more than 16,000 alumni, 25 departments on the Memphis campus, nine departments on the Knoxville campus, ten departments on the Chattanooga campus, and 84 Graduate Medical Education training programs, the UTHSC College of Medicine is the largest medical school in the state of Tennessee. Students train on the Memphis campus in their first two years and then rotate across the three campuses during their clinical training. The College of Medicine also trains Physician Assistants. The University of Tennessee Health Science Center currently is the only state-supported Physician Assistant program in the state of Tennessee.
The UTHSC pediatric residency program is affiliated with Le Bonheur Children's Medical Center, and residents in pediatrics, radiology, and other fields spend time working at St. Jude Children's Research Hospital in Memphis.
Areas of excellence include the Center for Addiction Sciences, which was named in 2016 as the first center of excellence in addiction medicine in the country by the Addiction Medicine Foundation, three trauma centers, a burn center, a transplant institute, and a maternal-fetal medicine institute. The college also operates the UTHSC College of Medicine Mobile Stroke Unit, the world's first mobile stroke unit with advanced CT imaging capabilities, including CT angiography imaging for the brain and blood vessels. The college also has a clinical practice, University Clinical Health.
=== College of Nursing ===
Tracing its history to 1898, making it the oldest nursing college in the state of Tennessee, the UTHSC College of Nursing offers three degree programs: BSN, DNP, and PhD.
The college also offers RNs the option to earn the BSN degree online. The college has more than 5,400 alumni and an estimated 2,000 practicing nurses in the state of Tennessee.
=== College of Pharmacy ===
U.S. News & World Report has ranked the college as one of the top 20 pharmacy schools in the country as of 2010. It is the top-ranked school in the state of Tennessee. Founded in 1898, the college has campuses in Memphis, Nashville, and Knoxville. Degrees offered are the Doctor of Pharmacy (PharmD), Doctor of Philosophy in Pharmaceutical Sciences (PhD), dual PharmD/PhD, dual PharmD/Master of Health Informatics and Information Management, and dual PharmD/Master of Business Administration.
=== Hamilton Eye Institute ===
The Hamilton Eye Institute, located in Memphis, is the department of ophthalmology. It opened in 2004 in an eight-story building donated to the University of Tennessee by Baptist Memorial Hospital-Memphis. The capital campaign to establish the institute was initiated by department chair Barrett G. Haik, MD, FACS, and led by Robert B. Carter, chief information officer and executive vice-president of FedEx Information Services. The institute was named for the family of Ralph S. Hamilton, MD, a professor, and physician with the department, who contributed $6 million toward its construction. The mission of the institute is to provide advanced treatments for eye care, foster interplay of ideas among researchers, and transfer skills and knowledge to the next generation of ophthalmic physicians and researchers.
== Accreditation ==
The Health Science Center is accredited by the Commission on Colleges of the Southern Association of Colleges and Schools to award baccalaureate, master's, and doctoral degrees. Each of the professional colleges or programs is accredited by the appropriate agency for the profession or program.
== Notable alumni ==
Winfield C. Dunn, DDS, Class of 1955, Tennessee Governor 1971–1975
Christopher Duntsch, neurosurgeon sentenced to life in prison for intentionally botching 32 surgeries that killed two patients and paralyzed two others
William E. Evans, PharmD, Class of 1975, director and CEO of St. Jude Children's Research Hospital from 2004 to 2014.
Deborah Ferguson, DDS. American politician and member of the Arkansas House of Representatives representing District 51 since January 14, 2013
Randy McNally, MPharm, Class of 1969, Lieutenant Governor of Tennessee 2017–present.
Rhea Seddon, MD, Class of 1973, former NASA astronaut and eighth woman inducted into the U.S. Astronaut Hall of Fame
== Notable faculty ==
Samuel Dagogo-Jack, MD, professor of medicine; director of the Division of Endocrinology, Diabetes, Metabolism, and director of the Clinical Research Center; leader in diabetes research; past president of the American Diabetes Association
Lori Stewart Gonzalez, 23rd president of Ohio University
== See also ==
Medical District, Memphis
Le Bonheur Children's Medical Center
St. Jude Children's Research Hospital
University of Tennessee College of Medicine
== References ==
== External links ==
Official website | Wikipedia/University_of_Tennessee_Health_Science_Center |
Gene therapy for osteoarthritis is the application of gene therapy to treat osteoarthritis (OA). Unlike pharmacological treatments which are administered locally or systemically as a series of interventions, gene therapy aims to establish sustained therapeutic effect after a single, local injection.
The main risk factors for osteoarthritis are age and body mass index, as such, OA is predominantly considered a disease of aging. As the body ages, catabolic factors begin to predominate over anabolic factors resulting in a reduction of extracellular matrix gene expression and reduced cellularity in articular cartilage. Catabolism eventually predominates over anabolism to such an extent that severe cartilage erosions and bone marrow lesions / remodeling manifest in clinical osteoarthritis. Joint inflammation is also a key mechanism in OA, and a number of pro-inflammatory cytokines, particularly IL-1, have been implicated in pathophysiology, human genetics, and animal models of disease.
In addition, osteoarthritis has a number of heritable factors, and there may be additional genetic risk factors for the disease.
Gene augmentation, gene replacement, and novel transgene gene therapy strategies for the potential medical management of osteoarthritis are under preliminary research to define pathological mechanisms and possible treatments for this chronic disease. While viral vector gene therapies predominate, both viral and non-viral vectors have been developed as a means to deliver therapeutic genes.
== Other gene augmentation approaches ==
Other approaches have involved other anabolic and anti-catabolic factors. As the body ages, catabolic factors begin to predominate over anabolic factors. In osteoarthritis, catabolic factors promote the degradation of articular cartilage and decrease the total cell content of cartilage. While the body is young, anabolic factors are able to replace the lost cartilage and cartilage producing cells, however, this ability appears to decrease with age. Gene Augmentation approaches, such as the delivery of FGF18 and PRG4 aim to augment the natural anabolic processes within the joint, to delay the progression of cartilage degeneration. Anabolic factors appear to be successful in clinical studies when delivered in the form of repeat protein injections, however, due to the pharmacokinetics of articular joints, these approaches require up to 12 injections per year in bilateral osteoarthritis, and may need to be sustained indefinitely to prevent reversal of cartilage gains. Gene Augmentation approaches aim to replicate the success of anabolic protein therapies by delivering the genetic instructions for these factors in the form of single injection treatments.
== Gene replacement approaches ==
Passing from parents to children, genes are the building blocks of inheritance. They contain instructions for making proteins. If genes do not produce the right proteins in a correct way, a child can develop a genetic disorder. Gene therapy is a molecular method aiming to replace defective or absent genes, or to counteract the ones undergoing overexpression. For this purpose, genes may be inserted into delivery vectors and administered to target cells to augment or replace defective genetic material. The most common form of gene therapy involves inserting a normal gene to replace an abnormal gene. Other approaches include repairing an abnormal gene and altering the degree to which a gene is turned on or off. Two basic methodologies are utilized to transfer vectors into target tissues; Ex vivo gene transfer and In vivo gene transfer. One type of gene therapy, also often referred to as Cell Therapy (or genetically modified Cell Therapy) in which the gene transfer takes place outside the patient's body is called ex vivo gene therapy. This method of gene therapy is more complicated since the cells first have to be harvested from the patient in an invasive procedure. The harvested cells also need to be manipulated in a sterile manner and care must be taken to not damage the cells or their genetic material. Alternative approaches allow for the use of autologous stem cells, which have not been originally harvested from the patient undergoing treatment. Such approaches need to rely on "cloaking" technology to ensure that the cells are not eliminated from the body once detected as foreign. This "cloaking" often requires the use of additional genetic manipulation, such as the insertion of a CD47 gene to express a "don't eat me" signal on the surface of the cells to make them hypoimmune. A major challenge with the use of cell therapy for Osteoarthritis is the nature of the articular joints, which experience significant shear leading to rapid loss of transplanted cells. Genetically modified cell therapies for the treatment of osteoarthritis are currently strictly investigated and their safety and effectiveness claims have not been reviewed by the FDA.
== Significance and causes of osteoarthritis ==
Primary osteoarthritis (OA) is a degenerative joint disease which is the western world's leading cause of pain and disability. It is characterized by the progressive loss of normal structure and function of articular cartilage, the smooth tissue covering the end of the moving bones. This chronic disease not only affects the articular cartilage but also the subchondral bone, the synovium, and periarticular tissues. Individuals with OA can experience severe pain and limited motion, and the disease often tends to progress as the body ages. OA is mostly the result of natural aging of the joint due to biochemical changes in the cartilage extracellular matrix.
While age and BMI are the main risk factors for osteoarthritis, contributors such as joint trauma and mechanical overloading of joints or joint-instability can accelerate or exacerbate the condition. OA caused by secondary factors such as joint injury or damage to the subchondral bone is referred to as secondary osteoarthritis. Since the degeneration of cartilage is not naturally reversible, it will continue to progress, eventually resulting in the need for joint replacement as a potential terminal intervention. Due to the prevalence of OA, the repair and regeneration of articular cartilage has become a dominant area of research. The growing number of people suffering from osteoarthritis and the potential of some gene therapy approaches, attracts a great deal of attention to the development of genetic medicines for the treatment of this chronic disease.
== Vectors for osteoarthritis gene delivery ==
Various vectors have been developed to carry therapeutic genes to cells. There are two broad categories of gene delivery vectors: Viral vectors, involving viruses as the genetic carriers and non-viral agents, such as polymers, lipid nanoparticles, and liposomes.
=== Viral vectors ===
Viral vectors are the most widely used gene delivery method as they have evolved to do this job with a high degree of efficiency and specificity. When using viral vectors for gene delivery, researchers aim to remove all of the viruses undesired genes and replace them with at least one therapeutic gene. The combination of their evolutionary origin and broad use, makes viral vectors highly effective at delivering genetic cargo to cells, and significantly reduces the risks associated with using this delivery method.
When administered systemically, or in high doses, viral vectors may induce an inflammatory response, which can cause minor side effects such as edema or serious ones like multisystem organ failure. It may also be difficult to administer gene therapy repeatedly due to the immune system's enhanced response to viruses. However, viral vectors delivered locally to the joint, appear to be well contained within the joint area and are very well tolerated based on preclinical and early clinical studies. Furthermore, the durability of therapeutic transgene expression appears to be such, that a single injection therapy may be sufficient to reverse progression of a disease. The most commonly used viral vectors today are Adeno-Associated Viruses (AAVs), since AAVs do not appear to cause any disease in humans, have low immunogenicity, and are non-replicating, they have proven to be safe and effective in a number of indications. Adenoviruses have also been investigated in the clinic for the treatment of Osteoarthritis, however, since adenoviruses are highly immunogenic, their most successful application has been in the delivery of adenoviral vector vaccines.
=== Non-viral vectors ===
Non-viral methods involve complexing therapeutic DNA to various macromolecules including cationic lipids and liposomes, polymers, polyamines and polyethylenimine, and nanoparticles. FuGene 6 and modified cationic liposomes are two non-viral gene delivery methods that have so far been utilized for gene delivery to cartilage. FuGene 6 is a non-liposomal lipid formulation, which has proved to be successful in transfecting a variety of cell lines (cancerous cells used for in vitro research). Liposomes have shown to be a potential candidate for gene delivery, in this approach cationic liposomes are made to facilitate the interaction with the cell membranes to deliver nucleic acids. Non-viral vectors may have the capacity to deliver a large amount of therapeutic genes repeatedly and may be lower cost to produce at large scale. Another advantage of non-viral delivery methods is that they do not elicit a memory immune response and may be administered several times. In spite of having advantages, non-viral vectors have not yet replaced viral vectors due to relatively low efficiency, toxicity of the individual formulation components, and short-term transgene expression. As a result, while a number of viral vectors have successfully been used in several clinical studies, non-viral vectors for intra-articular delivery have thus far only been investigated preclinically.
== Target cells ==
The cells targeted for the treatment of osteoarthritis are chondrocytes, synoviocytes, and their progenitors. Since the joint capsule is relatively well contained, intra-articular injections are highly successful at delivering the therapeutic gene therapy locally to the target cell types.
Treatment of osteoarthritis may be successful via:
Stimulation of anabolic pathways to rebuild the matrix or chondrocyte content of cartilage. This approach may result in reversal of the disease (Examples include: FGF18).
Inhibition of catabolic pathways to prevent further degeneration of cartilage. This approach may result in slowing of the disease progression, but not reversal (Examples include: IL-1Ra).
Replacing of the damaged cells or tissues with cells with or without a matrix. This approach may result in reversal of the disease pathology, but has thus far only been successful for the treatment of focal cartilage lesions (Examples include: MACI and Hyalofast).
Avoiding the pathological or symptomatic complications such as the reduction of pain or formation of osteophytes (Examples include, steroids and viscosupplements).
Thus far, the most promising therapies appear to be those focused on promoting cartilage anabolism. Specifically, only the chondro-anabolic FGF18 therapy which uses the recombinant protein analog of FGF18, sprifermin, has been able to demonstrate an ability to increase cartilage thickness in a dose-dependent manner, arrest progression to joint replacement, and reduce pain and clinically meaningful symptom progression. Based on this success, FGF18 is also being investigated as a gene therapy for the treatment of OA.
While several anti-inflammatory or anti-catabolic approaches have been reported in preclinical studies, none of the clinical studies to date have produced any evidence of efficacy in modifying disease progression (e.g. IGF-I/IL-1RA, steroids). Some anti-inflammatory treatments, have actually been demonstrated to promote cartilage degeneration with long-term use.
== Gene defects leading to osteoarthritis ==
While Osteoarthritis is mainly a disease of aging, it has some degree of heritability. Epidemiological studies have shown that a genetic component may be an important risk factor in OA. Insulin-like growth factor I genes (IGF-1), Transforming growth factorβ, cartilage oligomeric matrix protein, bone morphogenetic protein, and other anabolic gene candidates are among the candidate genes for OA. Genetic changes in OA can lead to defects of a structural protein such as collagen, or changes in the metabolism of bone and cartilage. OA is rarely considered as a simple disorder following Mendelian inheritance being predominantly a multifactorial disease.
However, in the field of OA gene therapy, researches has focused on gene transfer as a delivery system for therapeutic gene products, rather counteracting genetic abnormalities or polymorphisms. Genes, which contribute to protect and restore the matrix of articular cartilage, are attracting the most attention. These Genes are listed in Table 1. Among all candidates listed below, only FGF18 has been successful at a protein level in initial clinical studies. Other candidates, such as proteins that block the actions of interleukin-1 (IL-1) (interleukin-1 receptor antagonists / IL-1Ra) have been evaluated as both protein or gene therapy injections and were either abandoned (as in the case of the protein) or did not report any efficacy in disease modification (as in the case of gene therapies).
== Osteoarthritis targets ==
=== Interleukin-1 ===
Preclinical studies suggest that a pro-inflammatory Interleukin-1 (IL1) is a contributor to joint pain, cartilage loss, and inflammation. Although prior approaches with recombinant proteins have shown mixed results, gene therapy remains a promising avenue for IL-1 inhibition. A therapeutic gene with potential to counteract the effect of Interleukin-1, the Interleukin 1 receptor antagonist (IL-1Ra), is currently being evaluated in early clinical trials with several delivery vectors including AAV and Adenovirus. The natural agonist of IL-1, is a protein that binds non-productively to the cell surface of interleukin-1 receptor, blocking the activity of IL-1 via the IL-1 receptor. A number of studies in dogs, rabbits, and horses suggested that local IL-1Ra gene therapy is safe and effective in animal models of OA, however, none of these findings have translated to clinical efficacy despite both the protein and gene therapy being evaluated in multiple clinical trials.
=== FGF18 ===
Another gene therapy approach uses FGF-18 as a potential anabolic agent. A prior clinical trial using sprifermin (FGF-18 protein, rather than gene therapy) showed that spirefermin was able to increase cartilage thickness in a dose dependent manner in placebo controlled, randomized clinical studies. The trial also demonstrated the potential of FGF18 to arrest progression to joint replacement over the study period. Finally, FGF18 was able to reduce pain (WOMAC) and clinically meaningful symptom progression, in both the full trial population and the high-risk subgroup. Based on these highly promising clinical results, FGF18 is being investigated as a gene therapy for the treatment of osteoarthritis.
== Strategies ==
In the context of OA, the most attractive intra-articular sites for gene transfer are the synovium and the articular cartilage. Most experimental progress has been made with gene transfer to a convenient intra-articular tissue, such as the hyaline cartilage or the synovium, tissues amenable to genetic modification by a variety of vectors, using both in vivo and ex vivo protocols.
=== Gene transfer to cartilage ===
Chondrocytes are non-dividing cells (with the exception of chondrocyte progenitors), embedded in a network of collagens and proteoglycans; however researches suggest that genes can be transferred to chondrocytes within normal or arthritic cartilage by intraarticular injection of AAVs or liposomes containing sendai virus (HVJ- liposomes). Since chondrocytes are considered resident cells of the joint, with lower turnover rates than synoviocytes, gene delivery strategies to chondrocytes may provide a higher degree of durability.
Most efficient methods of gene transfer to cartilage have involved in vivo strategies delivering AAVs directly to joints via intra-articular injection. Of the AAV serotypes studied, AAV2 appears to be particularly effective at transducing Chondrocytes and Synoviocytes, whereas AAV serotype 2.5 has shown efficient delivery to human cartilage explants and to horse joints in vivo.
Some currently evaluated strategies for gene delivery to chondrocytes include FGF18, PRG4, and IL-1Ra.
=== Gene transfer to synovium ===
The major purpose of gene delivery is to alter the lining of the joint in a way that enables them to serve as an endogenous source of therapeutic molecules that can diffuse and influence the metabolism of adjacent tissues such as cartilage. Genes may be delivered to synovium in animal models of RA and OA by direct, in vivo injection of vector or by indirect, ex vivo methods involving autologous synovial cells, skin fibroblasts, or other cell types such as mesenchymal stem cells. Synoviocytes, which are the predominant cell type in the synovium are closely related to fibroblasts, and have relatively high turnover rates (when compared to for example chondrocyte cells). As such, gene therapy treatment of the synovium is likely to be challenged by low durability. Also, since osteoarthritis is the disease of cartilage tissues, treating the synovium is an indirect approach and may be complicated by lack of therapeutic activity.
However, gene therapy administered into the intra-articular space is likely to deliver the therapeutic gene to both cartilage and synovial tissues, the preference for the tissue type may be further modified by selecting a specific delivery vector. Some delivery vectors and their advantages and limitations are listed in Table 2:
The indirect ex vivo approach involves harvest of synovium, cartilage, or bone marrow cells, isolation and culture of the harvested cells, in vitro transduction with the therapeutic gene of interest, and injection of engineered cells into the joint.
== Safety ==
One important issue related to human gene therapy is safety, particularly for the gene therapy of a debilitating, but non-fatal disease such as OA. The main concern is the high immunogenicity of certain viral vectors such as Adenoviruses, which may further exacerbate the pathology. Retroviral vectors permanently integrate into the chromosomes of the cells they infect, there will be always a chance of integrating into a tumor suppressor gene or an oncogene, leading to oncogenic transformation of the cell. As a result, the most advanced therapies focus on the use of non-integrating vectors, low doses, and intra-articular (rather than systemic) delivery. All approaches involving genetic modification are currently only investigational, not approved by the FDA, EMA, or any other regulator; as such, their safety and efficacy statements have not been reviewed or approved by regulatory agencies and the treatments are not approved for commercial use.
== See also ==
Disease Modifying Osteoarthritis Drug
Vectors in gene therapy
Protein therapy
Adeno-associated virus
Gene therapy for epilepsy
Management of Parkinson's disease
== References == | Wikipedia/Gene_therapy_for_osteoarthritis |
Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by several methods, summarized below. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).
== Viruses ==
All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. This genetic material contains basic 'instructions' of how to produce more copies of these viruses, hacking the body's normal production machinery to serve the needs of the virus. The host cell will carry out these instructions and produce additional copies of the virus, leading to more and more cells becoming infected. Some types of viruses insert their genome into the host's cytoplasm, but do not actually enter the cell. Others penetrate the cell membrane disguised as protein molecules and enter the cell.
There are two main types of virus infection: lytic and lysogenic. Shortly after inserting its DNA, viruses of the lytic cycle quickly produce more viruses, burst from the cell and infect more cells. Lysogenic viruses integrate their DNA into the DNA of the host cell and may live in the body for many years before responding to a trigger. The virus reproduces as the cell does and does not inflict bodily harm until it is triggered. The trigger releases the DNA from that of the host and employs it to create new viruses.
=== Retroviruses ===
The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes, namely reverse transcriptase and integrase, into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be integrated into the genetic material of the host cell. The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase.
Now that the genetic material of the virus has been inserted, it can be said that the host cell has been modified to contain new genes. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.
One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus into any arbitrary position in the genome of the host; it randomly inserts the genetic material into a chromosome. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.
Gene therapy trials using retroviral vectors to treat X-linked severe combined immunodeficiency (X-SCID) represent the most successful application of gene therapy to date. More than twenty patients have been treated in France and Britain, with a high rate of immune system reconstitution observed. Similar trials were restricted or halted in the US when leukemia was reported in patients treated in the French X-SCID gene therapy trial. To date, four children in the French trial and one in the British trial have developed leukemia as a result of insertional mutagenesis by the retroviral vector. All but one of these children responded well to conventional anti-leukemia treatment. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme (one form of SCID) continue with relative success in the US, Britain, Ireland, Italy and Japan.
=== Adenoviruses ===
Adenoviruses are viruses that carry their genetic material in the form of double-stranded DNA. They cause respiratory, intestinal, and eye infections in humans (especially the common cold). When these viruses infect a host cell, they introduce their DNA molecule into the host. The genetic material of the adenoviruses is not incorporated (transient) into the host cell's genetic material. The DNA molecule is left free in the nucleus of the host cell, and the instructions in this extra DNA molecule are transcribed just like any other gene. The only difference is that these extra genes are not replicated when the cell is about to undergo cell division so the descendants of that cell will not have the extra gene.
As a result, treatment with the adenovirus will require re-administration in a growing cell population although the absence of integration into the host cell's genome should prevent the type of cancer seen in the SCID trials. This vector system has been promoted for treating cancer and indeed the first gene therapy product to be licensed to treat cancer, Gendicine, is an adenovirus. Gendicine, an adenoviral p53-based gene therapy was approved by the Chinese food and drug regulators in 2003 for treatment of head and neck cancer. Advexin, a similar gene therapy approach from Introgen, was turned down by the US Food and Drug Administration (FDA) in 2008.
Concerns about the safety of adenovirus vectors were raised after the 1999 death of Jesse Gelsinger while participating in a gene therapy trial. Since then, work using adenovirus vectors has focused on genetically limited versions of the virus.
=== Cytomegalovirus ===
Cytomegalovirus (CMV) is part of the β-herpesvirus subfamily that includes roseoloviruses. CMV coevolved with an assortment of mammalian hosts, including human CMV (HCMV), murine CMV (MCMV) and rhesus CMV (RhCMV). CMVs are characterized by large DNA genomes and typically asymptomatic infection in healthy hosts.
The first investigation into cytomegalovirus (CMV) as a gene therapy vector was published in 2000. CMV's tropism for hematopoietic progenitor cells and its large genome (230 kbp) initially attracted researchers. CMV-based vaccine vectors have since been used to induce T Cell response. More recently, CMV containing telomerase and follistatin was intravenously and intranasally delivered in mouse studies with the intention of extending healthspan.
=== Envelope protein pseudotyping of viral vectors ===
The viral vectors described above have natural host cell populations that they infect most efficiently. Retroviruses have limited natural host cell ranges, and although adenovirus and adeno-associated virus are able to infect a relatively broader range of cells efficiently, some cell types are resistant to infection by these viruses as well. Attachment to and entry into a susceptible cell is mediated by the protein envelope on the surface of a virus. Retroviruses and adeno-associated viruses have a single protein coating their membrane, while adenoviruses are coated with both an envelope protein and fibers that extend away from the surface of the virus. The envelope proteins on each of these viruses bind to cell-surface molecules such as heparin sulfate, which localizes them upon the surface of the potential host, as well as with the specific protein receptor that either induces entry-promoting structural changes in the viral protein, or localizes the virus in endosomes wherein acidification of the lumen induces this refolding of the viral coat. In either case, entry into potential host cells requires a favorable interaction between a protein on the surface of the virus and a protein on the surface of the cell.
For the purposes of gene therapy, one might either want to limit or expand the range of cells susceptible to transduction by a gene therapy vector. To this end, many vectors have been developed in which the endogenous viral envelope proteins have been replaced by either envelope proteins from other viruses, or by chimeric proteins. Such chimera would consist of those parts of the viral protein necessary for incorporation into the virion as well as sequences meant to interact with specific host cell proteins. Viruses in which the envelope proteins have been replaced as described are referred to as pseudotyped viruses. For example, the most popular retroviral vector for use in gene therapy trials has been the lentivirus Simian immunodeficiency virus coated with the envelope proteins, G-protein, from Vesicular stomatitis virus. This vector is referred to as VSV G-pseudotyped lentivirus, and infects an almost universal set of cells. This tropism is characteristic of the VSV G-protein with which this vector is coated. Many attempts have been made to limit the tropism of viral vectors to one or a few host cell populations. This advance would allow for the systemic administration of a relatively small amount of vector. The potential for off-target cell modification would be limited, and many concerns from the medical community would be alleviated. Most attempts to limit tropism have used chimeric envelope proteins bearing antibody fragments. These vectors show great promise for the development of "magic bullet" gene therapies.
=== Replication-competent vectors ===
A replication-competent vector called ONYX-015 is used in replicating tumor cells. It was found that in the absence of the E1B-55Kd viral protein, adenovirus caused very rapid apoptosis of infected, p53(+) cells, and this results in dramatically reduced virus progeny and no subsequent spread. Apoptosis was mainly the result of the ability of EIA to inactivate p300. In p53(-) cells, deletion of E1B 55kd has no consequence in terms of apoptosis, and viral replication is similar to that of wild-type virus, resulting in massive killing of cells.
A replication-defective vector deletes some essential genes. These deleted genes are still necessary in the body so they are replaced with either a helper virus or a DNA molecule.
=== Cis and trans-acting elements ===
Replication-defective vectors always contain a "transfer construct". The transfer construct carries the gene to be transduced or "transgene". The transfer construct also carries the sequences which are necessary for the general functioning of the viral genome: packaging sequence, repeats for replication and, when needed, priming of reverse transcription. These are denominated cis-acting elements, because they need to be on the same piece of DNA as the viral genome and the gene of interest. Trans-acting elements are viral elements, which can be encoded on a different DNA molecule. For example, the viral structural proteins can be expressed from a different genetic element than the viral genome.
=== Herpes simplex virus ===
The herpes simplex virus is a human neurotropic virus. This is mostly examined for gene transfer in the nervous system. The wild type HSV-1 virus is able to infect neurons and evade the host immune response, but may still become reactivated and produce a lytic cycle of viral replication. Therefore, it is typical to use mutant strains of HSV-1 that are deficient in their ability to replicate. Though the latent virus is not transcriptionally apparent, it does possess neuron specific promoters that can continue to function normally. Antibodies to HSV-1 are common in humans, however complications due to herpes infection are somewhat rare. Caution for rare cases of encephalitis must be taken and this provides some rationale to using HSV-2 as a viral vector as it generally has tropism for neuronal cells innervating the urogenital area of the body and could then spare the host of severe pathology in the brain.
== Non-viral methods ==
Non-viral methods present certain advantages over viral methods, with simple large scale production and low host immunogenicity being just two. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques with transfection efficiencies similar to those of viruses.
=== Injection of naked DNA ===
This is the simplest method of non-viral transfection. Clinical trials carried out of intramuscular injection of a naked DNA plasmid have occurred with some success; however, the expression has been very low in comparison to other methods of transfection. In addition to trials with plasmids, there have been trials with naked PCR product, which have had similar or greater success. Cellular uptake of naked DNA is generally inefficient. Research efforts focusing on improving the efficiency of naked DNA uptake have yielded several novel methods, such as electroporation, sonoporation, and the use of a "gene gun", which shoots DNA coated gold particles into the cell using high pressure gas.
=== Physical methods to enhance delivery ===
==== Electroporation ====
Electroporation is a method that uses short pulses of high voltage to carry DNA across the cell membrane. This shock is thought to cause temporary formation of pores in the cell membrane, allowing DNA molecules to pass through. Electroporation is generally efficient and works across a broad range of cell types. However, a high rate of cell death following electroporation has limited its use, including clinical applications.
More recently a newer method of electroporation, termed electron-avalanche transfection, has been used in gene therapy experiments. By using a high-voltage plasma discharge, DNA was efficiently delivered following very short (microsecond) pulses. Compared to electroporation, the technique resulted in greatly increased efficiency and less cellular damage.
==== Gene gun ====
The use of particle bombardment, or the gene gun, is another physical method of DNA transfection. In this technique, DNA is coated onto gold particles and loaded into a device which generates a force to achieve penetration of the DNA into the cells, leaving the gold behind on a "stopping" disk.
==== Sonoporation ====
Sonoporation uses ultrasonic frequencies to deliver DNA into cells. The process of acoustic cavitation is thought to disrupt the cell membrane and allow DNA to move into cells.
==== Magnetofection ====
In a method termed magnetofection, DNA is complexed to magnetic particles, and a magnet is placed underneath the tissue culture dish to bring DNA complexes into contact with a cell monolayer.
==== Hydrodynamic delivery ====
Hydrodynamic delivery involves rapid injection of a high volume of a solution into vasculature (such as into the inferior vena cava, bile duct, or tail vein). The solution contains molecules that are to be inserted into cells, such as DNA plasmids or siRNA, and transfer of these molecules into cells is assisted by the elevated hydrostatic pressure caused by the high volume of injected solution.
=== Chemical methods to enhance delivery ===
==== Oligonucleotides ====
The use of synthetic oligonucleotides in gene therapy is to deactivate the genes involved in the disease process. There are several methods by which this is achieved. One strategy uses antisense specific to the target gene to disrupt the transcription of the faulty gene. Another uses small molecules of RNA called siRNA to signal the cell to cleave specific unique sequences in the mRNA transcript of the faulty gene, disrupting translation of the faulty mRNA, and therefore expression of the gene. A further strategy uses double stranded oligodeoxynucleotides as a decoy for the transcription factors that are required to activate the transcription of the target gene. The transcription factors bind to the decoys instead of the promoter of the faulty gene, which reduces the transcription of the target gene, lowering expression. Additionally, single stranded DNA oligonucleotides have been used to direct a single base change within a mutant gene. The oligonucleotide is designed to anneal with complementarity to the target gene with the exception of a central base, the target base, which serves as the template base for repair. This technique is referred to as oligonucleotide mediated gene repair, targeted gene repair, or targeted nucleotide alteration.
==== Lipoplexes ====
To improve the delivery of the new DNA into the cell, the DNA must be protected from damage and positively charged. Initially, anionic and neutral lipids were used for the construction of lipoplexes for synthetic vectors. However, in spite of the facts that there is little toxicity associated with them, that they are compatible with body fluids and that there was a possibility of adapting them to be tissue specific; they are complicated and time-consuming to produce so attention was turned to the cationic versions.
Cationic lipids, due to their positive charge, were first used to condense negatively charged DNA molecules so as to facilitate the encapsulation of DNA into liposomes. Later it was found that the use of cationic lipids significantly enhanced the stability of lipoplexes. Also as a result of their charge, cationic liposomes interact with the cell membrane, endocytosis was widely believed as the major route by which cells uptake lipoplexes. Endosomes are formed as the results of endocytosis, however, if genes can not be released into cytoplasm by breaking the membrane of endosome, they will be sent to lysosomes where all DNA will be destroyed before they could achieve their functions. It was also found that although cationic lipids themselves could condense and encapsulate DNA into liposomes, the transfection efficiency is very low due to the lack of ability in terms of "endosomal escaping". However, when helper lipids (usually electroneutral lipids, such as DOPE) were added to form lipoplexes, much higher transfection efficiency was observed. Later on, it was discovered that certain lipids have the ability to destabilize endosomal membranes so as to facilitate the escape of DNA from endosome, therefore those lipids are called fusogenic lipids. Although cationic liposomes have been widely used as an alternative for gene delivery vectors, a dose dependent toxicity of cationic lipids were also observed which could limit their therapeutic usages.
The most common use of lipoplexes has been in gene transfer into cancer cells, where the supplied genes have activated tumor suppressor control genes in the cell and decrease the activity of oncogenes. Recent studies have shown lipoplexes to be useful in transfecting respiratory epithelial cells.
==== Polymersomes ====
Polymersomes are synthetic versions of liposomes (vesicles with a lipid bilayer), made of amphiphilic block copolymers. They can encapsulate either hydrophilic or hydrophobic contents and can be used to deliver cargo such as DNA, proteins, or drugs to cells. Advantages of polymersomes over liposomes include greater stability, mechanical strength, blood circulation time, and storage capacity.
==== Polyplexes ====
Complexes of polymers with DNA are called polyplexes. Most polyplexes consist of cationic polymers and their fabrication is based on self-assembly by ionic interactions. One important difference between the methods of action of polyplexes and lipoplexes is that polyplexes cannot directly release their DNA load into the cytoplasm. As a result, co-transfection with endosome-lytic agents such as inactivated adenovirus was required to facilitate nanoparticle escape from the endocytic vesicle made during particle uptake. However, a better understanding of the mechanisms by which DNA can escape from endolysosomal pathway, i.e. proton sponge effect, has triggered new polymer synthesis strategies such as incorporation of protonable residues in polymer backbone and has revitalized research on polycation-based systems.
Due to their low toxicity, high loading capacity, and ease of fabrication, polycationic nanocarriers demonstrate great promise compared to their rivals such as viral vectors which show high immunogenicity and potential carcinogenicity, and lipid-based vectors which cause dose dependence toxicity. Polyethyleneimine and chitosan are among the polymeric carriers that have been extensively studied for development of gene delivery therapeutics. Other polycationic carriers such as poly(beta-amino esters) and polyphosphoramidate are being added to the library of potential gene carriers. In addition to the variety of polymers and copolymers, the ease of controlling the size, shape, surface chemistry of these polymeric nano-carriers gives them an edge in targeting capability and taking advantage of enhanced permeability and retention effect.
==== Dendrimers ====
A dendrimer is a highly branched macromolecule with a spherical shape. The surface of the particle may be functionalized in many ways and many of the properties of the resulting construct are determined by its surface.
In particular it is possible to construct a cationic dendrimer, i.e. one with a positive surface charge. When in the presence of genetic material such as DNA or RNA, charge complementarity leads to a temporary association of the nucleic acid with the cationic dendrimer. On reaching its destination the dendrimer-nucleic acid complex is then taken into the cell via endocytosis.
In recent years the benchmark for transfection agents has been cationic lipids. Limitations of these competing reagents have been reported to include: the lack of ability to transfect some cell types, the lack of robust active targeting capabilities, incompatibility with animal models, and toxicity. Dendrimers offer robust covalent construction and extreme control over molecule structure, and therefore size. Together these give compelling advantages compared to existing approaches.
Producing dendrimers has historically been a slow and expensive process consisting of numerous slow reactions, an obstacle that severely curtailed their commercial development. The Michigan-based company Dendritic Nanotechnologies discovered a method to produce dendrimers using kinetically driven chemistry, a process that not only reduced cost by a magnitude of three, but also cut reaction time from over a month to several days. These new "Priostar" dendrimers can be specifically constructed to carry a DNA or RNA payload that transfects cells at a high efficiency with little or no toxicity.
==== Inorganic nanoparticles ====
Inorganic nanoparticles, such as gold, silica, iron oxide (ex. magnetofection) and calcium phosphates have been shown to be capable of gene delivery. Some of the benefits of inorganic vectors is in their storage stability, low manufacturing cost and often time, low immunogenicity, and resistance to microbial attack. Nanosized materials less than 100 nm have been shown to efficiently trap the DNA or RNA and allows its escape from the endosome without degradation. Inorganics have also been shown to exhibit improved in vitro transfection for attached cell lines due to their increased density and preferential location on the base of the culture dish. Quantum dots have also been used successfully and permits the coupling of gene therapy with a stable fluorescence marker. Engineered organic nanoparticles are also under development, which could be used for co-delivery of genes and therapeutic agents.
==== Cell-penetrating peptides ====
Cell-penetrating peptides (CPPs), also known as peptide transduction domains (PTDs), are short peptides (< 40 amino acids) that efficiently pass through cell membranes while being covalently or non-covalently bound to various molecules, thus facilitating these molecules' entry into cells. Cell entry occurs primarily by endocytosis but other entry mechanisms also exist. Examples of cargo molecules of CPPs include nucleic acids, liposomes, and drugs of low molecular weight.
CPP cargo can be directed into specific cell organelles by incorporating localization sequences into CPP sequences. For example, nuclear localization sequences are commonly used to guide CPP cargo into the nucleus. For guidance into mitochondria, a mitochondrial targeting sequence can be used; this method is used in protofection (a technique that allows for foreign mitochondrial DNA to be inserted into cells' mitochondria).
== Hybrid methods ==
Due to every method of gene transfer having shortcomings, there have been some hybrid methods developed that combine two or more techniques. Virosomes are one example; they combine liposomes with an inactivated HIV or influenza virus. This has been shown to have more efficient gene transfer in respiratory epithelial cells than either viral or liposomal methods alone. Other methods involve mixing other viral vectors with cationic lipids or hybridising viruses.
== See also ==
Genosome (lipoplex)
Techniques of genetic engineering
Transformation
Transfection
Transduction
== References == | Wikipedia/Vectors_in_Gene_Therapy |
A designer baby is an embryo or fetus whose genetic makeup has been intentionally selected or altered, often to exclude a particular gene or to remove genes associated with disease, to achieve desired traits. This process usually involves preimplantation genetic diagnosis (PGD), which analyzes multiple human embryos to identify genes associated with specific diseases and characteristics, then selecting embryos that have the desired genetic makeup. While screening for single genes is commonly practiced, advancements in polygenic screening are becoming more prominent, though only a few companies currently offer it. This technique uses an algorithm to aggregate the estimated effects of numerous genetic variants tied to an individual's risk for a particular condition or trait. Other methods of altering a baby's genetic information involve directly editing the genome before birth, using technologies such as CRISPR. A controversial example of this can be seen in the 2018 case involving Chinese twins Lulu and Nana, which had their genomes edited to resist HIV infection, sparking widespread criticism and legal debates.
This highlights the implications of germline engineering, which involves introducing the desired genetic material into the embryo or parental germ cells. This process is typically prohibited by law, however, regulations vary globally. Editing embryos in this manner can result in genetic changes that are passed down to future generations, raising significant controversy and ethical concerns. While some scientists advocate for its use in treating genetic diseases, others warn that it could lead to misuse for non-medical purposes, such as cosmetic enhancements and modification of human traits.
== Pre-implantation genetic diagnosis ==
Pre-implantation genetic diagnosis (PGD or PIGD) is a procedure in which embryos are screened prior to implantation. The technique is used alongside in vitro fertilisation (IVF) to obtain embryos for evaluation of the genome – alternatively, oocytes can be screened prior to fertilisation. The technique was first used in 1989.
PGD is used primarily to select embryos for implantation in the case of possible genetic defects, allowing identification of mutated or disease-related alleles and selection against them. It is especially useful in embryos from parents where one or both carry a heritable disease. PGD can also be used to select for embryos of a certain sex, most commonly when a disease is more strongly associated with one sex than the other (as is the case for X-linked disorders which are more common in males, such as haemophilia). Infants born with traits selected following PGD are sometimes considered to be designer babies.
One application of PGD is the selection of 'saviour siblings', children who are born to provide a transplant (of an organ or group of cells) to a sibling with a usually life-threatening disease. Saviour siblings are conceived through IVF and then screened using PGD to analyze genetic similarity to the child needing a transplant, to reduce the risk of rejection.
=== Process ===
Embryos for PGD are obtained from IVF procedures in which the oocyte is artificially fertilised by sperm. Oocytes from the woman are harvested following controlled ovarian hyperstimulation (COH), which involves fertility treatments to induce production of multiple oocytes. After harvesting the oocytes, they are fertilised in vitro, either during incubation with multiple sperm cells in culture, or via intracytoplasmic sperm injection (ICSI), where sperm is directly injected into the oocyte. The resulting embryos are usually cultured for 3–6 days, allowing them to reach the blastomere or blastocyst stage.
Once embryos reach the desired stage of development, cells are biopsied and genetically screened. The screening procedure varies based on the nature of the disorder being investigated.
Polymerase chain reaction (PCR) is a process in which DNA sequences are amplified to produce many more copies of the same segment, allowing screening of large samples and identification of specific genes. The process is often used when screening for monogenic disorders, such as cystic fibrosis.
Another screening technique, fluorescent in situ hybridisation (FISH) uses fluorescent probes which specifically bind to highly complementary sequences on chromosomes, which can then be identified using fluorescence microscopy. FISH is often used when screening for chromosomal abnormalities such as aneuploidy, making it a useful tool when screening for disorders such as Down syndrome.
Following the screening, embryos with the desired trait (or lacking an undesired trait such as a mutation) are transferred into the mother's uterus, then allowed to develop naturally.
=== Regulation ===
PGD regulation is determined by individual countries' governments, with some prohibiting its use entirely, including in Austria, China, and Ireland.
In many countries, PGD is permitted under very stringent conditions for medical use only, as is the case in France, Switzerland, Italy and the United Kingdom. Whilst PGD in Italy and Switzerland is only permitted under certain circumstances, there is no clear set of specifications under which PGD can be carried out, and selection of embryos based on sex is not permitted. In France and the UK, regulations are much more detailed, with dedicated agencies setting out framework for PGD. Selection based on sex is permitted under certain circumstances, and genetic disorders for which PGD is permitted are detailed by the countries' respective agencies.
In contrast, the United States federal law does not regulate PGD, with no dedicated agencies specifying regulatory framework by which healthcare professionals must abide. Elective sex selection is permitted, accounting for around 9% of all PGD cases in the U.S., as is selection for desired conditions such as deafness or dwarfism.
=== Polygenic risk score (PRS) screening ===
In the 2020s, companies such as Orchid Bioscience began offering polygenic risk scores (PRS) analysis for embryos during IVF. PRS estimates the likelihood of complex traits, such as height and intelligence, or diseases like diabetes, by summarizing data from thousands of genetic markers. However, many geneticists and bioethicists argue that PRS predictions lack clinical validity and promote eugenic practices that can prioritize socially desirable characteristics. They believe this approach risks reinforcing societal biases that may not be realistic and limits the autonomy and identity of the child as it restricts their life within a framework of genetic predictions. A 2021 study found that PRS explains only 5-10% of variance in educational attainment, highlighting its limited predictive ability.
== Pre-implantation Genetic Testing ==
Based on the specific analysis conducted:
PGT-M (Preimplantation Genetic Testing for monogenic diseases) is a technique used during IVF to detect hereditary diseases caused by mutations or alterations of the DNA sequence with a single gene.
PGT-A (Preimplantation Genetic Testing for aneuploidy): It is used to diagnose numerical abnormalities (aneuploidies).
== Human germline engineering ==
Human germline engineering is a process in which the human genome is edited within a germ cell, such as a sperm cell or oocyte (causing heritable changes), or in the zygote or embryo following fertilization. Germline engineering results in changes in the genome being incorporated into every cell in the body of the offspring (or of the individual following embryonic germline engineering). This process differs from somatic cell engineering, which does not result in heritable changes. Most human germline editing is performed on individual cells and non-viable embryos, which are destroyed at a very early stage of development. In November 2018, however, a Chinese scientist, He Jiankui, announced that he had created the first human germline genetically edited babies.
Genetic engineering relies on a knowledge of human genetic information, made possible by research such as the Human Genome Project, which identified the position and function of all the genes in the human genome. As of 2019, high-throughput sequencing methods allow genome sequencing to be conducted very rapidly, making the technology widely available to researchers.
Germline modification is typically accomplished through techniques which incorporate a new gene into the genome of the embryo or germ cell in a specific location. This can be achieved by introducing the desired DNA directly to the cell for it to be incorporated, or by replacing a gene with one of interest. These techniques can also be used to remove or disrupt unwanted genes, such as ones containing mutated sequences.
Whilst germline engineering has mostly been performed in mammals and other animals, research on human cells in vitro is becoming more common. Most commonly used in human cells are germline gene therapy and the engineered nuclease system CRISPR/Cas9.
=== Germline gene modification ===
Gene therapy is the delivery of a nucleic acid (usually DNA or RNA) into a cell as a pharmaceutical agent to treat disease. Most commonly it is carried out using a vector, which transports the nucleic acid (usually DNA encoding a therapeutic gene) into the target cell. A vector can transduce a desired copy of a gene into a specific location to be expressed as required. Alternatively, a transgene can be inserted to deliberately disrupt an unwanted or mutated gene, preventing transcription and translation of the faulty gene products to avoid a disease phenotype.
Gene therapy in patients is typically carried out on somatic cells in order to treat conditions such as some leukaemias and vascular diseases.
Human germline gene therapy in contrast is restricted to in vitro experiments in some countries, whilst others prohibited it entirely, including Australia, Canada, Germany and Switzerland.
Whilst the National Institutes of Health in the US does not currently allow in utero germline gene transfer clinical trials, in vitro trials are permitted. The NIH guidelines state that further studies are required regarding the safety of gene transfer protocols before in utero research is considered, requiring current studies to provide demonstrable efficacy of the techniques in the laboratory. Research of this sort is currently using non-viable embryos to investigate the efficacy of germline gene therapy in treatment of disorders such as inherited mitochondrial diseases.
Gene transfer to cells is usually by vector delivery. Vectors are typically divided into two classes – viral and non-viral.
==== Viral vectors ====
Viruses infect cells by transducing their genetic material into a host's cell, using the host's cellular machinery to generate viral proteins needed for replication and proliferation. By modifying viruses and loading them with the therapeutic DNA or RNA of interest, it is possible to use these as a vector to provide delivery of the desired gene into the cell.
Retroviruses are some of the most commonly used viral vectors, as they not only introduce their genetic material into the host cell, but also copy it into the host's genome. In the context of gene therapy, this allows permanent integration of the gene of interest into the patient's own DNA, providing longer lasting effects.
Viral vectors work efficiently and are mostly safe but present with some complications, contributing to the stringency of regulation on gene therapy. Despite partial inactivation of viral vectors in gene therapy research, they can still be immunogenic and elicit an immune response. This can impede viral delivery of the gene of interest, as well as cause complications for the patient themselves when used clinically, especially in those who already have a serious genetic illness. Another difficulty is the possibility that some viruses will randomly integrate their nucleic acids into the genome, which can interrupt gene function and generate new mutations.
This is a significant concern when considering germline gene therapy, due to the potential to generate new mutations in the embryo or offspring.
==== Non-viral vectors ====
Non-viral methods of nucleic acid transfection involved injecting a naked DNA plasmid into cell for incorporation into the genome. This method used to be relatively ineffective with low frequency of integration, however, efficiency has since greatly improved, using methods to enhance the delivery of the gene of interest into cells. Furthermore, non-viral vectors are simple to produce on a large scale and are not highly immunogenic.
Some non-viral methods are detailed below:
Electroporation is a technique in which high voltage pulses are used to carry DNA into the target cell across the membrane. The method is believed to function due to the formation of pores across the membrane, but although these are temporary, electroporation results in a high rate of cell death which has limited its use. An improved version of this technology, electron-avalanche transfection, has since been developed, which involves shorter (microsecond) high voltage pulses which result in more effective DNA integration and less cellular damage.
The gene gun is a physical method of DNA transfection, where a DNA plasmid is loaded onto a particle of heavy metal (usually gold) and loaded onto the 'gun'. The device generates a force to penetrate the cell membrane, allowing the DNA to enter whilst retaining the metal particle.
Oligonucleotides are used as chemical vectors for gene therapy, often used to disrupt mutated DNA sequences to prevent their expression. Disruption in this way can be achieved by introduction of small RNA molecules, called siRNA, which signal cellular machinery to cleave the unwanted mRNA sequences to prevent their transcription. Another method utilises double-stranded oligonucleotides, which bind transcription factors required for transcription of the target gene. By competitively binding these transcription factors, the oligonucleotides can prevent the gene's expression.
=== ZFNs ===
Zinc-finger nucleases (ZFNs) are enzymes generated by fusing a zinc finger DNA-binding domain to a DNA-cleavage domain. Zinc finger recognizes between 9 and 18 bases of sequence. Thus by mixing those modules, it becomes easier to target any sequence researchers wish to alter ideally within complex genomes. A ZFN is a macromolecular complex formed by monomers in which each subunit contains a zinc domain and a FokI endonuclease domain. The FokI domains must dimerize for activities, thus narrowing target area by ensuring that two close DNA-binding events occurs.
The resulting cleavage event enables most genome-editing technologies to work. After a break is created, the cell seeks to repair it.
A method is NHEJ, in which the cell polishes the two ends of broken DNA and seals them back together, often producing a frame shift.
An alternative method is homology-directed repairs. The cell tries to fix the damage by using a copy of the sequence as a backup. By supplying their own template, researcher can have the system to insert a desired sequence instead.
The success of using ZFNs in gene therapy depends on the insertion of genes to the chromosomal target area without causing damage to the cell. Custom ZFNs offer an option in human cells for gene correction.
=== TALENs ===
There is a method called TALENs that targets singular nucleotides. TALENs stand for transcription activator-like effector nucleases. TALENs are made by TAL effector DNA-binding domain to a DNA cleavage domain. All these methods work by as the TALENs are arranged. TALENs are "built from arrays of 33-35 amino acid modules…by assembling those arrays…researchers can target any sequence they like". This event is referred as Repeat Variable Diresidue (RVD). The relationship between the amino acids enables researchers to engineer a specific DNA domain. The TALEN enzymes are designed to remove specific parts of the DNA strands and replace the section; which enables edits to be made. TALENs can be used to edit genomes using non-homologous end joining (NHEJ) and homology directed repair.
=== CRISPR/Cas9 ===
The CRISPR/Cas9 system (CRISPR – Clustered Regularly Interspaced Short Palindromic Repeats, Cas9 – CRISPR-associated protein 9) is a genome editing technology based on the bacterial antiviral CRISPR/Cas system. The bacterial system has evolved to recognize viral nucleic acid sequences and cut these sequences upon recognition, damaging infecting viruses. The gene editing technology uses a simplified version of this process, manipulating the components of the bacterial system to allow location-specific gene editing.
The CRISPR/Cas9 system broadly consists of two major components – the Cas9 nuclease and a guide RNA (gRNA). The gRNA contains a Cas-binding sequence and a ~20 nucleotide spacer sequence, which is specific and complementary to the target sequence on the DNA of interest. Editing specificity can therefore be changed by modifying this spacer sequence.
Upon system delivery to a cell, Cas9 and the gRNA bind, forming a ribonucleoprotein complex. This causes a conformational change in Cas9, allowing it to cleave DNA if the gRNA spacer sequence binds with sufficient homology to a particular sequence in the host genome. When the gRNA binds to the target sequence, Cas will cleave the locus, causing a double-strand break (DSB).
The resulting DSB can be repaired by one of two mechanisms –
Non-Homologous End Joining (NHEJ) - an efficient but error-prone mechanism, which often introduces insertions and deletions (indels) at the DSB site. This means it is often used in knockout experiments to disrupt genes and introduce loss of function mutations.
Homology Directed Repair (HDR) - a less efficient but high-fidelity process which is used to introduce precise modifications into the target sequence. The process requires adding a DNA repair template including a desired sequence, which the cell's machinery uses to repair the DSB, incorporating the sequence of interest into the genome.
Since NHEJ is more efficient than HDR, most DSBs will be repaired via NHEJ, introducing gene knockouts. To increase frequency of HDR, inhibiting genes associated with NHEJ and performing the process in particular cell cycle phases (primarily S and G2) appear effective.
CRISPR/Cas9 is an effective way of manipulating the genome in vivo in animals as well as in human cells in vitro, but some issues with the efficiency of delivery and editing mean that it is not considered safe for use in viable human embryos or the body's germ cells. As well as the higher efficiency of NHEJ making inadvertent knockouts likely, CRISPR can introduce DSBs to unintended parts of the genome, called off-target effects. These arise due to the spacer sequence of the gRNA conferring sufficient sequence homology to random loci in the genome, which can introduce random mutations throughout. If performed in germline cells, mutations could be introduced to all the cells of a developing embryo.
There are developments to prevent unintended consequences otherwise known as off-target effects due to gene editing. There is a race to develop new gene editing technologies that prevent off-target effects from occurring with some of the technologies being known as biased off-target detection, and Anti-CRISPR Proteins. For biased off-target effects detection, there are several tools to predict the locations where off-target effects may take place. Within the technology of biased off-target effects detection, there are two main models, Alignment Based Models that involve having the sequences of gRNA being aligned with sequences of genome, after which then the off-target locations are predicted. The second model is known as the Scoring-Based Model where each piece of gRNA is scored for their off-target effects in accordance with their positioning.
==== Regulation on CRISPR use ====
In 2015, the International Summit on Human Gene Editing was held in Washington D.C., hosted by scientists from China, the UK and the U.S. The summit concluded that genome editing of somatic cells using CRISPR and other genome editing tools would be allowed to proceed under FDA regulations, but human germline engineering would not be pursued.
In February 2016, scientists at the Francis Crick Institute in London were given a license permitting them to edit human embryos using CRISPR to investigate early development. Regulations were imposed to prevent the researchers from implanting the embryos and to ensure experiments were stopped and embryos destroyed after seven days.
In November 2018, Chinese scientist He Jiankui announced that he had performed the first germline engineering on viable human embryos, which have since been brought to term. The research claims received significant criticism, and Chinese authorities suspended He's research activity. Following the event, scientists and government bodies have called for more stringent regulations to be imposed on the use of CRISPR technology in embryos, with some calling for a global moratorium on germline genetic engineering. Chinese authorities have announced stricter controls will be imposed, with Communist Party general secretary Xi Jinping and government premier Li Keqiang calling for new gene-editing legislations to be introduced.
As of January 2020, germline genetic alterations are prohibited in 24 countries by law and also in 9 other countries by their guidelines. The Council of Europe's Convention on Human Rights and Biomedicine, also known as the Oviedo Convention, has stated in its article 13 "Interventions on the human genome" as follows: "An intervention seeking to modify the human genome may only be undertaken for preventive, diagnostic or therapeutic purposes and only if its aim is not to introduce any modification in the genome of any descendants". Nonetheless, wide public debate has emerged, targeting the fact that the Oviedo Convention Article 13 should be revisited and renewed, especially due to the fact that it was constructed in 1997 and may be out of date, given recent technological advancements in the field of genetic engineering.
In 2020, Canada amended its Human Reproduction Act to criminalize heritable genome edits, in which penalties include fines up to CAD$500,000 and 10 years imprisonment. The World Health Organization established a global registry for such practices in 2021 to enhance transparency
==== Recent Advancements ====
Following the 2018 incident of the first CRISPR-edited babies by He Jiankui, efforts to strengthen regulatory oversights have helped to improve the precision of the procedure. These advancements in genome editing now reduce off-target effects, allowing for more controlled and predictable modifications. Techniques such as prime editing and base editing have offered greater accuracy and fewer unintended mutations. Even so, ethical concerns persist as regulatory enforcement remains inconsistent in nations without strict biosafety laws
== Lulu and Nana controversy ==
The Lulu and Nana controversy refers to the two Chinese twin girls born in November 2018, who had been genetically modified as embryos by the Chinese scientist He Jiankui. The twins are believed to be the first genetically modified babies. The girls' parents had participated in a clinical project run by He, which involved IVF, PGD and genome editing procedures in an attempt to edit the gene CCR5. CCR5 encodes a protein used by HIV to enter host cells, so by introducing a specific mutation into the gene CCR5 Δ32 He claimed that the process would confer innate resistance to HIV.
The project run by He recruited couples wanting children where the man was HIV-positive and the woman uninfected. During the project, He performed IVF with sperm and eggs from the couples and then introduced the CCR5 Δ32 mutation into the genomes of the embryos using CRISPR/Cas9. He then used PGD on the edited embryos during which he sequenced biopsied cells to identify whether the mutation had been successfully introduced. He reported some mosaicism in the embryos, whereby the mutation had integrated into some cells but not all, suggesting the offspring would not be entirely protected against HIV. He claimed that during the PGD and throughout the pregnancy, fetal DNA was sequenced to check for off-target errors introduced by the CRISPR/Cas9 technology, however the NIH released a statement in which they announced "the possibility of damaging off-target effects has not been satisfactorily explored". The girls were born in early November 2018, and were reported by He to be healthy.
His research was conducted in secret until November 2018, when documents were posted on the Chinese clinical trials registry and MIT Technology Review published a story about the project. Following this, He was interviewed by the Associated Press and presented his work on 27 November at the Second International Human Genome Editing Summit which was held in Hong Kong.
Although the information available about this experiment is relatively limited, it is deemed that the scientist erred against many ethical, social and moral rules but also China's guidelines and regulations, which prohibited germ-line genetic modifications in human embryos, while conducting this trial. From a technological point of view, the CRISPR/Cas9 technique is one of the most precise and least expensive methods of gene modification to this day, whereas there are still a number of limitations that keep the technique from being labelled as safe and efficient. During the First International Summit on Human Gene Editing in 2015 the participants agreed that a halt must be set on germline genetic alterations in clinical settings unless and until: "(1) the relevant safety and efficacy issues have been resolved, based on appropriate understanding and balancing of risks, potential benefits, and alternatives, and (2) there is broad societal consensus about the appropriateness of the proposed application". However, during the second International Summit in 2018 the topic was once again brought up by stating: "Progress over the last three years and the discussions at the current summit, however, suggest that it is time to define a rigorous, responsible translational pathway toward such trials". Inciting that the ethical and legal aspects should indeed be revisited G. Daley, representative of the summit's management and Dean of Harvard Medical School depicted Dr. He's experiment as "a wrong turn on the right path".
The experiment was met with widespread criticism and was very controversial, globally as well as in China. Several bioethicists, researchers and medical professionals have released statements condemning the research, including Nobel laureate David Baltimore who deemed the work "irresponsible" and one pioneer of the CRISPR/Cas9 technology, biochemist Jennifer Doudna at University of California, Berkeley. The director of the NIH, Francis S. Collins stated that the "medical necessity for inactivation of CCR5 in these infants is utterly unconvincing" and condemned He Jiankui and his research team for 'irresponsible work'. Other scientists, including geneticist George Church of Harvard University suggested gene editing for disease resistance was "justifiable" but expressed reservations regarding the conduct of He's work.
The Safe Genes program by DARPA has the goal to protect soldiers against gene editing war tactics. They receive information from ethical experts to better predict and understand future and current potential gene editing issues.
The World Health Organization has launched a global registry to track research on human genome editing, after a call to halt all work on genome editing.
The Chinese Academy of Medical Sciences responded to the controversy in the journal Lancet, condemning He for violating ethical guidelines documented by the government and emphasizing that germline engineering should not be performed for reproductive purposes. The academy ensured they would "issue further operational, technical and ethical guidelines as soon as possible" to impose tighter regulation on human embryo editing.
As of 2023, He has resumed research in genetic medicine after his three year imprisonment by the Chinese government for his "illegal medical practices." He has since shifted his focus to the treatment of genetic diseases, including Duchenne muscular dystrophy (DMD), after his release. Despite backlashes from the Lulu and Nana case, he has been appointed as the inaugural director of the Genetic Medicine Institute at Wuchang University of Technology in Wuhan in September 2023. He's application to work in Hong Kong was initially granted a visa, however, it was later revoked due to ongoing ethical and legal challenges surrounding his career.
== Ethical considerations ==
Editing embryos, germ cells and the generation of designer babies is the subject of ethical debate, as a result of the implications in modifying genomic information in a heritable manner. This includes arguments over unbalanced gender selection and gamete selection.
Despite regulations set by individual countries' governing bodies, the absence of a standardized regulatory framework leads to frequent discourse in discussion of germline engineering among scientists, ethicists and the general public. Arthur Caplan, the head of the Division of Bioethics at New York University suggests that establishing an international group to set guidelines for the topic would greatly benefit global discussion and proposes instating "religious and ethics and legal leaders" to impose well-informed regulations.
In many countries, editing embryos and germline modification for reproductive use is illegal. As of 2017, the U.S. restricts the use of germline modification and the procedure is under heavy regulation by the FDA and NIH. The American National Academy of Sciences and National Academy of Medicine indicated they would provide qualified support for human germline editing "for serious conditions under stringent oversight", should safety and efficiency issues be addressed. In 2019, World Health Organization called human germline genome editing as "irresponsible".
Since genetic modification poses risk to any organism, researchers and medical professionals must give the prospect of germline engineering careful consideration. The main ethical concern is that these types of treatments will produce a change that can be passed down to future generations and therefore any error, known or unknown, will also be passed down and will affect the offspring. Theologian Ronald Green of Dartmouth College has raised concern that this could result in a decrease in genetic diversity and the accidental introduction of new diseases in the future.
When considering support for research into germline engineering, ethicists have often suggested that it can be considered unethical not to consider a technology that could improve the lives of children who would be born with congenital disorders. Geneticist George Church claims that he does not expect germline engineering to increase societal disadvantage, and recommends lowering costs and improving education surrounding the topic to dispel these views. He emphasizes that allowing germline engineering in children who would otherwise be born with congenital defects could save around 5% of babies from living with potentially avoidable diseases. Jackie Leach Scully, professor of social and bioethics at Newcastle University, acknowledges that the prospect of designer babies could leave those living with diseases and unable to afford the technology feeling marginalized and without medical support. However, Professor Leach Scully also suggests that germline editing provides the option for parents "to try and secure what they think is the best start in life" and does not believe it should be ruled out. Similarly, Nick Bostrom, an Oxford philosopher known for his work on the risks of artificial intelligence, proposed that "super-enhanced" individuals could "change the world through their creativity and discoveries, and through innovations that everyone else would use".
Many bioethicists emphasize that germline engineering is usually considered in the best interest of a child, therefore associated should be supported. Dr James Hughes, a bioethicist at Trinity College, Connecticut, suggests that the decision may not differ greatly from others made by parents which are well accepted – choosing with whom to have a child and using contraception to denote when a child is conceived. Julian Savulescu, a bioethicist and philosopher at Oxford University believes parents "should allow selection for non‐disease genes even if this maintains or increases social inequality", coining the term procreative beneficence to describe the idea that the children "expected to have the best life" should be selected. The Nuffield Council on Bioethics said in 2017 that there was "no reason to rule out" changing the DNA of a human embryo if performed in the child's interest, but stressed that this was only provided that it did not contribute to societal inequality. Furthermore, Nuffield Council in 2018 detailed applications, which would preserve equality and benefit humanity, such as elimination of hereditary disorders and adjusting to warmer climate. Philosopher and Director of Bioethics at non-profit Invincible Wellbeing David Pearce argues that "the question [of designer babies] comes down to an analysis of risk-reward ratios - and our basic ethical values, themselves shaped by our evolutionary past." According to Pearce,"it's worth recalling that each act of old-fashioned sexual reproduction is itself an untested genetic experiment", often compromising a child's wellbeing and pro-social capacities even if the child grows in a healthy environment. Pearce thinks that as technology matures, more people may find it unacceptable to rely on "genetic roulette of natural selection".
Conversely, several concerns have been raised regarding the possibility of generating designer babies, especially concerning the inefficiencies currently presented by the technologies. Green stated that although the technology was "unavoidably in our future", he foresaw "serious errors and health problems as unknown genetic side effects in 'edited' children" arise. Furthermore, Green warned against the possibility that "the well-to-do" could more easily access the technologies "..that make them even better off". This concern regarding germline editing exacerbating a societal and financial divide is shared amongst other researches, with the chair of the Nuffield Bioethics Council Professor Karen Yeung stressing that if funding of the procedures "were to exacerbate social injustice, in our view that would not be an ethical approach".
Since 2020, there have been discussions about American studies that use embryos without embryonic implantation with the CRISPR/Cas9 technique that had been modified with HDR (homology-directed repair), and the conclusions from the results were that gene editing technologies are currently not mature enough for real world use and that there is a need for more studies that generate safe results over a longer period of time.
An article in the journal Bioscience Reports discussed how health in terms of genetics is not straightforward and thus there should be extensive deliberation for operations involving gene editing when the technology gets mature enough for real world use, where all of the potential effects are known on a case-by-case basis to prevent undesired effects on the subject or patient being operated on.
Social aspects also raise concern, as highlighted by Josephine Quintavelle, director of Comment on Reproductive Ethics at Queen Mary University of London, who states that selecting children's traits is "turning parenthood into an unhealthy model of self-gratification rather than a relationship". In addition, some disability advocates argue that selecting against traits like deafness reinforces societal stigma. This promotes a narrow definition of normalcy. They also warn of the consequences of increased inequality if genetic enhancements become solely accessible to the wealthy.
One major worry among scientists, including Marcy Darnovsky at the Center for Genetics and Society in California, is that permitting germline engineering for correction of disease phenotypes is likely to lead to its use for cosmetic purposes and enhancement. Meanwhile, Henry Greely, a bioethicist at Stanford University in California, states that "almost everything you can accomplish by gene editing, you can accomplish by embryo selection", suggesting the risks undertaken by germline engineering may not be necessary. Alongside this, Greely emphasizes that the beliefs that genetic engineering will lead to enhancement are unfounded, and that claims that we will enhance intelligence and personality are far off – "we just don't know enough and are unlikely to for a long time – or maybe for ever".
=== Religious Opinions ===
Religious worries also arise over the possibility of editing human embryos. In a survey conducted by the Pew Research Centre, it was found that only a third of the Americans surveyed who identified as strongly Christian approved of germline editing. Catholic leaders are in the middle ground. This stance is because, according to Catholicism, a baby is a gift from God, and Catholics believe that people are created to be perfect in God's eyes. Thus, altering the genetic makeup of an infant is unnatural. In 1984, Pope John Paul II addressed that genetic manipulation in aiming to heal diseases is acceptable in the Church. He stated that it "will be considered in principle as desirable provided that it tends to the real promotion of the personal well-being of man, without harming his integrity or worsening his life conditions". However, it is unacceptable if designer babies are used to create a super/superior race including cloning humans. The Catholic Church rejects human cloning even if its purpose is to produce organs for therapeutic usage. The Vatican has stated that "The fundamental values connected with the techniques of artificial human procreation are two: the life of the human being called into existence and the special nature of the transmission of human life in marriage". According to them, it violates the dignity of the individual and is morally illicit.
In Islam, a positive view towards genetic engineering is based on the general principle that Islam aims at facilitating human life. However, according to Islamic law, gene editing can only be permitted if several conditions are met, such as definitively proving the safety and efficacy of the procedures in question. Nevertheless, some researchers consider genetic engineering a promising field of research that is capable of meeting the conditions mentioned above in the future. In addition, a negative view comes from the process used to create a designer baby. Oftentimes, it involves the destruction of some embryos, which may be against the teaching of the Qur'an, Hadith, and Shari'ah law, that stress the responsibility to protect human life. However, there is a consensus among Islamic scholars that ensoulment occurs 120 days after conception, well after the embryonic stage of development. Some scholars see the procedure as "acting like God/Allah" and a violation of the religious prohibition against "changing God's/Allah's creation". Other arguments include the possibility of introducing unforeseen mutations and genetic deficiencies, which would be counter to the principle of protecting human life, and undermining the traditional institutions of lineage, marriage and childbirth. With the idea that parents could choose the gender of their child, some Muslims believe that humans have no decision to choose the gender, and that "gender selection is only up to God".
=== Public Opinon ===
Surveys of public attitudes towards designer babies and genetic editing have revealed concerns against the technological advancements, showing fears of eugenics and socioeconomic inequality. A 2018 Pew Research Center study found that 72% of the U.S. adults believed non-medical uses of the technologies would be taking it too far, with many drawing parallels to historical Eugenic practices. Similarly, a 2020 international survey published in Science (journal) reported widespread public concern about the unintended health consequences of genetically modified children and the potential erosion of genetic diversity.
Scientists and policymakers have called for a more inclusive and transparent approach in regulation of the technologies, which underscores the need for collaborative governance frameworks and communication between scientists, policymakers, and the people.
== See also ==
== References ==
== Further reading == | Wikipedia/Designer_baby |
Lentiviral vectors in gene therapy is a method by which genes can be inserted, modified, or deleted in organisms using lentiviruses.
Lentiviruses are a family of viruses that are responsible for diseases like AIDS, which infect by inserting DNA into their host cells' genome. Many such viruses have been the basis of research using viruses in gene therapy, but the lentivirus is unique in its ability to infect non-dividing cells, and therefore has a wider range of potential applications. Lentiviruses can become endogenous (ERV), integrating their genome into the host germline genome, so that the virus is henceforth inherited by the host's descendants. Scientists use the lentivirus' mechanisms of infection to achieve a desired outcome to gene therapy. Lentiviral vectors in gene therapy have been pioneered by Luigi Naldini.
The lentivirus is a retrovirus, meaning it has a single stranded RNA genome with a reverse transcriptase enzyme. Lentiviruses also have a viral envelope with protruding glycoproteins that aid in attachment to the host cell's outer membrane. The virus contains a reverse transcriptase molecule found to perform transcription of the viral genetic material upon entering the cell. Within the viral genome are RNA sequences that code for specific proteins that facilitate the incorporation of the viral sequences into the host cell genome. The "gag" gene codes for the structural components of the viral nucleocapsid proteins: the matrix (MA/p17), the capsid (CA/p24) and the nucleocapsid (NC/p7) proteins. The "pol" domain codes for the reverse transcriptase and integrase enzymes. Lastly, the "env" domain of the viral genome encodes for the glycoproteins and envelope on the surface of the virus.
There are multiple steps involved in the infection and replication of a lentivirus in a host cell. In the first step the virus uses its surface glycoproteins for attachment to the outer surface of a cell. More specifically, lentiviruses attach to the CD4 glycoproteins on the surface of a host's target cell. The viral material is then injected into the host cell's cytoplasm. Within the cytoplasm, the viral reverse transcriptase enzyme performs reverse transcription of the viral RNA genome to create a viral DNA genome. The viral DNA is then sent into the nucleus of the host cell where it is incorporated into the host cell's genome with the help of the viral enzyme integrase. From now on, the host cell starts to transcribe the entire viral RNA and express the structural viral proteins, in particular those that form the viral capsid and the envelope. The lentiviral RNA and the viral proteins then assemble and the newly formed virions leave the host cell when enough are made.
Two methods of gene therapy using lentiviruses have been proposed. In the ex vivo methodology, cells are extracted from a patient and then cultured. A lentiviral vector carrying therapeutic transgenes are then introduced to the culture to infect them. The now modified cells continue to be cultured until they can be infused into the patient. In vivo gene therapy is the sample injection of viral vectors containing transgenes into the patient.
== Designing a lentivirus vector ==
Lentiviruses are modified to act as a vector to insert beneficial genes into cells. Unlike other retroviruses, which cannot penetrate the nuclear envelope and can therefore only act on cells while they are undergoing mitosis, lentiviruses can infect cells whether or not they are dividing (shown to be largely due to the capsid protein). Many cell types, like neurons, do not divide in adult organisms, so lentiviral gene therapy is a good candidate for treating conditions that affect those cell types.
Some experimental applications of lentiviral vectors have been done in gene therapy in order to cure diseases like Diabetes mellitus, Murine haemophilia A, prostate cancer, chronic granulomatous disease, and vascular diseases.
HIV-derived lentiviral vectors have been widely developed for their ability to target specific genes through the coactivator PSIP1. This target specificity allows for the development of lentiviral gene vectors that do not carry the risk of randomly inserting themselves into normally functioning genes. As HIV is pathogenic, it must be genetically modified to remove its disease-causing properties and its ability to replicate itself. This can be achieved by deleting viral genes that are unnecessary for transduction of therapeutic transgenes. It has been proposed that by targeting the "gag" and "env" domains, enough of the HIV-1 genome can be deleted without losing its effectiveness in gene therapy while minimizing viral genes integrated into the patient. Genes may also be replaced rather than disrupted as another method to reduce the risks associated with the use of HIV-1.
Other lentiviruses such as Feline immunodeficiency virus and Equine infectious anemia virus have been developed for use in gene therapy and are of interest due to the inability to cause serious disease in human hosts. Equine infectious anemia virus in particular has been shown to perform somewhat better than HIV-1 in hematopoietic stem cells
== Insertional mutagenesis ==
Historically, lentiviral vectors included strong viral promoters which had a side effect of insertional mutagenesis, nuclear DNA mutations that affect the function of a gene. These strong viral promotors were shown to be the main cause of cancer formation. As a result, viral promotors have been replaced by cellular promotors and regulatory sequences.
== Contrast with other viral vectors ==
As mentioned, lentiviruses have the unique ability to infect non-dividing cells. Beyond that, there are several other properties that distinguish lentiviral vectors from other viral vectors. Such properties are important to consider when determining whether lentiviruses are appropriate for a given treatment.
=== Gammaretroviruses ===
Gammaretroviruses are retroviruses like lentiviruses. Murine leukemia viruses (MLVs) were among the first to be investigated for their use in gene therapy. However, recent research has favored lentiviruses for their ability to integrate into non-dividing cells. More practically, gammaretroviruses have an affinity for integrating themselves near oncogene promoters, bringing forward an adverse risk of tumors. MLVs may be replication competent, meaning they can replicate in the host cell. These replication-competent viruses offer stable gene transfer and tumor and tissue specific targeting.
=== Adenoviruses ===
In gene therapy, adenoviruses differ from lentiviruses in many ways, some of which provide advantages over lentiviruses. Transduction efficiency is higher in adenoviruses compared to lentiviruses. Secondly, most human cells have receptors for adenoviruses likely as a result of the wide variety of adenovirus diseases in humans. As adenoviruses frequently infect humans, this could build an immune response in the body. Such a response can reduce the efficiency of adenoviral vector therapies and can result in adverse reactions such as inflammation of tissues. Research has been conducted to exploit this immune response to target cancerous cells and to develop vaccines. Hybrid adenovirus-retroviruses (specifically MLVs) have also been developed to exploit the benefits of MLVs and adenoviruses.
== Applications ==
=== Severe combined immunodeficiency disease ===
The ADA deficient variant of severe combined immunodeficiency (SCID) was treated highly successfully in a multi-year study reported in 2021. Over 95% of treated patients continued to be event free after 36 months, and 100% of patients survived this normally lethal disease. A self-inactivating lentiviral vector, EFS-ADA LV, was used to insert a functional ADA gene in autologous CD34+ hematopoietic stem and progenitor cells (HSPCs).
=== Vascular transplants ===
In a study designed to enhance the outcomes of vascular transplant through vascular endothelial cell gene therapy, the third generation of Lentivirus showed to be effective in the delivery of genes to moderate venous grafts and transplants in procedures like coronary artery bypass. Because the virus has been adapted to lose most of its genome, the virus becomes safer and more effective in transplanting the required genes into the host cell. A drawback to this therapy is explained in the study that long-term gene expression may require the use of promoters and can aid in a greater trans-gene expression. The researchers accomplished this by the addition of self-inactivating plasmids and creating a more universal tropism by pseudotyping a vesicular stomatitis virus glycoprotein.
=== Chronic granulomatous disease ===
In chronic granulomatous disease (CGD), immune functioning is deficient as a result of the mutations in components of the nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) enzyme in phagocyte cells, which catalyzes the production of superoxide free radicals. If this enzyme becomes deficient, the phagocytes can't kill effectively the engulfed bacteria, so granulomas can be formed. Study performed in mice emphasizes the use of lineage-specific lentiviral vectors to express a normal version of one of the mutant CGD proteins, allowing white blood cells to now make a functional version of the NADPH oxidase. Scientists developed this strain of lentivirus by transinfecting 293T cells with pseudotyped virus with the vesicular stomatitis G protein. The viral vector's responsibility was to increase the production of a functional NADPH oxidase gene in these phagocytic cells. They did this to create an affinity for myeloid cells.
=== Prostate cancer ===
With prostate cancer, the lentivirus is transformed by being bound to trastuzumab to attach to androgen-sensitive LNCaP and castration-resistant C4-2 human prostate cancer cell lines. These two cells are primarily responsible for secretion of excess human epidermal growth factor receptor 2 (HER-2), which is a hormone linked to prostate cancer. By attaching to these cells and changing their genomes, the lentivirus can slow down, and even kill, the cancer-causing cells. Researchers caused the specificity of the vector by manipulating the Fab region of the viral genome and pseudotyped it with the Sindbis virus.
=== Haemophilia A ===
Haemophilia A has also been studied in gene therapy with a lentiviral vector in mice. The vector targets the haematopoietic cells in order to increase the amount of factor VIII, which is affected in haemophilia A. But this continues to be a subject of study as the lentivirus vector was not completely successful in achieving this goal. They did this by trans-infecting the virus in a 293T cell, creating a virus known as 2bF8 expressing generation of viral vectors.
=== Rheumatoid arthritis ===
Studies have also found that injection of a lentiviral vector with IL-10 expressing genes in utero in mice can suppress, and prevent, rheumatoid arthritis and create new cells with constant gene expression. This contributes to the data on stem cells and in utero inoculation of viral vectors for gene therapy. The target for the viral vector in this study, were the synovial cells. Normally functioning synovial cells produce TNFα and IL-1.
=== Diabetes mellitus ===
Like many of the in utero studies, the lentiviral vector gene therapy for diabetes mellitus is more effective in utero as the stem cells that become affected by the gene therapy create new cells with the new gene created by the actual viral intervention. The vector targets the cells within the pancreas to add insulin secreting genes to help control diabetes mellitus. Vectors were cloned using a cytomegalovirus promoter and then co-transinfected in the 293T cell.
=== Neurological disease ===
As mature neurons do not divide, lentiviruses are ideal for division independent gene therapy. Studies of lentiviral gene therapy have been conducted on patients with advanced Parkinson's disease and aging-related atrophy of neurons in primates.
== See also ==
Retinal gene therapy using lentiviral vectors
== References ==
== Further reading ==
== External links ==
The Place of Retroviruses in Biology
Synthesis of Gag and Gag-Pro-Pol Proteins in Retroviruses
About: Retroviruses Resource Overview | Wikipedia/Lentiviral_vector_in_gene_therapy |
Gene therapy utilizes the delivery of DNA into cells, which can be accomplished by several methods, summarized below. The two major classes of methods are those that use recombinant viruses (sometimes called biological nanoparticles or viral vectors) and those that use naked DNA or DNA complexes (non-viral methods).
== Viruses ==
All viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle. This genetic material contains basic 'instructions' of how to produce more copies of these viruses, hacking the body's normal production machinery to serve the needs of the virus. The host cell will carry out these instructions and produce additional copies of the virus, leading to more and more cells becoming infected. Some types of viruses insert their genome into the host's cytoplasm, but do not actually enter the cell. Others penetrate the cell membrane disguised as protein molecules and enter the cell.
There are two main types of virus infection: lytic and lysogenic. Shortly after inserting its DNA, viruses of the lytic cycle quickly produce more viruses, burst from the cell and infect more cells. Lysogenic viruses integrate their DNA into the DNA of the host cell and may live in the body for many years before responding to a trigger. The virus reproduces as the cell does and does not inflict bodily harm until it is triggered. The trigger releases the DNA from that of the host and employs it to create new viruses.
=== Retroviruses ===
The genetic material in retroviruses is in the form of RNA molecules, while the genetic material of their hosts is in the form of DNA. When a retrovirus infects a host cell, it will introduce its RNA together with some enzymes, namely reverse transcriptase and integrase, into the cell. This RNA molecule from the retrovirus must produce a DNA copy from its RNA molecule before it can be integrated into the genetic material of the host cell. The process of producing a DNA copy from an RNA molecule is termed reverse transcription. It is carried out by one of the enzymes carried in the virus, called reverse transcriptase. After this DNA copy is produced and is free in the nucleus of the host cell, it must be incorporated into the genome of the host cell. That is, it must be inserted into the large DNA molecules in the cell (the chromosomes). This process is done by another enzyme carried in the virus called integrase.
Now that the genetic material of the virus has been inserted, it can be said that the host cell has been modified to contain new genes. If this host cell divides later, its descendants will all contain the new genes. Sometimes the genes of the retrovirus do not express their information immediately.
One of the problems of gene therapy using retroviruses is that the integrase enzyme can insert the genetic material of the virus into any arbitrary position in the genome of the host; it randomly inserts the genetic material into a chromosome. If genetic material happens to be inserted in the middle of one of the original genes of the host cell, this gene will be disrupted (insertional mutagenesis). If the gene happens to be one regulating cell division, uncontrolled cell division (i.e., cancer) can occur. This problem has recently begun to be addressed by utilizing zinc finger nucleases or by including certain sequences such as the beta-globin locus control region to direct the site of integration to specific chromosomal sites.
Gene therapy trials using retroviral vectors to treat X-linked severe combined immunodeficiency (X-SCID) represent the most successful application of gene therapy to date. More than twenty patients have been treated in France and Britain, with a high rate of immune system reconstitution observed. Similar trials were restricted or halted in the US when leukemia was reported in patients treated in the French X-SCID gene therapy trial. To date, four children in the French trial and one in the British trial have developed leukemia as a result of insertional mutagenesis by the retroviral vector. All but one of these children responded well to conventional anti-leukemia treatment. Gene therapy trials to treat SCID due to deficiency of the Adenosine Deaminase (ADA) enzyme (one form of SCID) continue with relative success in the US, Britain, Ireland, Italy and Japan.
=== Adenoviruses ===
Adenoviruses are viruses that carry their genetic material in the form of double-stranded DNA. They cause respiratory, intestinal, and eye infections in humans (especially the common cold). When these viruses infect a host cell, they introduce their DNA molecule into the host. The genetic material of the adenoviruses is not incorporated (transient) into the host cell's genetic material. The DNA molecule is left free in the nucleus of the host cell, and the instructions in this extra DNA molecule are transcribed just like any other gene. The only difference is that these extra genes are not replicated when the cell is about to undergo cell division so the descendants of that cell will not have the extra gene.
As a result, treatment with the adenovirus will require re-administration in a growing cell population although the absence of integration into the host cell's genome should prevent the type of cancer seen in the SCID trials. This vector system has been promoted for treating cancer and indeed the first gene therapy product to be licensed to treat cancer, Gendicine, is an adenovirus. Gendicine, an adenoviral p53-based gene therapy was approved by the Chinese food and drug regulators in 2003 for treatment of head and neck cancer. Advexin, a similar gene therapy approach from Introgen, was turned down by the US Food and Drug Administration (FDA) in 2008.
Concerns about the safety of adenovirus vectors were raised after the 1999 death of Jesse Gelsinger while participating in a gene therapy trial. Since then, work using adenovirus vectors has focused on genetically limited versions of the virus.
=== Cytomegalovirus ===
Cytomegalovirus (CMV) is part of the β-herpesvirus subfamily that includes roseoloviruses. CMV coevolved with an assortment of mammalian hosts, including human CMV (HCMV), murine CMV (MCMV) and rhesus CMV (RhCMV). CMVs are characterized by large DNA genomes and typically asymptomatic infection in healthy hosts.
The first investigation into cytomegalovirus (CMV) as a gene therapy vector was published in 2000. CMV's tropism for hematopoietic progenitor cells and its large genome (230 kbp) initially attracted researchers. CMV-based vaccine vectors have since been used to induce T Cell response. More recently, CMV containing telomerase and follistatin was intravenously and intranasally delivered in mouse studies with the intention of extending healthspan.
=== Envelope protein pseudotyping of viral vectors ===
The viral vectors described above have natural host cell populations that they infect most efficiently. Retroviruses have limited natural host cell ranges, and although adenovirus and adeno-associated virus are able to infect a relatively broader range of cells efficiently, some cell types are resistant to infection by these viruses as well. Attachment to and entry into a susceptible cell is mediated by the protein envelope on the surface of a virus. Retroviruses and adeno-associated viruses have a single protein coating their membrane, while adenoviruses are coated with both an envelope protein and fibers that extend away from the surface of the virus. The envelope proteins on each of these viruses bind to cell-surface molecules such as heparin sulfate, which localizes them upon the surface of the potential host, as well as with the specific protein receptor that either induces entry-promoting structural changes in the viral protein, or localizes the virus in endosomes wherein acidification of the lumen induces this refolding of the viral coat. In either case, entry into potential host cells requires a favorable interaction between a protein on the surface of the virus and a protein on the surface of the cell.
For the purposes of gene therapy, one might either want to limit or expand the range of cells susceptible to transduction by a gene therapy vector. To this end, many vectors have been developed in which the endogenous viral envelope proteins have been replaced by either envelope proteins from other viruses, or by chimeric proteins. Such chimera would consist of those parts of the viral protein necessary for incorporation into the virion as well as sequences meant to interact with specific host cell proteins. Viruses in which the envelope proteins have been replaced as described are referred to as pseudotyped viruses. For example, the most popular retroviral vector for use in gene therapy trials has been the lentivirus Simian immunodeficiency virus coated with the envelope proteins, G-protein, from Vesicular stomatitis virus. This vector is referred to as VSV G-pseudotyped lentivirus, and infects an almost universal set of cells. This tropism is characteristic of the VSV G-protein with which this vector is coated. Many attempts have been made to limit the tropism of viral vectors to one or a few host cell populations. This advance would allow for the systemic administration of a relatively small amount of vector. The potential for off-target cell modification would be limited, and many concerns from the medical community would be alleviated. Most attempts to limit tropism have used chimeric envelope proteins bearing antibody fragments. These vectors show great promise for the development of "magic bullet" gene therapies.
=== Replication-competent vectors ===
A replication-competent vector called ONYX-015 is used in replicating tumor cells. It was found that in the absence of the E1B-55Kd viral protein, adenovirus caused very rapid apoptosis of infected, p53(+) cells, and this results in dramatically reduced virus progeny and no subsequent spread. Apoptosis was mainly the result of the ability of EIA to inactivate p300. In p53(-) cells, deletion of E1B 55kd has no consequence in terms of apoptosis, and viral replication is similar to that of wild-type virus, resulting in massive killing of cells.
A replication-defective vector deletes some essential genes. These deleted genes are still necessary in the body so they are replaced with either a helper virus or a DNA molecule.
=== Cis and trans-acting elements ===
Replication-defective vectors always contain a "transfer construct". The transfer construct carries the gene to be transduced or "transgene". The transfer construct also carries the sequences which are necessary for the general functioning of the viral genome: packaging sequence, repeats for replication and, when needed, priming of reverse transcription. These are denominated cis-acting elements, because they need to be on the same piece of DNA as the viral genome and the gene of interest. Trans-acting elements are viral elements, which can be encoded on a different DNA molecule. For example, the viral structural proteins can be expressed from a different genetic element than the viral genome.
=== Herpes simplex virus ===
The herpes simplex virus is a human neurotropic virus. This is mostly examined for gene transfer in the nervous system. The wild type HSV-1 virus is able to infect neurons and evade the host immune response, but may still become reactivated and produce a lytic cycle of viral replication. Therefore, it is typical to use mutant strains of HSV-1 that are deficient in their ability to replicate. Though the latent virus is not transcriptionally apparent, it does possess neuron specific promoters that can continue to function normally. Antibodies to HSV-1 are common in humans, however complications due to herpes infection are somewhat rare. Caution for rare cases of encephalitis must be taken and this provides some rationale to using HSV-2 as a viral vector as it generally has tropism for neuronal cells innervating the urogenital area of the body and could then spare the host of severe pathology in the brain.
== Non-viral methods ==
Non-viral methods present certain advantages over viral methods, with simple large scale production and low host immunogenicity being just two. Previously, low levels of transfection and expression of the gene held non-viral methods at a disadvantage; however, recent advances in vector technology have yielded molecules and techniques with transfection efficiencies similar to those of viruses.
=== Injection of naked DNA ===
This is the simplest method of non-viral transfection. Clinical trials carried out of intramuscular injection of a naked DNA plasmid have occurred with some success; however, the expression has been very low in comparison to other methods of transfection. In addition to trials with plasmids, there have been trials with naked PCR product, which have had similar or greater success. Cellular uptake of naked DNA is generally inefficient. Research efforts focusing on improving the efficiency of naked DNA uptake have yielded several novel methods, such as electroporation, sonoporation, and the use of a "gene gun", which shoots DNA coated gold particles into the cell using high pressure gas.
=== Physical methods to enhance delivery ===
==== Electroporation ====
Electroporation is a method that uses short pulses of high voltage to carry DNA across the cell membrane. This shock is thought to cause temporary formation of pores in the cell membrane, allowing DNA molecules to pass through. Electroporation is generally efficient and works across a broad range of cell types. However, a high rate of cell death following electroporation has limited its use, including clinical applications.
More recently a newer method of electroporation, termed electron-avalanche transfection, has been used in gene therapy experiments. By using a high-voltage plasma discharge, DNA was efficiently delivered following very short (microsecond) pulses. Compared to electroporation, the technique resulted in greatly increased efficiency and less cellular damage.
==== Gene gun ====
The use of particle bombardment, or the gene gun, is another physical method of DNA transfection. In this technique, DNA is coated onto gold particles and loaded into a device which generates a force to achieve penetration of the DNA into the cells, leaving the gold behind on a "stopping" disk.
==== Sonoporation ====
Sonoporation uses ultrasonic frequencies to deliver DNA into cells. The process of acoustic cavitation is thought to disrupt the cell membrane and allow DNA to move into cells.
==== Magnetofection ====
In a method termed magnetofection, DNA is complexed to magnetic particles, and a magnet is placed underneath the tissue culture dish to bring DNA complexes into contact with a cell monolayer.
==== Hydrodynamic delivery ====
Hydrodynamic delivery involves rapid injection of a high volume of a solution into vasculature (such as into the inferior vena cava, bile duct, or tail vein). The solution contains molecules that are to be inserted into cells, such as DNA plasmids or siRNA, and transfer of these molecules into cells is assisted by the elevated hydrostatic pressure caused by the high volume of injected solution.
=== Chemical methods to enhance delivery ===
==== Oligonucleotides ====
The use of synthetic oligonucleotides in gene therapy is to deactivate the genes involved in the disease process. There are several methods by which this is achieved. One strategy uses antisense specific to the target gene to disrupt the transcription of the faulty gene. Another uses small molecules of RNA called siRNA to signal the cell to cleave specific unique sequences in the mRNA transcript of the faulty gene, disrupting translation of the faulty mRNA, and therefore expression of the gene. A further strategy uses double stranded oligodeoxynucleotides as a decoy for the transcription factors that are required to activate the transcription of the target gene. The transcription factors bind to the decoys instead of the promoter of the faulty gene, which reduces the transcription of the target gene, lowering expression. Additionally, single stranded DNA oligonucleotides have been used to direct a single base change within a mutant gene. The oligonucleotide is designed to anneal with complementarity to the target gene with the exception of a central base, the target base, which serves as the template base for repair. This technique is referred to as oligonucleotide mediated gene repair, targeted gene repair, or targeted nucleotide alteration.
==== Lipoplexes ====
To improve the delivery of the new DNA into the cell, the DNA must be protected from damage and positively charged. Initially, anionic and neutral lipids were used for the construction of lipoplexes for synthetic vectors. However, in spite of the facts that there is little toxicity associated with them, that they are compatible with body fluids and that there was a possibility of adapting them to be tissue specific; they are complicated and time-consuming to produce so attention was turned to the cationic versions.
Cationic lipids, due to their positive charge, were first used to condense negatively charged DNA molecules so as to facilitate the encapsulation of DNA into liposomes. Later it was found that the use of cationic lipids significantly enhanced the stability of lipoplexes. Also as a result of their charge, cationic liposomes interact with the cell membrane, endocytosis was widely believed as the major route by which cells uptake lipoplexes. Endosomes are formed as the results of endocytosis, however, if genes can not be released into cytoplasm by breaking the membrane of endosome, they will be sent to lysosomes where all DNA will be destroyed before they could achieve their functions. It was also found that although cationic lipids themselves could condense and encapsulate DNA into liposomes, the transfection efficiency is very low due to the lack of ability in terms of "endosomal escaping". However, when helper lipids (usually electroneutral lipids, such as DOPE) were added to form lipoplexes, much higher transfection efficiency was observed. Later on, it was discovered that certain lipids have the ability to destabilize endosomal membranes so as to facilitate the escape of DNA from endosome, therefore those lipids are called fusogenic lipids. Although cationic liposomes have been widely used as an alternative for gene delivery vectors, a dose dependent toxicity of cationic lipids were also observed which could limit their therapeutic usages.
The most common use of lipoplexes has been in gene transfer into cancer cells, where the supplied genes have activated tumor suppressor control genes in the cell and decrease the activity of oncogenes. Recent studies have shown lipoplexes to be useful in transfecting respiratory epithelial cells.
==== Polymersomes ====
Polymersomes are synthetic versions of liposomes (vesicles with a lipid bilayer), made of amphiphilic block copolymers. They can encapsulate either hydrophilic or hydrophobic contents and can be used to deliver cargo such as DNA, proteins, or drugs to cells. Advantages of polymersomes over liposomes include greater stability, mechanical strength, blood circulation time, and storage capacity.
==== Polyplexes ====
Complexes of polymers with DNA are called polyplexes. Most polyplexes consist of cationic polymers and their fabrication is based on self-assembly by ionic interactions. One important difference between the methods of action of polyplexes and lipoplexes is that polyplexes cannot directly release their DNA load into the cytoplasm. As a result, co-transfection with endosome-lytic agents such as inactivated adenovirus was required to facilitate nanoparticle escape from the endocytic vesicle made during particle uptake. However, a better understanding of the mechanisms by which DNA can escape from endolysosomal pathway, i.e. proton sponge effect, has triggered new polymer synthesis strategies such as incorporation of protonable residues in polymer backbone and has revitalized research on polycation-based systems.
Due to their low toxicity, high loading capacity, and ease of fabrication, polycationic nanocarriers demonstrate great promise compared to their rivals such as viral vectors which show high immunogenicity and potential carcinogenicity, and lipid-based vectors which cause dose dependence toxicity. Polyethyleneimine and chitosan are among the polymeric carriers that have been extensively studied for development of gene delivery therapeutics. Other polycationic carriers such as poly(beta-amino esters) and polyphosphoramidate are being added to the library of potential gene carriers. In addition to the variety of polymers and copolymers, the ease of controlling the size, shape, surface chemistry of these polymeric nano-carriers gives them an edge in targeting capability and taking advantage of enhanced permeability and retention effect.
==== Dendrimers ====
A dendrimer is a highly branched macromolecule with a spherical shape. The surface of the particle may be functionalized in many ways and many of the properties of the resulting construct are determined by its surface.
In particular it is possible to construct a cationic dendrimer, i.e. one with a positive surface charge. When in the presence of genetic material such as DNA or RNA, charge complementarity leads to a temporary association of the nucleic acid with the cationic dendrimer. On reaching its destination the dendrimer-nucleic acid complex is then taken into the cell via endocytosis.
In recent years the benchmark for transfection agents has been cationic lipids. Limitations of these competing reagents have been reported to include: the lack of ability to transfect some cell types, the lack of robust active targeting capabilities, incompatibility with animal models, and toxicity. Dendrimers offer robust covalent construction and extreme control over molecule structure, and therefore size. Together these give compelling advantages compared to existing approaches.
Producing dendrimers has historically been a slow and expensive process consisting of numerous slow reactions, an obstacle that severely curtailed their commercial development. The Michigan-based company Dendritic Nanotechnologies discovered a method to produce dendrimers using kinetically driven chemistry, a process that not only reduced cost by a magnitude of three, but also cut reaction time from over a month to several days. These new "Priostar" dendrimers can be specifically constructed to carry a DNA or RNA payload that transfects cells at a high efficiency with little or no toxicity.
==== Inorganic nanoparticles ====
Inorganic nanoparticles, such as gold, silica, iron oxide (ex. magnetofection) and calcium phosphates have been shown to be capable of gene delivery. Some of the benefits of inorganic vectors is in their storage stability, low manufacturing cost and often time, low immunogenicity, and resistance to microbial attack. Nanosized materials less than 100 nm have been shown to efficiently trap the DNA or RNA and allows its escape from the endosome without degradation. Inorganics have also been shown to exhibit improved in vitro transfection for attached cell lines due to their increased density and preferential location on the base of the culture dish. Quantum dots have also been used successfully and permits the coupling of gene therapy with a stable fluorescence marker. Engineered organic nanoparticles are also under development, which could be used for co-delivery of genes and therapeutic agents.
==== Cell-penetrating peptides ====
Cell-penetrating peptides (CPPs), also known as peptide transduction domains (PTDs), are short peptides (< 40 amino acids) that efficiently pass through cell membranes while being covalently or non-covalently bound to various molecules, thus facilitating these molecules' entry into cells. Cell entry occurs primarily by endocytosis but other entry mechanisms also exist. Examples of cargo molecules of CPPs include nucleic acids, liposomes, and drugs of low molecular weight.
CPP cargo can be directed into specific cell organelles by incorporating localization sequences into CPP sequences. For example, nuclear localization sequences are commonly used to guide CPP cargo into the nucleus. For guidance into mitochondria, a mitochondrial targeting sequence can be used; this method is used in protofection (a technique that allows for foreign mitochondrial DNA to be inserted into cells' mitochondria).
== Hybrid methods ==
Due to every method of gene transfer having shortcomings, there have been some hybrid methods developed that combine two or more techniques. Virosomes are one example; they combine liposomes with an inactivated HIV or influenza virus. This has been shown to have more efficient gene transfer in respiratory epithelial cells than either viral or liposomal methods alone. Other methods involve mixing other viral vectors with cationic lipids or hybridising viruses.
== See also ==
Genosome (lipoplex)
Techniques of genetic engineering
Transformation
Transfection
Transduction
== References == | Wikipedia/Vectors_in_gene_therapy |
Rab escort protein 1 (REP1) also known as rab proteins geranylgeranyltransferase component A 1 is an enzyme that in humans is encoded by the CHM gene.
== Function ==
This gene encodes component A of the RAB geranylgeranyl transferase holoenzyme. In the dimeric holoenzyme, this subunit binds unprenylated Rab GTPases and then presents them to the catalytic Rab GGTase subunit for the geranylgeranyl transfer reaction. Rab GTPases need to be geranylgeranyled on either one or two cysteine residues in their C-terminus to localize to the correct intracellular membrane.
== Interactions ==
CHM (gene) has been shown to interact with RAB1A, RAB7A and RAB3A.
== Clinical significance ==
Mutations in this gene are a cause of choroideremia; also known as tapetochoroidal dystrophy (TCD). This X-linked disease is characterized by progressive dystrophy of the choroid, retinal pigment epithelium and retina.
== See also ==
Rab (G-protein)
== References ==
== Further reading ==
== External links ==
GeneReviews/NCBI/NIH/UW entry on Choroideremia
Rab+escort+protein+1,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Rab_escort_protein |
A subclinical infection—sometimes called a preinfection or inapparent infection—is an infection by a pathogen that causes few or no signs or symptoms of infection in the host. Subclinical infections can occur in both humans and animals. Depending on the pathogen, which can be a virus or intestinal parasite, the host may be infectious and able to transmit the pathogen without ever developing symptoms; such a host is called an asymptomatic carrier. Many pathogens, including HIV, typhoid fever, and coronaviruses such as COVID-19 spread in their host populations through subclinical infection.
Not all hosts of asymptomatic subclinical infections will become asymptomatic carriers. For example, hosts of Mycobacterium tuberculosis bacteria will only develop active tuberculosis in approximately one-tenth of cases; the majority of those infected by Mtb bacteria have latent tuberculosis, a non-infectious type of tuberculosis that does not produce symptoms in individuals with sufficient immune responses.
Because subclinical infections often occur without eventual overt sign, in some cases their presence is only identified by microbiological culture or DNA techniques such as polymerase chain reaction (PCR) tests.
== Transmission ==
=== In humans ===
Many pathogens are transmitted through their host populations by hosts with few or no symptoms, including sexually transmitted infections such as syphilis and genital warts. In other cases, a host may develop more symptoms as the infection progresses beyond its incubation period. These hosts create a natural reservoir of individuals that can transmit a pathogen to other individuals. Because cases often do not come to clinical attention, health statistics frequently are unable to measure the true prevalence of an infection in a population. This prevents accurate modeling of its transmissibility.
=== In animals ===
Some animal pathogens are also transmitted through subclinical infections. The A(H5) and A(H7) strains of avian influenza are divided into two categories: low pathogenicity avian influenza (LPAI) viruses and highly pathogenic avian influenza (HPAI) viruses. While HPAI viruses have a very high mortality rate for chickens, LPAI viruses are very mild and produce few, if any symptoms; outbreaks in a flock may go undetected without ongoing testing.
Wild ducks and other waterfowl are asymptomatic carriers of avian influenza, notably HPAI, and can be infected without showing signs of illness. The prevalence of subclinical HPAI infection in waterfowl has contributed to the international outbreak of highly lethal H5N8 virus that began in early 2020.
== Pathogens known to cause subclinical infection ==
The following pathogens (together with their symptomatic illnesses) are known to be carried asymptomatically, often in a large percentage of the potential host population:
== See also ==
== References ==
== Further reading ==
Endara, Pablo; Trueba, Gabriel; Solberg, Owen D.; Bates, Sarah J.; Ponce, Karina; Cevallos, William; Matthijnssens, Jelle; Eisenberg, Joseph N.S. (April 2007). "Symptomatic and Subclinical Infection with Rotavirus P[8]G9, Rural Ecuador". Emerging Infectious Diseases. 13 (4): 574–580. doi:10.3201/eid1304.061285. PMC 2391297. PMID 17553272. | Wikipedia/Subclinical_infection |
Diseases of poverty, also known as poverty-related diseases (PRDs), are diseases that are more prevalent in low-income populations. They include infectious diseases, as well as diseases related to malnutrition and poor health behaviour. Poverty is one of the major social determinants of health. The World Health Report (2002) states that diseases of poverty account for 45% of the disease burden in the countries with high poverty rate which are preventable or treatable with existing interventions. Diseases of poverty are often co-morbid and ubiquitous with malnutrition. Poverty increases the chances of having these diseases as the deprivation of shelter, safe drinking water, nutritious food, sanitation, and access to health services contributes towards poor health behaviour. At the same time, these diseases act as a barrier for economic growth to affected people and families caring for them which in turn results into increased poverty in the community. These diseases produced in part by poverty are in contrast to diseases of affluence, which are diseases thought to be a result of increasing wealth in a society.
Poverty and infectious diseases are causally related. Even before the time of vaccines and antibiotics, before 1796, it can be speculated that, leaders were adequately protected in their castles with decent food and standard accommodation, conversely, the vast majority of people were living in modest, unsanitary homes; cohabiting with their animals. During this time people were unknowingly dying of infectious diseases in an event that; they touched their sick animals, had cuts in their skins, drank something that was not boiled or ate food that was contaminated by microbes. To exacerbate the situation, epidemics known as plagues then would emerge and wipe out the whole community. During this time, people had no knowledge on infectious diseases and their causes. After speculations that their illnesses were being caused by an invisible army of tiny living beings, microorganisms, Antonie van Leeuwenhoek invented the first microscope that confirmed the existence of microorganisms that cannot be visualised with the naked eye (around the 17th century).
Human immunodeficiency virus (HIV), malaria, and tuberculosis (TB), also known as "the big three", have been acknowledged as infectious diseases that disproportionately affect developing countries. HIV is a viral illness that can be transmitted sexually, by transfusion, shared needles and during child birth from mother to child. Due to its long latent period, there is a danger of its spread without action. It affects the human body by targeting T-cells, that are responsible for protection from uncommon infections and cancers. It is managed by life prolonging drugs known as antiretroviral drugs (ARVs). TB was discovered by Robert Koch in 1882. It is characterised by fever, weight loss, poor appetite and night sweats. Throughout the years, there has been an improvement in mortality and morbidity caused by TB. This improvement has been attributed to the introduction of the TB vaccine in 1906. Despite this, each year the majority infected by TB are the poor. Finally, malaria used to be prevalent throughout the world. It is now limited to developing and warm regions; Africa, Asia, and South America.
== Contributing factors ==
The prevalence of unfavorable environmental and social factors that contribute to disease are highest among individuals living in poverty. These communities are at a higher risk of adverse health outcomes, particularly with infectious diseases and noncommunicable diseases.
=== Physical activity ===
Physical activity is a protective factor against chronic conditions such as type 2 diabetes, high blood pressure, and coronary heart disease. Lack of physical activity is related to socioeconomic status, with a higher prevalence of sedentary lifestyles among less affluent groups. There are several factors which contribute to the barriers of exercise among these groups.
Within low-income communities in the US, there is reduced access to environments that promote physical activity including parks, recreational facilities, and gyms. Only about one in five homes in low-income areas have parks within a half-mile distance, and about the same number have a fitness or recreation center within that distance. Expanded availability of local environments enabling exercise is associated with an increase in physical activity and a decrease in individuals with an overweight status.
In addition, concerns of unsafe neighborhoods in low-income areas may result in reduced physical activity in both adults and children. Children from low-income families are more likely to engage in sedentary, indoor activities due to challenges in obtaining adult supervision of outdoor play and parental concern for noise complaints. One in three children are physically active on a daily basis, and children spend seven or more hours a day is spent in front of a screen whether it be a computer, a TV, or video games. Children and adults who do not exercise frequently lower their quality of life, which will impact them as they age.
=== Mental health ===
Mental health is "a state of successful performance of mental function, resulting in productive activities, fulfilling relationships with other people, and the ability to adapt to change and to cope with adversity". Poverty has a profound effect on a person's mental health. According to Alyssa Brown of the Washington D.C. Gallup, 31% of people living in poverty have reported at some point been diagnosed with depression compared with 15.8% of those not in poverty. There is evidence that low income or loss of income are associated with worsening mental health while wealth and gain of income are linked with improvements in mental health. Furthermore, individuals living in poverty are disproportionally exposed to air pollution, temperature extremes, and violence, which all negatively impact mental health. These factors can induce chronic stress, which result in high cortisol levels. Excess cortisol is associated with unfavorable health outcomes, such as hypertension, diabetes, osteoporosis, and increased risk of infections.
It is uncertain whether poverty induces depression or depression causes poverty. What is certain is that the two are closely linked. A reason for this link could be due to the lack of support groups such as community centers. Isolation plays an integral role in depression. Results from a cohort study of approximately 2,000 older adults aged 65 years and older from the New Haven Established Populations for the Epidemiological Study of the Elderly found that social engagement was associated with lower depression scores after adjustment for various demographic characteristics, physical activity and functional status.
=== Contaminated water ===
Each year many children and adults die as a result of a lack of access to clean drinking water and poor sanitation, which enables the spread of poverty-related diseases. Contaminated water enables the spread of various waterborne-pathogens, including bacteria (E. coli, cholera), viruses (hepatitis A, norovirus), and protozoa (schistosomiasis). According to UNICEF, 3,000 children die every day, worldwide due to contaminated drinking water and poor sanitation.
Although the Millennium Development Goal (MDG) of halving the number of people who did not have access to clean water by 2015 was reached five years ahead of schedule in 2010, there are still 783 million people who rely on unimproved water sources. In 2010 the United Nations declared access to clean water a fundamental human right, integral to the achievement of other rights. This made it enforceable and justifiable to permit governments to ensure their populations access to clean water. There have been efforts to improve water quality using new technology, which allows water to be disinfected immediately upon collection and during the storage process. Clean water is necessary for cooking, cleaning, and laundry because many people come into contact with disease-causing pathogens through their food, or while bathing or washing.
Though access to water has improved for some, it continues to be especially difficult for women and children as they bear most of the burden for accessing water and supplying it to their households. In India, Sub-Saharan Africa, and parts of Latin America, women are required to travel long distances in order to access a clean water source and then bring some water home. This has a significant impact on girls' educational attainment.
An ongoing issue of contaminated water in the United States has been taking place in Flint, Michigan since 2014. The issue of lead-contaminated water began after the source of drinking water was changed from Lake Huron to the Flint River, resulting in corrosion of supply pipes and lead leaching into the city's water supply. Exposure to lead has serious health complications in developing fetuses, children, and adults. Children are particularly vulnerable to low levels of lead, and can display behavioral changes, hearing problems, and other neurologic consequences as a result of lead ingestion.
=== Air pollution ===
Studies show that there is an association between low socioeconomic status and exposure to higher concentrations of air pollution. This relationship is especially apparent in North America, New Zealand, Asia, and Africa. Exposure to environmental toxins, like ambient particulate matter (or air pollution), has been linked to the development of diseases like cancer, immune system impairment, and reproductive dysfunction.
According to the World Health Organization, 2.4 billion people are exposed to household air pollution through the use of open fire cooking and inefficient stoves. This resulted in 3.2 million deaths per year in 2020 and countless cases of stroke, heart disease, and lung cancer. Exposure to household air pollution is especially prevalent in lower-resourced areas, contributing to the high burden of air pollution-related disease in locations considered "impoverished." Women and children, especially those who bear the burden of household chores in under-resourced areas, face increased risks of household air pollution associated complications because they are the most exposed to cooking, burning, and other household pollution emitting chores.
=== Education ===
Education is affected by poverty, which is known as the income achievement gap. This gap shows that children living in poverty or have lower-income are less likely to have the cognitive development and early literacy levels of those who do not. The amount of income affects the amount of extra money a family has to spend on additional educational programs; including summer camps and out of school assistance. In addition to finances, environmental toxins, including lead and stress and lack of nutritious food can diminish cognitive development. In later education, low-income individuals or those living in poverty are more likely to dropout of school or only receive a high school diploma. The failure to achieve higher levels of education attributes to the cycle of poverty which can continue for generations in the same family and even in the community. Studies have linked adults with low educational achievement to worse general health and increases in chronic conditions and disabilities. These individuals are more likely to engage in behaviors that worsen health, such as smoke, have an unhealthy diet, and are less likely to exercise. Higher educational achievement correlates with more opportunities for secure jobs, which enables individuals to generate wealth that can be used to improve factors that impact health outcomes.
=== Sanitation and hygiene ===
Inadequate sanitation is attributed to approximately 432,000 deaths in LMIC each year. Poor sanitation can lead to diarrheal disease and malnutrition, which can result in serious illness. Globally, 2.3 billion people do not have access to basic sanitation services, which include access to unshared facilities for disposal of human waste and waste management services. These inequalities in access result in open defecation and improperly treated wastewater that is used for food production. Countries where open defecation is seen have higher levels of poverty, adverse health outcomes, and death in children due to diarrheal disease.
Further, one in four individuals lack access to a handwashing station with soap and water, thereby enabling the transmission of respiratory and diarrheal disease. In 2016, inadequate handwashing was attributed to 370,000 respiratory deaths and 165,000 diarrheal deaths. Diarrheal diseases contribute not only to the decreased health of an individual, but also to an increase in poverty. Diseases of this nature cause an inability to attend school and work, thus directly decreasing income as well as educational development. The problem of inadequate sanitation is cyclical in nature—just as it is caused by poverty, it also worsens poverty.
=== Poor nutrition ===
Malnutrition disproportionately affects those in sub-Saharan Africa. Over 35 percent of children under the age of 5 in sub-Saharan Africa show physical signs of malnutrition. Malnutrition, the immune system, and infectious diseases operate in a cyclical manner: infectious diseases have deleterious effects on nutritional status, and nutritional deficiencies can lower the strength of the immune system which affects the body's ability to resist infections. Similarly, malnutrition of both macronutrients (such as protein and energy) and micronutrients (such as iron, zinc, and vitamins) increase susceptibility to HIV infections by interfering with the immune system and promoting viral replication that contributes to greater risks of HIV transmission from mother-to-child as well as those through sexual transmission. Increased mother-to-child transmission is related to specific deficiencies in micro-nutrients such as vitamin A. Further, anemia, a decrease in the number of red blood cells, increases viral shedding in the birth canal, which also increases risk of mother-to-child transmission. Without these vital nutrients, the body lacks the defense mechanisms to resist infections. At the same time, HIV lowers the body's ability to intake essential nutrients. HIV infection can affect the production of hormones that interfere with the metabolism of carbohydrates, proteins, and fats.
In the United States, 11.1 percent of households struggle with food insecurity. Food insecurity refers to the lack of access to quality food for a healthy lifestyle. The rate of hunger and malnutrition in female headed households was three times the national average at 30.2 percent. According to the Food and Agriculture Organization of the United Nations, 10 percent of the population in Latin America and the Caribbean are affected by hunger and malnutrition.
=== Poor housing conditions ===
Families living in poverty often struggle not only with housing problems, but neighborhood safety and affordability problems as well. Avoiding neighborhood safety problems often means staying home which reduces opportunity for exercise outside the home which exacerbates health issues due to lack of exercise. Staying in the home can mean exposure to lead, mold and rodents within that home that can lead to an increased risk of illness due to these inadequate housing issues.
=== Lack of access to health services ===
According to WHO, medical strategies report, approximately 30% of the global population does not have regular access to medicines. In the poorest parts of Africa and Asia, this percent goes up to 50%. The population below the poverty line lacks access due to higher retail price and unavailability of the medicines. The higher cost can be due to the higher manufacturing price or due to local or regional tax and Value Added Tax. There is a significant disparity in the research conducted in the health sector. It is claimed that only 10% of the health research conducted globally focuses on 90% disease burden. However, diseases such as cancer, cardiovascular diseases etc. that traditionally were associated with the wealthier community are now becoming more prevalent in the poor communities as well. Hence, the research conducted now is relevant to poor population. Political priority is also one of the contributing factors of inaccessibility. The government of poor countries may allocate less funding to public health due to the scarcity of resources.
Beyond the cost of medicines, systemic issues within healthcare access contribute to disparities in disease treatment and prevention. Implementation research has shown that strategies such as mobile clinics, community-based health workers, and telemedicine have expanded healthcare coverage in underserved areas. Without these interventions, poverty-related diseases will continue to disproportionately impact low-income populations.
=== Cycle of poverty ===
The cycle of poverty is the process through which families already in poverty are likely to remain in those circumstances unless there is an intervention of some kind. This cycle of poverty has an impact on the types of diseases that are experienced by these individuals, and will often be passed down through generations. Mental illnesses are particularly important when discussing the cycle of poverty, because these mental illnesses prevent individuals from obtaining gainful employment. The stressful experience of living in poverty can also exacerbate mental illnesses.
This cycle of poverty also impacts the familial diseases that are passed down each generation. By experiencing the same stressful situations for decades, individuals become more susceptible to diseases like cardiovascular disease, obesity, diabetes, and mental illnesses including schizophrenia and bipolar disorder.
Health disparities contribute significantly to the cycle of poverty. Chronic conditions such as diabetes and hypertension reduce an individual’s ability to work, further deepening economic hardship. Studies have shown that children in low-income families are at greater risk of malnutrition, which can lead to long-term cognitive and physical health issues. Addressing these health disparities requires policies that integrate healthcare, education, and economic support systems
== Infectious diseases ==
Together, diseases of poverty kill approximately 14 million people annually. Gastroenteritis with its associated diarrhea results in about 1.8 million deaths in children yearly with most of these in the world's poorest nations.
At the global level, the three primary PRDs are tuberculosis, AIDS/HIV and malaria. Developing countries account for 95% of the global AIDS prevalence and 98% of active tuberculosis infections. Furthermore, 90% of malaria deaths occur in African countries. Together, these three diseases account for 10% of global mortality.
While infectious diseases such as HIV, tuberculosis, and malaria remain significant health threats, they are not the only major health concerns for impoverished populations. Research indicates that chronic diseases are becoming increasingly prevalent in these communities due to changing lifestyles and environmental factors. Expanding healthcare interventions to address both infectious and non-communicable diseases can provide a more comprehensive approach to reducing the global disease burden.
Treatable childhood diseases are another set which have disproportionately higher rates in poor countries despite the availability of cures for decades. These include measles, pertussis and polio. The largest three PRDs—AIDS, malaria, and tuberculosis—account for 18% of diseases in poor countries. The disease burden of treatable childhood diseases in high-mortality, poor countries is 5.2% in terms of disability-adjusted life years but just 0.2% in the case of advanced countries.
In addition, infant mortality and maternal mortality are far more prevalent among the poor. For example, 98% of the 11,600 daily maternal and neonatal deaths occur in developing countries.
Three other diseases, measles, pneumonia, and diarrheal diseases, are also closely associated with poverty, and are often included with AIDS, malaria, and tuberculosis in broader definitions and discussions of diseases of poverty.
=== Neglected diseases ===
Based upon the spread of research in cures for diseases, certain diseases are identified and referred to as "neglected diseases". These include the following diseases:
African trypanosomiasis
Chagas disease
Leishmaniasis
Lymphatic filariasis
Dracunculiasis ("Guinea worm disease")
Onchocerciasis
Schistosomiasis
Trichomoniasis
Tropical diseases such as these tend to be neglected in research and development efforts. Of 1393 new drugs brought into use over a period of 25 years (1975–1999), only a total of thirteen, less than 1%, related to these diseases. Of 20 multinational drug companies surveyed for research on PRDs, only two had projects targeted towards these neglected PRDs. However, the combined total number of deaths due to these diseases is dwarfed by the enormous number of patients affected by PRDs such as respiratory infections, HIV/AIDS, diarrhea and tuberculosis, besides many others.
Similar to the spread of tropical neglected diseases in developing nations, these neglected infections disproportionately affect poor and minority populations in the United States. These diseases have been identified by the Centers for Disease Control and Prevention, as priorities for public health action based on the number of people infected, the severity of the illnesses, and the ability to prevent and treat them.
=== Trichomoniasis ===
Trichomoniasis is the most common sexually transmitted infection affecting more than 200 million people worldwide. It is especially prevalent among young, poor and African American women. This infection is also common in poor communities in Sub-Saharan Africa and impoverished parts of Asia. This neglected infection is one of special concern because it is associated with a heightened risk for contracting HIV and pre-term deliveries.
In addition, availability of cures and recent advances in medicine have led to only three diseases being considered neglected diseases, namely, African trypanosomiasis, Chagas disease and Leishmaniasis.
=== Malaria ===
Africa accounts for a majority of malaria infections and deaths worldwide. Over 80 percent of the 300 to 500 million malaria infections occurring annually worldwide are in Africa. Each year, about one million children under the age of five die from malaria. Children who are poor, have mothers with little to no education, and live in rural areas are more susceptible to malaria and more likely to die from it. Malaria is directly related to the spread of HIV in sub-Saharan Africa. It increases viral load seven to ten times, which increases the chances of transmission of HIV through sexual intercourse from a patient with malaria to an uninfected partner. After the first pregnancy, HIV can also decrease the immunity to malaria. This contributes to the increase of the vulnerability to HIV and higher mortality from HIV, especially for women and infants. HIV and malaria interact in a cyclical manner—being infected with malaria increases susceptibility to HIV infection, and HIV infections increase malarial episodes. The co-existence of HIV and malaria infections helps spread both diseases, particularly in Sub-Saharan Africa. Malaria vaccines are an area of intensive research.
=== Intestinal parasites ===
Intestinal parasites are extremely prevalent in tropical areas. These include helminths like hookworms, roundworms, and flukes and protozoa like giardia, amoebas and Leishmania. They can aggravate malnutrition by depleting essential nutrients through intestinal blood loss and chronic diarrhea. Chronic worm infections can further burden the immune system. At the same time, chronic worm infections can cause immune activation that increases susceptibility of HIV infection and vulnerability to HIV replication once infected.
=== Schistosomiasis ===
Schistosomiasis (bilharzia) is a parasitic disease caused by the parasitic flatworm trematodes. Moreover, more than 80 percent of the 200 million people worldwide who have schistosomiasis live in sub-Saharan Africa. Infections often occur in contaminated water where freshwater snails release larval forms of the parasite. After penetrating the skin and eventually traveling to the intestines or the urinary tract, the parasite lays eggs and infects those organs. It damages the intestines, bladder, and other organs and can lead to anemia and protein-energy deficiency. Along with malaria, schistosomiasis is one of the most important parasitic co-factors aiding in HIV transmission. Epidemiological data shows schistosome-endemic areas coincide with areas of high HIV prevalence, suggesting that parasitic infections such as schistosomiasis increase risk of HIV transmission.
=== Tuberculosis ===
Tuberculosis is the leading cause of death around the world for an infectious disease. This disease is especially prevalent in sub-Saharan Africa, and the Latin American and Caribbean region. While the tuberculosis rate is decreasing in the rest of the world, it is increasing by rate of 6 percent per year in Sub-Saharan Africa. It is the leading cause of death for people with HIV in Africa. Tuberculosis (TB) is closely related to lifestyles of poverty, overcrowded conditions, alcoholism, stress, drug addiction and malnutrition. This disease spreads quickly among people who are undernourished. According to the Center for Disease Control and Prevention, in the United States, tuberculosis is more prevalent among foreign born persons, and ethnic minorities. The rates are especially high among Hispanics, Blacks and Asians.
HIV infection and TB are also closely tied. Being infected with HIV increases the rate of activation of latent TB infections, and having TB, increases the rate of HIV replication, therefore accelerating the progression of AIDS.
=== AIDS ===
AIDS is a disease of the human immune system caused by the human immunodeficiency virus (HIV). Primary modes of HIV transmission in sub-Saharan Africa are sexual intercourse, mother-to-child transmission (vertical transmission), and through HIV-infected blood. Since rate of HIV transmission via heterosexual intercourse is so low, it is insufficient to cause AIDS disparities between countries. Critics of AIDS policies promoting safe sexual behaviors believe that these policies miss the biological mechanisms and social risk factors that contribute to the high HIV rates in poorer countries. In these developing countries, especially those in sub-Saharan Africa, certain health factors predispose the population to HIV infections.
Many of the countries in Sub-Saharan Africa are ravaged with poverty and many people live on less than one United States dollar a day. The poverty in these countries gives rise to many other factors that explain the high prevalence of AIDS. The poorest people in most African countries are malnourished, lack of access to clean water, and have improper sanitation. Because of a lack of clean water many people are plagued by intestinal parasites that significantly increase their chances of contracting HIV due to compromised immune system. Malaria, a disease still rampant in Africa also increases the risk of contracting HIV. These parasitic diseases, affect the body's immune response to HIV, making people more susceptible to contracting the disease once exposed. Genital schistosomiasis, also prevalent in the topical areas of Sub-Saharan Africa and many countries worldwide, produces genital lesions and attract CD4 cells to the genital region which promotes HIV infection. All these factors contribute to the high rate of HIV in Sub-Saharan Africa. Many of the factors seen in Africa are also present in Latin America and the Caribbean and contribute to the high rates of infections seen in those regions. In the United States, poverty is a contributing factor to HIV infections. There is also a large racial disparity, with African Americans having a significantly higher rate of infection than their white counterparts.
== Noncommunicable diseases ==
Noncommunicable diseases (NCD) such as cardiovascular disease, chronic respiratory diseases, cancer, and diabetes place a significant burden of disease in low- and middle-income countries (LMIC). NCD cause 41 million deaths each year, which account for 71% of all deaths globally of which 77% are in LMIC.
=== Chronic diseases and poverty ===
Poverty also significantly contributes to chronic diseases, including diabetes, cardiovascular disease, and mental illness. A study by Johns Hopkins Public Health highlights that people living in poverty have a heightened risk of developing non-communicable diseases (NCDs) due to inadequate access to nutritious food, preventive medical care, and healthcare services. Poor dietary habits, increased stress, and environmental factors such as air pollution further exacerbate these health risks. Addressing these chronic illnesses is critical to understanding the full impact of poverty on health.
=== Respiratory diseases ===
More than 300 million people worldwide have asthma. The rate of asthma increases as countries become more urbanized and in many parts of the world those who develop asthma do not have access to medication and medical care. Within the United States, African Americans and Latinos are four times more likely to have severe asthma than whites. The disease is closely tied to poverty and poor living conditions. Asthma is also prevalent in children in low income countries. Homes with roaches and mice, as well as mold and mildew put children at risk for developing asthma as well as exposure to cigarette smoke.
Unlike many other Western countries, the mortality rate for asthma has steadily risen in the United States over the last two decades. Mortality rates for African American children due to asthma are also far higher than that of other racial groups. For African Americans, the rate of visits to the emergency room is 330 percent higher than their white counterparts. The hospitalization rate is 220 percent higher and the death rate is 190 percent higher. Among Hispanics, Puerto Ricans are disporpotionatly affected by asthma with a disease rate that is 113 percent higher than non-Hispanic Whites and 50 percent higher than non-Hispanic Blacks. Studies have shown that asthma morbidity and mortality are concentrated in inner city neighborhoods characterized by poverty and large minority populations and this affects both genders at all ages. Asthma continues to have an adverse effects on the health of the poor and school attendance rates among poor children. 10.5 million days of school are missed each year due to asthma.
=== Cardiovascular disease ===
Though heart disease is not exclusive to the poor, there are aspects of a life of poverty that contribute to its development. This category includes coronary heart disease, stroke and heart attack. Heart disease is the leading cause of death worldwide and there are disparities of morbidity between the rich and poor. Studies from around the world link heart disease to poverty. Low neighborhood income and education were associated with higher risk factors. Poor diet, lack of exercise and limited (or no) access to a specialist were all factors related to poverty, thought to contribute to heart disease. Both low income and low education were predictors of coronary heart disease, a subset of cardiovascular disease. Of those admitted to hospital in the United States for heart failure, women and African Americans were more likely to reside in lower income neighborhoods. In the developing world, there is a 10 fold increase in cardiac events in the black and urban populations.
=== Cancer ===
While cancer affects all populations, certain populations are disproportionally affected by the disease due to differences in risk factor exposures. People living in poverty are at an increased risk of cancer incidence and mortality, with annual death rates being 12% higher in countries living in poverty. Globally, two out of three cancer deaths are attributed to lifestyle and behaviors such as smoking, poor diet, physical inactivity, and insufficient cancer screenings. Individuals living in LMIC have greater exposure to these risk factors in the setting of reduced access to health care services. Inadequate access to health care presents a major barrier as individuals are less likely to receive regular cancer screenings resulting in a late-stage diagnosis, which is associated with worse health outcomes. People living in poverty have also higher levels of chronic stress, which also increases an individual's risk of cancer due to inflammatory changes.
=== Obesity ===
Obesity is a chronic non-communicable disease (NCD) that is diagnosed in individuals who have a body mass index (BMI) greater than 30 kg/m2. Generally, low-income populations, whether they live in high-income countries or in low-middle income countries (LMIC) suffer higher disease burden for chronic conditions including obesity when compared to their higher income counterparts. Higher obesity rates tend to be observed in LMICs and it has been believed that lower socioeconomic statuses (SES) leads to higher obesity rates because individuals living in poverty are limited in their abilities to engage in healthy exercising and dieting practices. In the United States, there tends to be higher obesity rates in lower SES neighborhoods, which are called food deserts. A food desert lacks supermarkets that offer healthy and fresh food options and instead have highly processed foods. Because of the limited access to healthy foods, it follows that individuals who live farther away from supermarkets tend to have higher rates of obesity. Besides food access, individuals living in poverty may also be limited in their healthcare access, leading to later diagnosis and management of chronic conditions like obesity. Conversely, chronic conditions such as obesity can also increase rates of poverty via increased healthcare expenditures, wage loss during peak productive years, and missed schooling. These points underscore the positive effect poverty alleviation has on improving health outcomes as it concerns obesity and other chronic NCDs. In spite of this data, pervasive attitudes remain that individual behavior, not SES, is responsible for obesity. These attitudes stigmatize individuals with obesity, which further hampers public health interventions to reduce obesity rates and accelerates health disparities along SES lines.
=== Social and economic determinants of health ===
Poverty related diseases are not just biological but are deeply influenced by social and economic conditions. According to the Centers for Disease Control and Prevention (CDC), factors such as income security, stable housing, education, and employment opportunities play a critical role in determining health outcomes. Individuals in poverty often live in environments with higher exposure to pollutants, limited access to fresh food, and higher stress levels, all of which contribute to poor health.
=== Healthcare access and policy solutions ===
Access to healthcare remains a crucial determinant of health outcomes for individuals in poverty. Research demonstrates that healthcare system improvements in low- and middle-income countries (LMICs) can significantly reduce the burden of poverty-related diseases. However, many impoverished communities continue to face barriers such as high medical costs, lack of healthcare infrastructure, and limited insurance coverage. Implementing policies that prioritize equitable healthcare access, such as universal health coverage and community health programs, can help mitigate these disparities
== Other health complications ==
=== Maternal health ===
Obstetric fistula or vaginal fistula is a medical condition in which a fistula (hole) develops between either the rectum and vagina (see rectovaginal fistula) or between the bladder and vagina (see vesicovaginal fistula) after severe or failed childbirth, when adequate medical care is not available. It is considered a disease of poverty because of its tendency to occur women in poor countries who do not have health resources comparable to developed nations.
=== Dental decay ===
Dental decay or dental caries is the gradual destruction of tooth enamel. Poverty is a significant determinant for oral health. Dental caries is one of the most common chronic diseases worldwide. In the United States it is the most common chronic disease of childhood. Risk factors for dental caries includes living in poverty, poor education, low socioeconomic status, being part of an ethnic minority group, having a developmental disability, recent immigrants and people infected with HIV/AIDS. In Peru, poverty was found to be positively correlated with dental caries among children. According to a report by U.S. health surveillance, tooth decay peaks earlier in life and is more severe in children with families living below the poverty line. Tooth decay is also strongly linked to dietary behaviors, and in poor rural areas where nutrient dense foods, fruits and vegetables are unavailable, the consumption of sugary and fatty food increases the risk of dental decay. Because the mouth is a gateway to the respiratory and digestive tracts, oral health has a significant impact on other health outcomes. Gum disease has been linked to diseases such as cardiovascular disease.
== Societal consequences ==
Diseases of poverty reflect the dynamic relationship between poverty and poor health; while such diseases result directly from poverty, they also perpetuate and deepen impoverishment by sapping personal and national health and financial resources. For example, malaria decreases GDP growth by up to 1.3% in some developing nations, and by killing tens of millions in sub-Saharan Africa, AIDS alone threatens "the economies, social structures, and political stability of entire societies".
=== For women ===
Women and children are often put at a high risk of being infected by schistosomiasis, which in turn puts them at a higher risk of acquiring HIV. Since the mode of schistosomiasis transmission is usually through contaminated water in streams and lakes, women and children who do their household chores by the water are more likely to acquire the disease. Activities that women and children often do around waterfront include washing clothes, collecting water, bathing, and swimming. Women who have schistosomiasis lesions are three times more likely to be infected with HIV.
Women also have a higher risk of HIV transmission through the use of medical equipment such as needles. Because more women than men use health services, especially during pregnancy, they are more likely to come across unsterilized needles for injections. Although statistics estimate that unsterilized needles only account for 5 to 10 percent of primary HIV infections, studies show this mode of HIV transmission may be higher than reported. This increased risk of contracting HIV through non-sexual means has social consequences for women as well. Over half of the husbands of HIV-positive women in Africa tested HIV-negative. When HIV-positive women reveal their HIV status to their HIV-negative husbands, they are often accused of infidelity and face violence and abandonment from their family and community.
=== Relating to human capabilities ===
Malnutrition associated with HIV impacts people's ability to provide for themselves and their dependents, thus limiting the human capabilities of both themselves and their dependents. HIV can negatively affect work output, which impacts the ability to generate income. This is crucial in parts of Africa where farming is the primary occupation and obtaining food is dependent on the agricultural outcome. Without adequate food production, malnutrition becomes more prevalent. Children are often collateral damage in the AIDS crisis. As dependents, they can be burdened by the illness and eventual death of one or both parents due to HIV/AIDS. Studies have shown that orphaned children are more likely to display physical symptoms of malnutrition than children whose parents are both alive.
== Public policy proposals ==
There are a number of proposals for reducing the diseases of poverty and eliminating health disparities within and between countries. The World Health Organization proposes closing the gaps by acting on social determinants.
Their first recommendation is to improve daily living conditions. This area involves improving the lives of women and girls so that their children are born in healthy environments and placing an emphasis on early childhood health.
Their second recommendation is to tackle the inequitable distribution of money, power and resources. This would involve building stronger public sectors and changing the way in which society is organized.
Their third recommendation is to measure and understand the problem and assess the impact of action. This would involve training policy makers and healthcare practitioners to recognize problems and form policy solutions.
=== Health in All Policies ===
The 8th Global Conference on Health Promotion held in Helsinki in June 2013 has proposed an approach termed Health in All Policies. Health inequalities are shaped by many powerful forces and social, political, and economic determinants. Governments have a responsibility to ensure that their people are able to live healthy lives and have equitable access to achieving a reasonable state of good health. Policies that governments craft and implement in all sectors have a significant and ongoing impact on public health, health equity, and the lives of their citizens. Increases in technology, medical innovation, and living conditions have led to the disappearance of diseases and other factors contributing to poor health. However, there are many diseases of poverty that still persist in developed and developing countries. Tackling these health inequalities and diseases of poverty requires a willingness to engage the whole government in health. The Helsinki Statement lays out a framework of action for countries and calls on governments to make a commitment to building health equity within their country.
Health in All Policies (HiAP) is an approach to public policies across all sectors of government that takes into account the health implications of all government and policy decisions to improve health equity across all populations residing within the borders of a country. This concept is built upon principles in line with the Universal Declaration of Human Rights, The United Nations Millennium Development Declaration, and principles of good governance: legitimacy given by national and international law, accountability of government, transparency of policy making, participation of citizens, sustainability ensuring policies meet the needs of both present and future generations, and collaboration across sectors and levels of government.
Finally the Framework lists and expands upon six steps for implementation that may be undertaken by a country in taking action towards Health in All Policies. These are components of action and not a rigid checklist of steps to adhere to. The most important aspect of this policy is that governments should adapt the policy to suit the needs of their citizens, their socioeconomic situation, and their governance system.
Establish the need and priorities for HiAP
Frame planned action
Identify supportive structures and processes
Facilitate assessment and engagement
Ensure monitoring, evaluation, and reporting
Build capacity.
=== HIV/AIDS policy ===
Nutrition Supplements: Focusing on reversing the pattern of malnutrition in sub-Saharan African and other poor countries is a one possible way of decreasing susceptibility to HIV infections. Micro-nutrients such as iron and vitamin A can be delivered and provided at a very low cost. For example, vitamin A supplements cost $0.02 per capsule if provided twice a year. Iron supplements per child cost $0.02 if provided weekly or $0.08 if provided daily.
Eliminating Co-factors: Tackling the very diseases that increase risk of HIV infections can help slow down the rates of HIV transmission. Co-factors such as malaria and parasitic infections can be combated in an effective and cost-efficient manner. For example, mosquito nets can be easily used to prevent malaria. Parasites can be eliminated with medication that is cost-effective and easy to administer. Twice-yearly treatments range from $0.02 to $0.25 depending on the type of worm.
== See also ==
== References ==
== External links ==
United Nations Population Fund: State of World Population 2002
RESULTS: World Health/Diseases of Poverty
Roll Back Malaria Global Partnership
Agriculture and HIV/AIDS : understanding the links between agriculture and health (brief) by Stuart Gillespie (2006) International Food Policy Research Institute
The Poor Pay More—POVERTY'S HIGH COST TO HEALTH | Wikipedia/Diseases_of_poverty |
The Centers for Disease Control and Prevention (CDC) is the national public health agency of the United States. It is a United States federal agency under the Department of Health and Human Services (HHS), and is headquartered in Atlanta, Georgia. The CDC's current nominee for director is Susan Monarez. She became acting director on January 23, 2025, but stepped down on March 24, 2025 when nominated for the director position. On May 14, 2025, Robert F. Kennedy Jr. stated that lawyer Matthew Buzzelli is acting CDC director. However, the CDC web site does not state the acting director's name.
The agency's main goal is the protection of public health and safety through the control and prevention of disease, injury, and disability in the US and worldwide. The CDC focuses national attention on developing and applying disease control and prevention. It especially focuses its attention on infectious disease, food borne pathogens, environmental health, occupational safety and health, health promotion, injury prevention, and educational activities designed to improve the health of United States citizens. The CDC also conducts research and provides information on non-infectious diseases, such as obesity and diabetes, and is a founding member of the International Association of National Public Health Institutes.
As part of the announced 2025 HHS reorganization, CDC is planned to be reoriented towards infectious disease programs. It is planned to absorb the Administration for Strategic Preparedness and Response, while the National Institute for Occupational Safety and Health is planned to move into the new Administration for a Healthy America.
== History ==
=== Establishment ===
The Communicable Disease Center was founded July 1, 1946, as the successor to the World War II Malaria Control in War Areas program of the Office of National Defense Malaria Control Activities.
Preceding its founding, organizations with global influence in malaria control were the Malaria Commission of the League of Nations and the Rockefeller Foundation. The Rockefeller Foundation greatly supported malaria control, sought to have the governments take over some of its efforts, and collaborated with the agency.
The new agency was a branch of the U.S. Public Health Service and Atlanta was chosen as the location because malaria was endemic in the Southern United States. The agency changed names (see infobox on top) before adopting the name Communicable Disease Center in 1946. Offices were located on the sixth floor of the Volunteer Building on Peachtree Street.
With a budget at the time of about $1 million, 59 percent of its personnel were engaged in mosquito abatement and habitat control with the objective of control and eradication of malaria in the United States (see National Malaria Eradication Program).
Among its 369 employees, the main jobs at CDC were originally entomology and engineering. In CDC's initial years, more than six and a half million homes were sprayed, mostly with DDT. In 1946, there were only seven medical officers on duty and an early organization chart was drawn. Under Joseph Walter Mountin, the CDC continued to be an advocate for public health issues and pushed to extend its responsibilities to many other communicable diseases.
In 1947, the CDC made a token payment of $10 to Emory University for 15 acres (61,000 m2) of land on Clifton Road in DeKalb County, still the home of CDC headquarters as of 2025. CDC employees collected the money to make the purchase. The benefactor behind the "gift" was Robert W. Woodruff, chairman of the board of the Coca-Cola Company. Woodruff had a long-time interest in malaria control, which had been a problem in areas where he went hunting. The same year, the PHS transferred its San Francisco based plague laboratory into the CDC as the Epidemiology Division, and a new Veterinary Diseases Division was established.
=== Growth ===
In 1951, Chief Epidemiologist Alexander Langmuir's warnings of potential biological warfare during the Korean War spurred the creation of the Epidemic Intelligence Service (EIS) as a two-year postgraduate training program in epidemiology. The success of the EIS program led to the launch of Field Epidemiology Training Programs (FETP) in 1980, training more than 18,000 disease detectives in over 80 countries. In 2020, FETP celebrated the 40th anniversary of the CDC's support for Thailand's Field Epidemiology Training Program. Thailand was the first FETP site created outside of North America and is found in numerous countries, reflecting CDC's influence in promoting this model internationally. The Training Programs in Epidemiology and Public Health Interventions Network (TEPHINET) has graduated 950 students.
The mission of the CDC expanded beyond its original focus on malaria to include sexually transmitted diseases when the Venereal Disease Division of the U.S. Public Health Service (PHS) was transferred to the CDC in 1957. Shortly thereafter, Tuberculosis Control was transferred (in 1960) to the CDC from PHS, and then in 1963 the Immunization program was established.
It became the National Communicable Disease Center effective July 1, 1967, and the Center for Disease Control on June 24, 1970. At the end of the Public Health Service reorganizations of 1966–1973, it was promoted to being a principal operating agency of PHS.
=== Recent history ===
It was renamed to the plural Centers for Disease Control effective October 14, 1980, as the modern organization of having multiple constituent centers was established. By 1990, it had four centers formed in the 1980s: the Center for Infectious Diseases, Center for Chronic Disease Prevention and Health Promotion, the Center for Environmental Health and Injury Control, and the Center for Prevention Services; as well as two centers that had been absorbed by CDC from outside: the National Institute for Occupational Safety and Health in 1973, and the National Center for Health Statistics in 1987.
An act of the United States Congress appended the words "and Prevention" to the name effective October 27, 1992. However, Congress directed that the initialism CDC be retained because of its name recognition. Since the 1990s, the CDC focus has broadened to include chronic diseases, disabilities, injury control, workplace hazards, environmental health threats, and terrorism preparedness. CDC combats emerging diseases and other health risks, including birth defects, West Nile virus, obesity, avian, swine, and pandemic flu, E. coli, and bioterrorism, to name a few. The organization would also prove to be an important factor in preventing the abuse of penicillin. In May 1994 the CDC admitted having sent samples of communicable diseases to the Iraqi government from 1984 through 1989 which were subsequently repurposed for biological warfare, including Botulinum toxin, West Nile virus, Yersinia pestis and Dengue fever virus.
On April 21, 2005, then–CDC director Julie Gerberding formally announced the reorganization of CDC to "confront the challenges of 21st-century health threats". She established four coordinating centers. In 2009 the Obama administration re-evaluated this change and ordered them cut as an unnecessary management layer.
As of 2013, the CDC's Biosafety Level 4 laboratories were among the few that exist in the world. They included one of only two official repositories of smallpox in the world, with the other one located at the State Research Center of Virology and Biotechnology VECTOR in the Russian Federation. In 2014, the CDC revealed they had discovered several misplaced smallpox samples while their lab workers were "potentially infected" with anthrax.
The city of Atlanta annexed the property of the CDC headquarters effective January 1, 2018, as a part of the city's largest annexation within a period of 65 years; the Atlanta City Council had voted to do so the prior December. The CDC and Emory University had requested that the Atlanta city government annex the area, paving the way for a MARTA expansion through the Emory campus, funded by city tax dollars. The headquarters were located in an unincorporated area, statistically in the Druid Hills census-designated place.
On August 17, 2022, Walensky said the CDC would make drastic changes in the wake of mistakes during the COVID-19 pandemic. She outlined an overhaul of how the CDC would analyze and share data and how they would communicate information to the general public. In her statement to all CDC employees, she said: "For 75 years, CDC and public health have been preparing for COVID-19, and in our big moment, our performance did not reliably meet expectations." Based on the findings of an internal report, Walensky concluded that "The CDC must refocus itself on public health needs, respond much faster to emergencies and outbreaks of disease, and provide information in a way that ordinary people and state and local health authorities can understand and put to use" (as summarized by the New York Times).
==== Second Trump administration ====
In January 2025, it was reported that a CDC official had ordered all CDC staff to stop working with the World Health Organization. Around January 31, 2025, several CDC websites, pages, and datasets related to HIV and STI prevention, LGBT and youth health became unavailable for viewing after the agency was ordered to comply with Donald Trump's executive order to remove all material of "diversity, equity, and inclusion" and "gender identity". Shortly thereafter, the CDC ordered its scientists to retract or pause the publication of all research which had been submitted or accepted for publication, but not yet published, which included any of the following banned terms: "Gender, transgender, pregnant person, pregnant people, LGBT, transsexual, non-binary, nonbinary, assigned male at birth, assigned female at birth, biologically male, biologically female."
Also in January 2025, due to a pause in communications imposed by the second Trump administration at federal health agencies, publication of the Morbidity and Mortality Weekly Report (MMWR) was halted, the first time that had happened since its inception in 1960. The president of the Infectious Diseases Society of America (IDSA) called the pause in publication a "disaster." Attempts to halt publication had been made by the first Trump administration after MMWR published information about COVID-19 that "conflicted with messaging from the White House." The pause in communications also caused the cancellation of a meeting between the CDC and IDSA about threats to public health regarding the H5N1 influenza virus.
On February 14, 2025, around 1,300 CDC employees were laid off by the administration, which included all first-year officers of the Epidemic Intelligence Service. The cuts also terminated 16 of the 24 Laboratory Leadership Service program fellows, a program designed for early-career lab scientists to address laboratory testing shortcomings of the CDC. In the following month, the Trump administration quietly withdrew its CDC director nominee, Dave Weldon, just minutes before his scheduled Senate confirmation hearing on March 13.
In April 2025, it was reported that among the reductions is the elimination of the Freedom of Information Act team, the Division of Violence Prevention, laboratories involved in testing for antibiotic resistance, and the team responsible for determining recalls of hazardous infant products. Additional cuts affect the technology branch of the Center for Forecasting and Outbreak Analytics, which includes software engineers and computer scientists supporting the centre established during the COVID-19 pandemic to improve disease outbreak prediction.
== Organization ==
The CDC is organized into centers, institutes, and offices (CIOs), with each organizational unit implementing the agency's activities in a particular area of expertise while also providing intra-agency support and resource-sharing for cross-cutting issues and specific health threats.
As of the most recent reorganization in February 2023, the CIOs are:
National Center for Immunization and Respiratory Diseases
National Center for Emerging and Zoonotic Infectious Diseases
Division of Global Migration Health
National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention
National Center on Birth Defects and Developmental Disabilities
National Center for Chronic Disease Prevention and Health Promotion
National Center for Environmental Health / Agency for Toxic Substances and Disease Registry
National Center for Injury Prevention and Control
National Institute for Occupational Safety and Health
Public Health Infrastructure Center
Global Health Center
Immediate Office of the Director
Chief of Staff
Office of the Chief Operating Officer
Office of Policy, Performance, and Evaluation
Office of Equal Employment Opportunity and Workplace Equity
Office of Communications
Office of Health Equity
Office of Science
CDC Washington Office
Office of Laboratory Science and Safety
Office of Readiness and Response
Center for Forecasting and Outbreak Analytics
Office of Public Health Data, Surveillance, and Technology
National Center for Health Statistics
The Office of Public Health Preparedness was created during the 2001 anthrax attacks shortly after the terrorist attacks of September 11, 2001. Its purpose was to coordinate among the government the response to a range of biological terrorism threats.
=== Locations ===
Most CDC centers are located in the Atlanta metropolitan area, where it has three major campuses:
The Chamblee Campus in Chamblee, Georgia, opened in 1946, inheriting the site and buildings of Lawson General Hospital immediately adjacent to but not part of Naval Air Station Atlanta. Although it was initially planned to be shut down when the Roybal Campus opened, it was found that the latter was not suitable for live animal facilities. The buildings were slowly replaced with modern buildings over time.
The Roybal Campus in Atlanta is the largest, named in honor of the late representative Edward R. Roybal. It was originally called the Clifton Road Campus. Although its land was donated by adjacent Emory University in 1947, it did not open until 1960. Its Building 18, which opened in 2005, contains the premier BSL4 laboratory in the United States.
The Lawrenceville Campus in Lawrenceville, Georgia, was acquired as a destination for Chamblee's animal facilities if that campus was shut down. It was first developed in the early 1960s.
A few of the centers are based in or operate other domestic locations:
The National Center for Health Statistics is primarily located in Hyattsville, Maryland, with a branch in Research Triangle Park in North Carolina.
The National Institute for Occupational Safety and Health's primary locations are Cincinnati; Morgantown, West Virginia; Pittsburgh; Spokane, Washington; and Washington, D.C., with branches in Denver; Anchorage, Alaska; and Atlanta.
The CDC Washington Office is based in Washington, D.C.
Two divisions of the National Center for Emerging and Zoonotic Infectious Diseases are based outside Atlanta. The Division of Vector-Borne Diseases is based in Fort Collins, Colorado, with a branch in San Juan, Puerto Rico. The Arctic Investigations Program is based in Anchorage.
In addition, CDC operates quarantine facilities in 20 cities in the U.S.
== Budget ==
The CDC budget for fiscal year 2024 is $11.581 billion.
== Workforce ==
As of 2021, CDC staff numbered approximately 15,000 personnel (including 6,000 contractors and 840 United States Public Health Service Commissioned Corps officers) in 170 occupations. Eighty percent held bachelor's degrees or higher; almost half had advanced degrees (a master's degree or a doctorate such as a PhD, D.O., or M.D.).
Common CDC job titles include engineer, entomologist, epidemiologist, biologist, physician, veterinarian, behavioral scientist, nurse, medical technologist, economist, public health advisor, health communicator, toxicologist, chemist, computer scientist, and statistician. The CDC also operates a number of notable training and fellowship programs, including those indicated below.
=== Epidemic Intelligence Service (EIS) ===
The Epidemic Intelligence Service (EIS) is composed of "boots-on-the-ground disease detectives" who investigate public health problems domestically and globally. When called upon by a governmental body, EIS officers may embark on short-term epidemiological assistance assignments, or "Epi-Aids", to provide technical expertise in containing and investigating disease outbreaks. The EIS program is a model for the international Field Epidemiology Training Program.
=== Public Health Associates Program ===
The CDC also operates the Public Health Associate Program (PHAP), a two-year paid fellowship for recent college graduates to work in public health agencies all over the United States. PHAP was founded in 2007 and currently has 159 associates in 34 states.
== Leadership ==
The director of the CDC is a position that currently requires Senate confirmation. The director serves at the pleasure of the President and may be fired at any time. The CDC director concurrently serves as the Administrator of the Agency for Toxic Substances and Disease Registry.
Prior to January 20, 2025, it was a Senior Executive Service position that could be filled either by a career employee, or as a political appointment that does not require Senate confirmation, with the latter method typically being used. The change to requiring Senate confirmation was due to a provision in the Consolidated Appropriations Act, 2023.
Twenty directors have served the CDC or its predecessor agencies, including three who have served during the Trump administration (including Anne Schuchat who twice served as acting director) and three who have served during the Carter administration (including one acting director not shown here). Two served under Bill Clinton, but only one under the Nixon to Ford terms.
=== List of directors ===
The following persons have served as the director of the Centers for Disease Control and Prevention (or chief of the Communicable Disease Center):
== Datasets and survey systems ==
CDC Scientific Data, Surveillance, Health Statistics, and Laboratory Information.
Behavioral Risk Factor Surveillance System (BRFSS), the world's largest, ongoing telephone health-survey system.
Pregnancy Risk Assessment Monitoring System (PRAMS), a surveillance system on maternal and infant health with telephone and mail questionnaires in English and Spanish in 50 US jurisdictions.
Mortality Medical Data System.
Abortion statistics in the United States
CDC WONDER (Wide-ranging ONline Data for Epidemiologic Research)
Data systems of the National Center for Health Statistics
== Areas of focus ==
=== Communicable diseases ===
The CDC's programs address more than 400 diseases, health threats, and conditions that are major causes of death, disease, and disability. The CDC's website has information on various infectious (and noninfectious) diseases, including smallpox, measles, and others.
==== Influenza ====
The CDC targets the transmission of influenza, including the H1N1 swine flu, and launched websites to educate people about hygiene.
==== Division of Select Agents and Toxins ====
Within the division are two programs: the Federal Select Agent Program (FSAP) and the Import Permit Program. The FSAP is run jointly with an office within the U.S. Department of Agriculture, regulating agents that can cause disease in humans, animals, and plants. The Import Permit Program regulates the importation of "infectious biological materials."
The CDC runs a program that protects the public from rare and dangerous substances such as anthrax and the Ebola virus. The program, called the Federal Select Agent Program, calls for inspections of labs in the U.S. that work with dangerous pathogens.
During the 2014 Ebola outbreak in West Africa, the CDC helped coordinate the return of two infected American aid workers for treatment at Emory University Hospital, the home of a special unit to handle highly infectious diseases.
As a response to the 2014 Ebola outbreak, Congress passed a Continuing Appropriations Resolution allocating $30,000,000 towards CDC's efforts to fight the virus.
=== Non-communicable diseases ===
The CDC also works on non-communicable diseases, including chronic diseases caused by obesity, physical inactivity and tobacco-use. The work of the Division for Cancer Prevention and Control, led from 2010 by Lisa C. Richardson, is also within this remit.
=== Antibiotic resistance ===
The CDC implemented their National Action Plan for Combating Antibiotic Resistant Bacteria as a measure against the spread of antibiotic resistance in the United States. This initiative has a budget of $161 million and includes the development of the Antibiotic Resistance Lab Network.
=== Global health ===
Globally, the CDC works with other organizations to address global health challenges and contain disease threats at their source. They work with many international organizations such as the World Health Organization (WHO) as well as ministries of health and other groups on the front lines of outbreaks. The agency maintains staff in more than 60 countries, including some from the U.S. but more from the countries in which they operate. The agency's global divisions include the Division of Global HIV and TB (DGHT), the Division of Parasitic Diseases and Malaria (DPDM), the Division of Global Health Protection (DGHP), and the Global Immunization Division (GID).
The CDC has been working with the WHO to implement the International Health Regulations (IHR), an agreement between 196 countries to prevent, control, and report on the international spread of disease, through initiatives including the Global Disease Detection Program (GDD).
The CDC has also been involved in implementing the U.S. global health initiatives President's Emergency Plan for AIDS Relief (PEPFAR) and President's Malaria Initiative.
=== Travelers' health ===
The CDC collects and publishes health information for travelers in a comprehensive book, CDC Health Information for International Travel, which is commonly known as the "yellow book." The book is available online and in print as a new edition every other year and includes current travel health guidelines, vaccine recommendations, and information on specific travel destinations. The CDC also issues travel health notices on its website, consisting of three levels:
"Watch": Level 1 (practice usual precautions)
"Alert": Level 2 (practice enhanced precautions)
"Warning": Level 3 (avoid nonessential travel)
=== Vaccine safety ===
The CDC uses a number of tools to monitor the safety of vaccines. The Vaccine Adverse Event Reporting System (VAERS), a national vaccine safety surveillance program run by CDC and the FDA. "VAERS detects possible safety issues with U.S. vaccines by collecting information about adverse events (possible side effects or health problems) after vaccination." The CDC's Safety Information by Vaccine page provides a list of the latest safety information, side effects, and answers to common questions about CDC recommended vaccines.
The Vaccine Safety Datalink (VSD) works with a network of healthcare organizations to share data on vaccine safety and adverse events. The Clinical Immunization Safety Assessment (CISA) project is a network of vaccine experts and health centers that research and assist the CDC in the area of vaccine safety.
CDC also runs a program called V-safe, a smartphone web application that allows COVID-19 vaccine recipients to be surveyed in detail about their health in response to getting the shot.
== CDC Foundation ==
The CDC Foundation operates independently from CDC as a private, nonprofit 501(c)(3) organization incorporated in the State of Georgia. The creation of the Foundation was authorized by section 399F of the Public Health Service Act to support the mission of CDC in partnership with the private sector, including organizations, foundations, businesses, educational groups, and individuals. From 1995 to 2022, the foundation raised over $1.6 billion and launched more than 1,200 health programs. Bill Cosby formerly served as a member of the foundation's Board of Directors, continuing as an honorary member after completing his term.
=== Activities ===
The foundation engages in research projects and health programs in more than 160 countries every year, including in focus areas such as cardiovascular disease, cancer, emergency response, and infectious diseases, particularly HIV/AIDS, Ebola, rotavirus, and COVID-19.
EmPOWERED Health Program: Launched in November 2019 with funding from Amgen, the program works to empower cancer patients to become actively involved in the decision making around their treatments.
Fries Prize for Improving Health: An annual prize first awarded in 1992 that "recognizes an individual who has made major accomplishments in health improvement and with the general criteria of the greatest good for the greatest number".
=== Criticism ===
In 2015, BMJ associate editor Jeanne Lenzer raised concerns that the CDC's recommendations and publications may be influenced by donations received through the Foundation, which includes pharmaceutical companies.
== Controversies ==
=== Tuskegee study of untreated syphilis in Black men ===
For 15 years, the CDC had direct oversight over the Tuskegee syphilis experiment. In the study, which lasted from 1932 to 1972, a group of Black men (nearly 400 of whom had syphilis) were studied to learn more about the disease. The disease was left untreated in the men, who had not given their informed consent to serve as research subjects. The Tuskegee Study was initiated in 1932 by the Public Health Service, with the CDC taking over the Tuskegee Health Benefit Program in 1995.
=== Gun control ===
An area of partisan dispute related to CDC funding is studying firearms effectiveness. Although the CDC was one of the first government agencies to study gun related data, in 1996 the Dickey Amendment, passed with the support of the National Rifle Association of America, states "none of the funds available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control". Advocates for gun control oppose the amendment and have tried to overturn it.
Looking at the history of the passage of the Dickey Amendment, in 1992, Mark L. Rosenberg and five CDC colleagues founded the CDC's National Center for Injury Prevention and Control, with an annual budget of approximately $260,000. They focused on "identifying causes of firearm deaths, and methods to prevent them". Their first report, published in the New England Journal of Medicine in 1993 entitled "Guns are a Risk Factor for Homicide in the Home", reported "mere presence of a gun in a home increased the risk of a firearm-related death by 2.7 percent, and suicide fivefold – a "huge" increase." In response, the NRA launched a "campaign to shut down the Injury Center." Two conservative pro-gun groups, Doctors for Responsible Gun Ownership and Doctors for Integrity and Policy Research joined the pro-gun effort, and, by 1995, politicians also supported the pro-gun initiative. In 1996, Jay Dickey (R) Arkansas introduced the Dickey Amendment statement stating "none of the funds available for injury prevention and control at the Centers for Disease Control and Prevention may be used to advocate or promote gun control" as a rider. in the 1996 appropriations bill." In 1997, "Congress re-directed all of the money for gun research to the study of traumatic brain injury." David Satcher, CDC head 1993–98 advocated for firearms research. In 2016 over a dozen "public health insiders, including current and former CDC senior leaders" told The Trace interviewers that CDC senior leaders took a cautious stance in their interpretation of the Dickey Amendment and that they could do more but were afraid of political and personal retribution.
In 2013, the American Medical Association, the American Psychological Association, and the American Academy of Pediatrics sent a letter to the leaders of the Senate Appropriations Committee asking them "to support at least $10 million within the Centers for Disease Control and Prevention (CDC) in FY 2014 along with sufficient new taxes at the National Institutes of Health to support research into the causes and prevention of violence. Furthermore, we urge Members to oppose any efforts to reduce, eliminate, or condition CDC funding related to violence prevention research." Congress maintained the ban in subsequent budgets.
=== Ebola ===
In October 2014, the CDC gave a nurse with a fever who was later diagnosed with Ebola permission to board a commercial flight to Cleveland.
=== COVID-19 ===
The CDC has been widely criticized for its handling of the COVID-19 pandemic. In 2022, CDC director Rochelle Walensky acknowledged "some pretty dramatic, pretty public mistakes, from testing to data to communications", based on the findings of an internal examination.
The first confirmed case of COVID-19 was discovered in the U.S. on January 20, 2020. However, widespread COVID-19 testing in the United States was effectively stalled until February 28, when federal officials revised a faulty CDC test, and days afterward, when the Food and Drug Administration began loosening rules that had restricted other labs from developing tests. In February 2020, as the CDC's early coronavirus test malfunctioned nationwide, CDC Director Robert R. Redfield reassured fellow officials on the White House Coronavirus Task Force that the problem would be quickly solved, according to White House officials. It took about three weeks to sort out the failed test kits, which may have been contaminated during their processing in a CDC lab. Later investigations by the FDA and the Department of Health and Human Services found that the CDC had violated its own protocols in developing its tests. In November 2020, NPR reported that an internal review document they obtained revealed that the CDC was aware that the first batch of tests which were issued in early January had a chance of being wrong 33 percent of the time, but they released them anyway.
In May 2020, The Atlantic reported that the CDC was conflating the results of two different types of coronavirus tests – tests that diagnose current coronavirus infections, and tests that measure whether someone has ever had the virus. The magazine said this distorted several important metrics, provided the country with an inaccurate picture of the state of the pandemic, and overstated the country's testing ability.
In July 2020, the Trump administration ordered hospitals to bypass the CDC and instead send all COVID-19 patient information to a database at the Department of Health and Human Services. Some health experts opposed the order and warned that the data might become politicized or withheld from the public. On July 15, the CDC alarmed health care groups by temporarily removing COVID-19 dashboards from its website. It restored the data a day later.
In August 2020, the CDC recommended that people showing no COVID-19 symptoms do not need testing. The new guidelines alarmed many public health experts. The guidelines were crafted by the White House Coronavirus Task Force without the sign-off of Anthony Fauci of the NIH. Objections by other experts at the CDC went unheard. Officials said that a CDC document in July arguing for "the importance of reopening schools" was also crafted outside the CDC. On August 16, the chief of staff, Kyle McGowan, and his deputy, Amanda Campbell, resigned from the agency. The testing guidelines were reversed on September 18, 2020, after public controversy.
In September 2020, the CDC drafted an order requiring masks on all public transportation in the United States, but the White House Coronavirus Task Force blocked the order, refusing to discuss it, according to two federal health officials.
In October 2020, it was disclosed that White House advisers had repeatedly altered the writings of CDC scientists about COVID-19, including recommendations on church choirs, social distancing in bars and restaurants, and summaries of public-health reports.
In the lead up to 2020 Thanksgiving, the CDC advised Americans not to travel for the holiday saying, "It's not a requirement. It's a recommendation for the American public to consider." The White House coronavirus task force had its first public briefing in months on that date but travel was not mentioned.
The New York Times later concluded that the CDC's decisions to "ben[d] to political pressure from the Trump White House to alter key public health guidance or withhold it from the public [...] cost it a measure of public trust that experts say it still has not recaptured" as of 2022.
In May 2021, following criticism by scientists, the CDC updated its COVID-19 guidance to acknowledge airborne transmission of COVID-19, after having previously claimed that the majority of infections occurred via "close contact, not airborne transmission".
In December 2021, following a request from the CEO of Delta Air Lines, CDC shortened its recommended isolation period for asymptomatic individuals infected with COVID-19 from 10 days to five.
Until 2022, the CDC withheld critical data about COVID-19 vaccine boosters, hospitalizations and wastewater data.
On June 10, 2022, the Biden Administration ordered the CDC to remove the COVID-19 testing requirement for air travelers entering the United States.
==== Controversy over the Morbidity and Mortality Weekly Report ====
During the pandemic, the CDC Morbidity and Mortality Weekly Report (MMWR) came under pressure from political appointees at the Department of Health and Human Services (HHS) to modify its reporting so as not to conflict with what Trump was saying about the pandemic.
Starting in June 2020, Michael Caputo, the HHS assistant secretary for public affairs, and his chief advisor Paul Alexander tried to delay, suppress, change, and retroactively edit MMR releases about the effectiveness of potential treatments for COVID-19, the transmissibility of the virus, and other issues where the president had taken a public stance. Alexander tried unsuccessfully to get personal approval of all issues of MMWR before they went out.
Caputo claimed this oversight was necessary because MMWR reports were being tainted by "political content"; he demanded to know the political leanings of the scientists who reported that hydroxychloroquine had little benefit as a treatment while Trump was saying the opposite. In emails Alexander accused CDC scientists of attempting to "hurt the president" and writing "hit pieces on the administration".
In October 2020, emails obtained by Politico showed that Alexander requested multiple alterations in a report. The published alterations included a title being changed from "Children, Adolescents, and Young Adults" to "Persons." One current and two former CDC officials who reviewed the email exchanges said they were troubled by the "intervention to alter scientific reports viewed as untouchable prior to the Trump administration" that "appeared to minimize the risks of the coronavirus to children by making the report's focus on children less clear."
==== Eroding trust in the CDC as a result of COVID-19 controversies ====
A poll conducted in September 2020 found that nearly 8 in 10 Americans trusted the CDC, a decrease from 87 percent in April 2020. Another poll showed an even larger drop in trust with the results dropping 16 percentage points. By January 2022, according to an NBC News poll, only 44% of Americans trusted the CDC compared to 69% at the beginning of the pandemic. As the trustworthiness eroded, so too did the information it disseminates. The diminishing level of trust in the CDC and the information releases also incited "vaccine hesitancy" with the result that "just 53 percent of Americans said they would be somewhat or extremely likely to get a vaccine."
In September 2020, amid the accusations and the faltering image of the CDC, the agency's leadership was called into question. Former acting director at the CDC, Richard Besser, said of Redfield that "I find it concerning that the CDC director has not been outspoken when there have been instances of clear political interference in the interpretation of science." In addition, Mark Rosenberg, the first director of CDC's National Center for Injury Prevention and Control, also questioned Redfield's leadership and his lack of defense of the science.
Historically, the CDC has not been a political agency; however, the COVID-19 pandemic, and specifically the Trump administration's handling of the pandemic, resulted in a "dangerous shift" according to a previous CDC director and others. Four previous directors claim that the agency's voice was "muted for political reasons." Politicization of the agency has continued into the Biden administration as COVID-19 guidance is contradicted by State guidance and the agency is criticized as "CDC's credibility is eroding".
In 2021, the CDC, then under the leadership of the Biden administration, received criticism for its mixed messaging surrounding COVID-19 vaccines, mask-wearing guidance, and the state of the pandemic.
=== Gender censorship ===
On February 1, 2025, the CDC ordered its scientists to retract any not yet published research they had produced which included any of the following banned terms: "Gender, transgender, pregnant person, pregnant people, LGBT, transsexual, non-binary, nonbinary, assigned male at birth, assigned female at birth, biologically male, biologically female”. Larry Gostin, director of the World Health Organization Center on Global Health Law, said that the directive amounted to censorship of not only government employees, but private citizens as well. For example, if the lead author of a submitted paper works for the CDC and withdraws their name from the submission, that kills the submission even if coauthors who are private scientists remain on it. Other censored topics include DEI, climate change, and HIV.
Following extensive public backlash, some, but not all, of the removed pages were reinstated. The CDC's censorship led to many researchers and journalists to preserve databases themselves, with many removed articles being uploaded to archival sites such as the Internet Archive.
On February 4, Doctors for America filed a federal lawsuit against the CDC, Food and Drug Administration, and Department of Health and Human Services, asking the removed websites to be put back online. On February 11, a judge ordered removed pages to be restored temporarily while the suit is being considered, citing doctors who said the removed materials were "vital for real-time clinical decision-making".
== Publications ==
CDC publications
State of CDC report
CDC Programs in Brief
Morbidity and Mortality Weekly Report
Emerging Infectious Diseases (monthly journal)
Preventing Chronic Disease
Vital statistics
== Popular culture ==
=== Zombie Apocalypse campaign ===
On May 16, 2011, the Centers for Disease Control and Prevention's blog published an article instructing the public on what to do to prepare for a zombie invasion. While the article did not claim that such a scenario was possible, it did use the popular culture appeal as a means of urging citizens to prepare for all potential hazards, such as earthquakes, tornadoes, and floods.
According to David Daigle, the associate director for communications, public health preparedness and response, the idea arose when his team was discussing their upcoming hurricane-information campaign and Daigle mused that "we say pretty much the same things every year, in the same way, and I just wonder how many people are paying attention." A social-media employee mentioned that the subject of zombies had come up a lot on Twitter when she had been tweeting about the Fukushima Daiichi nuclear disaster and radiation. The team realized that a campaign like this would most likely reach a different audience from the one that normally pays attention to hurricane-preparedness warnings and went to work on the zombie campaign, launching it right before hurricane season began. "The whole idea was, if you're prepared for a zombie apocalypse, you're prepared for pretty much anything," said Daigle.
Once the blog article was posted, the CDC announced an open contest for YouTube submissions of the most creative and effective videos covering preparedness for a zombie apocalypse (or apocalypse of any kind), to be judged by the "CDC Zombie Task Force". Submissions were open until October 11, 2011. They also released a zombie-themed graphic novella available on their website. Zombie-themed educational materials for teachers are available on the site.
== See also ==
Gun violence in the United States
Haddon Matrix
List of national public health agencies
Safe Kids Worldwide
=== CDC Departments ===
ATSDR – CDC department
NIOSH – CDC department
N95 respirator – regulated by NIOSH
Division of Industrial Hygiene – predecessor to NIOSH
=== Other US Executive Departments ===
MSHA – co-regulator of respirators prior to 1998
Bureau of Mines – predecessor to MSHA
National Highway Traffic Safety Administration
OSHA
== References ==
=== Citations ===
=== Sources ===
== Further reading ==
Editorial (May 16, 2020). "Reviving the US CDC". The Lancet. 395 (10236): 1521. doi:10.1016/S0140-6736(20)31140-5. PMC 7255307. PMID 32416772.
Etheridge, Elizabeth W. (1992). Sentinel for Health: A History of the Centers for Disease Control. Berkeley, CA: University of California Press. ISBN 978-0-520-07107-0.
Meyerson, Beth E.; Martich, Frederick A.; Naehr, Gerald P. (2008). Ready to Go: The History and Contributions of U.S. Public Health Advisors. Research Triangle Park, NC: American Social Health Association. ISBN 978-0-615-20383-6. OCLC 244483702. Retrieved April 8, 2025.
Stobbe, Mike (2014). Surgeon General's Warning: How Politics Crippled the Nation's Doctor. Berkeley: Univ of California Press. ISBN 978-0-520-27229-3.
== External links ==
Official website
CDC in the Federal Register
CDC-Wide Activities and Program Support account on USAspending.gov
CDC Online Newsroom
CDC Public Health Image Library
CDC Global Communications Center
CDC Emerging Infectious Diseases Laboratory – Atlanta, Georgia (archived July 3, 2008)
CDC WONDER online databases.
Vaccine Safety Monitoring Systems and Methods (CDC) a slide deck presented at October 2019 Advisory Committee on Immunization Practices (ACIP) meeting | Wikipedia/Centers_for_Disease_Control |
Unnecessary health care (overutilization, overuse, or overtreatment) is health care provided with a higher volume or cost than is appropriate.
In the United States, where health care costs are the highest as a percentage of GDP, overuse was the predominant factor in its expense, accounting for about a third of its health care spending ($750 billion out of $2.6 trillion) in 2012.
Factors that drive overuse include paying health professionals more to do more (fee-for-service), defensive medicine to protect against litigiousness, and insulation from price sensitivity in instances where the consumer is not the payer—the patient receives goods and services but insurance pays for them (whether public insurance, private, or both). Such factors leave many actors in the system (doctors, patients, pharmaceutical companies, device manufacturers) with inadequate incentive to restrain health care prices or overuse. This drives payers, such as national health insurance systems or the U.S. Centers for Medicare and Medicaid Services, to focus on medical necessity as a condition for payment. However, the threshold between necessity and lack thereof can often be subjective.
Overtreatment, in the strict sense, may refer to unnecessary medical interventions, including treatment of a self-limited condition (overdiagnosis) or to extensive treatment for a condition that requires only limited treatment.
It is economically linked with overmedicalization.
== Definition ==
A forerunner of the term was what Jack Wennberg called unwarranted variation, different rates of treatments based upon where people lived, not clinical rationale. He had discovered that in studies that began in 1967 and were published in the 1970s and the 1980s: "The basic premise – that medicine was driven by science and by physicians capable of making clinical decisions based on well-established fact and theory – was simply incompatible with the data we saw. It was immediately apparent that suppliers were more important in driving demand than had been previously realized."
In 2008, US bioethicist Ezekiel J. Emanuel and health economist Victor R. Fuchs defined unnecessary health care as "overutilization", health care provided with a higher volume or cost than is appropriate. Recently, economists have sought to understand unnecessary health care in terms of misconsumption rather than overconsumption.
In 2009 two US physicians wrote in an editorial, that unnecessary care was "defined as services which show no demonstrable benefit to patients" and might represent 30% of U.S. medical care. They referred to a 2003 study on regional variations in Medicare spending, which found, "Medicare enrollees in higher-spending regions receive more care than those in lower-spending regions, but do not have better health outcomes or satisfaction with care."
In January 2012, the American College of Physicians Ethics, Professionalism, and Human Rights Committee suggested that overtreatment can also be understood in contrast to 'parsimonious care', defined as "care that utilizes the most efficient means to effectively diagnose a condition and treat a patient."
In April 2012, Berwick, from the Institute for Healthcare Improvement, and Andrew Hackbarth from the RAND Corporation defined overtreatment as "subjecting patients to care that, according to sound science and the patients' own preferences, cannot possibly help them—care rooted in outmoded habits, supply-driven behaviors, and ignoring science." They wrote that trying to do something (treatment or testing) for all patients who might need it inevitably entails doing that same thing for some patients who might not need it." In uncertain situations, "some non-beneficial care was the necessary byproduct of optimal clinical decision making."
In October 2015, two pediatricians said that considering "overtreatment as an ethical violation" could help see the conflicting incentives of health care workers for treatment or nontreatment.
Low-value health care, for the most part, is administration of tests or treatment, which though useful initially, offer little value if given repeatedly as a part of routine care.
== Cost ==
In the US, the country which spends the most on health care per person globally, patients have fewer doctor visits and fewer days in hospitals than people in other countries do, but prices are high,
there is more use of some procedures and new drugs than elsewhere, and doctor salaries are double the levels in other countries.
The New York Times reported "no one knows for sure" how much unnecessary care exists in the United States.
Overuse of medical care is no longer a large fraction of total health care spending, which was $3.3 trillion in 2016.
Researchers in 2014 analyzed many services listed as low value by Choosing Wisely and other sources. They looked at spending in 2008–2009 and found that these services represented 0.6% or 2.7% of Medicare costs and there was no significant pattern of particular types of physicians ordering these low value services. The Institute of Medicine in 2010 gave two estimates of "unnecessary services," using different methodologies: 0.2% or 1% to 5% of health spending,
which was US$2.6 trillion.
The Institute of Medicine quoted that 2010 report in a 2012 report to support an estimate of 8% ($210 billion) in unnecessary services, without explaining the discrepancy.
This IOM 2012 report also said there were $555 billion in other wasted spending, which have an "unknown overlap" with each other and the $210 billion.
The United States National Academy of Sciences estimated in 2005, without giving its methods or sources, that "between $.30 and $.40 of every dollar spent on health care is spent on the costs of poor quality," amounting to" slightly more than a half-trillion dollars a year... wasted on overuse, underuse, misuse, duplication, system failures, unnecessary repetition, poor communication, and inefficiency. In 2003 Fisher et al. found that there was "no apparent regional health benefit for Medicare recipients from doing more, whether 'more' is expressed as hospitalizations, surgical procedures, or consultations within the hospital."
Up to 30% of Medicare spending could be cut in 2003 without harming patients.
A study of low-value care in laboratory testing suggested that Medicare may have overspent at least US$1.95 billion on laboratory tests in the year 2019. The study found excessively frequent ordering of Hemoglobin A1c, prostate-specific antigen, vitamin D 25-hydroxy, and lipid panels.
When care is overused, patients are put at risk of complications unnecessarily, with documented harm to patients from overuse of surgeries and other treatments.
== Causes ==
Physicians' decisions are the proximate cause of unnecessary care, though the potential incentives and penalties they face can influence their choices.
=== Third-party payers and fee-for-service ===
When public or private insurance cover expenses and doctors are paid under a fee-for-service (FFS) model, neither has an incentive to consider the cost of treatment, a combination that contributes to waste. Fee-for-service is a large incentive for overuse because health care providers (such as doctors and hospitals) receive revenue from the overtreatment.
Atul Gawande investigated Medicare FFS reimbursements in McAllen, Texas, for a 2009 article in the New Yorker. In 2006, the town of McAllen was the second-most expensive Medicare market, behind Miami. Costs per beneficiary were almost twice the national average.
In 1992, however, McAllen had been almost exactly in line with the Medicare spending average. After looking at other potential explanations such as relatively poorer health or medical malpractice, Gawande concluded the town was a chief example of the overuse of medical services. Gawande concluded that a business culture (physicians viewing their practices as a revenue stream) had established itself there, in contrast to a culture of low-cost high-quality medicine at the Mayo Clinic and in the Grand Junction, Colorado, market. Gawande advised:As America struggles to extend healthcare coverage while curbing health care costs, we face a decision that is more important than whether we have a public-insurance option, more important than whether we will have a single-payer system in the long run or a mixture of public and private insurance, as we do now. The decision is whether we are going to reward the leaders who are trying to build a new generation of Mayos and Grand Junctions. If we don't, McAllen won't be an outlier. It will be our future.
=== Medical malpractice laws and defensive medicine ===
To protect themselves from legal prosecution U.S. physicians have an incentive to order clinically unnecessary tests or tests of little potential value. While defensive medicine is a favored explanation for high medical costs by physicians, Gawande estimated in 2010 it only contributed to 2.4% of the total $2.3 trillion of U.S. health care spending in 2008.
=== Direct-to-consumer advertising ===
Direct-to-consumer advertising can encourage patients to ask for drugs, devices, diagnostics, or procedures. Sometimes service providers will simply give these treatments or services rather than attempting the potentially more unpleasant task of convincing the patient what they have requested is not needed, or is likely to cause more harm than good.
=== Physician predispositions ===
Dartmouth Medical School professor Gilbert Welch argued 2016 that certain predispositions by physicians and the general public may lead to unnecessary health care, including:
Attempting to mitigate a risk without considering how small or unlikely the potential benefit is
Attempting to fix an underlying problem, instead of using a less-risky monitoring or coping strategy
Acting too quickly, when waiting for more information might be wiser
Acting without considering the benefits of doing nothing
Discounting downsides of diagnostic testing
Preferring newer over older treatments without considering the cost of new treatments or the effectiveness of older ones
Treating patients with terminal illness to maximize life span over quality of life, without probing a patient's preferences
== Examples ==
=== Imaging ===
Overuse of diagnostic imaging, such as X-rays and CT scans, is defined as any application unlikely to improve patient care. Factors that contribute to overuse include "self-referral, patient wishes, inappropriate financially motivated factors, health system factors, industry, media, lack of awareness" and defensive medicine. Respected organizations—such as the American College of Radiology (ACR), Royal College of Radiologists (RCR) and the World Health Organization (WHO)—have developed "appropriateness criteria". The Canadian Association of Radiologists estimated in 2009 that 30% of imaging was unnecessary in the Canadian health care system. 2008 Medicare claims showed overuse with chest CT's. Financial incentives have also been shown to have a significant impact on dental X-ray use with dentists who are paid a separate fee for each X-ray providing more X-rays.
Overuse of imaging can lead to a diagnosis of a condition that would have otherwise remained irrelevant (overdiagnosis).
==== Physician self-referral ====
One type of overuse can be physician self-referral. Multiple studies have replicated the finding that when non-radiologists have an ownership interest in the fees generated by radiology equipment—and can self-refer—their use of imaging is unnecessarily higher. The majority of U.S. growth in imaging use (the fastest-growing physician service) comes from self-referring nonradiologists. In 2004, this overuse was estimated to contribute to $16 billion of annual U.S. health care costs.
As of a 2018 review evidence of overtreatment overmedicalization, and overdiagnosis in Pediatrics have been use of commercial rehydration solution, antidepressants, and parenteral nutrition; overmedicalization with planned early deliveries, immobilization of ankle injuries, use of hydrolyzed infant formula; and overdiagnosis of hypoxemia among children recovering from bronchiolitis.
=== Others ===
Hospitalizations for those with chronic conditions who could be treated as outpatients
Surgeries in Medicare patients in their last year of life; regions with high levels had higher death rates
Antibiotic use for viral or self-limiting infections (an overmedication that can promote antibiotic resistance)
Opiate prescriptions carry the risk of addiction. In some cases, the number of pills prescribed might exceed what is actually needed for pain relief from a given condition, or a different pain management technique or medication would be effective but less risky.
Many blood transfusions in the U.S. are given without checking to see if they are needed after a previous transfusion, or are given in cases where monitoring, recovering the patient's own blood, or iron therapy would be effective and reduce the risk of complications
An estimated one in eight coronary stents (used in $20,000 procedures) with nonacute indications (U.S.)
Stents performed by the formal chair of cardiology, Mark Midei, at St. Joseph Medical Center of Towson, Maryland
Heart bypass surgeries at Redding Medical Center which resulted in an FBI raid
Screening patients with advanced cancer for other cancers
Annual cervical cancer screening in women with medical histories of normal pap smear and HPV test results
== Reduction efforts ==
Utilization management (utilization review) has evolved over decades among both public and private payers in an attempt to reduce overuse. In this effort, insurers employ physicians to review the actions of other physicians and detect overuse. Utilization review has a poor reputation among most clinicians as a corrupted system in which utilization reviewers have their own perverse incentives (i.e., find ways to deny coverage no matter what) and in some cases are not practicing physicians, lacking real-world clinical insight or wisdom. Results of a recent systematic review found that many studies focused more on reductions in utilization than in improving clinically meaningful measures.
The 2010 U.S. health care reform, the Patient Protection and Affordable Care Act, did not contain serious strategies to reduce overuse; "the public has made it clear that it does not want to be told what medical care it can and cannot have." Uwe Reinhardt, a health economist at Princeton, said "the minute you attack overutilization, you will be called a Nazi before the day is out".
Professional societies and other groups have begun to push for policy changes that would encourage clinicians to avoid providing unnecessary care. Most physicians accept that laboratory tests are overused, but "it remains difficult to persuade them to consider the possibility that they, too, might be overutilizing laboratory tests."
In November 2011, the American Board of Internal Medicine Foundation began the Choosing Wisely campaign, which aims to raise awareness of overtreatment and change physician behavior by publicizing lists of tests and treatments that are often overused, and which doctors and patients should try to avoid.
The Clinical and Laboratory Standards Institute (CLSI) issued a 2017 guideline, "Developing and Managing a Medical Laboratory (Test) Utilization Program (GP49)", to help laboratories establish stewardship programs.
Clinical decision support tools can help decrease unnecessary laboratory testing. The PLUGS initiative (Patient-Centered Laboratory Utilization Guidance Services) aims to formalize laboratory stewardship practices. The TRUU-Lab (Test Renaming for Understanding and Utilization in the Laboratory) initiative is a cooperative effort of CDC, CMS, FDA, and CAP. The project aims to standardize the names of laboratory tests to limit errant test ordering. Genetic testing stewardship programs have been established to streamline molecular diagnostic ordering patterns.
The Joint Commission offers accreditation in patient blood management in conjunction with AABB. To become accredited, participating hospitals may distribute guidelines for appropriateness of blood transfusion, form a committee to audit blood utilization, identify areas for improvement, and monitor compliance.
In the UK, 2011, online platform AskMyGP was launched to decrease the amount of unnecessary medical appointments. In the app patients are given a questionnaire about their symptoms, which then assesses the patient's need for medical care. The program was a success, and as of January 2018 has managed over 29,000 patient episodes.
The Royal College of Pathologists issued 2021 guidelines for the minimum time that should elapse before a given laboratory test is repeated in a specific clinical scenario.
In April 2012, the Lown Institute and the New America Foundation Health Policy Program convened the 'Avoiding Avoidable Care' conference. It was the first major medical conference to focus entirely on overuse, and it included presentations from speakers including Bernard Lown, Don Berwick, Christine Cassel, Amitabh Chandra, JudyAnn Bigby, and Julio Frenk. A second meeting was planned for December 2013.
Since the meeting, the Lown Institute has focused its work on deepening the understanding of overuse and generating public discussion of the ethical and cultural drivers of overuse, especially on the role of the hidden curriculum in medical school and residency.
Patient safety committees, which are charged with reviewing the quality of care, can view overutilization as adverse event.
=== Consumer cost sharing ===
== See also ==
Medicare fraud – Claiming of Medicare health care reimbursement to which the claimant is not entitled
Moral hazard – Increases in the exposure to risk when insured, or when another bears the cost
Antibiotic misuse – Improper use of antibiotic medications
Antibiotic stewardship – Efforts to promote antimicrobial agentsPages displaying short descriptions of redirect targets
Choosing Wisely – U.S.-based educational campaign
Clinical decision support – Health information technologyPages displaying short descriptions of redirect targets
Overmedicalization – Categorization of human problems as medicalPages displaying short descriptions of redirect targets
Overdiagnosis – Diagnosis of disease that will never cause symptoms or death during a patient's lifetime
Overdose – Use of an excessive amount of a drugPages displaying short descriptions of redirect targets
Patient blood management – Set of medical practices
== References ==
=== Citations ===
=== Sources ===
== External links ==
"Disease Creep: How we're fooled into using more medicine than we need" by medical investigative journalist Jeanne Lenzer | Wikipedia/Overtreatment |
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin.
For some medical conditions, one or more causes are somewhat understood, but in a certain percentage of people with the condition, the cause may not be readily apparent or characterized. In these cases, the origin of the condition is said to be idiopathic. With some other medical conditions, the root cause for a large percentage of all cases has not been established—for example, focal segmental glomerulosclerosis or ankylosing spondylitis; the majority of these cases are deemed idiopathic. Certain medical conditions, when idiopathic, notably some forms of epilepsy and stroke, are preferentially described by the synonymous term of cryptogenic.
== Derivation ==
The term 'idiopathic' derives from Greek ἴδιος idios "one's own" and πάθος pathos "suffering", so idiopathy means approximately "a disease of its own kind".
== Examples ==
Diseases where the cause is seen as wholly or partly idiopathic include:
Idiopathic pulmonary fibrosis
Idiopathic pulmonary haemosiderosis
Idiopathic intracranial hypertension
Idiopathic chronic fatigue
Granulomatous prostatitis
== Medical advances and this term ==
Advances in medical science improve the understanding of causes of diseases and the classification of diseases; thus, regarding any particular condition or disease, as more root causes are discovered and as events that seemed spontaneous have their origins revealed, the percentage of cases designated as idiopathic will decrease. Environmental and occupational risk factors are increasingly being associated with diseases classified as idiopathic. Emerging evidence indicates a complex relationship between intrinsic (genetic) and extrinsic (environmental and occupational risk factors) factors in disease physiopathology.
== Usage of synonyms ==
The word essential is sometimes synonymous with idiopathic (as in essential hypertension, essential thrombocythemia, and essential tremor) and the same is true of primary (as in primary biliary cholangitis, or primary amenorrhea), with the latter term being used in such cases to contrast with secondary in the sense of "secondary to [i.e., caused by] some other condition." Another, less common synonym is agnogenic (agno-, "unknown" + -gen, "cause" + -ic).
The word cryptogenic (crypto-, "hidden" + -gen, "cause" + -ic) has a sense that is synonymous with idiopathic and a sense that is contradistinguished from it. Some disease classifications prefer the use of the synonymous term cryptogenic disease as in cryptogenic stroke, and cryptogenic epilepsy. The use of cryptogenic is also sometimes reserved for cases where it is presumed that the cause is simple and will be found in the future.
Some congenital conditions are idiopathic, and sometimes the word congenital is used synonymously with idiopathic; but careful usage prefers to reserve the word congenital for conditions to which the literal sense of the word applies (that is, those whose pathophysiology has existed since the neonatal period).
== Syndrome without a name ==
The term syndrome without a name (SWAN) is used "when a child or young adult is believed to have a genetic condition and testing has failed to identify its genetic cause". It is believed that "about half (50%) of children with learning disabilities and approximately 60% of children with congenital disabilities (disabilities which are apparent from birth) do not have a definitive diagnosis to explain the cause of their difficulties".
== See also ==
Diagnosis of exclusion
Embolic stroke of undetermined source
Functional disorder
Idiosyncratic drug reaction
Fever of unknown origin
== References ==
== External links ==
The dictionary definition of idiopathic disease at Wiktionary | Wikipedia/Cryptogenic_disease |
Female genital disease is a disorder of the structure or function of the female reproductive system that has a known cause and a distinctive group of symptoms, signs, or anatomical changes. The female reproductive system consists of the ovaries, fallopian tubes, uterus, vagina, and vulva. Female genital diseases can be classified by affected location or by type of disease, such as malformation, inflammation, or infection.
== Diagnosis ==
Female genital diseases are usually diagnosed by healthcare personnel in a healthcare setting. Diagnosis may be made using laboratory tests, physical examinations, and/or clinical signs and symptoms.
=== Barriers to diagnosis ===
Historically, discussions surrounding feminine reproductive and sexual health have been subject to social stigma within Western society. Women in Western society may avoid discussing problems relating to the female reproductive system, including problems related to female sexual health, with their healthcare providers. As a result, diagnosis of female genital diseases may be delayed or missed. Social determinants of health including economic and logistical burden of seeking healthcare may also interfere with timely diagnosis of female genital disease.
=== Gender considerations ===
Individuals who have female genitals and/or reproductive organs but who do not identify as women may experience additional difficulties in seeking diagnosis of female genital diseases. Societal discrimination, gender dysphoria, and insufficient transgender healthcare education are some reasons that transgender individuals may be unable to obtain medical care for female genital diseases.
== Women's history in clinical trials ==
Medical professionals use a variety of resources that assist them in creating clinical decisions in providing care to the population, with one of the more utilized sources are known as clinical trials. Clinical trials are used to analyze the efficacy and safety of medications, medical intervention, and medical procedures. Historically, women representation in clinical trials has been suboptimal, oftentimes being excluded from trials due to "potential maternal-fetal liability", "have less experience, and are more costly to engage". However, through limiting the number of women eligible for various stages of these trials, outcomes and the burden of disease have been underrepresented in females, either underreported or not adjusted for. For example, due to the fact that women have different drug efficacies and safety profiles to men, it is estimated "in 2005 that eight out of ten prescription drugs were withdrawn from the US market because of women's health issues". Clinical trials that focused on preventative care, such as screenings, diagnostics, and health services in have an adjusted relative difference of 8.48% in female enrollment. Fortunately, over the years we have seen a rise in women participants, with an average of 60.0% females enrolled in clinical trials in 2018, up 18.9% from the lowest year of participants, in 2002, with a median of 41.1%.
Therefore, as we diminish the number of women who are a part of clinical trials, then guidelines that are used by medical professional stem majority from male subjects; this can then led into a variety of other factors to consider when making medical decisions towards women in the acute inpatient or chronic ambulatory care setting such as social and financial difference that can impact the care women receive. Importantly so, we decrease the number of studies that are geared towards women's reproductive issues, such as genital disease. In efforts to encourage women to participate in clinical research, the National Institute of Health (NIH) launched the women's health initiative in 1991 that focuses clinical trials and observational studies on post-menopausal women over a 15 year period of time. Additionally, by broadening what "women's health" encompasses, including not only reproductive and genital health, childbearing, and menstruation but also osteoporosis, breast cancer, and other disease states where women bear higher burden than men, the NIH can focus funding on these conditions.
== Perception ==
In society, having a disease related to a person's genitalia continues to be a stigma today. The stigma comes with shame and embarrassment that is not only internalized, but also emphasized by others through loss of support and discrimination. Some of that shame is rooted in spirituality and societal perception. In a study done in Lagos, Nigeria regarding uterine fibroids, majority of the women who participated in the study (67.0%) “perceived [uterine] fibroids as a spiritual problem” and believe that the best course of treatment is done spiritually through places of worship such as churches and mosques. The majority of women who participated in the study knew that uterine fibroids existed and were associated with obesity. In both developed and developing countries, individuals with female genital diseases experience shame through perception of these diseases by healthcare providers and the general public. In a multisite study in the United States focusing on English and Spanish speaking women regarding perception, knowledge, and experiences with vaginal prolapse, these women had feelings of shame regarding their condition since they blamed themselves for their condition and felt that their condition was “unnatural or less like a woman”. One woman mentioned that they were humiliated by a physician for their condition. Given the stigma regarding genital diseases, a common theme from the participants was that they did not know that vaginal prolapse can occur in women. Another study in India was done where researchers called people recently diagnosed with sexually transmitted infections regarding the stigma towards their condition. Researchers found that 49 out of 487 people wanted to participate in their study, which they inferred was related to the "shame and stigma in the Indian population".
== Classification by type of disease ==
=== Malformation ===
Malformations can be congenital. They are classified by location of the malformation, such as uterine malformation.
=== Inflammation or infection ===
An example is oophoritis.
=== Cancers ===
Cancers of the female internal genitalia (such as ovarian cancer) and vulva are not uncommon.
== Classification by location ==
=== Diseases of the vulva ===
==== Bartholin's cyst ====
A Bartholin's cyst is an abscess of a Bartholin's gland. Bartholin's glands are located within the labia, or the skin folds surrounding the vaginal opening. Bartholin's cysts can be painful and may require drainage or surgical removal in order to resolve.
==== Vulvodynia ====
Vulvodynia is a chronic pain condition which involves the sensation of pain in the area surrounding the vaginal opening in response to physical stimulation such as vaginal penetration. This condition can be distressing to people who have it as it can interfere with intimacy. There is no standardized treatment for vulvodynia, but some options include pelvic floor physical therapy and pharmacologic pain management.
=== Disease of the vagina ===
==== Vaginal prolapse ====
Vaginal prolapse, otherwise known as pelvic organ prolapse, is when a person's vagina descends due to pelvic organ pressure or due to tissue injury and/or muscle weakness. Some of the risk factors include previous pelvic surgeries as well as activities and conditions that increase intrabdominal pressure such as childbirth, obesity, and older age. Symptoms of vaginal prolapse are vaginal bulge, urinary and fecal incontinence, and sexual dysfunction. Treatment for vaginal prolapse can be either conservative or surgical according to Kapoor et al. Some of the conservative treatments include Kegel exercises that strengthen the pelvic floor and pessaries which aim to put the vagina in a normal position. Surgical treatment options include colpocleisis, vaginal reconstruction, and abdominal sacrocolpopexy. Colpocleisis is an obliterative procedure that would remove the possibility of vaginal intercourse. Therefore, a person's desire to get pregnant is considered when deciding treatment for this condition.
==== Bacterial vaginosis ====
Bacterial vaginosis is a condition that occurs when there is an overgrowth of normal bacteria in the vagina. The community of bacteria that normally exists in the vagina is called the vaginal flora. The flora serves as a defense against the invasion and colonization of opportunistic pathogens including bacterial vaginosis, fungi, viruses, and protozoa. Historically, it was believed that the bacterium Gardnerella caused bacterial vaginosis, but studies have shown that bacterial vaginosis can be caused by a variety of bacteria. Women are at an increased risk of having bacterial vaginosis if they smoke cigarettes, recently used antibiotics, use an intrauterine device, have multiple sexual partners, and practice vaginal douching.
==== Trichomoniasis ====
Trichomoniasis, also known as "trich", is a sexually transmitted infection caused by a protozoan parasite called trichomonas vaginalis. It is the most common protozoal infection in the United States. This motile organism is not exclusive to women, but can also be found in the prostate and urethra of men. Individuals are at an increased risk of contracting trich if they have a history of sexually transmitted infections, have new or multiple sex partners, abuse IV drugs, and do not use any type of protection during sex.
=== Disease of the cervix ===
==== Cervicitis ====
Cervicitis is inflammation of the cervix in individuals with a uterus, most commonly identified in those presenting as women. While some patients report pus and mucus like discharge, a majority of individuals with this condition do not present with any symptoms. Less than half of the cases of cervicitis are linked to either Neisseria gonorrhoeae or Chlamydia trachomatis, likely sexually transmitted. However, more than half have unknown infectious etiology. Complications can result in pelvic inflammatory disease, difficulties bearing pregnancy, and endometriosis. Due to these adverse outcomes, the CDC recommends that women undergo routine nucleic acid amplification technique (NAAT) testing, which can aid in the detection of chlamydia and gonorrhea.
=== Diseases of the uterus ===
==== Uterine malformation ====
Uterine malformations are sometimes referred to as congenital uterine anomalies. A uterine malformation is an abnormality in the development of a person's uterus. This condition can result in fertility problems such as increased risk of miscarriage.
==== Uterine fibroids ====
Uterine fibroids, also known as uterine leiomyomas, are solid growths of noncancerous smooth muscle cells that are located on the uterus. There is no cause, but risk factors such as family history, reproductive issues, hormones, and viruses are associated with fibroid growth. Previous research suggested an association between diet and hormonal changes that has the potential to form fibroids and give them the environment to grow. Despite other research contradicting this statement, further research stated that low fruit and vegetable intake as well as Vitamin D insufficiency and food contaminants have been correlated to fibroid formation and growth. In most cases, uterine fibroids are asymptomatic and therefore will not need treatment. Giuliani et al. found that asymptomatic uterine fibroids are present in 70% of individuals who were diagnosed with it, suggesting that it plays a role in epidemiologic studies underestimating its prevalence. Uterine fibroids are treated if the person is experiencing symptoms such as anemia, infertility, and pelvic and back pain. These treatments aim to decrease the uterine fibroid size, prevent their growth, and improve symptoms the person deals with. Treatments that are currently being used to treat uterine fibroids are medications, surgeries such as hysteroscopy and laparoscopy, and radiologic treatments such as radiofrequency ablation. Most of these treatments affect a person's ability to get pregnant.
==== Endometriosis ====
Endometriosis is when a person has their uterine endometrial tissue that is growing somewhere besides its normal location, most commonly at the pelvic peritoneum. This can also be regarded as "lesions outside of the uterus". This condition has been described as "benign and estrogen dependent", therefore impacting those who produce estrogen. Other locations where this may occur, although more rare, include ovaries, pericardium, rectovaginal septum, bladder, and more. Most commonly, this can be associated with pelvic pain and infertility.
=== Diseases of the fallopian tubes ===
==== Salpingitis ====
Salpingitis, or salpingitis isthmica nodosa, is a disease involving inflammation within the fallopian tubes. This condition can be caused by infections, such as sexually transmitted infections. Salpingitis may be associated with fertility problems, such as infertility and ectopic pregnancy.
==== Ectopic pregnancy ====
Ectopic pregnancy, or tubal ectopic pregnancy, is a condition that occurs when a developing pregnancy implants outside of the uterus, such as in the fallopian tubes. This condition is an emergency and can be fatal to the pregnant person. Treatment usually involves a salpingectomy, or the removal of the affected fallopian tube.
=== Diseases of the ovaries ===
==== Oophoritis ====
Oophoritis is a condition affecting one or both of the ovaries which results in inflammation. Oophoritis can be caused by an infection or by an autoimmune disease called primary ovarian insufficiency.
== Sexually transmitted infections ==
A sexually transmitted infection (STI) is an infection caused by a virus, fungus, bacteria, or parasite that is spread through sexual contact. STIs are very common and can be passed from one person to another through vaginal, oral, and anal sex.
=== Complications ===
Sexually transmitted infections can impact female reproductive health worldwide. Women experience a larger impact on their health compared to men because of how exposed and vulnerable their urogenital anatomy is. The vaginal mucosa is thin and can be easily penetrated by infectious agents. Some complications that women experience from STIs are infertility, chronic pelvic pain, increased peripartum morbidity, and increased
peripartum mortality.
=== Economic burden ===
In 2018, $15.9 billion was spent on lifetime medical cost attributable to STIs such as chlamydia, trichomoniasis, gonorrhea, genital herpes, syphilis, human papillomavirus (HPV), HIV, and hepatitis B. When HIV is not included in the cost, STIs in women account for about three fourths of lifetime direct medical costs annually.
== See also ==
Male genital disease
== References ==
== External links == | Wikipedia/Female_genital_disease |
A rare disease is any disease that affects a small percentage of the population. In some parts of the world, the term orphan disease describes a rare disease whose rarity results in little or no funding or research for treatments, without financial incentives from governments or other agencies. Orphan drugs are medications targeting orphan diseases.
Most rare diseases are genetic in origin and thus are present throughout the person's entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30% of children with rare diseases will die before reaching their fifth birthdays. Fields condition is considered the rarest known disease, affecting three known individuals, two of whom are identical twins. With four diagnosed patients in 27 years, ribose-5-phosphate isomerase deficiency is considered the second rarest.
While no single number has been agreed upon for which a disease is considered rare, several efforts have been undertaken to estimate the number of unique rare diseases. In 2019, the Monarch Initiative released a rare disease subset of the Mondo ontology that reconciles a wide variety of rare disease knowledge sources, such as OMIM and Orphanet. This was the first count since 1983, demonstrating that there were >10,500 rare diseases where prior estimates had been ~7,000 in the Orphan Drug Act. Global Genes has also estimated that currently approximately 10,000 rare diseases exist globally, with 80% of these having identified genetic origins.
== Definition ==
There is no single, widely accepted definition for rare diseases. Some definitions rely solely on the number of people living with a disease, and other definitions include other factors, such as the existence of adequate treatments or the severity of the disease.
In the United States, the Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, specifically "any disease or condition that affects fewer than 200,000 people in the United States", or about 1 in 1,500 people. This definition is essentially the same as that of the Orphan Drug Act of 1983, a federal law that was written to encourage research into rare diseases and possible cures.
In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients in Japan, or about 1 in 2,500 people.
The European Commission on Public Health defines rare diseases as "life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them". The term low prevalence is later defined as generally meaning fewer than 1 in 2,000 people. Diseases that are statistically rare, but not also life-threatening, chronically debilitating, or inadequately treated, are excluded from their definition.
The definitions used in the medical literature and by national health plans are similarly divided, with definitions ranging from 1/1,000 to 1/200,000.
== Relationship to orphan diseases ==
Because of definitions that include reference to treatment availability, a lack of resources, and severity of the disease, the term orphan disease is frequently used as a synonym for rare disease. But in the United States and the European Union, "orphan diseases" have a distinct legal meaning.
The United States' Orphan Drug Act includes both rare diseases and any non-rare diseases "for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will [be] recovered from sales in the United States of such drug" as orphan diseases.
The European Organization for Rare Diseases (EURORDIS) also includes both rare diseases and neglected diseases into a larger category of "orphan diseases".
== Prevalence ==
Prevalence (number of people living with a disease at a given moment), rather than incidence (number of new diagnoses in a given year), is used to describe the impact of rare diseases. The Global Genes Project estimates some 300 million people worldwide are affected by a rare disease.
The European Organization for Rare Diseases (EURORDIS) estimates that between 3.5 and 5.9% of the world's population is affected by one of approx. 6,000 distinct rare diseases identified to-date. European Union has suggested that between 6 and 8% of the European population could be affected by a rare disease sometime in their lives.
About 80% of rare diseases have a genetic component and only about 400 have therapies, according to Rare Genomics Institute.
Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases. An example is cystic fibrosis, a genetic disease: it is rare in most parts of Asia but relatively common in Europe and in populations of European descent. In smaller communities, the founder effect can result in a disease that is very rare worldwide being prevalent within the smaller community. Many infectious diseases are prevalent in a given geographic area but rare everywhere else. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare. The classification of other conditions depends in part on the population being studied: All forms of cancer in children are generally considered rare, because so few children develop cancer, but the same cancer in adults may be more common.
Estimating the incidence and prevalence of rare diseases is a complex process due to their wide range of prevalence rates. Rare diseases with higher prevalences can be estimated through a screening panel or patient registries, while diseases which are exceedingly rare may only be able to be estimated through a multi-step nationwide reporting process or case reports. Therefore, the data is often incomplete and complex to amalgamate, compare, and update continually. The Genetic and Rare Diseases Information Center at the National Center for Advancing Translational Sciences curates and compiles rare disease prevalence and incidence from PubMed articles and abstracts using a combination of deep learning algorithms and rare disease experts.
About 40 rare diseases have a far higher prevalence in Finland; these are known collectively as Finnish heritage disease. Similarly, there are rare genetic diseases among the Amish religious communities in the US and among ethnically Jewish people.
== Characteristics ==
A rare disease is defined as one that affects fewer than 200,000 people across a broad range of possible disorders. Chronic genetic diseases are commonly classified as rare. Among numerous possibilities, rare diseases may result from bacterial or viral infections, allergies, chromosome disorders, degenerative and proliferative causes, affecting any body organ. Rare diseases may be chronic or incurable, although many short-term medical conditions are also rare diseases.
== Public research and government policy ==
=== United States ===
The NIH's Office of Rare Diseases Research (ORDR) was established by H.R. 4013/Public Law 107–280 in 2002. H.R. 4014, signed the same day, refers to the "Rare Diseases Orphan Product Development Act". Similar initiatives have been proposed in Europe. The ORDR also runs the Rare Diseases Clinical Research Network (RDCRN). The RDCRN provides support for clinical studies and facilitating collaboration, study enrollment and data sharing.
=== United Kingdom ===
In 2013, the United Kingdom government published The UK Strategy for Rare Diseases which "aims to ensure no one gets left behind just because they have a rare disease", with 51 recommendations for care and treatment across the UK to be implemented by 2020. Health services in the four constituent countries agreed to adopt implementation plans by 2014, but by October 2016, the Health Service in England had not produced a plan and the all-party parliamentary group on Rare, Genetic and Undiagnosed Conditions produced a report Leaving No One Behind: Why England needs an implementation plan for the UK Strategy for Rare Diseases in February 2017. In March 2017 it was announced that NHS England would develop an implementation plan. In January 2018 NHS England published its Implementation Plan for the UK Strategy for Rare Diseases. In January 2021 the Department of Health and Social Care published the UK Rare Diseases Framework, a policy paper which included a commitment that the four nations would develop action plans, working with the rare disease community, and that "where possible, each nation will aim to publish the action plans in 2021". NHS England published England Rare Diseases Action Plan 2022 in February 2022.
=== International ===
Organisations around the world are exploring ways of involving people affected by rare diseases in helping shape future research, including using online methods to explore the perspectives of multiple stakeholders.
== Public awareness ==
Rare Disease Day is held in Europe, Canada, the United States, and India on the last day of February (thus, in leap years, on February 29, the rarest day) to raise awareness for rare diseases. There are a number of non-profit and charitable organisations which push for further awareness, interest, and engagement in the subject of rare diseases, including EURORDIS, Genetic Alliance UK, and the Rare Revolution Magazine.
== See also ==
== References ==
== External links ==
ICD-11 FAQ
Database of rare diseases at GARD, The United States Genetic and Rare Diseases Information Center
Database of rare diseases at Orphanet
National Organization for Rare Disorders (United States)
Rare Disease UK
Rare diseases search engine
Rare Revolution Magazine | Wikipedia/Rare_disease |
A non-communicable disease (NCD) is a disease that is not transmissible directly from one person to another. NCDs include Parkinson's disease, autoimmune diseases, strokes, heart diseases, cancers, diabetes, chronic kidney disease, osteoarthritis, osteoporosis, Alzheimer's disease, cataracts, and others. NCDs may be chronic or acute. Most are non-infectious, although there are some non-communicable infectious diseases, such as parasitic diseases in which the parasite's life cycle does not include direct host-to-host transmission.
The four main NCDs that are the leading causes of death globally are cardiovascular disease, cancer, chronic respiratory diseases, and diabetes. NCDs account for seven out of the ten leading causes of death worldwide. Figures given for 2019 are 41 million deaths due to NCDs worldwide. Of these 17.9 million were due to cardiovascular disease; 9.3 million due to cancer; 4.1 million to chronic respiratory diseases, and 2.0 million to diabetes. Over 80% of the deaths from these four groups were premature, not reaching the age of 70.
Risk factors such as a person's background, lifestyle and environment increase the likelihood of certain NCDs. Every year, at least 5 million people die because of tobacco use and about 2.8 million die from being overweight. High cholesterol accounts for roughly 2.6 million deaths and 7.5 million die because of high blood pressure.
== Risk factors ==
Risk factors such as a person's background; lifestyle and environment are known to increase the likelihood of certain non-communicable diseases. They include age, gender, genetics, exposure to air pollution, and behaviors such as smoking, unhealthy diet and physical inactivity which can lead to hypertension and obesity, in turn leading to increased risk of many NCDs. Most NCDs are considered preventable because they are caused by modifiable risk factors.
The WHO's World Health Report 2002 identified five important risk factors for non-communicable disease in the top ten leading risks to health. These are raised blood pressure, raised cholesterol, tobacco use, alcohol consumption, and being overweight. The other factors associated with higher risk of NCDs include a person's economic and social conditions, also known as the social determinants of health.
It has been estimated that if the primary risk factors were eliminated, 80% of the cases of heart disease, stroke and type 2 diabetes and 40% of cancers could be prevented. Interventions targeting the main risk factors could have a significant impact on reducing the burden of disease worldwide. Efforts focused on better diet and increased physical activity have been shown to control the prevalence of NCDs .
== Environmental diseases ==
NCDs include many environmental diseases covering a broad category of avoidable and unavoidable human health conditions caused by external factors, such as sunlight, nutrition, pollution, and lifestyle choices. The diseases of affluence are non-infectious diseases with environmental causes. Examples include:
Many types of cardiovascular disease (CVD)
Chronic obstructive pulmonary disease (COPD) caused by smoking tobacco
Diabetes mellitus type 2
Noise-induced hearing loss
Lower back pain caused by too little exercise
Malnutrition caused by too little food, or eating the wrong kinds of food (e.g. scurvy from lack of Vitamin C)
Skin cancer caused by radiation from the sun
Obesity
=== Inherited diseases ===
Genetic disorders are caused by errors in genetic information that produce diseases in the affected people.
The origin of these genetic errors can be:
Spontaneous errors or mutations to the genome:
A change in chromosome numbers, such as Down syndrome.
A defect in a gene caused by mutation, such as Cystic fibrosis.
An increase in the amount of genetic information, such as Chimerism or Heterochromia.
Cystic fibrosis is an example of an inherited disease that is caused by a mutation on a gene. The faulty gene impairs the normal movement of sodium chloride in and out of cells, which causes the mucus-secreting organs to produce abnormally thick mucus. The gene is recessive, meaning that a person must have two copies of the faulty gene for them to develop the disease. Cystic fibrosis affects the respiratory, digestive and reproductive systems, as well as the sweat glands. The mucus secreted is very thick and blocks passageways in the lungs and digestive tracts. This mucus causes problems with breathing and with the digestion and absorption of nutrients.
Inherited genetic errors from parents:
Dominant genetic diseases, such as Huntingtons, require the inheritance of one erroneous gene to be expressed.
Recessive genetic diseases require the inheritance of erroneous genes to be expressed and this is one reason they work together.
== Global health ==
Referred to as a "lifestyle" disease, because the majority of these diseases are preventable illnesses, the most common causes for non-communicable diseases (NCD) include tobacco use (smoking), hazardous alcohol use, poor diets (high consumption of sugar, salt, saturated fats, and trans fatty acids) and physical inactivity. Currently, NCD kills 36 million people a year, a number that by some estimates is expected to rise by 17–24% within the next decade.
The World Health Organization has reported that, "At a global level, 7 of the 10 leading causes of deaths in 2021 were noncommunicable diseases, accounting for 38% of all deaths, or 68% of the top 10 causes."
Historically, many NCDs were associated with economic development and were so-called a "diseases of the rich". The burden of non-communicable diseases in developing countries has increased however, with an estimated 80% of the four main types of NCDs — cardiovascular diseases, cancers, chronic respiratory diseases and diabetes — now occurring in low- and middle-income countries. Action Plan for the Global Strategy for the Prevention and Control of non-communicable Diseases and with two-thirds of people who are affected by diabetes now residing in developing nations, NCD can no longer be considered just a problem affecting affluent estimation of the economic impact of chronic non-communicable diseases in selected countries. New WHO report: deaths from non-communicable diseases are on the rise, with developing world hit hardest. As previously stated, in 2008 alone, NCD's were the cause of 63% of deaths worldwide; a number that is expected to rise considerably in the near future if measures are not taken.
If present growth trends are maintained, by 2020, NCDs will attribute to 7 out of every 10 deaths in developing countries, killing 52 million people annually worldwide by 2030. With statistics such as these, it comes as no surprise that international entities such as the World Health Organization & World Bank Human Development Network have identified the prevention and control of NCDs as an increasingly important discussion item on the global health agenda.
Thus, should policy makers and communities mobilize "and make prevention and targeted treatment of such diseases a priority," sustainable measures can be implemented to stagnate (and eventually even reverse) this emerging global health threat. Potential measures currently being discussed by the(World Health Organization)-Food and Agriculture Organization includes reducing the levels of salt in foods, limiting inappropriate marketing of unhealthy foods and non-alcoholic beverages to children, imposing controls on harmful alcohol use, raising taxes on tobacco, and legislating to curb smoking in public places.
=== United Nations ===
The World Health Organization is the specialized agency of the United Nations (UN) that acts as coordinating authority on international public health issues, including NCDs. In May 2008, the 193 Member States of the WHO approved a six-year plan to address non-communicable diseases, especially the rapidly increasing burden in low- and middle-income countries. The plan calls for raising the priority given to NCDs in international development work'.
During the 64th session of the United Nations General Assembly in 2010, a resolution was passed to call for a high-level meeting of the General Assembly on the prevention and treatment NCDs with the participation of heads of state and government. The resolution also encouraged UN Member States to address the issue of non-communicable diseases at the 2010 Review Summit for the Millennium Development Goals.
=== Global Non-communicable Disease Network ===
In order to better coordinate efforts around the globe, in 2009 the WHO announced the launch of the Global Non-communicable Disease Network (NCDnet). NCDnet will consist of leading health organizations and experts from around the world in order to fight against diseases such as cancer, cardiovascular disease, and diabetes. Ala Alwan, assistant director-general for Non-communicable Diseases and Mental Health at the WHO, said: "integrating the prevention of non-communicable diseases and injuries into the national and global development agendas is not only achievable but also a priority for developing countries."
=== NCD Alliance ===
The NCD Alliance is a global partnership founded in May 2009 by four international federations representing cardiovascular disease, diabetes, cancer, and chronic respiratory disease. The NCD Alliance brings together roughly 900 national member associations to fight non-communicable disease. Long-term aims of the Alliance include:
NCD/disease national plans for all
A tobacco free world
Improved lifestyles
Strengthened health systems
Global access to affordable and good quality medicines and technologies
Human rights for people with NCDs.
=== Task Force ===
The United Nations Interagency Task Force on the Prevention and Control of Non-communicable Diseases (UNIATF) was established by the United Nations Secretary-General in 2013 in order to provide scaled up action across the UN system to support governments, in particular in low- and middle-income countries, to tackle non-communicable diseases.
=== Young Professionals Chronic Disease Network ===
The Young Professionals Chronic Disease Network, or commonly referred to as YP-CDN, is a global network of roughly 5000 young professionals across 157 countries. The organization aims to mobilize these young people "to take action against social injustice driven by NCDs.".
Now redirected to the Sustainable development knowledge platform.
== Economics ==
Previously, chronic NCDs were considered a problem limited mostly to high income countries, while infectious diseases seemed to affect low income countries. The burden of disease attributed to NCDs has been estimated at 85% in industrialized nations, 70% in middle income nations, and nearly 50% in countries with the lowest national incomes. In 2008, chronic NCDs accounted for more than 60% (over 35 million) of the 57 million deaths worldwide. Given the global population distribution, almost 80% of deaths due to chronic NCDs worldwide now occur in low and middle income countries, while only 20% occur in higher income countries.
National economies are reportedly suffering significant losses due to premature deaths or inability to work resulting from heart disease, stroke, diabetes, and the broader impacts of physical inactivity, which is a significant contributor to NCDs globally. For instance, China is expected to lose roughly $558 billion in national income between 2005 and 2015 due to early deaths. In 2005, heart disease, stroke and diabetes caused an estimated loss in international dollars of national income of 9 billion in India and 3 billion in Brazil.
Following up on the 2023 edition of the FAO report – The State of Food and Agriculture – the subsequent edition provides a detailed breakdown of the hidden costs associated with unhealthy dietary patterns and non-communicable diseases for 156 countries. These hidden costs were measured as productivity losses due to disease-burden. The report finds that in 2020, global health hidden costs amounted 8.1 trillion 2020 PPP dollars, 70 percent of all of the hidden costs of agrifood systems. Diets low in whole grains are the leading concern (18 percent of global quantified health hidden costs), alongside diets high in sodium and low in fruits (16 percent each), although there is significant variation across countries.
=== Absenteeism and presenteeism ===
The burden of chronic NCDs including mental health conditions is felt in workplaces around the world, notably due to elevated levels of absenteeism, or absence from work because of illness, and presenteeism, or productivity lost from staff coming to work and performing below normal standards due to poor health. For example, the United Kingdom experienced a loss of about 175 million days in 2006 to absence from illness among a working population of 37.7 million people. The estimated cost of absences due to illness was over 20 billion pounds in the same year. The cost due to presenteeism is likely even larger, although methods of analyzing the economic impacts of presenteeism are still being developed. Methods for analyzing the distinct workplace impacts of NCDs versus other types of health conditions are also still being developed.
== Key diseases ==
=== Cancer ===
For the vast majority of cancers, risk factors are environmental or lifestyle-related, thus cancers are mostly preventable NCD. Greater than 30% of cancer is preventable via avoiding risk factors including: tobacco, being overweight or obesity, low fruit and vegetable intake, physical inactivity, alcohol, sexually transmitted infections, and air pollution. Infectious agents are responsible for some cancers, for instance almost all cervical cancers are caused by human papillomavirus infection.
=== Cardiovascular disease ===
The first studies on cardiovascular health were performed in 1949 by Jerry Morris using occupational health data and were published in 1958. The causes, prevention, and/or treatment of all forms of cardiovascular disease remain active fields of biomedical research, with hundreds of scientific studies being published on a weekly basis. A trend has emerged, particularly in the early 2000s, in which numerous studies have revealed a link between fast food and an increase in heart disease. These studies include those conducted by the Ryan Mackey Memorial Research Institute, Harvard University and the Sydney Center for Cardiovascular Health. Many major fast food chains, particularly McDonald's, have protested the methods used in these studies and have responded with healthier menu options.
A fairly recent emphasis is on the link between low-grade inflammation that hallmarks atherosclerosis and its possible interventions. C-reactive protein (CRP) is a common inflammatory marker that has been found to be present in increased levels in patients at risk for cardiovascular disease. Also osteoprotegerin which involved with regulation of a key inflammatory transcription factor called NF-κB has been found to be a risk factor of cardiovascular disease and mortality.
=== Diabetes ===
Type 2 Diabetes Mellitus is a chronic condition which is largely preventable and manageable but difficult to cure. Management concentrates on keeping blood sugar levels as close to normal ("euglycemia") as possible without presenting undue patient danger. This can usually be with close dietary management, exercise, and use of appropriate medications (insulin only in the case of type 1 diabetes mellitus. Oral medications may be used in the case of type 2 diabetes, as well as insulin).
Patient education, understanding, and participation is vital since the complications of diabetes are far less common and less severe in people who have well-managed blood sugar levels.
Wider health problems may accelerate the deleterious effects of diabetes. These include smoking, elevated cholesterol levels, obesity, high blood pressure, and lack of regular exercise.
=== Chronic kidney disease ===
Although chronic kidney disease (CKD) is not currently identified as one of WHO's main targets for global NCD control, there is compelling evidence that CKD is not only common, harmful and treatable but also a major contributing factor to the incidence and outcomes of at least three of the diseases targeted by WHO (diabetes, hypertension and CVD).
CKD strongly predisposes to hypertension and CVD; diabetes, hypertension and CVD are all major causes of CKD; and major risk factors for diabetes, hypertension and CVD (such as obesity and smoking) also cause or exacerbate CKD. In addition, among people with diabetes, hypertension, or CVD, the subset who also have CKD are at highest risk of adverse outcomes and high health care costs. Thus, CKD, diabetes and cardiovascular disease are closely associated conditions that often coexist; share common risk factors and treatments; and would benefit from a coordinated global approach to prevention and control.
=== Chronic respiratory disease ===
Chronic respiratory diseases (CRDs) are diseases of the lungs and airways. According to the World Health Organization (WHO) hundreds of millions of people have CRDs. Common CRDs are: asthma, chronic obstructive pulmonary disease, occupational lung disease, and pulmonary hypertension. While CRDs are not curable, various treatments are available to help improve quality of life for individuals who have them. Most treatments involve dilating major airways to improve shortness of breath among other symptoms. The main risk factors for developing CRDs are: tobacco smoking, indoor and outdoor air pollution, allergens, and occupational risks.
WHO helped launch the Global Alliance against Chronic Respiratory Diseases (GARD) in 2006. GARD is voluntarily composed of national and international organizations and works toward "reducing the global burden of chronic respiratory diseases" and focus mainly on vulnerable populations and low and middle-income countries.
== See also ==
List of countries by risk of death from non-communicable disease
Chronic disease
Global health
The INCTR Challenge Fund project of the International Network for Cancer Treatment and Research
== References ==
This article incorporates text from a free content work. Licensed under CC BY 4.0 (license statement/permission). Text taken from In Brief to The State of Food and Agriculture 2024, FAO, FAO.
== Further reading ==
== External links ==
WHO fact sheet on non-communicable diseases
WHO Regional Office for the Eastern Mediterranean website on non-communicable diseases
"NCDnet — Global Noncommunicable Disease Network". World Health Organization. Archived from the original on December 23, 2009. | Wikipedia/Non-communicable_disease |
A chronic condition (also known as chronic disease or chronic illness) is a health condition or disease that is persistent or otherwise long-lasting in its effects or a disease that comes with time. The term chronic is often applied when the course of the disease lasts for more than three months.
Common chronic diseases include diabetes, functional gastrointestinal disorder, eczema, arthritis, asthma, chronic obstructive pulmonary disease, autoimmune diseases, genetic disorders and some viral diseases such as hepatitis C and acquired immunodeficiency syndrome.
An illness which is lifelong because it ends in death is a terminal illness. It is possible and not unexpected for an illness to change in definition from terminal to chronic as medicine progresses. Diabetes and HIV for example were once terminal yet are now considered chronic, due to the availability of insulin for diabetics and daily drug treatment for individuals with HIV, which allow these individuals to live while managing symptoms.
In medicine, chronic conditions are distinguished from those that are acute. An acute condition typically affects one portion of the body and responds to treatment. A chronic condition, on the other hand, usually affects multiple areas of the body, is not fully responsive to treatment, and persists for an extended period of time.
Chronic conditions may have periods of remission or relapse where the disease temporarily goes away, or subsequently reappear. Periods of remission and relapse are commonly discussed when referring to substance abuse disorders which some consider to fall under the category of chronic condition.
Chronic conditions are often associated with non-communicable diseases which are distinguished by their non-infectious causes. Some chronic conditions though, are caused by transmissible infections such as HIV/AIDS.
63% of all deaths worldwide are from chronic conditions. Chronic diseases constitute a major cause of mortality, and the World Health Organization (WHO) attributes 38 million deaths a year to non-communicable diseases. In the United States approximately 40% of adults have at least two chronic conditions.
Having more than one chronic condition is referred to as multimorbidity.
== Types ==
Chronic conditions have often been used to describe the various health related states of the human body such as syndromes, physical impairments, disabilities as well as diseases. Epidemiologists have found interest in chronic conditions due to the fact they contribute to disease, disability, and diminished physical and/or mental capacity.
For example, high blood pressure or hypertension is considered to be not only a chronic condition itself but also correlated with diseases such as heart attack or stroke.
Researchers, particularly those studying the United States, utilize the Chronic Condition Indicator (CCI) which maps ICD codes as "chronic" or "non-chronic".
The list below includes these chronic conditions and diseases:
In 2015 the World Health Organization produced a report on non-communicable diseases, citing the four major types as:
Cancers
Cardiovascular diseases, including cerebrovascular disease, heart failure, and ischemic cardiopathy
Chronic respiratory diseases, such as asthma and chronic obstructive pulmonary disease (COPD)
Diabetes mellitus (type 1, type 2, pre-diabetes)
Other examples of chronic diseases and health conditions include:
Alzheimer's disease
Atrial fibrillation
Attention deficit hyperactivity disorder
Autism Spectrum Disorder
Autoimmune diseases, such as ulcerative colitis, lupus erythematosus, Crohn's disease, coeliac disease, Hashimoto's thyroiditis, and relapsing polychondritis
Blindness
Cerebral palsy (all types)
Chronic graft-versus-host disease
Chronic hepatitis
Chronic pancreatitis
Chronic kidney disease
Chronic osteoarticular diseases, such as osteoarthritis and rheumatoid arthritis
Chronic pain syndromes, such as post-vasectomy pain syndrome and complex regional pain syndrome
Dermatological conditions such as atopic dermatitis and psoriasis
Down Syndrome
Dwarfism
Deafness and hearing impairment
Ehlers–Danlos syndrome (various types)
Endometriosis
Epilepsy
Fetal alcohol spectrum disorder
Fibromyalgia
HIV/AIDS
Hereditary spherocytosis
Huntington's disease
Hypertension
Mental illness
Migraines
Multiple sclerosis
Myalgic encephalomyelitis (a.k.a. chronic fatigue syndrome)
Narcolepsy
Obesity
Osteogenesis Imperfecta
Osteoporosis
Parkinson's disease
Periodontal disease
Polycystic Ovarian Syndrome
Postural orthostatic tachycardia syndrome
Prader-Willi Syndrome
Sickle cell anemia and other hemoglobin disorders
Substance Abuse Disorders
Sleep apnea
Thyroid disease
Tuberculosis
Williams Syndrome
And many more.
== Risk factors ==
While risk factors vary with age and gender, many of the common chronic diseases in the US are caused by dietary, lifestyle and metabolic risk factors. Therefore, these conditions might be prevented by behavioral changes, such as quitting smoking, adopting a healthy diet, and increasing physical activity. Social determinants are important risk factors for chronic diseases. Social factors, e.g., socioeconomic status, education level, and race/ethnicity, are a major cause for the disparities observed in the care of chronic disease. Lack of access and delay in receiving care result in worse outcomes for patients from minorities and underserved populations. Those barriers to medical care complicate patients monitoring and continuity in treatment.
In the US, minorities and low-income populations are less likely to seek, access and receive preventive services necessary to detect conditions at an early stage.
The majority of US health care and economic costs associated with medical conditions are incurred by chronic diseases and conditions and associated health risk behaviors. Eighty-four percent of all health care spending in 2006 was for the 50% of the population who have one or more common chronic medical conditions (CDC, 2014).
There are several psychosocial risk and resistance factors among children with chronic illness and their family members. Adults with chronic illness were significantly more likely to report life dissatisfaction than those without chronic illness. Compared to their healthy peers, children with chronic illness have about a twofold increase in psychiatric disorders. Higher parental depression and other family stressors predicted more problems among patients. In addition, sibling problems along with the burden of illness on the family as a whole led to more psychological strain on the patients and their families.
Africa
African countries are currently grappling with a double health burden—while infectious diseases continue to be a major cause of death, chronic illnesses are increasingly becoming more deadly, particularly in sub-Saharan Africa. This region reports some of the highest chronic disease mortality rates globally, impacting both men and women alike.
The surge in chronic conditions such as diabetes, hypertension, and cardiovascular disease is being driven by poor lifestyle choices like unhealthy diets, physical inactivity, smoking, and obesity. These modifiable behaviors are becoming widespread across both rural and urban areas. In addition to lifestyle factors, genetics also plays a role in the region’s chronic disease profile, particularly for conditions like high blood pressure and diabetes.
Compounding the problem is the state of healthcare systems, which often lack the infrastructure, funding, and public awareness needed to respond effectively to this growing crisis.
Asia
Asia's chronic disease burden is rising sharply, driven by a mix of aging populations, genetic predispositions, and fast-paced urbanization. The transition to more sedentary lifestyles and Westernized diets brought on by industrialization and economic growth—has contributed significantly to the growing number of non-communicable diseases (NCDs). South Asians, in particular, are at greater risk, developing these conditions earlier in life and often at lower body weights compared to global norms, resulting in higher healthcare costs and lower productivity.
Tobacco use remains a critical risk factor across South Asia, with a strong link to chronic illnesses. For instance, the Maldives has reported some of the highest rates of NCD-related deaths among women. Poor diets and smoking rank among the top contributors to early death and disability, made worse by limited access to healthcare and low levels of health awareness in many communities.
Latin America and the Caribbean
In Latin America and the Caribbean, changing lifestyles and environmental conditions are key contributors to the rise in chronic diseases. Many young people, including students, are engaging in habits such as poor nutrition, high consumption of processed foods and sugary drinks, and low levels of physical activity all of which increase their vulnerability to conditions like diabetes and heart disease.
The region’s rapid urban growth and influence from global food and media trends have also shifted daily routines toward more sedentary and unhealthy patterns. Combined with existing social and economic challenges, these changes are putting additional pressure on public health systems, underscoring the urgent need for prevention strategies and stronger public policies.
== Cause ==
Some people suffered from chronic symptoms that developed soon after Covid-19 injections, and this long term condition is known as post-vaccination syndrome (PVS). In February 2025, research from Yale University School of Medicine showed that more frequent Epstein-Barr virus (EBV) reactivation and elevated levels of circulating spike protein were observed in PVS participants, including those who were not infected, compared to healthy controls.
== Prevention ==
A growing body of evidence supports that prevention is effective in reducing the effect of chronic conditions; in particular, early detection results in less severe outcomes. Clinical preventive services include screening for the existence of the disease or predisposition to its development, counseling and immunizations against infectious agents. Despite their effectiveness, the utilization of preventive services is typically lower than for regular medical services. In contrast to their apparent cost in time and money, the benefits of preventive services are not directly perceived by patient because their effects are on the long term or might be greater for society as a whole than at the individual level.
Therefore, public health programs are important in educating the public, and promoting healthy lifestyles and awareness about chronic diseases. While those programs can benefit from funding at different levels (state, federal, private) their implementation is mostly in charge of local agencies and community-based organizations.
Studies have shown that public health programs are effective in reducing mortality rates associated to cardiovascular disease, diabetes and cancer, but the results are somewhat heterogeneous depending on the type of condition and the type of programs involved. For example, results from different approaches in cancer prevention and screening depended highly on the type of cancer.
The rising number of patient with chronic diseases has renewed the interest in prevention and its potential role in helping control costs. In 2008, the Trust for America's Health produced a report that estimated investing $10 per person annually in community-based programs of proven effectiveness and promoting healthy lifestyle (increase in physical activity, healthier diet and preventing tobacco use) could save more than $16 billion annually within a period of just five years.
A 2017 review (updated in 2022) found that it is uncertain whether school-based policies on targeting risk factors on chronic diseases such as healthy eating policies, physical activity policies, and tobacco policies can improve student health behaviours or knowledge of staffs and students. The updated review in 2022 did determine a slight improvement in measures of obesity and physical activity as the use of improved strategies lead to increased implementation interventions but continued to call for additional research to address questions related to alcohol use and risk. Encouraging those with chronic conditions to continue with their outpatient (ambulatory) medical care and attend scheduled medical appointments may help improve outcomes and reduce medical costs due to missed appointments. Finding patient-centered alternatives to doctors or consultants scheduling medical appointments has been suggested as a means of improving the number of people with chronic conditions that miss medical appointments, however there is no strong evidence that these approaches make a difference.
== Nursing ==
Nursing can play an important role in assisting patients with chronic diseases achieve longevity and experience wellness. Scholars point out that the current neoliberal era emphasizes self-care, in both affluent and low-income communities. This self-care focus extends to the nursing of patients with chronic diseases, replacing a more holistic role for nursing with an emphasis on patients managing their own health conditions. Critics note that this is challenging if not impossible for patients with chronic disease in low-income communities where health care systems, and economic and social structures do not fully support this practice.
A study in Ethiopia showcases a nursing-heavy approach to the management of chronic disease. Foregrounding the problem of distance from healthcare facility, the study recommends patients increase their request for care. It uses nurses and health officers to fill, in a cost-efficient way, the large unmet need for chronic disease treatment. They led their health centers staffed by nurses and health officers; so, there are specific training required for involvement in the programmed must be carried out regularly, to ensure that new staff is educated in administering chronic disease care. The program shows that community-based care and education, primarily driven by nurses and health officers, works. It highlights the importance of nurses following up with individuals in the community, and allowing nurses flexibility in meeting their patients' needs and educating them for self-care in their homes.
== Epidemiology ==
The epidemiology of chronic disease is diverse and the epidemiology of some chronic diseases can change in response to new treatments. In the treatment of HIV, the success of anti-retroviral therapies means that many patients will experience this infection as a chronic disease that for many will span several decades of their chronic life.
Some epidemiology of chronic disease can apply to multiple diagnosis. Obesity and body fat distribution for example contribute and are risk factors for many chronic diseases such as diabetes, heart, and kidney disease. Other epidemiological factors, such as social, socioeconomic, and environment do not have a straightforward cause and effect relationship with chronic disease diagnosis. While typically higher socioeconomic status is correlated with lower occurrence of chronic disease, it is not known is there is a direct cause and effect relationship between these two variables.
The epidemiology of communicable chronic diseases such as AIDS is also different from that of noncommunicable chronic disease. While Social factors do play a role in AIDS prevalence, only exposure is truly needed to contract this chronic disease. Communicable chronic diseases are also typically only treatable with medication intervention, rather than lifestyle change as some non-communicable chronic diseases can be treated.
=== United States ===
As of 2003, there are a few programs which aim to gain more knowledge on the epidemiology of chronic disease using data collection. The hope of these programs is to gather epidemiological data on various chronic diseases across the United States and demonstrate how this knowledge can be valuable in addressing chronic disease.
In the United States, as of 2004 nearly one in two Americans (133 million) has at least one chronic medical condition, with most subjects (58%) between the ages of 18 and 64. The number is projected to increase by more than one percent per year by 2030, resulting in an estimated chronically ill population of 171 million. The most common chronic conditions are high blood pressure, arthritis, respiratory diseases like emphysema, and high cholesterol.
Based on data from 2014 Medical Expenditure Panel Survey (MEPS), about 60% of adult Americans were estimated to have one chronic illness, with about 40% having more than one; this rate appears to be mostly unchanged from 2008. MEPS data from 1998 showed 45% of adult Americans had at least one chronic illness, and 21% had more than one.
According to research by the CDC, chronic disease is also especially a concern in the elderly population in America. Chronic diseases like stroke, heart disease, and cancer were among the leading causes of death among Americans aged 65 or older in 2002, accounting for 61% of all deaths among this subset of the population. It is estimated that at least 80% of older Americans are currently living with some form of a chronic condition, with 50% of this population having two or more chronic conditions. The two most common chronic conditions in the elderly are high blood pressure and arthritis, with diabetes, coronary heart disease, and cancer also being reported among the elder population.
In examining the statistics of chronic disease among the living elderly, it is also important to make note of the statistics pertaining to fatalities as a result of chronic disease. Heart disease is the leading cause of death from chronic disease for adults older than 65, followed by cancer, stroke, diabetes, chronic lower respiratory diseases, influenza and pneumonia, and, finally, Alzheimer's disease. Though the rates of chronic disease differ by race for those living with chronic illness, the statistics for leading causes of death among elderly are nearly identical across racial/ethnic groups.
Chronic illnesses cause about 70% of deaths in the US and in 2002 chronic conditions (heart disease, cancers, stroke, chronic respiratory diseases, diabetes, Alzheimer's disease, mental illness and kidney diseases) were six of the top ten causes of mortality in the general US population.
=== Canada ===
The government of Canada put a high emphasis on chronic conditions in the country [1]. At least 45.1% of Canadians will experience one chronic condition in their lifetime. On December 11, 2024, Sun Life, a prominent health insurance provider in Canada, reported an increase in chronic diseases across all age groups. They emphasize that chronic conditions affect both young individuals and the elderly. Sun Life highlights that a growing number of young people are facing chronic issues such as diabetes, asthma, high blood pressure, and elevated cholesterol levels. The report examined drug claims for chronic conditions from over three million Sun Life plan members [2].
It is important to note that diabetes is one of the fastest-growing chronic conditions in Canada, having increased by approximately 30% from 2019 to 2023. Claims for diabetes medications have surged more rapidly among Canadians under the age of 30 [3].
Chronic diseases are prevalent among older Canadians. A report indicates that 73% of individuals aged 65 and older have at least one of ten common chronic conditions. The ten most frequent chronic diseases in Canada include hypertension, affecting 65.7% of the elderly, periodontal disease at 52.0%, osteoarthritis at 38.0%, ischemic heart disease at 27.0%, diabetes at 26.8%, osteoporosis at 25.1%, cancer at 21.5%, COPD at 20.2%, asthma at 10.7%, and mood and anxiety disorders at 10.5%. Additionally, COVID-19 has impacted chronic conditions in seniors, and its effects are currently being studied [4].
== Economic impact ==
=== United States ===
Chronic diseases are a major factor in the continuous growth of medical care spending. In 2002, the U.S. Department of Health and Human Services stated that the health care for chronic diseases cost the most among all health problems in the U.S. Healthy People 2010 reported that more than 75% of the $2 trillion spent annually in U.S. medical care are due to chronic conditions; spending are even higher in proportion for Medicare beneficiaries (aged 65 years and older). Furthermore, in 2017 it was estimated that 90% of the $3.3 billion spent on healthcare in the United States was due to the treatment of chronic diseases and conditions. Spending growth is driven in part by the greater prevalence of chronic illnesses and the longer life expectancy of the population. Also, improvement in treatments has significantly extended the lifespans of patients with chronic diseases but results in additional costs over long period of time. A striking success is the development of combined antiviral therapies that led to remarkable improvement in survival rates and quality of life of HIV-infected patients.
In addition to direct costs in health care, chronic diseases are a significant burden to the economy, through limitations in daily activities, loss in productivity and loss of days of work. A particular concern is the rising rates of overweight and obesity in all segments of the U.S. population. Obesity itself is a medical condition and not a disease, but it constitutes a major risk factor for developing chronic illnesses, such as diabetes, stroke, cardiovascular disease and cancers. Obesity results in significant health care spending and indirect costs, as illustrated by a recent study from the Texas comptroller reporting that obesity alone cost Texas businesses an extra $9.5 billion in 2009, including more than $4 billion for health care, $5 billion for lost productivity and absenteeism, and $321 million for disability.
=== Canada ===
The Public Health Agency of Canada states that chronic disease has a negative impact on the labor force participant of individuals. In particular, people with chronic diseases “are likely to have recurrent sick leave, long-term absences from work, and often face an early retirement from the labour force.”
In 2000, the Public Health Agency of Canada stated that the total economic burden of arthritis totaled 6.4 billion Canadian dollars per year, representing 28.9% of all musculoskeletal disease expenditures. 65% of the total economic cost was incurred by those aged 35-64 years old. It is anticipated that people aged 55 and older will most significantly contribute to the prevalence of arthritis. This is projected to result in reduced labor force participant and a substantial increase in morbidity costs. The Public Health Agency of Canada recommends focusing on prevention strategies, minimizing costs by improving health and reducing disability, and providing support to people with arthritis to remain active in the workforce.
=== Japan ===
As of 2004, the estimated economic burden of Chronic obstructive pulmonary disease (COPD) is 805.5 billion yen per year. Direct costs, which include inpatient care, outpatient care, and home oxygen therapy, account for 645.1 billion yen per year. Meanwhile, indirect costs are estimated to cost 160.4 billion yen per year in lost productivity due to absenteeism from work. The high smoking rate and increasing size of the elderly population are likely to exacerbate the economic impact of COPD in Japan.
Major indirect costs of COPD are a decrease in labor force participation, increased cost of healthcare due to assisted living expenses, increased prevalence of premature death, and care giver support cost. In 1999, a survey demonstrated that patients with chronic bronchitis, COPD, or emphysema missed an average of 42.2 days of work per year due to their condition.
== Social and personal impact ==
There have been recent links between social factors and prevalence as well as outcome of chronic conditions.
=== Mental health ===
The connection between loneliness, overall health, and chronic conditions has recently been highlighted. Some studies have shown that loneliness has detrimental health effects similar to that of smoking and obesity. One study found that feelings of isolation are associated with higher self reporting of health as poor, and feelings of loneliness increased the likelihood of mental health disorders in individuals.
The connection between chronic illness and loneliness is established, yet oftentimes ignored in treatment. One study for example found that a greater number of chronic illnesses per individual were associated with feelings of loneliness. Some of the possible reasons for this listed are an inability to maintain independence as well as the chronic illness being a source of stress for the individual. A study of loneliness in adults over age 65 found that low levels of loneliness as well as high levels of familial support were associated with better outcomes of multiple chronic conditions such as hypertension and diabetes.
There are some recent movements in the medical sphere to address these connections when treating patients with chronic illness. The biopsychosocial approach for example, developed in 2006 focuses on patients "patient's personality, family, culture, and health dynamics." Physicians are leaning more towards a psychosocial approach to chronic illness to aid the increasing number of individuals diagnosed with these conditions. Despite this movement, there is still criticism that chronic conditions are not being treated appropriately, and there is not enough emphasis on the behavioral aspects of chronic conditions or psychological types of support for patients.
The mental health intersectionality on those with chronic conditions is a large aspect often overlooked by doctors. And chronic illness therapists are available for support to help with the mental toll of chronic illness a it is often underestimated in society. Adults with chronic illness that restrict their daily life present with more depression and lower self-esteem than healthy adults and adults with non-restricting chronic illness. The emotional influence of chronic illness also has an effect on the intellectual and educational development of the individual. For example, people living with type 1 diabetes endure a lifetime of monotonous and rigorous health care management usually involving daily blood glucose monitoring, insulin injections, and constant self-care. This type of constant attention that is required by type 1 diabetes and other chronic illness can result in psychological maladjustment. There have been several theories, namely one called diabetes resilience theory, that posit that protective processes buffer the impact of risk factors on the individual's development and functioning.
=== Financial cost ===
People with chronic conditions pay more out-of-pocket; a study found that Americans spent $2,243 more on average. The financial burden can increase medication non-adherence.
In some countries, laws protect patients with chronic conditions from excessive financial responsibility; for example, as of 2008 France limited copayments for those with chronic conditions, and Germany limits cost sharing to 1% of income versus 2% for the general public.
Within the medical-industrial complex, chronic illnesses can impact the relationship between pharmaceutical companies and people with chronic conditions. Life-saving drugs, or life-extending drugs, can be inflated for a profit. There is little regulation on the cost of chronic illness drugs, which suggests that abusing the lack of a drug cap can create a large market for drug revenue. Likewise, certain chronic conditions can last throughout one's lifetime and create pathways for pharmaceutical companies to take advantage of this.
=== Gender ===
Gender influences how chronic disease is viewed and treated in society. Women's chronic health issues are often considered to be most worthy of treatment or most severe when the chronic condition interferes with a woman's fertility. Historically, there is less of a focus on a woman's chronic conditions when it interferes with other aspects of her life or well-being. Many women report feeling less than or even "half of a woman" due to the pressures that society puts on the importance of fertility and health when it comes to typically feminine ideals. These kinds of social barriers interfere with women's ability to perform various other activities in life and fully work toward their aspirations.
=== Socioeconomic class and race ===
Race is also implicated in chronic illness, although there may be many other factors involved. Racial minorities are 1.5-2 times more likely to have most chronic diseases than white individuals. Non-Hispanic blacks are 40% more likely to have high blood pressure that non-Hispanic whites, diagnosed diabetes is 77% higher among non-Hispanic blacks, and American Indians and Alaska Natives are 60% more likely to be obese than non-Hispanic whites. Some of this prevalence has been suggested to be in part from environmental racism. Flint, Michigan, for example, had high levels of lead poisoning in their drinkable water after waste was dumped into low-value housing areas. There are also higher rates of asthma in children who live in lower income areas due to an abundance of pollutants being released on a much larger scale in these areas.
== Advocacy and research organizations ==
In Europe, the European Chronic Disease Alliance was formed in 2011, which represents over 100,000 healthcare workers.
In the United States, there are a number of nonprofits focused on chronic conditions, including entities focused on specific diseases such as the American Diabetes Association, Alzheimer's Association, or Crohn's and Colitis Foundation. There are also broader groups focused on advocacy or research into chronic illness in general, such as the National Association of Chronic Disease Directors, Partnership to Fight Chronic Disease, the Chronic Disease Coalition which arose in Oregon in 2015, and the Chronic Policy Care Alliance.
== See also ==
Chronic care management
Chronic disease in China
Chronic disease in Northern Ontario
Chronic Illness (journal)
Chronic pain
Long COVID
Course (medicine)
Disability studies
Disease management (health)
Dynamic treatment regimes
Medical tattoo
Multimorbidity
Natural history of disease
Virtual Wards (a UK term)
== References ==
== Further reading ==
== External links ==
"List of Chronic Human Diseases Linked to Infectious Pathogens". Archived from the original on 2021-01-18.
Center for Managing Chronic Disease, University of Michigan
CHRODIS: EU Joint Action on Chronic Diseases and Promoting Healthy Ageing Across the Life-Cycle
MEDICC Review theme issue on Confronting Chronic Diseases With longer life expectancies in most countries and the globalization of "Western" diets and sedentarism, the main burden of disease and death from these conditions is falling on already-disadvantaged developing countries and poor communities everywhere.
Public Health Agency of Canada: Chronic Disease
World Health Organization: Chronic Disease and Health Promotion | Wikipedia/Chronic_disease |
A disease is an abnormal condition that affects the body of an organism.
Disease or The Disease may also refer to:
Disease (Beartooth album) or the title song, 2018
Disease (G.G.F.H. album) or the title song, 1993
The Disease EP or the title song, by the Eyes of a Traitor, 2011
"Disease" (Matchbox Twenty song), 2002
"Disease" (Lady Gaga song), 2024
"Disease", a song by Hollywood Undead from Day of the Dead, 2015
"Disease", a song by Insight 23 from Obsess, 1995
"Dis-ease", a song by BTS from Be, 2020
"The Disease", a song by Heaven Shall Burn from Iconoclast (Part 1: The Final Resistance), 2008
"The Disease", an episode of Star Trek: Voyager
== See also ==
List of diseases | Wikipedia/Disease_(disambiguation) |
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosome abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development (a de novo mutation), or it can be inherited from two parents who are carriers of a faulty gene (autosomal recessive inheritance) or from a parent with the disorder (autosomal dominant inheritance). When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA (due to their size).
There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature. More than 600 genetic disorders are treatable. Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves.
Genetic disorders are present before birth, and some genetic disorders produce birth defects, but birth defects can also be developmental rather than hereditary. The opposite of a hereditary disease is an acquired disease. Most cancers, although they involve genetic mutations to a small proportion of cells in the body, are acquired diseases. Some cancer syndromes, however, such as BRCA mutations, are hereditary genetic disorders.
== Single-gene ==
A single-gene disorder (or monogenic disorder) is the result of a single mutated gene. Single-gene disorders can be passed on to subsequent generations in several ways. Genomic imprinting and uniparental disomy, however, may affect inheritance patterns. The divisions between recessive and dominant types are not "hard and fast", although the divisions between autosomal and X-linked types are (since the latter types are distinguished purely based on the chromosomal location of the gene). For example, the common form of dwarfism, achondroplasia, is typically considered a dominant disorder, but children with two genes for achondroplasia have a severe and usually lethal skeletal disorder, one that achondroplasics(ones affected with achondroplasia) could be considered carriers for. Sickle cell anemia is also considered a recessive condition, but heterozygous carriers have increased resistance to malaria in early childhood, which could be described as a related dominant condition. When a couple where one partner or both are affected or carriers of a single-gene disorder wish to have a child, they can do so through in vitro fertilization, which enables preimplantation genetic diagnosis to occur to check whether the embryo has the genetic disorder.
Most congenital metabolic disorders known as inborn errors of metabolism result from single-gene defects. Many such single-gene defects can decrease the fitness of affected people and are therefore present in the population in lower frequencies compared to what would be expected based on simple probabilistic calculations.
=== Autosomal dominant ===
Only one mutated copy of the gene will be necessary for a person to be affected by an autosomal dominant disorder. Each affected person usually has one affected parent.: 57 The chance a child will inherit the mutated gene is 50%. Autosomal dominant conditions sometimes have reduced penetrance, which means although only one mutated copy is needed, not all individuals who inherit that mutation go on to develop the disease. Examples of this type of disorder are Huntington's disease,: 58 neurofibromatosis type 1, neurofibromatosis type 2, Marfan syndrome, hereditary nonpolyposis colorectal cancer, hereditary multiple exostoses (a highly penetrant autosomal dominant disorder), tuberous sclerosis, Von Willebrand disease, and acute intermittent porphyria. Birth defects are also called congenital anomalies.
=== Autosomal recessive ===
Two copies of the gene must be mutated for a person to be affected by an autosomal recessive disorder. An affected person usually has unaffected parents who each carry a single copy of the mutated gene and are referred to as genetic carriers. Each parent with a defective gene normally do not have symptoms. Two unaffected people who each carry one copy of the mutated gene have a 25% risk with each pregnancy of having a child affected by the disorder. Examples of this type of disorder are albinism, medium-chain acyl-CoA dehydrogenase deficiency, cystic fibrosis, sickle cell disease, Tay–Sachs disease, Niemann–Pick disease, spinal muscular atrophy, and Roberts syndrome. Certain other phenotypes, such as wet versus dry earwax, are also determined in an autosomal recessive fashion. Some autosomal recessive disorders are common because, in the past, carrying one of the faulty genes led to a slight protection against an infectious disease or toxin such as tuberculosis or malaria. Such disorders include cystic fibrosis, sickle cell disease, phenylketonuria and thalassaemia.
=== X-linked dominant ===
X-linked dominant disorders are caused by mutations in genes on the X chromosome. Only a few disorders have this inheritance pattern, with a prime example being X-linked hypophosphatemic rickets. Males and females are both affected in these disorders, with males typically being more severely affected than females. Some X-linked dominant conditions, such as Rett syndrome, incontinentia pigmenti type 2, and Aicardi syndrome, are usually fatal in males either in utero or shortly after birth, and are therefore predominantly seen in females. Exceptions to this finding are extremely rare cases in which boys with Klinefelter syndrome (44+xxy) also inherit an X-linked dominant condition and exhibit symptoms more similar to those of a female in terms of disease severity. The chance of passing on an X-linked dominant disorder differs between men and women. The sons of a man with an X-linked dominant disorder will all be unaffected (since they receive their father's Y chromosome), but his daughters will all inherit the condition. A woman with an X-linked dominant disorder has a 50% chance of having an affected foetus with each pregnancy, although in cases such as incontinentia pigmenti, only female offspring are generally viable.
=== X-linked recessive ===
X-linked recessive conditions are also caused by mutations in genes on the X chromosome. Males are much more frequently affected than females, because they only have the one X chromosome necessary for the condition to present. The chance of passing on the disorder differs between men and women. The sons of a man with an X-linked recessive disorder will not be affected (since they receive their father's Y chromosome), but his daughters will be carriers of one copy of the mutated gene. A woman who is a carrier of an X-linked recessive disorder (XRXr) has a 50% chance of having sons who are affected and a 50% chance of having daughters who are carriers of one copy of the mutated gene. X-linked recessive conditions include the serious diseases hemophilia A, Duchenne muscular dystrophy, and Lesch–Nyhan syndrome, as well as common and less serious conditions such as male pattern baldness and red–green color blindness. X-linked recessive conditions can sometimes manifest in females due to skewed X-inactivation or monosomy X (Turner syndrome).
=== Y-linked ===
Y-linked disorders are caused by mutations on the Y chromosome. These conditions may only be transmitted from the heterogametic sex (e.g. male humans) to offspring of the same sex. More simply, this means that Y-linked disorders in humans can only be passed from men to their sons; females can never be affected because they do not possess Y-allosomes.
Y-linked disorders are exceedingly rare but the most well-known examples typically cause infertility. Reproduction in such conditions is only possible through the circumvention of infertility by medical intervention.
=== Mitochondrial ===
This type of inheritance, also known as maternal inheritance, is the rarest and applies to the 13 genes encoded by mitochondrial DNA. Because only egg cells contribute mitochondria to the developing embryo, only mothers (who are affected) can pass on mitochondrial DNA conditions to their children. An example of this type of disorder is Leber's hereditary optic neuropathy.
It is important to stress that the vast majority of mitochondrial diseases (particularly when symptoms develop in early life) are actually caused by a nuclear gene defect, as the mitochondria are mostly developed by non-mitochondrial DNA. These diseases most often follow autosomal recessive inheritance.
== Multifactorial disorder ==
Genetic disorders may also be complex, multifactorial, or polygenic, meaning they are likely associated with the effects of multiple genes in combination with lifestyles and environmental factors. Multifactorial disorders include heart disease and diabetes. Although complex disorders often cluster in families, they do not have a clear-cut pattern of inheritance. This makes it difficult to determine a person's risk of inheriting or passing on these disorders. Complex disorders are also difficult to study and treat because the specific factors that cause most of these disorders have not yet been identified. Studies that aim to identify the cause of complex disorders can use several methodological approaches to determine genotype–phenotype associations. One method, the genotype-first approach, starts by identifying genetic variants within patients and then determining the associated clinical manifestations. This is opposed to the more traditional phenotype-first approach, and may identify causal factors that have previously been obscured by clinical heterogeneity, penetrance, and expressivity.
On a pedigree, polygenic diseases do tend to "run in families", but the inheritance does not fit simple patterns as with Mendelian diseases. This does not mean that the genes cannot eventually be located and studied. There is also a strong environmental component to many of them (e.g., blood pressure).
Other such cases include:
asthma
autoimmune diseases such as multiple sclerosis
cancers
ciliopathies
cleft palate
diabetes
heart disease
hypertension
inflammatory bowel disease
intellectual disability
mood disorder
obesity
refractive error
infertility
== Chromosomal disorder ==
A chromosomal disorder is a missing, extra, or irregular portion of chromosomal DNA. It can be from an atypical number of chromosomes or a structural abnormality in one or more chromosomes. An example of these disorders is Trisomy 21 (the most common form of Down syndrome), in which there is an extra copy of chromosome 21 in all cells.
== Diagnosis ==
Due to the wide range of genetic disorders that are known, diagnosis is widely varied and dependent of the disorder. Most genetic disorders are diagnosed pre-birth, at birth, or during early childhood however some, such as Huntington's disease, can escape detection until the patient begins exhibiting symptoms well into adulthood.
The basic aspects of a genetic disorder rests on the inheritance of genetic material. With an in depth family history, it is possible to anticipate possible disorders in children which direct medical professionals to specific tests depending on the disorder and allow parents the chance to prepare for potential lifestyle changes, anticipate the possibility of stillbirth, or contemplate termination. Prenatal diagnosis can detect the presence of characteristic abnormalities in fetal development through ultrasound, or detect the presence of characteristic substances via invasive procedures which involve inserting probes or needles into the uterus such as in amniocentesis.
== Prognosis ==
Not all genetic disorders directly result in death; however, there are no known cures for genetic disorders. Many genetic disorders affect stages of development, such as Down syndrome, while others result in purely physical symptoms such as muscular dystrophy. Other disorders, such as Huntington's disease, show no signs until adulthood. During the active time of a genetic disorder, patients mostly rely on maintaining or slowing the degradation of quality of life and maintain patient autonomy. This includes physical therapy and pain management.
== Treatment ==
The treatment of disorder an ongoing battle, with over 1,800 gene therapy clinical trials having been completed, are ongoing, or have been approved worldwide. Despite this, most treatment options revolve around treating the symptoms of the disorders in an attempt to improve patient quality of life.
Gene therapy refers to a form of treatment where a healthy gene is introduced to a patient. This should alleviate the defect caused by a faulty gene or slow the progression of the disease. A major obstacle has been the delivery of genes to the appropriate cell, tissue, and organ affected by the disorder. Researchers have investigated how they can introduce a gene into the potentially trillions of cells that carry the defective copy. Finding an answer to this has been a roadblock between understanding the genetic disorder and correcting the genetic disorder.
== Epidemiology ==
Around 1 in 50 people are affected by a known single-gene disorder, while around 1 in 263 are affected by a chromosomal disorder. Around 65% of people have some kind of health problem as a result of congenital genetic mutations. Due to the significantly large number of genetic disorders, approximately 1 in 21 people are affected by a genetic disorder classified as "rare" (usually defined as affecting less than 1 in 2,000 people). Most genetic disorders are rare in themselves. There are well over 6,000 known genetic disorders, and new genetic disorders are constantly being described in medical literature.
== History ==
The earliest known genetic condition in a hominid was in the fossil species Paranthropus robustus, with over a third of individuals displaying amelogenesis imperfecta.
== See also ==
FINDbase (the Frequency of Inherited Disorders database)
Genetic epidemiology
List of genetic disorders
Population groups in biomedicine
Mendelian error
== References ==
== External links ==
Public Health Genomics at CDC
OMIM — Online Mendelian Inheritance in Man, a catalog of human genes and genetic disorders
Genetic and Rare Diseases Information Center (GARD) Office of Rare Diseases (ORD), National Institutes of Health (NIH)
CDC's National Center on Birth Defects and Developmental Disabilities
Genetic Disease Information from the Human Genome Project
Global Genes Project, Genetic and Rare Diseases Organization
List of Genetic Disorders - Genome.gov | Wikipedia/Genetic_disease |
In epidemiology, environmental diseases are diseases that can be directly attributed to environmental factors (as distinct from genetic factors or infection). Apart from the true monogenic genetic disorders, which are rare, environment is a major determinant of the development of disease. Diet, exposure to toxins, pathogens, radiation, and chemicals found in almost all personal care products and household cleaners, stress, racism, and physical and mental abuse are causes of a large segment of non-hereditary disease. If a disease process is concluded to be the result of a combination of genetic and environmental factor influences, its etiological origin can be referred to as having a multifactorial pattern.
There are many different types of environmental disease including:
Disease caused by physical factors in the environment, such as skin cancer caused by excessive exposure to ultraviolet radiation in sunlight
Disease caused by exposure to toxic or irritant chemicals in the environment such as toxic metals
Disease caused by exposures to toxins from biologic agents in the environment, such as aflatoxicosis from molds that produce aflatoxin
Disease caused by exposure to toxic social factors in the environment, such as racism
Lifestyle disease such as cardiovascular disease, diseases caused by substance abuse such as alcoholism, and smoking-related disease
== Environmental diseases vs. pollution-related diseases ==
Environmental diseases are a direct result from the environment. Meanwhile, pollution-related diseases are attributed to exposure to toxicants or toxins in the air, water, and soil. Therefore, all pollution-related disease are environmental diseases, but not all environmental diseases are pollution-related diseases.
== Urban-associated diseases ==
Urban areas are highly dense regions that currently hold ~50% of the global population, a number expected to grow to 70% by 2050, and produce over 80% of the global GDP. These areas are known to have a higher incidence of certain diseases, which is of particular concern given their rapid growth. The urban environment includes many risk factors for a variety of different environmental diseases. Some of these risk factors, for instance, air-pollution, are well known, while others such as altered microbial exposure are less familiar to the general public. For instance, asthma can be induced and exacerbated by combustion related pollution, which is more prevalent in urban areas. On the other hand, urban areas, compared to their rural counterparts, lack diverse microbial communities, which can help prevent the development of asthma. Both of these effects lead to a higher incidence of asthma in cities. Infectious diseases are also often more common in cities, as transfer between hosts is facilitated by high population densities. However, recent research shows that increased access to healthcare weakens the urban association with these diseases, and the net effect is still unclear. Many mental health disorders have also been associated with urban areas, especially in low socioeconomic areas. Increased levels of stress, air & light & noise pollution, and reduced "green" space are all urban-associated environmental effects that are adversely linked to mental health. Though urban areas are often correlated with dirtiness and disease, they are likely to have more access to higher quality health care which can lead to more positive health outcomes. This benefit will continue to grow as innovation in health technologies steadily rises. Taking this into account, while overall trends do exist, urban risk factors are nuanced and often city and context dependent.
== Chemicals ==
=== Metals ===
Poisoning by lead and mercury has been known since antiquity. Other toxic metals or metals that are known to evoke adverse immune reactions are arsenic, phosphorus, zinc, beryllium, cadmium, chromium, manganese, nickel, cobalt, osmium, platinum, selenium, tellurium, thallium, uranium, and vanadium.
=== Halogens ===
There are many other diseases likely to have been caused by common anions found in natural drinking water. Fluoride is one of the most common found in drier climates where the geology favors release of fluoride ions to soil as the rocks decompose. In Sri Lanka, 90% of the country is underlain by crystalline metamorphic rocks of which most carry mica as a major mineral. Mica carries fluoride in their structure and releases to soil when decomposes. In the dry and arid climates, fluoride concentrates on top soil and slowly dissolves in shallow groundwater. This has been the cause of high fluoride levels in drinking water where the majority of the rural Sri Lankans obtain their drinking water from backyard wells. High fluoride in drinking water has caused a high incidence of fluorosis among dry zone population in Sri Lanka. However, in the wet zone, high rainfall effectively removes fluoride from soils where no fluorosis is evident. In some parts of Sri Lanka iodine deficiency has also been noted which has been identified as a result of iodine fixation by hydrated iron oxide found in lateritic soils in wet coastal lowlands.
=== Organic compounds ===
Additionally, there are environmental diseases caused by the aromatic carbon compounds including : benzene, hexachlorocyclohexane, toluene diisocyanate, phenol, pentachlorophenol, quinone and hydroquinone.
Also included are the aromatic nitro-, amino-, and pyridilium-deratives: nitrobenzene, dinitrobenzene, trinitrotoluene, paramethylaminophenol sulfate (Metol), dinitro-ortho-cresol, aniline, trinitrophenylmethylnitramine (tetryl), hexanitrodiphenylamine (aurantia), phenylenediamines, and paraquat.
The aliphatic carbon compounds can also cause environmental disease. Included in these are methanol, nitroglycerine, nitrocellulose, dimethylnitrosamine, and the halogenated hydrocarbons: methyl chloride, methyl bromide, trichloroethylene, carbon tetrachloride, and the chlorinated naphthalenes. Also included are glycols: ethylene chlorhydrin and diethylene dioxide
=== Noxious gases ===
Noxious gases can be categorized as : Simple asphyxiants, chemical asphyxiants, and irritant gases. The simple asphixiants are nitrogen, methane, and carbon dioxide.
The chemical asphyxiants are carbon monoxide, sulfuretted hydrogen and hydrogen cyanide.
The irritant gases are sulfur dioxide, ammonia, nitrogen dioxide, chlorine, phosgene, and fluorine and its compounds, which include luroine and hydrofluoric acid, fluorspar, fluorapatite, cryolite, and organic fluorine compounds.
== Categorization and surveillance ==
The U.S. Coast Guard has developed a Coast Guard-wide comprehensive system for surveillance of workplace diseases.
The American Medical Association's fifth edition of the Current Medical Information and Terminology (CMIT) was used as a reference to expand the basic list of 50 Sentinel Health Events (Occupational) [SHE(O)] published by the National Institute for Occupational Health and Safety (NIOSH), September, 1983.
== See also ==
== References ==
== Notes ==
The Diseases of Occupations, Sixth Edition, Donald Hunter, C.B.E., D.Sc., M.D., F.R.C.P., Hodder and Stoughton, London. ISBN 0-340-22084-8, 1978.
Aviat Space Environ Med. 1991 Aug;62(8):795-7.
Use of sentinel health events (occupational) in computer assisted occupational health surveillance. Stockwell JR, Adess ML, Titlow TB, Zaharias GR. U.S. Coast Guard Office of Health Services, Washington, D.C. | Wikipedia/Environmental_disease |
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