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A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another protein (the substrate) by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates. Certain E3 ligases have been utilized in targeted protein degradation applications.
== Ubiquitination system ==
The ubiquitin ligase is referred to as an E3, and operates in conjunction with an E1 ubiquitin-activating enzyme and an E2 ubiquitin-conjugating enzyme. There is one major E1 enzyme, shared by all ubiquitin ligases, that uses ATP to activate ubiquitin for conjugation and transfers it to an E2 enzyme. The E2 enzyme interacts with a specific E3 partner and transfers the ubiquitin to the target protein. The E3, which may be a multi-protein complex, is, in general, responsible for targeting ubiquitination to specific substrate proteins.
The ubiquitylation reaction proceeds in three or four steps depending on the mechanism of action of the E3 ubiquitin ligase. In the conserved first step, an E1 cysteine residue attacks the ATP-activated C-terminal glycine on ubiquitin, resulting in a thioester Ub-S-E1 complex. The energy from ATP and diphosphate hydrolysis drives the formation of this reactive thioester, and subsequent steps are thermoneutral. Next, a transthiolation reaction occurs, in which an E2 cysteine residue attacks and replaces the E1. HECT domain type E3 ligases will have one more transthiolation reaction to transfer the ubiquitin molecule onto the E3, whereas the much more common RING finger domain type ligases transfer ubiquitin directly from E2 to the substrate. The final step in the first ubiquitylation event is an attack from the target protein lysine amine group, which will remove the cysteine, and form a stable isopeptide bond. One notable exception to this is p21 protein, which appears to be ubiquitylated using its N-terminal amine, thus forming a peptide bond with ubiquitin.
== Ubiquitin ligase families ==
Humans have an estimated 500-1000 E3 ligases, which impart substrate specificity onto the E1 and E2. The E3 ligases are classified into four families: HECT, RING-finger, U-box, and PHD-finger. The RING-finger E3 ligases are the largest family and contain ligases such as the anaphase-promoting complex (APC) and the SCF complex (Skp1-Cullin-F-box protein complex). SCF complexes consist of four proteins: Rbx1, Cul1, Skp1, which are invariant among SCF complexes, and an F-box protein, which varies. Around 70 human F-box proteins have been identified. F-box proteins contain an F-box, which binds the rest of the SCF complex, and a substrate binding domain, which gives the E3 its substrate specificity.
== Mono- and poly-ubiquitylation ==
Ubiquitin signaling relies on the diversity of ubiquitin tags for the specificity of its message. A protein can be tagged with a single ubiquitin molecule (monoubiquitylation), or variety of different chains of ubiquitin molecules (polyubiquitylation). E3 ubiquitin ligases catalyze polyubiquitination events much in the same way as the single ubiquitylation mechanism, using instead a lysine residue from a ubiquitin molecule currently attached to substrate protein to attack the C-terminus of a new ubiquitin molecule. For example, a common 4-ubiquitin tag, linked through the lysine at position 48 (K48) recruits the tagged protein to the proteasome, and subsequent degradation. However, all seven of the ubiquitin lysine residues (K6, K11, K27, K29, K33, K48, and K63), as well as the N-terminal methionine are used in chains in vivo.
Monoubiquitination has been linked to membrane protein endocytosis pathways. For example, phosphorylation of the Tyrosine at position 1045 in the Epidermal Growth Factor Receptor (EGFR) can recruit the RING type E3 ligase c-Cbl, via an SH2 domain. C-Cbl monoubiquitylates EGFR, signaling for its internalization and trafficking to the lysosome.
Monoubiquitination also can regulate cytosolic protein localization. For example, the E3 ligase MDM2 ubiquitylates p53 either for degradation (K48 polyubiquitin chain), or for nuclear export (monoubiquitylation). These events occur in a concentration dependent fashion, suggesting that modulating E3 ligase concentration is a cellular regulatory strategy for controlling protein homeostasis and localization.
== Substrate recognition ==
Ubiquitin ligases are the final, and potentially the most important determinant of substrate specificity in ubiquitination of proteins. The ligases must simultaneously distinguish their protein substrate from thousands of other proteins in the cell, and from other (ubiquitination-inactive) forms of the same protein. This can be achieved by different mechanisms, most of which involve recognition of degrons: specific short amino acid sequences or chemical motifs on the substrate.
=== N-degrons ===
Proteolytic cleavage can lead to exposure of residues at the N-terminus of a protein. According to the N-end rule, different N-terminal amino acids (or N-degrons) are recognized to a different extent by their appropriate ubiquitin ligase (N-recognin), influencing the half-life of the protein. For instance, positively charged (Arg, Lys, His) and bulky hydrophobic amino acids (Phe, Trp, Tyr, Leu, Ile) are recognized preferentially and thus considered destabilizing degrons since they allow faster degradation of their proteins.
=== Phosphodegrons ===
A degron can be converted into its active form by a post-translational modification such as phosphorylation of a tyrosine, serine or threonine residue. In this case, the ubiquitin ligase exclusively recognizes the phosphorylated version of the substrate due to stabilization within the binding site. For example, FBW7, the F-box substrate recognition unit of an SCFFBW7ubiquitin ligase, stabilizes a phosphorylated substrate by hydrogen binding its arginine residues to the phosphate, as shown in the figure to the right. In absence of the phosphate, residues of FBW7 repel the substrate.
=== Oxygen and small molecule dependent degrons ===
The presence of oxygen or other small molecules can influence degron recognition. The von Hippel-Lindau (VHL) protein (substrate recognition part of a specific E3 ligase), for instance, recognizes the hypoxia-inducible factor alpha (HIF-α) only under normal oxygen conditions, when its proline is hydroxylated. Under hypoxia, on the other hand, HIF-a is not hydroxylated, evades ubiquitination and thus operates in the cell at higher concentrations which can initiate transcriptional response to hypoxia. Another example of small molecule control of protein degradation is phytohormone auxin in plants. Auxin binds to TIR1 (the substrate recognition domain of SCFTIR1ubiquitin ligase) increasing the affinity of TIR1 for its substrates (transcriptional repressors: Aux/IAA), and promoting their degradation.
=== Misfolded and sugar degrons ===
In addition to recognizing amino acids, ubiquitin ligases can also detect unusual features on substrates that serve as signals for their destruction. For example, San1 (Sir antagonist 1), a nuclear protein quality control in yeast, has a disordered substrate binding domain, which allows it to bind to hydrophobic domains of misfolded proteins. Misfolded or excess unassembled glycoproteins of the ERAD pathway, on the other hand, are recognized by Fbs1 and Fbs2, mammalian F-box proteins of E3 ligases SCFFbs1and SCFFbs2. These recognition domains have small hydrophobic pockets allowing them to bind high-mannose containing glycans.
=== Structural motifs ===
In addition to linear degrons, the E3 ligase can in some cases also recognize structural motifs on the substrate. In this case, the 3D motif can allow the substrate to directly relate its biochemical function to ubiquitination. This relation can be demonstrated with TRF1 protein (regulator of human telomere length), which is recognized by its corresponding E3 ligase (FBXO4) via an intermolecular beta sheet interaction. TRF1 cannot be ubiquinated while telomere bound, likely because the same TRF1 domain that binds to its E3 ligase also binds to telomeres.
== Disease relevance ==
E3 ubiquitin ligases regulate homeostasis, cell cycle, and DNA repair pathways, and as a result, a number of these proteins are involved in a variety of cancers, including famously MDM2, BRCA1, and Von Hippel-Lindau tumor suppressor. For example, a mutation of MDM2 has been found in stomach cancer, renal cell carcinoma, and liver cancer (amongst others) to deregulate MDM2 concentrations by increasing its promoter’s affinity for the Sp1 transcription factor, causing increased transcription of MDM2 mRNA. Several proteomics-based experimental techniques are available for identifying E3 ubiquitin ligase-substrate pairs, such as proximity-dependent biotin identification (BioID), ubiquitin ligase-substrate trapping, and tandem ubiquitin-binding entities (TUBEs).
=== Examples ===
A RING (Really Interesting New Gene) domain binds the E2 conjugase and might be found to mediate enzymatic activity in the E2-E3 complex
An F-box domain (as in the SCF complex) binds the ubiquitinated substrate. (e.g., Cdc 4, which binds the target protein Sic1; Grr1, which binds Cln).
A HECT domain, which is involved in the transfer of ubiquitin from the E2 to the substrate.
== Targeted protein degradation ==
In 2001, work from the labs of Craig Crews and Raymond Deshaies described the development of proteolysis-targeting chimeras (PROTACs). Using a small molecule to recruit an E3 ubiquitin ligase to a target protein, this work demonstrated that induced proximity could be used to effect the ubiquitination and proteasomal degradation of a target protein. PROTACs have been frequently applied using the E3 ubiquitin ligases CRBN and VHL to degrade various targets of biological and therapeutic relevance. Multiple groups have sought out additional E3 ligases to co-opt for targeted protein degradation such as FBXO22 and KLHDC2.
While PROTACs generally are heterobifunctional compounds linking an E3 ligase binder to a target protein binder, molecular glues also exist that induce protein-protein interactions with E3 ligases, leading to degradation of various substrate proteins. Molecular glues often have been discovered through serendipity, though various methodologies have been explored to expedite the discovery of molecular glues.
Biologic modalities for targeted protein degradation have also been explored by fusing E3 ligases to target recognition domains such as nanobodies. These modalities are sometimes referred to as bioPROTACs. While bioPROTACs are advantageous for targeting proteins lacking small molecule ligands, challenges in delivery, pharmacokinetics, and immunogenicity have so far precluded clinical development. Studies exploring different delivery mechanisms have sought to address these shortcomings. In another variant of this idea, bispecific antibodies to recruit membrane-bound E3 ligases to cell surface proteins (AbTACs) have also been developed.
== Individual E3 ubiquitin ligases ==
== See also ==
ERAD
Ubiquitin
Ubiquitin-activating enzyme
Ubiquitin-conjugating enzyme
== References ==
== External links ==
Quips article describing E3 Ligase function Archived 2012-11-30 at the Wayback Machine at PDBe
Ubiquitin-Protein+Ligases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
EC 6.3.2.19 | Wikipedia/Ubiquitin--protein_ligase |
DNA synthesis is the natural or artificial creation of deoxyribonucleic acid (DNA) molecules. DNA is a macromolecule made up of nucleotide units, which are linked by covalent bonds and hydrogen bonds, in a repeating structure. DNA synthesis occurs when these nucleotide units are joined to form DNA; this can occur artificially (in vitro) or naturally (in vivo). Nucleotide units are made up of a nitrogenous base (cytosine, guanine, adenine or thymine), pentose sugar (deoxyribose) and phosphate group. Each unit is joined when a covalent bond forms between its phosphate group and the pentose sugar of the next nucleotide, forming a sugar-phosphate backbone. DNA is a complementary, double stranded structure as specific base pairing (adenine and thymine, guanine and cytosine) occurs naturally when hydrogen bonds form between the nucleotide bases.
There are several different definitions for DNA synthesis: it can refer to DNA replication - DNA biosynthesis (in vivo DNA amplification), polymerase chain reaction - enzymatic DNA synthesis (in vitro DNA amplification) or gene synthesis - physically creating artificial gene sequences. Though each type of synthesis is very different, they do share some features.
Nucleotides that have been joined to form polynucleotides can act as a DNA template for one form of DNA synthesis - PCR - to occur. DNA replication also works by using a DNA template, the DNA double helix unwinds during replication, exposing unpaired bases for new nucleotides to hydrogen bond to. Gene synthesis, however, does not require a DNA template and genes are assembled de novo.
DNA synthesis occurs in all eukaryotes and prokaryotes, as well as some viruses. The accurate synthesis of DNA is important in order to avoid mutations to DNA. In humans, mutations could lead to diseases such as cancer so DNA synthesis, and the machinery involved in vivo, has been studied extensively throughout the decades. In the future these studies may be used to develop technologies involving DNA synthesis, to be used in data storage.
== DNA replication ==
In nature, DNA molecules are synthesised by all living cells through the process of DNA replication. This typically occurs as a part of cell division. DNA replication occurs so, during cell division, each daughter cell contains an accurate copy of the genetic material of the cell. In vivo DNA synthesis (DNA replication) is dependent on a complex set of enzymes which have evolved to act during the S phase of the cell cycle, in a concerted fashion. In both eukaryotes and prokaryotes, DNA replication occurs when specific topoisomerases, helicases and gyrases (replication initiator proteins) uncoil the double-stranded DNA, exposing the nitrogenous bases. These enzymes, along with accessory proteins, form a macromolecular machine which ensures accurate duplication of DNA sequences. Complementary base pairing takes place, forming a new double-stranded DNA molecule. This is known as semi-conservative replication since one strand of the new DNA molecule is from the 'parent' strand.
Continuously, eukaryotic enzymes encounter DNA damage which can perturb DNA replication. This damage is in the form of DNA lesions that arise spontaneously or due to DNA damaging agents. DNA replication machinery is therefore highly controlled in order to prevent collapse when encountering damage. Control of the DNA replication system ensures that the genome is replicated only once per cycle; over-replication induces DNA damage. Deregulation of DNA replication is a key factor in genomic instability during cancer development.
This highlights the specificity of DNA synthesis machinery in vivo. Various means exist to artificially stimulate the replication of naturally occurring DNA, or to create artificial gene sequences. However, DNA synthesis in vitro can be a very error-prone process.
=== DNA repair synthesis ===
Damaged DNA is subject to repair by several different enzymatic repair processes, where each individual process is specialized to repair particular types of damage. The DNA of humans is subject to damage from multiple natural sources and insufficient repair is associated with disease and premature aging. Most DNA repair processes form single-strand gaps in DNA during an intermediate stage of the repair, and these gaps are filled in by repair synthesis. The specific repair processes that require gap filling by DNA synthesis include nucleotide excision repair, base excision repair, mismatch repair, homologous recombinational repair, non-homologous end joining and microhomology-mediated end joining.
== Reverse Transcription ==
Reverse transcription is part of the replication cycle of particular virus families, including retroviruses. It involves copying RNA into double-stranded complementary DNA (cDNA), using reverse transcriptase enzymes. In retroviruses, viral RNA is inserted into a host cell nucleus. There, a viral reverse transcriptase enzyme adds DNA nucleotides onto the RNA sequence, generating cDNA that is inserted into the host cell genome by the enzyme integrase, encoding viral proteins.
== Polymerase chain reaction ==
A polymerase chain reaction is a form of enzymatic DNA synthesis in the laboratory, using cycles of repeated heating and cooling of the reaction for DNA melting and enzymatic replication of the DNA.
DNA synthesis during PCR is very similar to living cells but has very specific reagents and conditions. During PCR, DNA is chemically extracted from host chaperone proteins then heated, causing thermal dissociation of the DNA strands. Two new cDNA strands are built from the original strand, these strands can be split again to act as the template for further PCR products. The original DNA is multiplied through many rounds of PCR. More than a billion copies of the original DNA strand can be made.
=== Random mutagenesis ===
For many experiments, such as structural and evolutionary studies, scientists need to produce a large library of variants of a particular DNA sequence. Random mutagenesis takes place in vitro, when mutagenic replication with a low fidelity DNA polymerase is combined with selective PCR amplification to produce many copies of mutant DNA.
=== RT-PCR ===
RT-PCR differs from conventional PCR as it synthesizes cDNA from mRNA, rather than template DNA. The technique couples a reverse transcription reaction with PCR-based amplification, as an RNA sequence acts as a template for the enzyme, reverse transcriptase. RT-PCR is often used to test gene expression in particular tissue or cell types at various developmental stages or to test for genetic disorders.
== Gene synthesis ==
Artificial gene synthesis is the process of synthesizing a gene in vitro without the need for initial template DNA samples.
In 2010 J. Craig Venter and his team were the first to use entirely synthesized DNA to create a self-replicating microbe, dubbed Mycoplasma laboratorium.
=== Oligonucleotide synthesis ===
Oligonucleotide synthesis is the chemical synthesis of sequences of nucleic acids. The majority of biological research and bioengineering involves synthetic DNA, which can include oligonucleotides, synthetic genes, or even chromosomes. Today, most synthetic DNA is custom-built using the phosphoramidite method by Marvin H. Caruthers. Oligos are synthesized from building blocks which replicate natural bases. Other techniques for synthesising DNA have been commercially made available, including Short Oligo Ligation Assembly. The process has been automated since the late 1970s and can be used to form desired genetic sequences as well as for other uses in medicine and molecular biology. However, creating sequences chemically is impractical beyond 200-300 bases, and is an environmentally hazardous process. These oligos, of around 200 bases, can be connected using DNA assembly methods, creating larger DNA molecules.
Some studies have explored the possibility of enzymatic synthesis using terminal deoxynucleotidyl transferase (TdT), a DNA polymerase that requires no template. However, this method is not yet as effective as chemical synthesis, and is not commercially available.
With advances in artificial DNA synthesis, the possibility of DNA data storage is being explored. With its ultrahigh storage density and long-term stability, synthetic DNA is an interesting option to store large amounts of data. Although information can be retrieved very quickly from DNA through next generation sequencing technologies, de novo synthesis of DNA is a major bottleneck in the process. Only one nucleotide can be added per cycle, with each cycle taking seconds, so the overall synthesis is very time-consuming, as well as very error prone. However, if biotechnology improves, synthetic DNA could one day be used in data storage.
=== Base pair synthesis ===
It has been reported that new nucleobase pairs can be synthesized, as well as A-T (adenine - thymine) and G-C (guanine - cytosine). Synthetic nucleotides can be used to expand the genetic alphabet and allow specific modification of DNA sites. Even just a third base pair would expand the number of amino acids that can be encoded by DNA from the existing 20 amino acids to a possible 172.
Hachimoji DNA is built from eight nucleotide letters, forming four possible base pairs. It therefore doubles the information density of natural DNA. In studies, RNA has even been produced from hachimoji DNA. This technology could also be used to allow data storage in DNA.
== References == | Wikipedia/DNA_synthesis |
In physics, mathematics, engineering, and related fields, a wave is a propagating dynamic disturbance (change from equilibrium) of one or more quantities. Periodic waves oscillate repeatedly about an equilibrium (resting) value at some frequency. When the entire waveform moves in one direction, it is said to be a travelling wave; by contrast, a pair of superimposed periodic waves traveling in opposite directions makes a standing wave. In a standing wave, the amplitude of vibration has nulls at some positions where the wave amplitude appears smaller or even zero.
There are two types of waves that are most commonly studied in classical physics: mechanical waves and electromagnetic waves. In a mechanical wave, stress and strain fields oscillate about a mechanical equilibrium. A mechanical wave is a local deformation (strain) in some physical medium that propagates from particle to particle by creating local stresses that cause strain in neighboring particles too. For example, sound waves are variations of the local pressure and particle motion that propagate through the medium. Other examples of mechanical waves are seismic waves, gravity waves, surface waves and string vibrations. In an electromagnetic wave (such as light), coupling between the electric and magnetic fields sustains propagation of waves involving these fields according to Maxwell's equations. Electromagnetic waves can travel through a vacuum and through some dielectric media (at wavelengths where they are considered transparent). Electromagnetic waves, as determined by their frequencies (or wavelengths), have more specific designations including radio waves, infrared radiation, terahertz waves, visible light, ultraviolet radiation, X-rays and gamma rays.
Other types of waves include gravitational waves, which are disturbances in spacetime that propagate according to general relativity; heat diffusion waves; plasma waves that combine mechanical deformations and electromagnetic fields; reaction–diffusion waves, such as in the Belousov–Zhabotinsky reaction; and many more. Mechanical and electromagnetic waves transfer energy, momentum, and information, but they do not transfer particles in the medium. In mathematics and electronics waves are studied as signals. On the other hand, some waves have envelopes which do not move at all such as standing waves (which are fundamental to music) and hydraulic jumps.
A physical wave field is almost always confined to some finite region of space, called its domain. For example, the seismic waves generated by earthquakes are significant only in the interior and surface of the planet, so they can be ignored outside it. However, waves with infinite domain, that extend over the whole space, are commonly studied in mathematics, and are very valuable tools for understanding physical waves in finite domains.
A plane wave is an important mathematical idealization where the disturbance is identical along any (infinite) plane normal to a specific direction of travel. Mathematically, the simplest wave is a sinusoidal plane wave in which at any point the field experiences simple harmonic motion at one frequency. In linear media, complicated waves can generally be decomposed as the sum of many sinusoidal plane waves having different directions of propagation and/or different frequencies. A plane wave is classified as a transverse wave if the field disturbance at each point is described by a vector perpendicular to the direction of propagation (also the direction of energy transfer); or longitudinal wave if those vectors are aligned with the propagation direction. Mechanical waves include both transverse and longitudinal waves; on the other hand electromagnetic plane waves are strictly transverse while sound waves in fluids (such as air) can only be longitudinal. That physical direction of an oscillating field relative to the propagation direction is also referred to as the wave's polarization, which can be an important attribute.
== Mathematical description ==
=== Single waves ===
A wave can be described just like a field, namely as a function
F
(
x
,
t
)
{\displaystyle F(x,t)}
where
x
{\displaystyle x}
is a position and
t
{\displaystyle t}
is a time.
The value of
x
{\displaystyle x}
is a point of space, specifically in the region where the wave is defined. In mathematical terms, it is usually a vector in the Cartesian three-dimensional space
R
3
{\displaystyle \mathbb {R} ^{3}}
. However, in many cases one can ignore one dimension, and let
x
{\displaystyle x}
be a point of the Cartesian plane
R
2
{\displaystyle \mathbb {R} ^{2}}
. This is the case, for example, when studying vibrations of a drum skin. One may even restrict
x
{\displaystyle x}
to a point of the Cartesian line
R
{\displaystyle \mathbb {R} }
– that is, the set of real numbers. This is the case, for example, when studying vibrations in a violin string or recorder. The time
t
{\displaystyle t}
, on the other hand, is always assumed to be a scalar; that is, a real number.
The value of
F
(
x
,
t
)
{\displaystyle F(x,t)}
can be any physical quantity of interest assigned to the point
x
{\displaystyle x}
that may vary with time. For example, if
F
{\displaystyle F}
represents the vibrations inside an elastic solid, the value of
F
(
x
,
t
)
{\displaystyle F(x,t)}
is usually a vector that gives the current displacement from
x
{\displaystyle x}
of the material particles that would be at the point
x
{\displaystyle x}
in the absence of vibration. For an electromagnetic wave, the value of
F
{\displaystyle F}
can be the electric field vector
E
{\displaystyle E}
, or the magnetic field vector
H
{\displaystyle H}
, or any related quantity, such as the Poynting vector
E
×
H
{\displaystyle E\times H}
. In fluid dynamics, the value of
F
(
x
,
t
)
{\displaystyle F(x,t)}
could be the velocity vector of the fluid at the point
x
{\displaystyle x}
, or any scalar property like pressure, temperature, or density. In a chemical reaction,
F
(
x
,
t
)
{\displaystyle F(x,t)}
could be the concentration of some substance in the neighborhood of point
x
{\displaystyle x}
of the reaction medium.
For any dimension
d
{\displaystyle d}
(1, 2, or 3), the wave's domain is then a subset
D
{\displaystyle D}
of
R
d
{\displaystyle \mathbb {R} ^{d}}
, such that the function value
F
(
x
,
t
)
{\displaystyle F(x,t)}
is defined for any point
x
{\displaystyle x}
in
D
{\displaystyle D}
. For example, when describing the motion of a drum skin, one can consider
D
{\displaystyle D}
to be a disk (circle) on the plane
R
2
{\displaystyle \mathbb {R} ^{2}}
with center at the origin
(
0
,
0
)
{\displaystyle (0,0)}
, and let
F
(
x
,
t
)
{\displaystyle F(x,t)}
be the vertical displacement of the skin at the point
x
{\displaystyle x}
of
D
{\displaystyle D}
and at time
t
{\displaystyle t}
.
=== Superposition ===
Waves of the same type are often superposed and encountered simultaneously at a given point in space and time. The properties at that point are the sum of the properties of each component wave at that point. In general, the velocities are not the same, so the wave form will change over time and space.
=== Wave spectrum ===
=== Wave families ===
Sometimes one is interested in a single specific wave. More often, however, one needs to understand large set of possible waves; like all the ways that a drum skin can vibrate after being struck once with a drum stick, or all the possible radar echoes one could get from an airplane that may be approaching an airport.
In some of those situations, one may describe such a family of waves by a function
F
(
A
,
B
,
…
;
x
,
t
)
{\displaystyle F(A,B,\ldots ;x,t)}
that depends on certain parameters
A
,
B
,
…
{\displaystyle A,B,\ldots }
, besides
x
{\displaystyle x}
and
t
{\displaystyle t}
. Then one can obtain different waves – that is, different functions of
x
{\displaystyle x}
and
t
{\displaystyle t}
– by choosing different values for those parameters.
For example, the sound pressure inside a recorder that is playing a "pure" note is typically a standing wave, that can be written as
F
(
A
,
L
,
n
,
c
;
x
,
t
)
=
A
(
cos
2
π
x
2
n
−
1
4
L
)
(
cos
2
π
c
t
2
n
−
1
4
L
)
{\displaystyle F(A,L,n,c;x,t)=A\left(\cos 2\pi x{\frac {2n-1}{4L}}\right)\left(\cos 2\pi ct{\frac {2n-1}{4L}}\right)}
The parameter
A
{\displaystyle A}
defines the amplitude of the wave (that is, the maximum sound pressure in the bore, which is related to the loudness of the note);
c
{\displaystyle c}
is the speed of sound;
L
{\displaystyle L}
is the length of the bore; and
n
{\displaystyle n}
is a positive integer (1,2,3,...) that specifies the number of nodes in the standing wave. (The position
x
{\displaystyle x}
should be measured from the mouthpiece, and the time
t
{\displaystyle t}
from any moment at which the pressure at the mouthpiece is maximum. The quantity
λ
=
4
L
/
(
2
n
−
1
)
{\displaystyle \lambda =4L/(2n-1)}
is the wavelength of the emitted note, and
f
=
c
/
λ
{\displaystyle f=c/\lambda }
is its frequency.) Many general properties of these waves can be inferred from this general equation, without choosing specific values for the parameters.
As another example, it may be that the vibrations of a drum skin after a single strike depend only on the distance
r
{\displaystyle r}
from the center of the skin to the strike point, and on the strength
s
{\displaystyle s}
of the strike. Then the vibration for all possible strikes can be described by a function
F
(
r
,
s
;
x
,
t
)
{\displaystyle F(r,s;x,t)}
.
Sometimes the family of waves of interest has infinitely many parameters. For example, one may want to describe what happens to the temperature in a metal bar when it is initially heated at various temperatures at different points along its length, and then allowed to cool by itself in vacuum. In that case, instead of a scalar or vector, the parameter would have to be a function
h
{\displaystyle h}
such that
h
(
x
)
{\displaystyle h(x)}
is the initial temperature at each point
x
{\displaystyle x}
of the bar. Then the temperatures at later times can be expressed by a function
F
{\displaystyle F}
that depends on the function
h
{\displaystyle h}
(that is, a functional operator), so that the temperature at a later time is
F
(
h
;
x
,
t
)
{\displaystyle F(h;x,t)}
=== Differential wave equations ===
Another way to describe and study a family of waves is to give a mathematical equation that, instead of explicitly giving the value of
F
(
x
,
t
)
{\displaystyle F(x,t)}
, only constrains how those values can change with time. Then the family of waves in question consists of all functions
F
{\displaystyle F}
that satisfy those constraints – that is, all solutions of the equation.
This approach is extremely important in physics, because the constraints usually are a consequence of the physical processes that cause the wave to evolve. For example, if
F
(
x
,
t
)
{\displaystyle F(x,t)}
is the temperature inside a block of some homogeneous and isotropic solid material, its evolution is constrained by the partial differential equation
∂
F
∂
t
(
x
,
t
)
=
α
(
∂
2
F
∂
x
1
2
(
x
,
t
)
+
∂
2
F
∂
x
2
2
(
x
,
t
)
+
∂
2
F
∂
x
3
2
(
x
,
t
)
)
+
β
Q
(
x
,
t
)
{\displaystyle {\frac {\partial F}{\partial t}}(x,t)=\alpha \left({\frac {\partial ^{2}F}{\partial x_{1}^{2}}}(x,t)+{\frac {\partial ^{2}F}{\partial x_{2}^{2}}}(x,t)+{\frac {\partial ^{2}F}{\partial x_{3}^{2}}}(x,t)\right)+\beta Q(x,t)}
where
Q
(
p
,
f
)
{\displaystyle Q(p,f)}
is the heat that is being generated per unit of volume and time in the neighborhood of
x
{\displaystyle x}
at time
t
{\displaystyle t}
(for example, by chemical reactions happening there);
x
1
,
x
2
,
x
3
{\displaystyle x_{1},x_{2},x_{3}}
are the Cartesian coordinates of the point
x
{\displaystyle x}
;
∂
F
/
∂
t
{\displaystyle \partial F/\partial t}
is the (first) derivative of
F
{\displaystyle F}
with respect to
t
{\displaystyle t}
; and
∂
2
F
/
∂
x
i
2
{\displaystyle \partial ^{2}F/\partial x_{i}^{2}}
is the second derivative of
F
{\displaystyle F}
relative to
x
i
{\displaystyle x_{i}}
. (The symbol "
∂
{\displaystyle \partial }
" is meant to signify that, in the derivative with respect to some variable, all other variables must be considered fixed.)
This equation can be derived from the laws of physics that govern the diffusion of heat in solid media. For that reason, it is called the heat equation in mathematics, even though it applies to many other physical quantities besides temperatures.
For another example, we can describe all possible sounds echoing within a container of gas by a function
F
(
x
,
t
)
{\displaystyle F(x,t)}
that gives the pressure at a point
x
{\displaystyle x}
and time
t
{\displaystyle t}
within that container. If the gas was initially at uniform temperature and composition, the evolution of
F
{\displaystyle F}
is constrained by the formula
∂
2
F
∂
t
2
(
x
,
t
)
=
α
(
∂
2
F
∂
x
1
2
(
x
,
t
)
+
∂
2
F
∂
x
2
2
(
x
,
t
)
+
∂
2
F
∂
x
3
2
(
x
,
t
)
)
+
β
P
(
x
,
t
)
{\displaystyle {\frac {\partial ^{2}F}{\partial t^{2}}}(x,t)=\alpha \left({\frac {\partial ^{2}F}{\partial x_{1}^{2}}}(x,t)+{\frac {\partial ^{2}F}{\partial x_{2}^{2}}}(x,t)+{\frac {\partial ^{2}F}{\partial x_{3}^{2}}}(x,t)\right)+\beta P(x,t)}
Here
P
(
x
,
t
)
{\displaystyle P(x,t)}
is some extra compression force that is being applied to the gas near
x
{\displaystyle x}
by some external process, such as a loudspeaker or piston right next to
p
{\displaystyle p}
.
This same differential equation describes the behavior of mechanical vibrations and electromagnetic fields in a homogeneous isotropic non-conducting solid. Note that this equation differs from that of heat flow only in that the left-hand side is
∂
2
F
/
∂
t
2
{\displaystyle \partial ^{2}F/\partial t^{2}}
, the second derivative of
F
{\displaystyle F}
with respect to time, rather than the first derivative
∂
F
/
∂
t
{\displaystyle \partial F/\partial t}
. Yet this small change makes a huge difference on the set of solutions
F
{\displaystyle F}
. This differential equation is called "the" wave equation in mathematics, even though it describes only one very special kind of waves.
== Wave in elastic medium ==
Consider a traveling transverse wave (which may be a pulse) on a string (the medium). Consider the string to have a single spatial dimension. Consider this wave as traveling
in the
x
{\displaystyle x}
direction in space. For example, let the positive
x
{\displaystyle x}
direction be to the right, and the negative
x
{\displaystyle x}
direction be to the left.
with constant amplitude
u
{\displaystyle u}
with constant velocity
v
{\displaystyle v}
, where
v
{\displaystyle v}
is
independent of wavelength (no dispersion)
independent of amplitude (linear media, not nonlinear).
with constant waveform, or shape
This wave can then be described by the two-dimensional functions
or, more generally, by d'Alembert's formula:
u
(
x
,
t
)
=
F
(
x
−
v
t
)
+
G
(
x
+
v
t
)
.
{\displaystyle u(x,t)=F(x-vt)+G(x+vt).}
representing two component waveforms
F
{\displaystyle F}
and
G
{\displaystyle G}
traveling through the medium in opposite directions. A generalized representation of this wave can be obtained as the partial differential equation
1
v
2
∂
2
u
∂
t
2
=
∂
2
u
∂
x
2
.
{\displaystyle {\frac {1}{v^{2}}}{\frac {\partial ^{2}u}{\partial t^{2}}}={\frac {\partial ^{2}u}{\partial x^{2}}}.}
General solutions are based upon Duhamel's principle.
=== Wave forms ===
The form or shape of F in d'Alembert's formula involves the argument x − vt. Constant values of this argument correspond to constant values of F, and these constant values occur if x increases at the same rate that vt increases. That is, the wave shaped like the function F will move in the positive x-direction at velocity v (and G will propagate at the same speed in the negative x-direction).
In the case of a periodic function F with period λ, that is, F(x + λ − vt) = F(x − vt), the periodicity of F in space means that a snapshot of the wave at a given time t finds the wave varying periodically in space with period λ (the wavelength of the wave). In a similar fashion, this periodicity of F implies a periodicity in time as well: F(x − v(t + T)) = F(x − vt) provided vT = λ, so an observation of the wave at a fixed location x finds the wave undulating periodically in time with period T = λ/v.
=== Amplitude and modulation ===
The amplitude of a wave may be constant (in which case the wave is a c.w. or continuous wave), or may be modulated so as to vary with time and/or position. The outline of the variation in amplitude is called the envelope of the wave. Mathematically, the modulated wave can be written in the form:
u
(
x
,
t
)
=
A
(
x
,
t
)
sin
(
k
x
−
ω
t
+
ϕ
)
,
{\displaystyle u(x,t)=A(x,t)\sin \left(kx-\omega t+\phi \right),}
where
A
(
x
,
t
)
{\displaystyle A(x,\ t)}
is the amplitude envelope of the wave,
k
{\displaystyle k}
is the wavenumber and
ϕ
{\displaystyle \phi }
is the phase. If the group velocity
v
g
{\displaystyle v_{g}}
(see below) is wavelength-independent, this equation can be simplified as:
u
(
x
,
t
)
=
A
(
x
−
v
g
t
)
sin
(
k
x
−
ω
t
+
ϕ
)
,
{\displaystyle u(x,t)=A(x-v_{g}t)\sin \left(kx-\omega t+\phi \right),}
showing that the envelope moves with the group velocity and retains its shape. Otherwise, in cases where the group velocity varies with wavelength, the pulse shape changes in a manner often described using an envelope equation.
=== Phase velocity and group velocity ===
There are two velocities that are associated with waves, the phase velocity and the group velocity.
Phase velocity is the rate at which the phase of the wave propagates in space: any given phase of the wave (for example, the crest) will appear to travel at the phase velocity. The phase velocity is given in terms of the wavelength λ (lambda) and period T as
v
p
=
λ
T
.
{\displaystyle v_{\mathrm {p} }={\frac {\lambda }{T}}.}
Group velocity is a property of waves that have a defined envelope, measuring propagation through space (that is, phase velocity) of the overall shape of the waves' amplitudes—modulation or envelope of the wave.
== Special waves ==
=== Sine waves ===
=== Plane waves ===
A plane wave is a kind of wave whose value varies only in one spatial direction. That is, its value is constant on a plane that is perpendicular to that direction. Plane waves can be specified by a vector of unit length
n
^
{\displaystyle {\hat {n}}}
indicating the direction that the wave varies in, and a wave profile describing how the wave varies as a function of the displacement along that direction (
n
^
⋅
x
→
{\displaystyle {\hat {n}}\cdot {\vec {x}}}
) and time (
t
{\displaystyle t}
). Since the wave profile only depends on the position
x
→
{\displaystyle {\vec {x}}}
in the combination
n
^
⋅
x
→
{\displaystyle {\hat {n}}\cdot {\vec {x}}}
, any displacement in directions perpendicular to
n
^
{\displaystyle {\hat {n}}}
cannot affect the value of the field.
Plane waves are often used to model electromagnetic waves far from a source. For electromagnetic plane waves, the electric and magnetic fields themselves are transverse to the direction of propagation, and also perpendicular to each other.
=== Standing waves ===
A standing wave, also known as a stationary wave, is a wave whose envelope remains in a constant position. This phenomenon arises as a result of interference between two waves traveling in opposite directions.
The sum of two counter-propagating waves (of equal amplitude and frequency) creates a standing wave. Standing waves commonly arise when a boundary blocks further propagation of the wave, thus causing wave reflection, and therefore introducing a counter-propagating wave. For example, when a violin string is displaced, transverse waves propagate out to where the string is held in place at the bridge and the nut, where the waves are reflected back. At the bridge and nut, the two opposed waves are in antiphase and cancel each other, producing a node. Halfway between two nodes there is an antinode, where the two counter-propagating waves enhance each other maximally. There is no net propagation of energy over time.
=== Solitary waves ===
A soliton or solitary wave is a self-reinforcing wave packet that maintains its shape while it propagates at a constant velocity. Solitons are caused by a cancellation of nonlinear and dispersive effects in the medium. (Dispersive effects are a property of certain systems where the speed of a wave depends on its frequency.) Solitons are the solutions of a widespread class of weakly nonlinear dispersive partial differential equations describing physical systems.
== Physical properties ==
=== Propagation ===
Wave propagation is any of the ways in which waves travel. With respect to the direction of the oscillation relative to the propagation direction, we can distinguish between longitudinal wave and transverse waves.
Electromagnetic waves propagate in vacuum as well as in material media. Propagation of other wave types such as sound may occur only in a transmission medium.
==== Reflection of plane waves in a half-space ====
The propagation and reflection of plane waves—e.g. Pressure waves (P wave) or Shear waves (SH or SV-waves) are phenomena that were first characterized within the field of classical seismology, and are now considered fundamental concepts in modern seismic tomography. The analytical solution to this problem exists and is well known. The frequency domain solution can be obtained by first finding the Helmholtz decomposition of the displacement field, which is then substituted into the wave equation. From here, the plane wave eigenmodes can be calculated.
==== SV wave propagation ====
The analytical solution of SV-wave in a half-space indicates that the plane SV wave reflects back to the domain as a P and SV waves, leaving out special cases. The angle of the reflected SV wave is identical to the incidence wave, while the angle of the reflected P wave is greater than the SV wave. For the same wave frequency, the SV wavelength is smaller than the P wavelength. This fact has been depicted in this animated picture.
==== P wave propagation ====
Similar to the SV wave, the P incidence, in general, reflects as the P and SV wave. There are some special cases where the regime is different.
=== Wave velocity ===
Wave velocity is a general concept, of various kinds of wave velocities, for a wave's phase and speed concerning energy (and information) propagation. The phase velocity is given as:
v
p
=
ω
k
,
{\displaystyle v_{\rm {p}}={\frac {\omega }{k}},}
where:
vp is the phase velocity (with SI unit m/s),
ω is the angular frequency (with SI unit rad/s),
k is the wavenumber (with SI unit rad/m).
The phase speed gives you the speed at which a point of constant phase of the wave will travel for a discrete frequency. The angular frequency ω cannot be chosen independently from the wavenumber k, but both are related through the dispersion relationship:
ω
=
Ω
(
k
)
.
{\displaystyle \omega =\Omega (k).}
In the special case Ω(k) = ck, with c a constant, the waves are called non-dispersive, since all frequencies travel at the same phase speed c. For instance electromagnetic waves in vacuum are non-dispersive. In case of other forms of the dispersion relation, we have dispersive waves. The dispersion relationship depends on the medium through which the waves propagate and on the type of waves (for instance electromagnetic, sound or water waves).
The speed at which a resultant wave packet from a narrow range of frequencies will travel is called the group velocity and is determined from the gradient of the dispersion relation:
v
g
=
∂
ω
∂
k
{\displaystyle v_{\rm {g}}={\frac {\partial \omega }{\partial k}}}
In almost all cases, a wave is mainly a movement of energy through a medium. Most often, the group velocity is the velocity at which the energy moves through this medium.
Waves exhibit common behaviors under a number of standard situations, for example:
=== Transmission and media ===
Waves normally move in a straight line (that is, rectilinearly) through a transmission medium. Such media can be classified into one or more of the following categories:
A bounded medium if it is finite in extent, otherwise an unbounded medium
A linear medium if the amplitudes of different waves at any particular point in the medium can be added
A uniform medium or homogeneous medium if its physical properties are unchanged at different locations in space
An anisotropic medium if one or more of its physical properties differ in one or more directions
An isotropic medium if its physical properties are the same in all directions
=== Absorption ===
Waves are usually defined in media which allow most or all of a wave's energy to propagate without loss. However materials may be characterized as "lossy" if they remove energy from a wave, usually converting it into heat. This is termed "absorption." A material which absorbs a wave's energy, either in transmission or reflection, is characterized by a refractive index which is complex. The amount of absorption will generally depend on the frequency (wavelength) of the wave, which, for instance, explains why objects may appear colored.
=== Reflection ===
When a wave strikes a reflective surface, it changes direction, such that the angle made by the incident wave and line normal to the surface equals the angle made by the reflected wave and the same normal line.
=== Refraction ===
Refraction is the phenomenon of a wave changing its speed. Mathematically, this means that the size of the phase velocity changes. Typically, refraction occurs when a wave passes from one medium into another. The amount by which a wave is refracted by a material is given by the refractive index of the material. The directions of incidence and refraction are related to the refractive indices of the two materials by Snell's law.
=== Diffraction ===
A wave exhibits diffraction when it encounters an obstacle that bends the wave or when it spreads after emerging from an opening. Diffraction effects are more pronounced when the size of the obstacle or opening is comparable to the wavelength of the wave.
=== Interference ===
When waves in a linear medium (the usual case) cross each other in a region of space, they do not actually interact with each other, but continue on as if the other one were not present. However at any point in that region the field quantities describing those waves add according to the superposition principle. If the waves are of the same frequency in a fixed phase relationship, then there will generally be positions at which the two waves are in phase and their amplitudes add, and other positions where they are out of phase and their amplitudes (partially or fully) cancel. This is called an interference pattern.
=== Polarization ===
The phenomenon of polarization arises when wave motion can occur simultaneously in two orthogonal directions. Transverse waves can be polarized, for instance. When polarization is used as a descriptor without qualification, it usually refers to the special, simple case of linear polarization. A transverse wave is linearly polarized if it oscillates in only one direction or plane. In the case of linear polarization, it is often useful to add the relative orientation of that plane, perpendicular to the direction of travel, in which the oscillation occurs, such as "horizontal" for instance, if the plane of polarization is parallel to the ground. Electromagnetic waves propagating in free space, for instance, are transverse; they can be polarized by the use of a polarizing filter.
Longitudinal waves, such as sound waves, do not exhibit polarization. For these waves there is only one direction of oscillation, that is, along the direction of travel.
=== Dispersion ===
Dispersion is the frequency dependence of the refractive index, a consequence of the atomic nature of materials.: 67
A wave undergoes dispersion when either the phase velocity or the group velocity depends on the wave frequency. Dispersion is seen by letting white light pass through a prism, the result of which is to produce the spectrum of colors of the rainbow. Isaac Newton was the first to recognize that this meant that white light was a mixture of light of different colors.: 190
=== Doppler effect ===
The Doppler effect or Doppler shift is the change in frequency of a wave in relation to an observer who is moving relative to the wave source. It is named after the Austrian physicist Christian Doppler, who described the phenomenon in 1842.
== Mechanical waves ==
A mechanical wave is an oscillation of matter, and therefore transfers energy through a medium. While waves can move over long distances, the movement of the medium of transmission—the material—is limited. Therefore, the oscillating material does not move far from its initial position. Mechanical waves can be produced only in media which possess elasticity and inertia. There are three types of mechanical waves: transverse waves, longitudinal waves, and surface waves.
=== Waves on strings ===
The transverse vibration of a string is a function of tension and inertia, and is constrained by the length of the string as the ends are fixed. This constraint limits the steady state modes that are possible, and thereby the frequencies.
The speed of a transverse wave traveling along a vibrating string (v) is directly proportional to the square root of the tension of the string (T) over the linear mass density (μ):
v
=
T
μ
,
{\displaystyle v={\sqrt {\frac {T}{\mu }}},}
where the linear density μ is the mass per unit length of the string.
=== Acoustic waves ===
Acoustic or sound waves are compression waves which travel as body waves at the speed given by:
v
=
B
ρ
0
,
{\displaystyle v={\sqrt {\frac {B}{\rho _{0}}}},}
or the square root of the adiabatic bulk modulus divided by the ambient density of the medium (see speed of sound).
=== Water waves ===
Ripples on the surface of a pond are actually a combination of transverse and longitudinal waves; therefore, the points on the surface follow orbital paths.
Sound, a mechanical wave that propagates through gases, liquids, solids and plasmas.
Inertial waves, which occur in rotating fluids and are restored by the Coriolis effect.
Ocean surface waves, which are perturbations that propagate through water.
=== Body waves ===
Body waves travel through the interior of the medium along paths controlled by the material properties in terms of density and modulus (stiffness). The density and modulus, in turn, vary according to temperature, composition, and material phase. This effect resembles the refraction of light waves. Two types of particle motion result in two types of body waves: Primary and Secondary waves.
=== Seismic waves ===
Seismic waves are waves of energy that travel through the Earth's layers, and are a result of earthquakes, volcanic eruptions, magma movement, large landslides and large man-made explosions that give out low-frequency acoustic energy. They include body waves—the primary (P waves) and secondary waves (S waves)—and surface waves, such as Rayleigh waves, Love waves, and Stoneley waves.
=== Shock waves ===
A shock wave is a type of propagating disturbance. When a wave moves faster than the local speed of sound in a fluid, it is a shock wave. Like an ordinary wave, a shock wave carries energy and can propagate through a medium; however, it is characterized by an abrupt, nearly discontinuous change in pressure, temperature and density of the medium.
=== Shear waves ===
Shear waves are body waves due to shear rigidity and inertia. They can only be transmitted through solids and to a lesser extent through liquids with a sufficiently high viscosity.
=== Other ===
Waves of traffic, that is, propagation of different densities of motor vehicles, and so forth, which can be modeled as kinematic waves
Metachronal wave refers to the appearance of a traveling wave produced by coordinated sequential actions.
== Electromagnetic waves ==
An electromagnetic wave consists of two waves that are oscillations of the electric and magnetic fields. An electromagnetic wave travels in a direction that is at right angles to the oscillation direction of both fields. In the 19th century, James Clerk Maxwell showed that, in vacuum, the electric and magnetic fields satisfy the wave equation both with speed equal to that of the speed of light. From this emerged the idea that light is an electromagnetic wave. The unification of light and electromagnetic waves was experimentally confirmed by Hertz in the end of the 1880s. Electromagnetic waves can have different frequencies (and thus wavelengths), and are classified accordingly in wavebands, such as radio waves, microwaves, infrared, visible light, ultraviolet, X-rays, and gamma rays. The range of frequencies in each of these bands is continuous, and the limits of each band are mostly arbitrary, with the exception of visible light, which must be visible to the normal human eye.
== Quantum mechanical waves ==
=== Schrödinger equation ===
The Schrödinger equation describes the wave-like behavior of particles in quantum mechanics. Solutions of this equation are wave functions which can be used to describe the probability density of a particle.
=== Dirac equation ===
The Dirac equation is a relativistic wave equation detailing electromagnetic interactions. Dirac waves accounted for the fine details of the hydrogen spectrum in a completely rigorous way. The wave equation also implied the existence of a new form of matter, antimatter, previously unsuspected and unobserved and which was experimentally confirmed. In the context of quantum field theory, the Dirac equation is reinterpreted to describe quantum fields corresponding to spin-1⁄2 particles.
=== de Broglie waves ===
Louis de Broglie postulated that all particles with momentum have a wavelength
λ
=
h
p
,
{\displaystyle \lambda ={\frac {h}{p}},}
where h is the Planck constant, and p is the magnitude of the momentum of the particle. This hypothesis was at the basis of quantum mechanics. Nowadays, this wavelength is called the de Broglie wavelength. For example, the electrons in a CRT display have a de Broglie wavelength of about 10−13 m.
A wave representing such a particle traveling in the k-direction is expressed by the wave function as follows:
ψ
(
r
,
t
=
0
)
=
A
e
i
k
⋅
r
,
{\displaystyle \psi (\mathbf {r} ,\,t=0)=Ae^{i\mathbf {k\cdot r} },}
where the wavelength is determined by the wave vector k as:
λ
=
2
π
k
,
{\displaystyle \lambda ={\frac {2\pi }{k}},}
and the momentum by:
p
=
ℏ
k
.
{\displaystyle \mathbf {p} =\hbar \mathbf {k} .}
However, a wave like this with definite wavelength is not localized in space, and so cannot represent a particle localized in space. To localize a particle, de Broglie proposed a superposition of different wavelengths ranging around a central value in a wave packet, a waveform often used in quantum mechanics to describe the wave function of a particle. In a wave packet, the wavelength of the particle is not precise, and the local wavelength deviates on either side of the main wavelength value.
In representing the wave function of a localized particle, the wave packet is often taken to have a Gaussian shape and is called a Gaussian wave packet. Gaussian wave packets also are used to analyze water waves.
For example, a Gaussian wavefunction ψ might take the form:
ψ
(
x
,
t
=
0
)
=
A
exp
(
−
x
2
2
σ
2
+
i
k
0
x
)
,
{\displaystyle \psi (x,\,t=0)=A\exp \left(-{\frac {x^{2}}{2\sigma ^{2}}}+ik_{0}x\right),}
at some initial time t = 0, where the central wavelength is related to the central wave vector k0 as λ0 = 2π / k0. It is well known from the theory of Fourier analysis, or from the Heisenberg uncertainty principle (in the case of quantum mechanics) that a narrow range of wavelengths is necessary to produce a localized wave packet, and the more localized the envelope, the larger the spread in required wavelengths. The Fourier transform of a Gaussian is itself a Gaussian. Given the Gaussian:
f
(
x
)
=
e
−
x
2
/
(
2
σ
2
)
,
{\displaystyle f(x)=e^{-x^{2}/\left(2\sigma ^{2}\right)},}
the Fourier transform is:
f
~
(
k
)
=
σ
e
−
σ
2
k
2
/
2
.
{\displaystyle {\tilde {f}}(k)=\sigma e^{-\sigma ^{2}k^{2}/2}.}
The Gaussian in space therefore is made up of waves:
f
(
x
)
=
1
2
π
∫
−
∞
∞
f
~
(
k
)
e
i
k
x
d
k
;
{\displaystyle f(x)={\frac {1}{\sqrt {2\pi }}}\int _{-\infty }^{\infty }\ {\tilde {f}}(k)e^{ikx}\ dk;}
that is, a number of waves of wavelengths λ such that kλ = 2 π.
The parameter σ decides the spatial spread of the Gaussian along the x-axis, while the Fourier transform shows a spread in wave vector k determined by 1/σ. That is, the smaller the extent in space, the larger the extent in k, and hence in λ = 2π/k.
== Gravity waves ==
Gravity waves are waves generated in a fluid medium or at the interface between two media when the force of gravity or buoyancy works to restore equilibrium. Surface waves on water are the most familiar example.
== Gravitational waves ==
Gravitational waves also travel through space. The first observation of gravitational waves was announced on 11 February 2016.
Gravitational waves are disturbances in the curvature of spacetime, predicted by Einstein's theory of general relativity.
== See also ==
Index of wave articles
=== Waves in general ===
==== Parameters ====
==== Waveforms ====
=== Electromagnetic waves ===
=== In fluids ===
=== In quantum mechanics ===
=== In relativity ===
=== Other specific types of waves ===
=== Related topics ===
== References ==
== Sources ==
== External links ==
The Feynman Lectures on Physics: Waves
Linear and nonlinear waves
Science Aid: Wave properties – Concise guide aimed at teens Archived 2019-09-04 at the Wayback Machine
"AT&T Archives: Similiarities of Wave Behavior" demonstrated by J.N. Shive of Bell Labs (video on YouTube) | Wikipedia/Waves_(physics) |
Wind power is the use of wind energy to generate useful work. Historically, wind power was used by sails, windmills and windpumps, but today it is mostly used to generate electricity. This article deals only with wind power for electricity generation.
Today, wind power is generated almost completely using wind turbines, generally grouped into wind farms and connected to the electrical grid.
In 2024, wind supplied over 2,494 TWh of electricity, which was 8.1% of world electricity.
With about 100 GW added during 2021, mostly in China and the United States, global installed wind power capacity exceeded 800 GW. 30 countries generated more than a tenth of their electricity from wind power in 2024 and wind generation has nearly tripled since 2015. To help meet the Paris Agreement goals to limit climate change, analysts say it should expand much faster – by over 1% of electricity generation per year.
Wind power is considered a sustainable, renewable energy source, and has a much smaller impact on the environment compared to burning fossil fuels. Wind power is variable, so it needs energy storage or other dispatchable generation energy sources to attain a reliable supply of electricity. Land-based (onshore) wind farms have a greater visual impact on the landscape than most other power stations per energy produced. Wind farms sited offshore have less visual impact and have higher capacity factors, although they are generally more expensive. Offshore wind power currently has a share of about 10% of new installations.
Wind power is one of the lowest-cost electricity sources per unit of energy produced.
In many locations, new onshore wind farms are cheaper than new coal or gas plants.
Regions in the higher northern and southern latitudes have the highest potential for wind power. In most regions, wind power generation is higher in nighttime, and in winter when solar power output is low. For this reason, combinations of wind and solar power are suitable in many countries.
== Wind energy resources ==
Wind is air movement in the Earth's atmosphere. In a unit of time, say 1 second, the volume of air that had passed an area
A
{\displaystyle A}
is
A
v
{\displaystyle Av}
. If the air density is
ρ
{\displaystyle \rho }
, the flow rate of this volume of air is
M
Δ
t
=
ρ
A
v
{\displaystyle {\tfrac {M}{\Delta t}}=\rho Av}
, and the power transfer, or energy transfer per second is
P
=
1
2
M
Δ
t
v
2
=
1
2
ρ
A
v
3
{\displaystyle P={\tfrac {1}{2}}{\tfrac {M}{\Delta t}}v^{2}={\tfrac {1}{2}}\rho Av^{3}}
. Wind power is thus proportional to the third power of the wind speed; the available power increases eightfold when the wind speed doubles. Change of wind speed by a factor of 2.1544 increases the wind power by one order of magnitude (multiply by 10).
The global wind kinetic energy averaged approximately 1.50 MJ/m2 over the period from 1979 to 2010, 1.31 MJ/m2 in the Northern Hemisphere with 1.70 MJ/m2 in the Southern Hemisphere. The atmosphere acts as a thermal engine, absorbing heat at higher temperatures, releasing heat at lower temperatures. The process is responsible for the production of wind kinetic energy at a rate of 2.46 W/m2 thus sustaining the circulation of the atmosphere against friction.
Through wind resource assessment, it is possible to estimate wind power potential globally, by country or region, or for a specific site. The Global Wind Atlas provided by the Technical University of Denmark in partnership with the World Bank provides a global assessment of wind power potential.
Unlike 'static' wind resource atlases which average estimates of wind speed and power density across multiple years, tools such as Renewables.ninja provide time-varying simulations of wind speed and power output from different wind turbine models at an hourly resolution. More detailed, site-specific assessments of wind resource potential can be obtained from specialist commercial providers, and many of the larger wind developers have in-house modeling capabilities.
The total amount of economically extractable power available from the wind is considerably more than present human power use from all sources. The strength of wind varies, and an average value for a given location does not alone indicate the amount of energy a wind turbine could produce there.
To assess prospective wind power sites, a probability distribution function is often fit to the observed wind speed data. Different locations will have different wind speed distributions. The Weibull model closely mirrors the actual distribution of hourly/ten-minute wind speeds at many locations. The Weibull factor is often close to 2 and therefore a Rayleigh distribution can be used as a less accurate, but simpler model.
== Wind farms ==
A wind farm is a group of wind turbines in the same location. A large wind farm may consist of several hundred individual wind turbines distributed over an extended area. The land between the turbines may be used for agricultural or other purposes. A wind farm may also be located offshore. Almost all large wind turbines have the same design — a horizontal axis wind turbine having an upwind rotor with 3 blades, attached to a nacelle on top of a tall tubular tower.
In a wind farm, individual turbines are interconnected with a medium voltage (often 34.5 kV) power collection system and communications network. In general, a distance of 7D (7 times the rotor diameter of the wind turbine) is set between each turbine in a fully developed wind farm. At a substation, this medium-voltage electric current is increased in voltage with a transformer for connection to the high voltage electric power transmission system.
=== Generator characteristics and stability ===
Most modern turbines use variable speed generators combined with either a partial or full-scale power converter between the turbine generator and the collector system, which generally have more desirable properties for grid interconnection and have low voltage ride through-capabilities. Modern turbines use either doubly fed electric machines with partial-scale converters or squirrel-cage induction generators or synchronous generators (both permanently and electrically excited) with full-scale converters. Black start is possible and is being further developed for places (such as Iowa) which generate most of their electricity from wind.
Transmission system operators will supply a wind farm developer with a grid code to specify the requirements for interconnection to the transmission grid. This will include the power factor, the constancy of frequency, and the dynamic behaviour of the wind farm turbines during a system fault.
=== Offshore wind power ===
Offshore wind power is wind farms in large bodies of water, usually the sea. These installations can use the more frequent and powerful winds that are available in these locations and have less visual impact on the landscape than land-based projects. However, the construction and maintenance costs are considerably higher.
As of November 2021, the Hornsea Wind Farm in the United Kingdom is the largest offshore wind farm in the world at 1,218 MW.
=== Collection and transmission network ===
Near offshore wind farms may be connected by AC and far offshore by HVDC.
Wind power resources are not always located near areas with a high population density. As transmission lines become longer, the losses associated with power transmission increase, as modes of losses at lower lengths are exacerbated and new modes of losses are no longer negligible as the length is increased; making it harder to transport large loads over large distances.
When the transmission capacity does not meet the generation capacity, wind farms are forced to produce below their full potential or stop running altogether, in a process known as curtailment. While this leads to potential renewable generation left untapped, it prevents possible grid overload or risk to reliable service.
One of the biggest current challenges to wind power grid integration in some countries is the necessity of developing new transmission lines to carry power from wind farms, usually in remote lowly populated areas due to availability of wind, to high load locations, usually on the coasts where population density is higher. Any existing transmission lines in remote locations may not have been designed for the transport of large amounts of energy. In particular geographic regions, peak wind speeds may not coincide with peak demand for electrical power, whether offshore or onshore. A possible future option may be to interconnect widely dispersed geographic areas with an HVDC super grid.
== Wind power capacity and production ==
=== Growth trends ===
In 2020, wind supplied almost 1600 TWh of electricity, which was over 5% of worldwide electrical generation and about 2% of energy consumption. With over 100 GW added during 2020, mostly in China, global installed wind power capacity reached more than 730 GW. But to help meet the Paris Agreement's goals to limit climate change, analysts say it should expand much faster – by over 1% of electricity generation per year. Expansion of wind power is being hindered by fossil fuel subsidies.
The actual amount of electric power that wind can generate is calculated by multiplying the nameplate capacity by the capacity factor, which varies according to equipment and location. Estimates of the capacity factors for wind installations are in the range of 35% to 44%.
=== Capacity factor ===
Since wind speed is not constant, a wind farm's annual energy production is never as much as the sum of the generator nameplate ratings multiplied by the total hours in a year. The ratio of actual productivity in a year to this theoretical maximum is called the capacity factor. Online data is available for some locations, and the capacity factor can be calculated from the yearly output.
=== Penetration ===
Wind energy penetration is the fraction of energy produced by wind compared with the total generation. Wind power's share of worldwide electricity usage in 2021 was almost 7%, up from 3.5% in 2015.
There is no generally accepted maximum level of wind penetration. The limit for a particular grid will depend on the existing generating plants, pricing mechanisms, capacity for energy storage, demand management, and other factors. An interconnected electric power grid will already include reserve generating and transmission capacity to allow for equipment failures. This reserve capacity can also serve to compensate for the varying power generation produced by wind stations. Studies have indicated that 20% of the total annual electrical energy consumption may be incorporated with minimal difficulty. These studies have been for locations with geographically dispersed wind farms, some degree of dispatchable energy or hydropower with storage capacity, demand management, and interconnected to a large grid area enabling the export of electric power when needed. Electrical utilities continue to study the effects of large-scale penetration of wind generation on system stability.
A wind energy penetration figure can be specified for different duration of time but is often quoted annually. To generate almost all electricity from wind annually requires substantial interconnection to other systems, for example some wind power in Scotland is sent to the rest of the British grid. On a monthly, weekly, daily, or hourly basis—or less—wind might supply as much as or more than 100% of current use, with the rest stored, exported or curtailed. The seasonal industry might then take advantage of high wind and low usage times such as at night when wind output can exceed normal demand. Such industry might include the production of silicon, aluminum, steel, or natural gas, and hydrogen, and using future long-term storage to facilitate 100% energy from variable renewable energy. Homes and businesses can also be programmed to vary electricity demand, for example by remotely turning up water heater thermostats.
=== Variability ===
Wind power is variable, and during low wind periods, it may need to be replaced by other power sources. Transmission networks presently cope with outages of other generation plants and daily changes in electrical demand, but the variability of intermittent power sources such as wind power is more frequent than those of conventional power generation plants which, when scheduled to be operating, may be able to deliver their nameplate capacity around 95% of the time.
Electric power generated from wind power can be highly variable at several different timescales: hourly, daily, or seasonally. Annual variation also exists but is not as significant. Because instantaneous electrical generation and consumption must remain in balance to maintain grid stability, this variability can present substantial challenges to incorporating large amounts of wind power into a grid system. Intermittency and the non-dispatchable nature of wind energy production can raise costs for regulation, incremental operating reserve, and (at high penetration levels) could require an increase in the already existing energy demand management, load shedding, storage solutions, or system interconnection with HVDC cables.
Fluctuations in load and allowance for the failure of large fossil-fuel generating units require operating reserve capacity, which can be increased to compensate for the variability of wind generation.
Utility-scale batteries are often used to balance hourly and shorter timescale variation, but car batteries may gain ground from the mid-2020s. Wind power advocates argue that periods of low wind can be dealt with by simply restarting existing power stations that have been held in readiness, or interlinking with HVDC.
The combination of diversifying variable renewables by type and location, forecasting their variation, and integrating them with dispatchable renewables, flexible fueled generators, and demand response can create a power system that has the potential to meet power supply needs reliably. Integrating ever-higher levels of renewables is being successfully demonstrated in the real world.
Solar power tends to be complementary to wind. On daily to weekly timescales, high-pressure areas tend to bring clear skies and low surface winds, whereas low-pressure areas tend to be windier and cloudier. On seasonal timescales, solar energy peaks in summer, whereas in many areas wind energy is lower in summer and higher in winter. Thus the seasonal variation of wind and solar power tend to cancel each other somewhat. Wind hybrid power systems are becoming more popular.
=== Predictability ===
For any particular generator, there is an 80% chance that wind output will change less than 10% in an hour and a 40% chance that it will change 10% or more in 5 hours.
In summer 2021, wind power in the United Kingdom fell due to the lowest winds in seventy years, In the future, smoothing peaks by producing green hydrogen may help when wind has a larger share of generation.
While the output from a single turbine can vary greatly and rapidly as local wind speeds vary, as more turbines are connected over larger and larger areas the average power output becomes less variable and more predictable. Weather forecasting permits the electric-power network to be readied for the predictable variations in production that occur.
It is thought that the most reliable low-carbon electricity systems will include a large share of wind power.
=== Energy storage ===
Typically, conventional hydroelectricity complements wind power very well. When the wind is blowing strongly, nearby hydroelectric stations can temporarily hold back their water. When the wind drops they can, provided they have the generation capacity, rapidly increase production to compensate. This gives a very even overall power supply and virtually no loss of energy and uses no more water.
Alternatively, where a suitable head of water is not available, pumped-storage hydroelectricity or other forms of grid energy storage such as compressed air energy storage and thermal energy storage can store energy developed by high-wind periods and release it when needed. The type of storage needed depends on the wind penetration level – low penetration requires daily storage, and high penetration requires both short- and long-term storage – as long as a month or more. Stored energy increases the economic value of wind energy since it can be shifted to displace higher-cost generation during peak demand periods. The potential revenue from this arbitrage can offset the cost and losses of storage. Although pumped-storage power systems are only about 75% efficient and have high installation costs, their low running costs and ability to reduce the required electrical base-load can save both fuel and total electrical generation costs.
=== Energy payback ===
The energy needed to build a wind farm divided into the total output over its life, Energy Return on Energy Invested, of wind power varies, but averages about 20–25. Thus, the energy payback time is typically around a year.
== Economics ==
Onshore wind is an inexpensive source of electric power, cheaper than coal plants and new gas plants. According to BusinessGreen, wind turbines reached grid parity (the point at which the cost of wind power matches traditional sources) in some areas of Europe in the mid-2000s, and in the US around the same time. Falling prices continue to drive the Levelized cost down and it has been suggested that it has reached general grid parity in Europe in 2010, and will reach the same point in the US around 2016 due to an expected reduction in capital costs of about 12%. In 2021, the CEO of Siemens Gamesa warned that increased demand for low-cost wind turbines combined with high input costs and high costs of steel result in increased pressure on the manufacturers and decreasing profit margins.
Northern Eurasia, Canada, some parts of the United States, and Patagonia in Argentina are the best areas for onshore wind: whereas in other parts of the world solar power, or a combination of wind and solar, tend to be cheaper.: 8
=== Electric power cost and trends ===
Wind power is capital intensive but has no fuel costs. The price of wind power is therefore much more stable than the volatile prices of fossil fuel sources. However, the estimated average cost per unit of electric power must incorporate the cost of construction of the turbine and transmission facilities, borrowed funds, return to investors (including the cost of risk), estimated annual production, and other components, averaged over the projected useful life of the equipment, which may be more than 20 years. Energy cost estimates are highly dependent on these assumptions so published cost figures can differ substantially.
The presence of wind energy, even when subsidized, can reduce costs for consumers (€5 billion/yr in Germany) by reducing the marginal price and by minimizing the use of expensive peaking power plants.
The cost has decreased as wind turbine technology has improved. There are now longer and lighter wind turbine blades, improvements in turbine performance, and increased power generation efficiency. Also, wind project capital expenditure costs and maintenance costs have continued to decline.
In 2021, a Lazard study of unsubsidized electricity said that wind power levelized cost of electricity continues to fall but more slowly than before. The study estimated new wind-generated electricity cost from $26 to $50/MWh, compared to new gas power from $45 to $74/MWh. The median cost of fully deprecated existing coal power was $42/MWh, nuclear $29/MWh and gas $24/MWh. The study estimated offshore wind at around $83/MWh. Compound annual growth rate was 4% per year from 2016 to 2021, compared to 10% per year from 2009 to 2021.
=== The value of wind power ===
While the levelised costs of wind power may have reached that of traditional combustion based power technologies, the market value of the generated power is also lower due to the merit order effect, which implies that electricity market prices are lower in hours with substantial generation of variable renewable energy due to the low marginal costs of this technology. The effect has been identified in several European markets. For wind power plants exposed to electricity market pricing in markets with high penetration of variable renewable energy sources, profitability can be challenged.
=== Incentives and community benefits ===
Turbine prices have fallen significantly in recent years due to tougher competitive conditions such as the increased use of energy auctions, and the elimination of subsidies in many markets. As of 2021, subsidies are still often given to offshore wind. However, they are generally no longer necessary for onshore wind in countries with even a very low carbon price such as China, provided there are no competing fossil fuel subsidies.
Secondary market forces provide incentives for businesses to use wind-generated power, even if there is a premium price for the electricity. For example, socially responsible manufacturers pay utility companies a premium that goes to subsidize and build new wind power infrastructure. Companies use wind-generated power, and in return, they can claim that they are undertaking strong "green" efforts. Wind projects provide local taxes, or payments in place of taxes and strengthen the economy of rural communities by providing income to farmers with wind turbines on their land.
The wind energy sector can also produce jobs during the construction and operating phase. Jobs include the manufacturing of wind turbines and the construction process, which includes transporting, installing, and then maintaining the turbines. An estimated 1.25 million people were employed in wind power in 2020.
== Small-scale wind power ==
Small-scale wind power is the name given to wind generation systems with the capacity to produce up to 50 kW of electrical power. Isolated communities, that may otherwise rely on diesel generators, may use wind turbines as an alternative. Individuals may purchase these systems to reduce or eliminate their dependence on grid electric power for economic reasons, or to reduce their carbon footprint. Wind turbines have been used for household electric power generation in conjunction with battery storage over many decades in remote areas.
Examples of small-scale wind power projects in an urban setting can be found in New York City, where, since 2009, several building projects have capped their roofs with Gorlov-type helical wind turbines. Although the energy they generate is small compared to the buildings' overall consumption, they help to reinforce the building's 'green' credentials in ways that "showing people your high-tech boiler" cannot, with some of the projects also receiving the direct support of the New York State Energy Research and Development Authority.
Grid-connected domestic wind turbines may use grid energy storage, thus replacing purchased electric power with locally produced power when available. The surplus power produced by domestic microgenerators can, in some jurisdictions, be fed into the network and sold to the utility company, producing a retail credit for the microgenerators' owners to offset their energy costs.
Off-grid system users can either adapt to intermittent power or use batteries, photovoltaic, or diesel systems to supplement the wind turbine. Equipment such as parking meters, traffic warning signs, street lighting, or wireless Internet gateways may be powered by a small wind turbine, possibly combined with a photovoltaic system, that charges a small battery replacing the need for a connection to the power grid.
Airborne wind turbines, such as kites, can be used in places at risk of hurricanes, as they can be taken down in advance.
== Impact on environment and landscape ==
The environmental impact of electricity generation from wind power is minor when compared to that of fossil fuel power. Wind turbines have some of the lowest life-cycle greenhouse-gas emissions of energy sources: far less greenhouse gas is emitted than for the average unit of electricity, so wind power helps limit climate change. Use of engineered wood may allow carbon negative wind power. Wind power consumes no fuel, and emits no local air pollution, unlike fossil fuel power sources. Large scale wind energy systems may contribute to land degradation.
Onshore wind farms can have a significant visual impact. Due to a very low surface power density and spacing requirements, wind farms typically need to be spread over more land than other power stations. Their network of turbines, access roads, transmission lines, and substations can result in "energy sprawl"; although land between the turbines and roads can still be used for agriculture. Some wind farms are opposed for potentially spoiling protected scenic areas, archaeological landscapes and heritage sites. A report by the Mountaineering Council of Scotland concluded that wind farms harmed tourism in areas known for natural landscapes and panoramic views.
Habitat loss and fragmentation are the greatest potential impacts on wildlife of onshore wind farms, but the worldwide ecological impact is minimal. Thousands of birds and bats, including rare species, have been killed by wind turbine blades, though wind turbines are responsible for far fewer bird deaths than fossil-fueled power stations when climate change effects are included. Not including these effects, modern wind turbines kill about 0.273 birds per GWh in comparison with 0.200 by coal power plants. The effects of wind turbines on birds can be mitigated with proper wildlife monitoring.
Many wind turbine blades are made of fiberglass, and have a lifetime of 20 years. Blades are hollow: some blades are crushed to reduce their volume and then landfilled. However, as they can take a lot of weight they can be made into long lasting small bridges for walkers or cyclists. Blade end-of-life is complicated, and blades manufactured in the 2020s are more likely to be designed to be completely recyclable.
Wind turbines also generate noise. At a distance of 300 metres (980 ft), this may be around 45 dB, which is slightly louder than a refrigerator. At 1.5 km (1 mi), they become inaudible. There are anecdotal reports of negative health effects on people who live very close to wind turbines. Peer-reviewed research has generally not supported these claims.
== Politics ==
=== Central government ===
Although wind turbines with fixed bases are a mature technology and new installations are generally no longer subsidized, floating wind turbines are a relatively new technology so some governments subsidize them, for example to use deeper waters.
Fossil fuel subsidies by some governments are slowing the growth of renewables.
Permitting of wind farms can take years and some governments are trying to speed up – the wind industry says this will help limit climate change and increase energy security – sometimes groups such as fishers resist this but governments say that rules protecting biodiversity will still be followed.
=== Public opinion ===
Surveys of public attitudes across Europe and in many other countries show strong public support for wind power. Bakker et al. (2012) found in their study that residents who did not want turbines built near them suffered significantly more stress than those who "benefited economically from wind turbines".
Although wind power is a popular form of energy generation, onshore or near offshore wind farms are sometimes opposed for their impact on the landscape (especially scenic areas, heritage areas and archaeological landscapes), as well as noise, and impact on tourism.
In other cases, there is direct community ownership of wind farms. The hundreds of thousands of people who have become involved in Germany's small and medium-sized wind farms demonstrate such support there.
A 2010 Harris Poll found strong support for wind power in Germany, other European countries, and the United States.
Public support in the United States has decreased from 75% in 2020 to 62% in 2021, with the Democratic Party supporting the use of wind energy twice as much as the Republican Party. President Biden has signed an executive order to begin building large scale wind farms.
In China, Shen et al. (2019) found that Chinese city-dwellers may be resistant to building wind turbines in urban areas, with a surprisingly high proportion of people citing an unfounded fear of radiation as driving their concerns. Also, the study finds that like their counterparts in OECD countries, urban Chinese respondents are sensitive to direct costs and wildlife externalities. Distributing relevant information about turbines to the public may alleviate resistance.
=== Community ===
Many wind power companies work with local communities to reduce environmental and other concerns associated with particular wind farms.
In other cases there is direct community ownership of wind farm projects. Appropriate government consultation, planning and approval procedures also help to minimize environmental risks.
Some may still object to wind farms but many say their concerns should be weighed against the need to address the threats posed by air pollution, climate change and the opinions of the broader community.
In the US, wind power projects are reported to boost local tax bases, helping to pay for schools, roads, and hospitals, and to revitalize the economies of rural communities by providing steady income to farmers and other landowners.
In the UK, both the National Trust and the Campaign to Protect Rural England have expressed concerns about the effects on the rural landscape caused by inappropriately sited wind turbines and wind farms.
Some wind farms have become tourist attractions. The Whitelee Wind Farm Visitor Centre has an exhibition room, a learning hub, a café with a viewing deck and also a shop. It is run by the Glasgow Science Centre.
In Denmark, a loss-of-value scheme gives people the right to claim compensation for loss of value of their property if it is caused by proximity to a wind turbine. The loss must be at least 1% of the property's value.
Despite this general support for the concept of wind power in the public at large, local opposition often exists and has delayed or aborted a number of projects.
As well as concerns about the landscape, there are concerns that some installations can produce excessive sound and vibration levels leading to a decrease in property values. A study of 50,000 home sales near wind turbines found no statistical evidence that prices were affected.
While aesthetic issues are subjective and some find wind farms pleasant and optimistic, or symbols of energy independence and local prosperity, protest groups are often formed to attempt to block some wind power stations for various reasons.
Some opposition to wind farms is dismissed as NIMBYism, but research carried out in 2009 found that there is little evidence to support the belief that residents only object to wind farms because of a "Not in my Back Yard" attitude.
=== Geopolitics ===
Wind cannot be cut off unlike oil and gas so can contribute to energy security.
== Turbine design ==
Wind turbines are devices that convert the wind's kinetic energy into electrical power. The result of over a millennium of windmill development and modern engineering, today's wind turbines are manufactured in a wide range of horizontal axis and vertical axis types. The smallest turbines are used for applications such as battery charging for auxiliary power. Slightly larger turbines can be used for making small contributions to a domestic power supply while selling unused power back to the utility supplier via the electrical grid. Arrays of large turbines, known as wind farms, have become an increasingly important source of renewable energy and are used in many countries as part of a strategy to reduce their reliance on fossil fuels.
Wind turbine design is the process of defining the form and specifications of a wind turbine to extract energy from the wind.
A wind turbine installation consists of the necessary systems needed to capture the wind's energy, point the turbine into the wind, convert mechanical rotation into electrical power, and other systems to start, stop, and control the turbine.
In 1919, the German physicist Albert Betz showed that for a hypothetical ideal wind-energy extraction machine, the fundamental laws of conservation of mass and energy allowed no more than 16/27 (59%) of the kinetic energy of the wind to be captured. This Betz limit can be approached in modern turbine designs, which may reach 70 to 80% of the theoretical Betz limit.
The aerodynamics of a wind turbine are not straightforward. The airflow at the blades is not the same as the airflow far away from the turbine. The very nature of how energy is extracted from the air also causes air to be deflected by the turbine. This affects the objects or other turbines downstream, which is known as "wake effect". Also, the aerodynamics of a wind turbine at the rotor surface exhibit phenomena that are rarely seen in other aerodynamic fields. The shape and dimensions of the blades of the wind turbine are determined by the aerodynamic performance required to efficiently extract energy from the wind, and by the strength required to resist the forces on the blade.
In addition to the aerodynamic design of the blades, the design of a complete wind power system must also address the design of the installation's rotor hub, nacelle, tower structure, generator, controls, and foundation.
== History ==
Wind power has been used as long as humans have put sails into the wind. Wind-powered machines used to grind grain and pump water, the windmill and wind pump, were developed in what is now Iran, Afghanistan, and Pakistan by the 9th century. Wind power was widely available and not confined to the banks of fast-flowing streams, or later, requiring sources of fuel. Wind-powered pumps drained the polders of the Netherlands, and in arid regions such as the American mid-west or the Australian outback, wind pumps provided water for livestock and steam engines.
The first wind turbine used for the production of electric power was built in Scotland in July 1887 by Prof James Blyth of Anderson's College, Glasgow (the precursor of Strathclyde University). Blyth's 10 metres (33 ft) high cloth-sailed wind turbine was installed in the garden of his holiday cottage at Marykirk in Kincardineshire, and was used to charge accumulators developed by the Frenchman Camille Alphonse Faure, to power the lighting in the cottage, thus making it the first house in the world to have its electric power supplied by wind power. Blyth offered the surplus electric power to the people of Marykirk for lighting the main street, however, they turned down the offer as they thought electric power was "the work of the devil". Although he later built a wind turbine to supply emergency power to the local Lunatic Asylum, Infirmary, and Dispensary of Montrose, the invention never really caught on as the technology was not considered to be economically viable.
Across the Atlantic, in Cleveland, Ohio, a larger and heavily engineered machine was designed and constructed in the winter of 1887–1888 by Charles F. Brush. This was built by his engineering company at his home and operated from 1886 until 1900. The Brush wind turbine had a rotor 17 metres (56 ft) in diameter and was mounted on an 18-metre (59ft) tall tower. Although large by today's standards, the machine was only rated at 12 kW. The connected dynamo was used either to charge a bank of batteries or to operate up to 100 incandescent light bulbs, three arc lamps, and various motors in Brush's laboratory.
With the development of electric power, wind power found new applications in lighting buildings remote from centrally generated power. Throughout the 20th century parallel paths developed small wind stations suitable for farms or residences.
From 1932 many isolated properties in Australia ran their lighting and electric fans from batteries, charged by a "Freelite" wind-driven generator, producing 100 watts of electrical power from as little wind speed as 10 miles per hour (16 km/h).
The 1973 oil crisis triggered the investigation in Denmark and the United States that led to larger utility-scale wind generators that could be connected to electric power grids for remote use of power. By 2008, the U.S. installed capacity had reached 25.4 gigawatts, and by 2012 the installed capacity was 60 gigawatts. Today, wind-powered generators operate in every size range, from tiny stations for battery charging at isolated residences, up to gigawatt-sized offshore wind farms that provide electric power to national electrical networks. The European Union is working to augment these prospects.
In 2023, the global wind power sector experienced significant growth, with 116.6 gigawatts (GW) of new capacity added to the power grid, representing a 50% increase over the amount added in 2022. This surge in capacity brought the total installed wind power capacity worldwide to 1,021 GW by the end of the year, marking a growth of 13% compared to the previous year.: 138
== See also ==
== Notes ==
== References ==
== External links ==
Official website of Global Wind Energy Council (GWEC)
Wind from Project Regeneration
Official website of World Wind Energy Association (WWEA)
Dynamic Data Dashboard from the International Energy Agency
Current global map of wind power density | Wikipedia/Wind_energy |
The groundwater energy balance is the energy balance of a groundwater body in terms of incoming hydraulic energy associated with groundwater inflow into the body, energy associated with the outflow, energy conversion into heat due to friction of flow, and the resulting change of energy status and groundwater level.
== Theory ==
When multiplying the horizontal velocity of groundwater (dimension, for example,
m
3
/
day
{\displaystyle m^{3}/{\text{day}}}
per
m
2
{\displaystyle m^{2}}
cross-sectional area) with the groundwater potential (dimension energy per volume of water, or
E
/
m
3
{\displaystyle E/m^{3}}
) one obtains an energy flow (flux) in
E
/
day
{\displaystyle E/{\text{day}}}
for the given flow and cross-sectional area.
Summation or integration of the energy flux in a vertical cross-section of unit width (say 1m) from the lower flow boundary (the impermeable layer or base) up to the water table in an unconfined aquifer gives the energy flow
f
E
{\displaystyle f_{E}}
through the cross-section in
E
/
day
{\displaystyle E/{\text{day}}}
per m width of the aquifer.
While flowing, the groundwater loses energy due to friction of flow, i.e. hydraulic energy is converted into heat. At the same time, energy may be added with the recharge of water coming into the aquifer through the water table. Thus one can make an hydraulic energy balance of a block of soil between two nearby cross-sections. In steady state, i.e. without change in energy status and without accumulation or depletion of water stored in the soil body, the energy flow in the first section plus the energy added by groundwater recharge between the sections minus the energy flow in the second section must equal the energy loss due to friction of flow.
In mathematical terms this balance can be obtained by differentiating the cross-sectional integral of Fe in the direction of flow using the Leibniz rule, taking into account that the level of the water table may change in the direction of flow.
The mathematics is simplified using the Dupuit–Forchheimer assumption.
The hydraulic friction losses can be described in analogy to Joule's law in electricity (see Joule's law#Hydraulic equivalent), where the friction losses are proportional to the square value of the current (flow) and the electrical resistance of the material through which the current occurs. In groundwater hydraulics (fluid dynamics, hydrodynamics) one often works with hydraulic conductivity (i.e. permeability of the soil for water), which is inversely proportional to the hydraulic resistance.
The resulting equation of the energy balance of groundwater flow can be used, for example, to calculate the shape of the water table between drains under specific aquifer conditions. For this a numerical solution can be used, taking small steps along the impermeable base. The drainage equation is to be solved by trial and error (iterations), because the hydraulic potential is taken with respect to a reference level taken as the level of the water table at the water divide midway between the drains. When calculating the shape of the water table, its level at the water divide is initially not known. Therefore, this level is to be assumed before the calculations on the shape of the water table can be started. According to the findings of the calculation procedure, the initial assumption is to be adjusted and the calculations are to be restarted until the level of the water table at the divide does not differ significantly from the assumed level.
The trial and error procedure is cumbersome and therefore computer programs may be developed to aid in the calculations.
== Application ==
The energy balance of groundwater flow can be applied to flow of groundwater to subsurface drains. The computer program EnDrain compares the outcome of the traditional drain spacing equation, based on Darcy's law together with the continuity equation (i.e. conservation of mass), with the solution obtained by the energy balance and it can be seen that drain spacings are wider in the latter case. This is owing to the introduction of the energy supplied by the incoming recharge.
== See also ==
DPHM-RS
Drainage equation
Groundwater discharge
Groundwater flow equation
Hydrogeology
== References ==
== External links ==
Articles on the energy balance of groundwater flow can be downloaded from : [5] under nr. 3 and 4. | Wikipedia/Groundwater_energy_balance |
Temperate deciduous or temperate broadleaf forests are a variety of temperate forest 'dominated' by deciduous trees that lose their leaves each winter. They represent one of Earth's major biomes, making up 9.69% of global land area. These forests are found in areas with distinct seasonal variation that cycle through warm, moist summers, cold winters, and moderate fall and spring seasons. They are most commonly found in the Northern Hemisphere, with particularly large regions in eastern North America, East Asia, and a large portion of Europe, though smaller regions of temperate deciduous forests are also located in South America. Examples of trees typically growing in the Northern Hemisphere's deciduous forests include oak, maple, basswood, beech and elm, while in the Southern Hemisphere, trees of the genus Nothofagus dominate this type of forest. Temperate deciduous forests provide several unique ecosystem services, including habitats for diverse wildlife, and they face a set of natural and human-induced disturbances that regularly alter their structure.
== Geography ==
Located below the northern boreal forests, temperate deciduous forests make up a significant portion of the land between the Tropic of Cancer (23
1
2
{\displaystyle {\tfrac {1}{2}}}
°N) and latitudes of 50° North, in addition to areas south of the Tropic of Capricorn (23
1
2
{\displaystyle {\tfrac {1}{2}}}
°S). Canada, the United States, China, and several European countries have the largest land area covered by temperate deciduous forests, with smaller portions present throughout South America, specifically Chile and Argentina.
== Climate ==
Temperate conditions refer to the cycle through four distinct seasons that occurs in areas between the polar regions and tropics. In these regions where temperate deciduous forest are found, warm and cold air circulation accounts for the biome's characteristic seasonal variation.
=== Temperature ===
The average annual temperature tends to be around 10 °Celsius, though this is dependent on the region. Due to shading from the canopy, the microclimate of temperate deciduous forests tends to be about 2.1 °Celsius cooler than the surroundings, whereas winter temperatures are from 0.4 to 0.9 °Celsius warmer within forests as a result of insulation from vegetation strata.
=== Precipitation ===
Annually, temperate deciduous forests experience approximately 750 to 1,500 millimeters of precipitation. As there is no distinct rainy season, precipitation is spread relatively evenly throughout the year. Snow makes up a portion of the precipitation present in temperate deciduous forests in the winter. Tree branches can intercept up to 80% of snowfall, affecting the amount of snow that ultimately reaches and melts on the forest floor.
=== Seasonal variation ===
A factor of temperate deciduous forests is their leaf loss during the transition from fall to winter, an adaptation that arose as a solution for the low sunlight conditions and bitter cold temperatures. In these forests, winter is a time of dormancy for plants, when broadleaf deciduous trees conserve energy and prevent water loss, and many animal species hibernate or migrate. Preceding winter is fruit-bearing autumn, a time when leaves change color to various shades of red, yellow, and orange as chlorophyll breakdown gives rise to anthocyanin, carotene, and xanthophyl pigments.
Besides the characteristic colorful autumns and leafless winters, temperate deciduous forests have a lengthy growing season during the spring and summer months that tends to last anywhere from 120 to 250 days. Spring in temperate deciduous forests is a period of ground vegetation and seasonal herb growth, a process that starts early in the season before trees have regrown their leaves and when ample sunlight is available. Once a suitable temperature is reached in mid- to late spring, budding and flowering of tall deciduous trees also begins. In the summer, when fully-developed leaves occupy all trees, a moderately-dense canopy creates shade, increasing the humidity of forested areas.
== Characteristics ==
=== Soil ===
Though there is latitudinal variation in soil quality of temperate deciduous forests, with those at central latitudes having a higher soil productivity than those more north or south, soil in this biome is overall highly fertile. The fallen leaves from deciduous trees introduce detritus to the forest floor, increasing levels of nutrients and organic matter in the soil. The high soil productivity of temperate deciduous forests puts them at a high risk of conversion to agricultural land for human use.
=== Flora ===
Temperate deciduous forests are characterized by a variety of temperate deciduous tree species that vary based on region. Most tree species present in temperate deciduous forests are broadleaf trees that lose their leaves in the fall, though some coniferous trees such as pines (Pinus) are present in northern temperate deciduous forests. Europe's temperate deciduous forests are rich with oaks of the genus Quercus, European beech trees (Fagus sylvatica), and hornbeams (Fagus grandifolia), while those in Asia tend to have maples of the genus Acer, a variety of ash trees (Fraxinus), and basswoods (Tilia). Similarly to Asia, North American forests have maples, especially Acer saccharum, and basswoods, in addition to hickories (Carya) and American chestnuts (Castanea dentata). Southern beech (Nothofagus) trees are prevalent in the temperate deciduous forests of South America. Elm trees (Ulmus) and willows (Salix) can also be found dispersed throughout the temperate deciduous forests of the world. While a wide variety of tree species can be found throughout the temperate deciduous forest biome, tree species richness is typically moderate in each individual ecosystem, with only 3 to 4 tree species per square kilometer.
Besides the old-growth trees that, with their domed tree crowns, form a canopy that lets little light filter through, a sub-canopy of shrubs such as mountain laurel and azaleas is present. These other plant species found in the canopy layers below the 35- to 40-meter mature trees are either adapted to low-light conditions or follow a seasonal schedule of growth that allows them to thrive before the formation of the canopy from mid-spring through mid-fall. Mosses and lichens make up significant ground cover, though they are also found growing on trees.
=== Fauna ===
In addition to characteristic flora, temperate deciduous forests are home to several animal species that rely on the trees and other plant life for shelter and resources, such as squirrels, rabbits, skunks, birds, mountain lions, bobcats, timber wolves, foxes, and black bears. Deer are also present in large populations, though they are clearing rather than true forest animals. Large deer populations have deleterious effects on tree regeneration overall, and grazing also has significant negative effects on the number and kind of herbaceous flowering plants. The continuous increase of deer populations and killing of top carnivores suggests that overgrazing by deer will continue.
== Ecosystem services ==
Temperate deciduous forests provide several provisioning, regulating, supporting, and cultural ecosystem services. With a higher biodiversity than boreal forests, temperate deciduous forests maintain their genetic diversity by providing the supporting service of habitat availability for a variety of plants and animal species dependent on shade. These forests play a role in the regulation of air and soil quality by preventing soil erosion and flooding, while also storing carbon in their soil. Provisioning services provided by temperate deciduous forests include access to sources of drinking water, oxygen, food, timber, and biomass. Humans depend on temperate deciduous forests for cultural services, using them as spaces for recreation and spiritual practices.
== Disturbances ==
Natural disturbances cause regular renewal of temperate deciduous forests and create a healthy, heterogeneous environment with constantly changing structures and populations. Weather events like snow, storms, and wind can cause varying degrees of change to the structure of forest canopies, creating log habitats for small animals and spaces for less shade-tolerant species to grow where fallen trees once stood. Other abiotic sources of disturbances to temperate deciduous forests include droughts, waterlogging, and fires. Natural surface fire patterns are especially important in pine reproduction. Biotic factors affecting forests take the form of fungal outbreaks in addition to mountain pine beetle and bark beetle infestations. These beetles are particularly prevalent in North America and kill trees by clogging their vascular tissue. Temperate deciduous forests tend to be resilient after minor weather-related disturbances, though major insect infestations, widespread anthropogenic disturbances, and catastrophic weather events can cause century-long succession or even the permanent conversion of the forest into a grassland.
=== Climate change ===
Rising temperatures and increased dryness in temperate deciduous forests have been noted in recent years as the climate changes. As a result, temperate deciduous forests have been experiencing an earlier onset to spring, as well as a global increase in the frequency and intensity of disturbances. They have been experiencing lower ecological resilience in the face of increasing mega-fires, longer droughts, and severe storms. Damaged wood from increased storm disturbance events provides nesting habitats for beetles, concurrently increasing bark beetle damage. Forest cover decreases with continuous severe disturbances, causing habitat loss and lower biodiversity.
== Human use and impact ==
Humans rely on wood from temperate deciduous forests for use in the timber industry as well as paper and charcoal production. Logging practices emit high levels of carbon while also causing erosion because fewer tree roots are present to provide soil support. During the European colonization of North America, potash made from tree ashes was exported back to Europe as fertilizer. At this time in history, clearcutting of the original temperate deciduous forests was also performed to make space for agricultural land use, so many forests now present are second-growth. Over 50% of temperate deciduous forests are affected by fragmentation, resulting in small fragments dissected by fields and roads; these islands of green often differ substantially from the original forests and cause challenges for species migration. Seminatural temperate deciduous forests with developed trail systems serve as sites for tourism and recreational activities, such as hiking and hunting. In addition to fragmentation, human use of land adjacent to temperate deciduous forests is associated with pollution that can stunt the growth rate of trees. Invasive species that outcompete native species and alter forest nutrient cycles, such as common buckthorn (Rhamnus cathartica), are also introduced by humans. The introduction of exotic diseases, especially, continues to be a threat to forest trees and, hence, the forest. Humans have also introduced earthworms in deciduous forests in Norh America, which has had a deep impact on the ecosystem and reduced biodiversity.
=== Conservation ===
A method for preserving temperate deciduous forests that has been used in the past is fire suppression. The process of preventing fires is associated with the build-up of biomass that, ultimately, increases the intensity of incidental fires. As an alternative, prescribed burning has been put into practice, in which regular, managed fires are administered to forest ecosystems to imitate the natural disturbances that play a significant role in preserving biodiversity. To combat the effects of deforestation, reforestation has been employed.
== See also ==
Temperate coniferous forest
Temperate broadleaf and mixed forest
International Year of Forests
Old-growth forest
Tropical evergreen forest
Tropical deciduous forest
Wood-pasture hypothesis
== References ==
== External links ==
Media related to Temperate deciduous forest at Wikimedia Commons
A map of biome distribution (Temperate Deciduous Forest is in dark green) | Wikipedia/Temperate_deciduous_forest |
Energy, nutrients, and contaminants derived from aquatic ecosystems and transferred to terrestrial ecosystems are termed aquatic-terrestrial subsidies or, more simply, aquatic subsidies. Common examples of aquatic subsidies include organisms that move across habitat boundaries and deposit their nutrients as they decompose in terrestrial habitats or are consumed by terrestrial predators, such as spiders, lizards, birds, and bats. Aquatic insects that develop within streams and lakes before emerging as winged adults and moving to terrestrial habitats contribute to aquatic subsidies. Fish removed from aquatic ecosystems by terrestrial predators are another important example. Conversely, the flow of energy and nutrients from terrestrial ecosystems to aquatic ecosystems are considered terrestrial subsidies; both aquatic subsidies and terrestrial subsidies are types of cross-boundary subsidies. Energy and nutrients are derived from outside the ecosystem where they are ultimately consumed.
Allochthonous describes resources and energy derived from another ecosystem; aquatic-terrestrial subsidies are examples of allochthonous resources. Autochthonous resources are produced by plants or algae within the local ecosystem Allochthonous resources, including aquatic-terrestrial subsidies, can subsidize predator populations and increase predator impacts on prey populations, sometimes initiating trophic cascades. Nutritional quality of autochthonous and allochthonous resources influences their use by animals and other consumers, even when they are readily available.
== Resource subsidies ==
Resource subsidies, in forms of nutrients, matter, or organisms, describe movements of essential resources across habitat boundaries to animals or other consumers. These inputs of resources can influence individual growth, species abundance and diversity, community structure, secondary productivity and food web dynamics. Allochthonous resources are defined as originating outside of the ecosystem while autochthonous resources are derived within the ecosystem. For example, leaf fall into a stream would be an allochthonous resource.
Resource subsidies supplement the productivity of the recipient consumer, but the consumer has little impact on productivity of the resource. As a result, resource subsidies are described as "donor-controlled". The flux rate of the subsidy is independent of productivity in the recipient habitat. Aquatic-terrestrial resource subsidies are often strongly seasonal. Aquatic insect emergence is typically highest during the warm season, while terrestrial leaf fall into aquatic habitats is associated with autumn in temperate biomes. The timing of these resource-subsidy pulses is important to how they are used by predators and other consumers, and the impacts on predator-prey dynamics in recipient habitats. In some cases, subsidies can destabilize predator-prey dynamics in recipient habitats. For example, blooms of algae can increase insect productivity and emergence, resulting in growth of terrestrial predator populations.
The rate of resource subsidy fluxes is mediated by the permeability of ecotones and modified by physical and biological factors. Species interactions within donor habitats and variability in climate can both alter rates of cross-habitat resource fluxes. The response of recipient consumers to an influx of resources depends on conditions within the recipient habitat; effects are largest when other resources are scarce within the recipient habitat. Flows between terrestrial and stream environments are among the best studied cross-boundary subsidies.
== Aquatic subsidies ==
Aquatic subsidies are energy or nutrients that are transferred from the aquatic environment to the terrestrial environment. These aquatic subsidies vary spatially and seasonally. Subsidies support ecosystem functions and link interactions between species.
Marine anadromous fishes such as salmon provide a subsidy to freshwater and then terrestrial ecosystems through spawning and carcasses. These marine-derived nutrients provide resources to a range of species both in the stream and on land. Terrestrial species that feed on salmon include river otters, mink, bald eagles and bears. Stream invertebrates such as stoneflies, caddisflies and midges also derive energy and nutrients from salmon and, in turn, provide food to terrestrial species such as birds and bats. Animals are not the only benefactors of these aquatic subsidies, riparian plants can receive up to 26% of their nitrogen from salmon.
Lateral movement of nutrients and energy from the stream to the surrounding riparian zone and terrestrial environment beyond serve an important role in food webs. Flooding of a stream and the movement of organisms both act to transfer nutrients and energy sources to the terrestrial environment. Algae and fine organic matter washed up from high flows provide resources to herbivorous species and promote plant germination. These lateral movements are limited in how far they make it away from the stream without help, but terrestrial species can increase the distance that these subsidies travel. For example, the emergence of adult aquatic insects from streams is one of the most distinct and well studied forms of aquatic subsidies. They supply 25–100% of the energy or carbon to riparian species such as spiders, bats, birds, and lizards. Emergence of aquatic insects typically peaks in the summer of temperate zones, prompting predators to aggregate and forage along riparian and stream boundaries. These species typically feed near the water's edge but then when they leave to travel elsewhere, their feces will add nutrients to other environments. Another example of a terrestrial species that moves aquatic subsidies further inland is that of the brown bear. Brown bears consume a massive amount of salmon from streams, so much so, they are considered a keystone species. Brown bears have been shown to deliver as much as 84% of the nitrogen found in white spruce trees that are up to 500 meters from the stream on the Kenai Peninsula (Alaska, USA) through their interactions with aquatic subsidies.
== Ecological importance of aquatic subsidies ==
Although inputs from the terrestrial environment to an aquatic one (terrestrial subsidies) have been studied extensively, aquatic inputs to the terrestrial environment (aquatic subsidies) haven't been as widely studied. Aquatic subsidies, however, can be extremely important in the terrestrial landscape and are generally of higher nutritional quality because they come from animal, rather than plant-based or detrital, sources. These aquatic subsidies may be more important than terrestrial prey for riparian predators in some ecosystems.
However, aquatic subsidies are also increasingly recognized as important sources of environmental contaminants to terrestrial food webs. Aquatic animals can accumulate pollutants in their tissues and exoskeletons (such as metals and polychlorinated biphenyls) and move them to riparian and terrestrial systems as they emerge or when they are consumed by terrestrial predators.
While aquatic subsidies provide a pathway for anthropogenic stressors to propagate from aquatic to terrestrial ecosystems, they are themselves being impacted by global change. Global warming and habitat modification change both the physiology and phenology of emerging aquatic insects as well as the physical boundary between water and land, which in turn affects their dispersal. In temperate regions, increasing temperature increases the growth and emergence rate of aquatic insects, while in tropical regions aquatic insect emergence rates decline.
== Terrestrial subsidies ==
Terrestrial subsidies are primary production on land that is transferred to aquatic ecosystems as litter fall or dissolved organic matter.
Terrestrial subsidies or allochthonous inputs into aquatic environments are a major component of organic carbon budgets for aquatic systems. In many ecosystems autochthonous production of carbon is not enough to support the food web and organisms rely on allochthonous to maintain secondary production. Aquatic ecosystems are generally heterotrophic; respiration exceeds production, suggesting the food web is supported externally. The carbon that enters the aquatic ecosystem from terrestrial inputs is taken up by micro-organisms like bacteria and fungi which are then consumed by higher trophic levels This microbial transfer of organic carbon has shown to support food webs in lakes and streams.
Organic carbon inputs into aquatic ecosystems come in multiple forms. The two main forms are dissolved organic carbon (DOC) or particulate organic carbon (POC). Particulate organic carbon includes living organisms like bacteria, phytoplankton, zooplankton, as well as detrital components. Dissolved organic carbon is organic carbon that has been broken down, is suspended, and considered soluble in water. Dissolved organic carbon has been shown to stimulate heterotrophic production in aquatic settings and heterotrophic bacteria can use dissolved organic carbon to support their growth. Particulate organic carbon also stimulates heterotrophic production which becomes available to bacteria or other micro-organisms through decomposition and other consumers by direct consumption.
Terrestrial invertebrates such as spiders, caterpillars, and ants are also an important form of terrestrial subsidy to aquatic ecosystems.
Drift-feeding fish can rely on falling terrestrial invertebrates for up to half of their annual energy budget. Variation in the flux of terrestrial invertebrates is dependent on the weather, time – annual and daily – and the riparian architecture. Warmer and more humid temperatures, generally associated with summer and early fall, facilitate greater invertebrate activity and thus larger subsidies, whereas wet seasons reduce the flux of terrestrial invertebrates. Daily, the input of terrestrial invertebrates is greatest during afternoons and evenings. Finally, riparian zones composed of closed canopy deciduous vegetation can support higher density and diversity of fishes compared to other vegetation types, due to the greater supply of terrestrial invertebrates.
Terrestrial leaf litter, wood inputs and deposition of pollen are important organic matter sources that augment benthic invertebrate productivity. In particular, these terrestrial subsidies are vital for detritivores and shredders and control their population sizes. Benthic invertebrate communities respond swiftly to changes in the supply of organic matter; the absence of litter stocks led to a drastic decline in productivity and predators in one experimental temperate stream system. Furthermore, provision of organic matter may increase productivity and create hypoxic conditions in streams; however, this is typically uncommon given the high turnover and low residence time of water. In the Mara River basin, though, substantial rates of organic matter and nutrient loading by hippopotami create subsidy overloads in hippo pools, stimulate anoxic conditions approximately three times a year, and cause multiple fish kill events.
== Contaminants as aquatic-terrestrial subsidies ==
Aquatic-terrestrial contaminant subsidies originating in the aquatic environment can be transported across ecosystem boundaries, primarily mediated by organisms. The transmission of contaminants can have negative ecological consequences that amplify up the food chain, including reduced nesting success of birds, disruptions to riparian food webs, and contamination of otherwise pristine environments. The mechanism of aquatic-terrestrial contaminant transfer can be especially influential when there are no additional sources of those contaminants to the terrestrial system.
=== Types of contaminant subsidies ===
Various organic compounds, trace elements, metals, algal toxins, pesticides, and pharmaceutical waste products resulting from intentional or incidental releases via human activities can act as contaminant subsidies. After being loaded into waterways, contaminants that accumulate in the aquatic food web can return to terrestrial environments through consumption by organisms.
=== Movement pathways through animals ===
Organisms serve as the vector for transportation of contaminant subsidies across trophic levels and aquatic-terrestrial ecosystem boundaries. Understanding the fate of aquatic-terrestrial subsidies is key to predicting their impact on terrestrial consumers.
==== Invertebrates ====
Aquatic invertebrates take up contaminants introduced to the environment via the water column, by grazing on surfaces, and from contaminated sediment. These contaminants can have several fates depending on their biochemical properties. One, that contaminants like metals and polycyclic aromatic hydrocarbons (PAHs) are preferentially shed into the exoskeleton during metamorphosis, and then recycled into the aquatic environment. Two, macroinvertebrates eaten during aquatic or larval stages transfer their contaminant burdens to higher aquatic trophic levels such as fish and those contaminants are retained by the aquatic environment. Contaminants that would otherwise be shed during metamorphosis are therefore most likely to be taken up by aquatic predators of larval stage insects. Three, larval aquatic macroinvertebrates can transfer contaminant subsidies directly to terrestrial environments following successful metamorphosis to their adult form. In particular, man-made organic contaminants like polychlorinated biphenyls (PCBs) can become concentrated in adults. Predator risk for the uptake of organic contaminants is higher when preying upon adult life stages of aquatic insects, and adult aquatic insects are more likely to be consumed by terrestrial predators such as birds. Terrestrial predatory invertebrates have also been identified as vectors of contaminant transport. In particular, riparian spiders have been shown to move contaminants, such as methylmercury, originating in aquatic prey to the terrestrial environment.
==== Fish ====
Because many fish species prey upon macroinvertebrates that may have taken up contaminants, fish are an important middle trophic level for contaminant transport. Subsequent consumption of fish from aquatic environments by terrestrial predators is a significant movement pathway for aquatic-terrestrial subsidies.
Anadromous migratory fish, such as salmon, transport contaminants far distances and across aquatic ecosystem boundaries. The consumption of salmon by terrestrial predators, such as bears, when salmon return to freshwater ecosystems to spawn transfers marine-derived contaminant subsidies to terrestrial systems far removed from areas of contaminant uptake by the aquatic food web. Salmon can be the largest dietary source of marine-derived contaminants consumed by bears. Salmon-derived contaminants are also transported to recipient aquatic ecosystems where salmon spawn and/or die. Contaminants may be maternally transferred to eggs or recycled to the base of aquatic food for subsequent trophic transfer to higher trophic levels. Consumption of animals containing these contaminants by terrestrial predators is another pathway of aquatic-terrestrial subsidy transfer across large spatial scales.
==== Birds ====
Fish-eating birds are at the topmost trophic level of many aquatic food webs. As a result, birds are often the recipients of aquatic contaminant subsidies and transporters of aquatic contaminants to the terrestrial environment. An area of much research in birds is the tendency for contaminants present in the aquatic environment to biomagnify to significant levels in predatory birds. This phenomenon was exemplified by DDT biomagnification in predatory birds during the 1960s in the US, which resulted in the collapse of many bird populations.
Migratory birds share the same capacity for contaminant transport across vast distances as fish. This may be of particular concern with Arctic migratory birds, as they have the ability to transport contaminants to environments with otherwise limited contaminant input. Birds can also recycle contaminants back to aquatic environments via guano.
=== Ecological consequences of contaminant subsidies ===
==== Impacts of contaminant subsidies on terrestrial predators ====
For flies and other metamorphosing insects, high burdens of Se, PCB, metals, synthetic nanoparticles, and other contaminants can decrease body and reproductive fitness, leading to reduced amounts of larvae metamorphosing and emerging from the water column as terrestrial adults. When contaminant exposure does not impact metamorphosis or emergence, emerging insects may carry high concentrations of contaminants that are readily bioavailable to the terrestrial food web. Consuming these contaminated prey items can result in severe histological, circulatory, digestive, and reproductive issues in terrestrial predators like spiders, amphibians, reptiles, mammals, and birds. The large number of insects that some predators need to consume in proportion to body mass for survival raises the risk of contaminant bioaccumulation, increasing the likelihood of developmental deformities and mortalities. This also can result in the biomagnification of organic and element subsidies like PCBs, selenium, and mercury by higher trophic levels that consume contaminated aquatic insects and their primary consumers like arthropods and fish. Contaminant levels in prey can be so highly concentrated that, for example, small-bodied songbird chicks can experience adverse physiological effects from feeding on a single spider containing high levels of PCB (at less than 6,000 parts per billion).
==== Ecosystem-wide impacts ====
Concentrated contamination of aquatic insect populations can facilitate a decline in the ecological health of aquatic and terrestrial ecosystems. Consumption of contaminated insects either continues the contaminant pathway up trophic levels or excretion returns the subsidies back into the sediment, a major sink of contaminants in aquatic environments. Due to the movement of subsidies through lotic systems and emergence patterns of flying insects, the source of contamination can be some distance away from the source of contamination and affected habitats. Furthermore, the massive biomass of insects compared to other animals, and the sequestration of organic contaminants in one water body, can lead to large amounts of contaminants being exported across many different terrestrial ecosystems. From a single creek, it was estimated that emerging insects exported around 6 grams of PCBs per year to land, which is equivalent to the amount exported by 50,000 migrating salmon in an entire watershed. The subsequent reduction in recruitment from a lack of prey or consumption of contaminant subsidies can lead to local extirpations of fish, and aquatic and arachnivorous birds. The loss of biomass and reduced subsidy pathways deteriorate the complexity of aquatic and terrestrial food webs. As the biodiversity of a habitat decreases, its ecological resilience to further contamination and food web restructuring also declines.
== Measuring aquatic-terrestrial connections ==
Researchers use several tools to assess how terrestrial and aquatic food webs are connected. Stable isotopes, particularly of carbon, nitrogen, hydrogen, and oxygen, can be used to determine what resources consumers are eating. Other compounds, such as fatty acids, can also be used to trace food web connections between aquatic and terrestrial ecosystems.
Stable carbon isotope ratios (ratio of carbon 13 (13C) to carbon 12 (12C)), are one of the most common methods used to measure the energy inputs and sources for aquatic ecosystems, and can be used to track flux of aquatic resources into riparian zones. Naturally-occurring variation in carbon stable isotope ratios can often distinguish organic matter produced by photosynthesis of terrestrial plants or aquatic algae. A more precise but also more expensive method requires adding a form of carbon labelled with an extreme ratio of carbon 13 (13C) to carbon 12 (12C) that does not naturally occur and which can be used to trace the movement of the added carbon through the ecosystem and food web. Once the tracer carbon has had time to go through the system, samples of water, algae, bacteria, and other organisms are collected and the ratios of carbon 13 (13C) to carbon 12 (12C) in their tissues are determined. A food web can then be drawn by tracing what organisms have taken up the tracer carbon and how much. Stable isotope ratios are measured using an isotope ratio mass spectrometer from dried organic samples.
There is sometimes overlap between terrestrial plants and algae in naturally-occurring stable carbon isotope ratios, complicating their use in identifying aquatic-terrestrial subsidies. Stable isotope ratios of hydrogen (ratio of deuterium to hydrogen) can be used to distinguish terrestrial and aquatic primary production when carbon isotope ratios overlap. However, stable hydrogen isotope ratios of aquatic organisms can also be influenced by variation in the isotope ratios present in the water molecules of the aquatic environment. Stable isotope ratios of nitrogen are particularly useful in tracing fluxes of marine-derived resources such as anadromous fish into riparian and terrestrial environments.
== Measuring contaminant subsidies and impacts ==
The movement of aquatic-terrestrial contaminant subsidies can first be measured by testing the water quality of sites with known contamination or near urban centers or factories that discharge chemical waste. This enables scientists to determine where contaminants are highly concentrated in aquatic habitats. Next, aquatic insects are often collected and analyzed for contaminant loads and to model any population changes. Aquatic insects are commonly studied to estimate water quality because many species are highly sensitive to pollution, resulting in community composition changes in contaminated waterbodies. Finally, researchers study histological, blood, gut, feather, and egg samples from predators to determine if contaminants are traveling up trophic levels via the consumption of contaminated prey and what negative effects this may have on predators.
== See also ==
Ecology portal
Environment portal
== References == | Wikipedia/Aquatic-terrestrial_subsidies |
Wiley-Blackwell is an international scientific, technical, medical, and scholarly publishing business of John Wiley & Sons. It was formed by the merger of John Wiley & Sons Global Scientific, Technical, and Medical business with Blackwell Publishing in 2007.
Wiley-Blackwell is now an imprint that publishes a diverse range of academic and professional fields, including biology, medicine, physical sciences, technology, social science, and the humanities.
== Blackwell Publishing history ==
Blackwell Publishing was formed by the 2001 merger of two Oxford-based academic publishing companies, Blackwell Science, founded in 1939 as Blackwell Scientific Publishing, and Blackwell Publishers, founded in 1922 as Basil Blackwell & Mott. Blackwell Publishers, founded in 1926, had its origins in the 19th century Blackwell's family bookshop and publishing business.
The merger between the two publishing companies created the world's leading learned society publisher. The group then acquired BMJ Books from the BMJ Publishing Group, publisher of The BMJ, a British medical journal, in 2004. Blackwell published over 805 journals and 650 text and reference books in 2006, across a wide range of academic, medical, and professional subjects.
On November 17, 2006, John Wiley & Sons announced it had "entered into a definitive agreement to acquire" Blackwell Publishing. The acquisition was completed in February 2007, at a purchase price of £572 million. Blackwell Publishing was merged into Wiley's Global Scientific, Technical, and Medical business to create Wiley-Blackwell. From June 30, 2008, the journals previously on Blackwell Synergy were delivered through Wiley InterScience.
== Controversy ==
In April 2022, the journal Science reported that a Ukrainian company, International Publisher Ltd., run by Ksenia Badziun, operates a Russian website where academics can purchase authorships in soon to be published academic papers. During the 2 year period analyzed by researchers, they found that at least 419 articles "appeared to match manuscripts that later appeared in dozens of different journals" and that "More than 100 of these identified papers were published in 68 journals run by established publishers, including Elsevier, Oxford University Press, Springer Nature, Taylor & Francis, Wolters Kluwer, and Wiley-Blackwell." Wiley-Blackwell claimed that they were examining the specific papers that were identified and brought to their attention.
== See also ==
List of journals published by Wiley-Blackwell
== References ==
== External links ==
Official website | Wikipedia/Blackwell_Science |
Peripheral membrane proteins, or extrinsic membrane proteins, are membrane proteins that adhere only temporarily to the biological membrane with which they are associated. These proteins attach to integral membrane proteins, or penetrate the peripheral regions of the lipid bilayer. The regulatory protein subunits of many ion channels and transmembrane receptors, for example, may be defined as peripheral membrane proteins. In contrast to integral membrane proteins, peripheral membrane proteins tend to collect in the water-soluble component, or fraction, of all the proteins extracted during a protein purification procedure. Proteins with GPI anchors are an exception to this rule and can have purification properties similar to those of integral membrane proteins.
The reversible attachment of proteins to biological membranes has shown to regulate cell signaling and many other important cellular events, through a variety of mechanisms. For example, the close association between many enzymes and biological membranes may bring them into close proximity with their lipid substrate(s). Membrane binding may also promote rearrangement, dissociation, or conformational changes within many protein structural domains, resulting in an activation of their biological activity. Additionally, the positioning of many proteins are localized to either the inner or outer surfaces or leaflets of their resident membrane.
This facilitates the assembly of multi-protein complexes by increasing the probability of any appropriate protein–protein interactions.
== Binding to the lipid bilayer ==
Peripheral membrane proteins may interact with other proteins or directly with the lipid bilayer. In the latter case, they are then known as amphitropic proteins.
Some proteins, such as G-proteins and certain protein kinases, interact with transmembrane proteins and the lipid bilayer simultaneously. Some polypeptide hormones, antimicrobial peptides, and neurotoxins accumulate at the membrane surface prior to locating and interacting with their cell surface receptor targets, which may themselves be peripheral membrane proteins.
The phospholipid bilayer that forms the cell surface membrane consists of a hydrophobic inner core region sandwiched between two regions of hydrophilicity, one at the inner surface and one at the outer surface of the cell membrane (see lipid bilayer article for a more detailed structural description of the cell membrane). The inner and outer surfaces, or interfacial regions, of model phospholipid bilayers have been shown to have a thickness of around 8 to 10 Å, although this may be wider in biological membranes that include large amounts of gangliosides or lipopolysaccharides.
The hydrophobic inner core region of typical biological membranes may have a thickness of around 27 to 32 Å, as estimated by Small angle X-ray scattering (SAXS).
The boundary region between the hydrophobic inner core and the hydrophilic interfacial regions is very narrow, at around 3 Å, (see lipid bilayer article for a description of its component chemical groups). Moving outwards away from the hydrophobic core region and into the interfacial hydrophilic region, the effective concentration of water rapidly changes across this boundary layer, from nearly zero to a concentration of around 2 M.
The phosphate groups within phospholipid bilayers are fully hydrated or saturated with water and are situated around 5 Å outside the boundary of the hydrophobic core region.
Some water-soluble proteins associate with lipid bilayers irreversibly and can form transmembrane alpha-helical or beta-barrel channels. Such transformations occur in pore forming toxins such as colicin A, alpha-hemolysin, and others. They may also occur in BcL-2 like protein , in some amphiphilic antimicrobial peptides , and in certain annexins . These proteins are usually described as peripheral as one of their conformational states is water-soluble or only loosely associated with a membrane.
== Membrane binding mechanisms ==
The association of a protein with a lipid bilayer may involve significant changes within tertiary structure of a protein. These may include the folding of regions of protein structure that were previously unfolded or a re-arrangement in the folding or a refolding of the membrane-associated part of the proteins. It also may involve the formation or dissociation of protein quaternary structures or oligomeric complexes, and specific binding of ions, ligands, or regulatory lipids.
Typical amphitropic proteins must interact strongly with the lipid bilayer in order to perform their biological functions. These include the enzymatic processing of lipids and other hydrophobic substances, membrane anchoring, and the binding and transfer of small nonpolar compounds between different cellular membranes. These proteins may be anchored to the bilayer as a result of hydrophobic interactions between the bilayer and exposed nonpolar residues at the surface of a protein, by specific non-covalent binding interactions with regulatory lipids , or through their attachment to covalently bound lipid anchors.
It has been shown that the membrane binding affinities of many peripheral proteins depend on the specific lipid composition of the membrane with which they are associated.
=== Non-specific hydrophobic association ===
Amphitropic proteins associate with lipid bilayers via various hydrophobic anchor structures. Such as amphiphilic α-helixes, exposed nonpolar loops, post-translationally acylated or lipidated amino acid residues, or acyl chains of specifically bound regulatory lipids such as phosphatidylinositol phosphates. Hydrophobic interactions have been shown to be important even for highly cationic peptides and proteins, such as the polybasic domain of the MARCKS protein or histactophilin, when their natural hydrophobic anchors are present.
=== Covalently bound lipid anchors ===
Lipid anchored proteins are covalently attached to different fatty acid acyl chains on the cytoplasmic side of the cell membrane via palmitoylation, myristoylation, or prenylation. On the exoplasmic face of the cell membrane, lipid anchored proteins are covalently attached to the lipids glycosylphosphatidylinositol (GPI) and cholesterol. Protein association with membranes through the use of acylated residues is a reversible process, as the acyl chain can be buried in a protein's hydrophobic binding pocket after dissociation from the membrane. This process occurs within the beta-subunits of G-proteins. Perhaps because of this additional need for structural flexibility, lipid anchors are usually bound to the highly flexible segments of proteins tertiary structure that are not well resolved by protein crystallographic studies.
=== Specific protein–lipid binding ===
Some cytosolic proteins are recruited to different cellular membranes by recognizing certain types of lipid found within a given membrane. Binding of a protein to a specific lipid occurs via specific membrane-targeting structural domains that occur within the protein and have specific binding pockets for the lipid head groups of the lipids to which they bind. This is a typical biochemical protein–ligand interaction, and is stabilized by the formation of intermolecular hydrogen bonds, van der Waals interactions, and hydrophobic interactions between the protein and lipid ligand. Such complexes are also stabilized by the formation of ionic bridges between the aspartate or glutamate residues of the protein and lipid phosphates via intervening calcium ions (Ca2+). Such ionic bridges can occur and are stable when ions (such as Ca2+) are already bound to a protein in solution, prior to lipid binding. The formation of ionic bridges is seen in the protein–lipid interaction between both protein C2 type domains and annexins..
=== Protein–lipid electrostatic interactions ===
Any positively charged protein will be attracted to a negatively charged membrane by nonspecific electrostatic interactions. However, not all peripheral peptides and proteins are cationic, and only certain sides of membrane are negatively charged. These include the cytoplasmic side of plasma membranes, the outer leaflet of bacterial outer membranes and mitochondrial membranes. Therefore, electrostatic interactions play an important role in membrane targeting of electron carriers such as cytochrome c, cationic toxins such as charybdotoxin, and specific membrane-targeting domains such as some PH domains, C1 domains, and C2 domains.
Electrostatic interactions are strongly dependent on the ionic strength of the solution. These interactions are relatively weak at the physiological ionic strength (0.14M NaCl): ~3 to 4 kcal/mol for small cationic proteins, such as cytochrome c, charybdotoxin or hisactophilin.
== Spatial position in membrane ==
Orientations and penetration depths of many amphitropic proteins and peptides in membranes are studied using site-directed spin labeling, chemical labeling, measurement of membrane binding affinities of protein mutants, fluorescence spectroscopy, solution or solid-state NMR spectroscopy,
ATR FTIR spectroscopy, X-ray or neutron diffraction, and computational methods.
Two distinct membrane-association modes of proteins have been identified. Typical water-soluble proteins have no exposed nonpolar residues or any other hydrophobic anchors. Therefore, they remain completely in aqueous solution and do not penetrate into the lipid bilayer, which would be energetically costly. Such proteins interact with bilayers only electrostatically, for example, ribonuclease and poly-lysine interact with membranes in this mode. However, typical amphitropic proteins have various hydrophobic anchors that penetrate the interfacial region and reach the hydrocarbon interior of the membrane. Such proteins "deform" the lipid bilayer, decreasing the temperature of lipid fluid-gel transition. The binding is usually a strongly exothermic reaction. Association of amphiphilic α-helices with membranes occurs similarly. Intrinsically unstructured or unfolded peptides with nonpolar residues or lipid anchors can also penetrate the interfacial region of the membrane and reach the hydrocarbon core, especially when such peptides are cationic and interact with negatively charged membranes.
== Categories ==
=== Enzymes ===
Peripheral enzymes participate in metabolism of different membrane components, such as lipids (phospholipases and cholesterol oxidases), cell wall oligosaccharides (glycosyltransferase and transglycosidases), or proteins (signal peptidase and palmitoyl protein thioesterases). Lipases can also digest lipids that form micelles or nonpolar droplets in water.
=== Membrane-targeting domains ("lipid clamps") ===
Membrane-targeting domains associate specifically with head groups of their lipid ligands embedded into the membrane. These lipid ligands are present in different concentrations in distinct types of biological membranes (for example, PtdIns3P can be found mostly in membranes of early endosomes, PtdIns(3,5)P2 in late endosomes, and PtdIns4P in the Golgi). Hence, each domain is targeted to a specific membrane.
C1 domains and phorbol esters.
C2 domains bind phosphatidylserine, phosphatidylcholine or PtdIns(3,4)P2 or PtdIns(4,5)P2.
Pleckstrin homology domains, PX domains, and Tubby domains bind different phosphoinositides
FYVE domains are more specific for PtdIns3P.
ENTH domains bind PtdIns(3,4)P2 or PtdIns(4,5)P2.
ANTH domain binds PtdIns(4,5)P2.
Proteins from ERM (ezrin/radixin/moesin) family bind PtdIns(4,5)P2.
Other phosphoinositide-binding proteins include phosphotyrosine-binding domain and certain PDZ domains. They bind PtdIns(4,5)P2.
Discoidin domains of blood coagulation factors
ENTH, VHS and ANTH domains
=== Structural domains ===
Structural domains mediate attachment of other proteins to membranes. Their binding to membranes can be mediated by calcium ions (Ca2+) that form bridges between the acidic protein residues and phosphate groups of lipids, as in annexins or GLA domains.
=== Transporters of small hydrophobic molecules ===
These peripheral proteins function as carriers of non-polar compounds between different types of cell membranes or between membranes and cytosolic protein complexes. The transported substances are phosphatidylinositol, tocopherol, gangliosides, glycolipids, sterol derivatives, retinol, fatty acids, water, macromolecules, red blood cells, phospholipids, and nucleotides.
Glycolipid transfer proteins
Lipocalins including retinol binding proteins and fatty acid-binding proteins
Polyisoprenoid-binding protein, such as YceI protein domain
Ganglioside GM2 activator proteins
CRAL-TRIO domain (α-Tocopherol and phosphatidylinositol sec14p transfer proteins)
Sterol carrier proteins
Phosphatidylinositol transfer proteins and STAR domains
Oxysterol-binding protein
=== Electron carriers ===
These proteins are involved in electron transport chains. They include cytochrome c, cupredoxins, high potential iron protein, adrenodoxin reductase, some flavoproteins, and others.
=== Polypeptide hormones, toxins, and antimicrobial peptides ===
Many hormones, toxins, inhibitors, or antimicrobial peptides interact specifically with transmembrane protein complexes. They can also accumulate at the lipid bilayer surface, prior to binding their protein targets. Such polypeptide ligands are often positively charged and interact electrostatically with anionic membranes.
Some water-soluble proteins and peptides can also form transmembrane channels. They usually undergo oligomerization, significant conformational changes, and associate with membranes irreversibly. 3D structure of one such transmembrane channel, α-hemolysin, has been determined. In other cases, the experimental structure represents a water-soluble conformation that interacts with the lipid bilayer peripherally, although some of the channel-forming peptides are rather hydrophobic and therefore were studied by NMR spectroscopy in organic solvents or in the presence of micelles.
== See also ==
Lipoproteins
Membrane proteins
== References ==
== Further reading ==
== External links ==
Peripheral membrane proteins in OPM database
DOLOP Genomics-oriented database of bacterial lipoproteins
Peptaibol database
Antimicrobial Peptide Database Archived 2011-07-20 at the Wayback Machine | Wikipedia/Peripheral_membrane_protein |
Vertebrate Palaeontology is a basic textbook on vertebrate paleontology by Michael J. Benton, published by Blackwell's. It has so far appeared in five editions, published in 1990, 1997, 2005, 2014, and 2024. It is designed for paleontology graduate courses in biology and geology as well as for the interested layman.
The book is widely used, and has received excellent reviews:
"This book is a ′must′ for a biology or geology student and researcher concerned by palaeontology. It perfectly succeeds in showing how palaeobiological information is obtained". Review of 3rd edition, Zentrallblatt fur Geologie und Palaontologie, 2007.
"One anticipates that Benton's Vertebrate Palaeontology will become the 'industry standard', and as such it should occupy space on the shelves of all involved in undergraduate teaching". Ivan Sansom, School of Earth Sciences, University of Birmingham. Review of the 2nd edition for the Micropalaeontological Society.
"... his expertise in a range of problems of vertebrate paleontology is amazing. As a result the contents of his book [are] very well balanced". Jerzy Dzik, Instytut Palaeobiologii PAN, Warsaw. Review of the 3rd edition for the Journal of Sedimentary Research.
The book gives an overall account of every major group of living and fossil vertebrate. At the rear of the book is a phylogenetic classification which combines both the Linnaean hierarchy and the cladistic arrangement, and has been used as a guideline for the Wikipedia pages on living and extinct vertebrate taxa. However, some of Benton's classification differs from that in the Tree of Life Web Project, especially as regards the relationship of early amphibian groups (Batrachomorpha and Reptiliomorpha).
== Bibliography ==
Benton, M. J. (2005), Vertebrate Palaeontology, 3rd ed. Blackwell Science Ltd
Benton, M. J. (2014), Vertebrate Palaeontology, 4th ed. Wiley-Blackwell
Publisher's Website and Book Overview: 3rd edition, edition
Benton, M. J. (1995) Paleontología y evolución de los Vertebrados. Ed. Perfils. ISBN 978-84-87695-16-2. Spanish translation by Aurora Grandal-d'Anglade upon the first edition.
Benton, M. J. (2007), Paläontologie der Wirbeltiere, Verlag Dr. Friedrich Pfeil. German translation by Hans-Ulrich Pfretzschner based upon the third edition.
== References == | Wikipedia/Vertebrate_Palaeontology_(book) |
Science Advances is a peer-reviewed multidisciplinary open-access scientific journal established in early 2015 and published by the American Association for the Advancement of Science. The journal's scope includes all areas of science.
== History ==
The journal was announced by the American Association for the Advancement of Science in February 2014, and the first articles were published in early 2015. In 2019, Science Advances surpassed Science Magazine in the number of monthly submissions, becoming the largest member in the Science family of journals. It is the only member of that family where all papers are gold open access.
== Editorial structure and journal scope ==
The journal's scope includes all areas of science, including life sciences, public health, neurosciences, physical sciences, social sciences, computer sciences, environmental sciences, and space sciences. Editorial decisions are made by the editorial board. The board is divided into topical areas, each led by a deputy editor and composed of a group of associate editors. Unlike other members of the Science family of journals published by AAAS, editors at Science Advances are working scientists.
== Open access policies ==
All content published in the journal is freely accessible to readers. As of 2019, the article processing charge for articles published under a Creative Commons license is $4,950. When the journal was launched, its policy of using a default open license which does not permit commercial usage (CC NC-BY) was criticized by open access advocates, who preferred the less restrictive license that allows any use as long as attribution is provided (CC BY).
== See also ==
Nature Communications, a journal related to Nature as Science Advances is to Science
== References ==
== External links ==
Official website | Wikipedia/Science_Advances |
José María Ferrater Mora (Catalan: Josep Ferrater i Mora; 30 October 1912 – 30 January 1991) was a Spanish philosopher, essayist and writer. He is considered the most prominent Catalan philosopher of the 20th-century and was the author of over 35 books, including a four-volume Diccionario de filosofía (Dictionary of Philosophy, 1941) and Being and Death: An Outline of Integrationist Philosophy (1962). Subjects he worked on include ontology, history of philosophy, metaphysics, anthropology, the philosophy of history and culture, epistemology, logic, philosophy of science, and ethics. He also directed several films.
Ferrater Mora was known for his inclusion of humans and non-human animals within the same moral sphere, or continuum, arguing that the difference was one of degree, not kind.
== Biography ==
Ferrater Mora was born in 1912, in Barcelona, Spain. He studied at Santa Maria del Collell, then at the University of Barcelona, where he earned a BA, in 1932, and his BPhil, in 1936.
During the Spanish Civil War, he enlisted in the Republican Army, serving as an intelligence clerk, before escaping the country in 1939. In exile, he spent three months in Paris, before moving to and lecturing in Havana, Cuba, and Santiago, Chile.
After receiving a Guggenheim Fellowship, he moved to the United States, first residing in New York City. In 1949, Ferrater Mora was hired by Bryn Mawr College to teach philosophy and Spanish literature, where he worked till his retirement, in 1981. He married Priscilla Cohn (his former doctoral student) in 1980.
Ferrater Mora died from a heart attack, on 30 January 1991, while visiting Barcelona.
== Philosophy ==
Ferrater Mora is the creator of a philosophical method he called integrationism, with which he sought to integrate opposite systems of thought. He argued that irreducible concepts, which are the source of many disputes and divisions in philosophy, do not denote existing realities in themselves but are "limit concepts"; that is to say, these "opposite poles" do not exist absolutely. They exist only as trends or directions of reality and therefore are complementary and are useful to talk about it.
His philosophical work also focused on questions of an ontological nature. He called his ontological position "monism sui generis", since it unites monism and pluralism; it is an emergentism in which the elements assemble themselves by virtue of their properties or functions, or properties-functions. Each structure, although it depends to exist on the elements that compose it, is not reducible to them because it acquires new properties-functions that cannot be explained based on those of the element. The structure also becomes an element for a new structure. Self-assembly begins from the physical level to the point where structures acquire more complex properties-functions and of a different order to give rise to a new biological level, and thus the continuum progresses until reaching the social and then the cultural level. It is a continuum that does not break and that goes from matter to reason.
He was one of the first philosophers to introduce applied ethics to the Spanish-speaking world and was a staunch supporter of animal rights.
His works combine a wide variety of influences, including the Spanish philosophers Miguel de Unamuno, Eugenio d'Ors and José Ortega y Gasset and numerous other representatives of both continental and analytic philosophy.
== Legacy ==
In January 1991, Ferrater Mora made public the decision to donate his personal library to the University of Girona. The collection consists of 7,255 books, 156 journal titles and correspondence, with 6,748 letters. The correspondence includes letters between Ferrater Mora and his friends, politicians and intellectuals of the time. This collection also includes letters from his departure into exile in the 1940s (Cuba, Chile and the United States), until his death in 1991. Other documents of interest include related writings, with politics and culture sent by personalities of the time: Xavier Benguerel, Enrique Tierno Galván, Néstor Almendros and Josep Trueta, among many others.
Founded in 1989, the Ferrater Mora Chair in Contemporary Thought, regularly organizes seminars and lessons on contemporary philosophy.
The Ferrater Mora Oxford Centre for Animal Ethics is named in his honour.
== Selected works ==
The following works are in Spanish, unless otherwise noted:
Dictionary of Philosophy (Mexico: Atlante, 1941)
Spain and Europe (Santiago de Chile: Cruz del Sur, 1942)
The Forms of Catalan Life (Santiago de Chile: Agrupació Patriòtica Catalana, 1944), in Catalan and Spanish
Unamuno: Outline of a Philosophy (Buenos Aires: Losada, 1944)
Four Visions of Universal History (Buenos Aires: Losada, 1945)
Spanish Issues (Mexico: Colegio de México, 1945)
Variations on the Spirit (Buenos Aires: South American, 1945)
The Irony, the Death and the Admiration (Santiago de Chile: Cruz del Sur, 1946)
The Meaning of Death (Buenos Aires: South American, 1947)
The Book of Meaning (Santiago de Chile: Pi de les Tres Branques, 1948), in Catalan
Hellenism and Christianity (Santiago de Chile: University of Chile, 1949)
The Man at the Crossroads (Buenos Aires: South American, 1952)
Disputed Questions: Essays on Philosophy (Madrid: Revista de Occidente, 1955)
Mathematical Logic (Mexico: Fondo de Cultura Económica, 1955), co-authored with Hugues Leblanc
Ortega y Gasset: An Outline of His Philosophy (London: Bowes and New Haven: Yale University, 1957), in English
What Is Logic (Buenos Aires: Columba, 1957)
Philosophy in Today's World (Madrid: Revista de Occidente, 1959)
Being and Death: Outline of Integrationist Philosophy (Madrid: Aguilar, 1962)
Three Worlds: Catalonia, Spain, Europe (Barcelona and Buenos Aires: EDHASA, 1963)
Being and Meaning (Madrid: Revista de Occidente, 1967)
Inquiries About Language (Madrid: Alianza, 1970)
Words and Men (Barcelona: 62, 1970), in Catalan
Man and His Environment and Other Essays (Madrid: Siglo Veintiuno, 1971)
Shift in Philosophy (Madrid: Alianza, 1974)
Cinema Without Philosophies (Madrid: Esti-Arte, 1974)
From Matter to Reason (Madrid: Alianza, 1979)
Seven Capital Stories (Barcelona: Planeta, 1979)
Applied Ethics: From Abortion to Violence (Madrid: Alianza, 1981), co-authored with Priscilla Cohn
Claudia, My Claudia (Madrid: Alianza, 1982)
The World of the Writer (Barcelona: Crítica, 1983)
Ways of Doing Philosophy (Barcelona: Crítica, 1985)
Voltaire in New York (Madrid: Alianza, 1985)
Foundations of Philosophy (Madrid: Alianza, 1985)
Made in Corona (Madrid: Alianza, 1986)
Window to the World (Barcelona: Crítica, 1986)
Dictionary of Great Philosophers 2 (Madrid: Alianza, 1986)
The Truth Game (Barcelona: Ediciones Destino, 1988)
Return from Hell (Barcelona: Anthropos, 1989)
Miss Goldie (Barcelona: Seix Barral, 1991)
Women on the Verge of Legend (Barcelona: Círculo de readers, 1991)
Butterflies and Superstrings: Dictionary for Our Time (Barcelona: Peninsula, 1994)
== Awards ==
Ferrater Mora received honorary degrees from the following universities: the Autonomous University of Barcelona (Spain, 1979), the University of the Republic (Uruguay, 1983), the National University of Tucumán (Argentina, 1983), the National University of Colombia (1983), the National University of Distance Education (Spain, 1986), the National University of Salta (Argentina, 1986), the National University of Cuyo (Argentina, 1988), the University of Barcelona (1988) and the University of Santiago de Compostela (posthumous; Spain, 1991).
In 1982, he was awarded the Cross of the Order of Isabella the Catholic.
In 1984, he was awarded the Creu de Sant Jordi of the Generalitat de Catalunya and the Grand Cross of the Civil Order of Alfonso X, the Wise.
In 1985, he was awarded the Prince of Asturias Award for Communication and Humanities.
In addition to being a numerus clausus member of the International Institute of Philosophy and various academic societies, he belonged to the North American Academy of the Spanish Language.
== See also ==
List of animal rights advocates
== References ==
== Further reading ==
Horta, Óscar. La filosofía moral de J. Ferrater Mora. Documenta Universitaria, Girona, 2008.
== External links ==
Works by José Ferrater Mora at Internet Archive
Josep Ferrater Mora Foundation
Ferrater Mora Collection (University of Girona Library)
Ferrater Mora Correspondence in the University of Girona DUGi Repository
Los derechos de los animales ("Animal rights"; the first essay on animal rights published in Spain) | Wikipedia/José_Ferrater_Mora |
Science is the peer-reviewed academic journal of the American Association for the Advancement of Science (AAAS) and one of the world's top academic journals. It was first published in 1880, is currently circulated weekly and has a subscriber base of around 130,000. Because institutional subscriptions and online access serve a larger audience, its estimated readership is over 400,000 people.
Science is based in Washington, D.C., United States, with a second office in Cambridge, UK.
== Contents ==
The major focus of the journal is publishing important original scientific research and research reviews, but Science also publishes science-related news, opinions on science policy and other matters of interest to scientists and others who are concerned with the wide implications of science and technology. Unlike most scientific journals, which focus on a specific field, Science and its rival Nature cover the full range of scientific disciplines. According to the Journal Citation Reports, Science's 2023 impact factor was 44.7.
Studies of methodological quality and reliability have found that some high-prestige journals including Science "publish significantly substandard structures", and overall "reliability of published research works in several fields may be decreasing with increasing journal rank".
Although it is the journal of the AAAS, membership in the AAAS is not required to publish in Science. Papers are accepted from authors around the world. Competition to publish in Science is very intense, as an article published in such a highly cited journal can lead to attention and career advancement for the authors. Fewer than 7% of articles submitted are accepted for publication.
== History ==
Science was founded by New York journalist John Michels in 1880 with financial support from Thomas Edison and later from Alexander Graham Bell. (Edison received favorable editorial treatment in return, without disclosure of the financial relationship, at a time when his reputation was suffering due to delays producing the promised commercially viable light bulb.) However, the journal never gained enough subscribers to succeed and ended publication in March 1882. Alexander Graham Bell and Gardiner Greene Hubbard bought the magazine rights and hired young entomologist Samuel H. Scudder to resurrect the journal one year later. They had some success while covering the meetings of prominent American scientific societies, including the AAAS. However, by 1894, Science was again in financial difficulty and was sold to psychologist James McKeen Cattell for $500 (equivalent to $18,170 in 2024).
In an agreement worked out by Cattell and AAAS secretary Leland O. Howard, Science became the journal of the American Association for the Advancement of Science in 1900. During the early part of the 20th century, important articles published in Science included papers on fruit fly genetics by Thomas Hunt Morgan, gravitational lensing by Albert Einstein, and spiral nebulae by Edwin Hubble. After Cattell died in 1944, the ownership of the journal was transferred to the AAAS.
After Cattell's death in 1944, the journal lacked a consistent editorial presence until Graham DuShane became editor in 1956. In 1958, under DuShane's leadership, Science absorbed The Scientific Monthly, thus increasing the journal's circulation by over 62% from 38,000 to more than 61,000. Physicist Philip Abelson, a co-discoverer of neptunium, served as editor from 1962 to 1984. Under Abelson the efficiency of the review process was improved and the publication practices were brought up to date. During this time, papers on the Apollo program missions and some of the earliest reports on AIDS were published.
Biochemist Daniel E. Koshland Jr. served as editor from 1985 until 1995. From 1995 until 2000, neuroscientist Floyd E. Bloom held that position. Biologist Donald Kennedy became the editor of Science in 2000. Biochemist Bruce Alberts took his place in March 2008. Geophysicist Marcia McNutt became editor-in-chief in June 2013. During her tenure the family of journals expanded to include Science Robotics and Science Immunology, and open access publishing with Science Advances. Jeremy M. Berg became editor-in-chief on July 1, 2016. Former Washington University in St. Louis Provost Holden Thorp was named editor-in-chief on Monday, August 19, 2019.
In February 2001, draft results of the human genome were simultaneously published by Nature and Science with Science publishing the Celera Genomics paper and Nature publishing the publicly funded Human Genome Project. In 2007, Science (together with Nature) received the Prince of Asturias Award for Communications and Humanity. In 2015, Rush D. Holt Jr., chief executive officer of the AAAS and executive publisher of Science, stated that the journal was becoming increasingly international: "[I]nternationally co-authored papers are now the norm—they represent almost 60 percent of the papers. In 1992, it was slightly less than 20 percent."
== Availability ==
The latest editions of the journal are available online, through the main journal website, only to subscribers, AAAS members, and for delivery to IP addresses at institutions that subscribe; students, K–12 teachers, and some others can subscribe at a reduced fee. However, research articles published after 1997 are available free (with online registration) one year after they are published i.e. delayed open access. Significant public-health related articles are also available free, sometimes immediately after publication. AAAS members may also access the pre-1997 Science archives at the Science website, where it is called "Science Classic".
The journal also participates in initiatives that provide free or low-cost access to readers in developing countries, including HINARI, OARE, AGORA, and Scidev.net.
Other features of the Science website include the free "ScienceNow" section with "up to the minute news from science", and "ScienceCareers", which provides free career resources for scientists and engineers. Science Express (Sciencexpress) provides advance electronic publication of selected Science papers.
== Affiliations ==
Science received funding for COVID-19-related coverage from the Pulitzer Center and the Heising-Simons Foundation.
== See also ==
AAAS publications
Breakthrough of the Year
List of scientific journals
== References ==
=== AAAS references ===
== External links ==
Official website | Wikipedia/Science_Magazine |
Nova ScienceNow (styled NOVΛ scienceNOW) is a spinoff of the long-running and venerable PBS science program Nova. Premiering on January 25, 2005, the series was originally hosted by Robert Krulwich, who described it as an experiment in coverage of "breaking science, science that's right out of the lab, science that sometimes bumps up against politics, art, culture". At the beginning of season two, Neil deGrasse Tyson replaced Krulwich as the show's host. Tyson announced he would leave the show and was replaced by David Pogue in season 6.
The show was originally intended to return with more new episodes in 2015.
== Production ==
Unlike the parent program Nova, Nova ScienceNow has a whimsical production style. It is not unusual for the show to explain topics as arcane as RNA interference using cartoons, or a solution to a two-thousand-year-old math problem related in song. Whereas Nova covered a single seamless subject in each hour-long episode, NOVA scienceNOW covers several related, but distinct, story segments during the course of each program. The show also features 30–60 second short segments between each story segment, taking the place and pace of commercials in an otherwise uninterrupted program flow.
The show's humor turns on cultural references aimed at viewers from a broad spectrum of age groups. These references, for example, come from movies, TV, music, history, literature, and of course, science.
Following the whimsical format, the show's animators often place jokes or sight gags into the show's background via humorous or incongruous bits of text in signs, newspapers, etc. These gags are intentionally subtle and meant to be difficult to recognize, presumably as a challenge to the viewer's observational skills.
When Tyson became host, he added a final segment in which he would add his own observations on the topic. At the end of this editorial, he always states, "And that... is the cosmic perspective."
The series has been nominated for four Emmy Awards and won a CINE Golden Eagle award.
== Cast ==
Host Robert Krulwich left the program at the end of the first season. He was replaced by astrophysicist Dr. Neil deGrasse Tyson, director of the Hayden Planetarium. In addition to the host, several correspondents report on many of the individual stories including Peter Standring, Chad Cohen, Ziya Tong, Carla Wohl, Rebecca Skloot, and David Duncan. David Pogue is the host of the show's sixth season.
== Seasons ==
== Episodes ==
=== Season 1 (2005–06) ===
=== Season 2 (2006–07) ===
=== Season 3 (2008) ===
=== Season 4 (2009) ===
=== Season 5 (2011) ===
=== Season 6 (2012) ===
== Reception ==
NOVΛ scienceNOW has received generally positive reviews from television critics and parents of young children. New York Daily News wrote, "★★★★ Lightyears from the norm."
== References ==
== External links ==
Nova ScienceNow Home page
NOVA scienceNOW at IMDb | Wikipedia/Nova_ScienceNow |
Any enzyme system that includes cytochrome P450 protein or domain can be called a P450-containing system.
P450 enzymes usually function as a terminal oxidase in multicomponent electron-transfer chains, called P450-containing monooxygenase systems, although self-sufficient, non-monooxygenase P450s have been also described. All known P450-containing monooxygenase systems share common structural and functional domain architecture. Apart from the cytochrome itself, these systems contain one or more fundamental redox domains: FAD-containing flavoprotein or domain, FMN domain, ferredoxin and cytochrome b5. These ubiquitous redox domains, in various combinations, are widely distributed in biological systems. FMN domain, ferredoxin or cytochrome b5 transfer electrons between the flavin reductase (protein or domain) and P450. While P450-containing systems are found throughout all kingdoms of life, some organisms lack one or more of these redox domains.
== FR/Fd/P450 systems ==
Mitochondrial and some bacterial P450 systems employ soluble Fe2S2 ferredoxins (Fd) that act as single electron carriers between FAD-containing ferredoxin reductase (FR) and P450. In mitochondrial monooxygenase systems, adrenodoxin functions as a soluble electron carrier between NADPH:adrenodoxin reductase and several membrane-bound P450s (CYP11A, CYP11B, CYP27). In bacteria, putidaredoxin, terpredoxin, and rhodocoxin serve as electron carriers between corresponding NADH-dependent ferredoxin reductases and soluble P450s (CYP101, CYP108, CYP116).
The general scheme of electron flow in the P450 systems containing adrenodoxin-type ferredoxins is:
The sterol demethylase system from Mycobacterium tuberculosis contains flavoprotein reductase A (FprA), bacterial-type Fe3S4 ferredoxin and CYP51 hemoprotein.
== CPR/P450 systems ==
Eukaryotic microsomal P450 enzymes and some bacterial P450s receive electrons from a FAD- and FMN-containing enzyme known as cytochrome P450 reductase (CPR; EC 1.6.2.4). Microsomal CPR is membrane-bound protein that interacts with different P450s. In Bacillus megaterium and Bacillus subtilis, CPR is a C-terminal domain of CYP102, a single polypeptide self-sufficient soluble P450 system (P450 is an N-terminal domain). The general scheme of electron flow in the CPR/P450 system is:
== CBR/b5/P450 systems ==
The ubiquitous electron-transport protein cytochrome b5 can serve as an effector (activator or inhibitor) of P450s. It was hypothesized that cytochrome b5 is involved in the transfer of the second electron to P450, either from CPR or from NADH:cytochrome b5 reductase (CBR; EC 1.6.2.2):
The ability of the CBR/cytochrome b5 system to support P450 catalysis has been demonstrated in vitro using purified CBR and cytochrome b5 from Saccharomyces cerevisiae and CYP51 enzyme from Candida albicans. In this system, both the first and second electrons are donated by CBR.
== FMN/Fd/P450 systems ==
An unusual one-component P450 system was originally found in Rhodococcus sp. NCIMB 9784 (CYP116B2). In this system, the N-terminal P450 domain is fused to the reductase domain that shows sequence similarity to phthalate dioxygenase reductase and consists, in its turn, of FMN-binding domain and C-terminal plant-type ferredoxin domain. Similar systems have been identified in the heavy-metal-tolerant bacterium Ralstonia metallidurans (CYP116A1) and in several species of Burkolderia.
The general scheme of electron flow in this system appears to be:
== P450-only systems ==
Nitric oxide reductase (P450nor) is a P450 enzyme involved in denitrification in several fungal species. The best-characterized P450nor is CYP55A1 from Fusarium oxysporum. This enzyme does not have monooxygenase activity but is able to reduce nitric oxide (NO·) to form nitrous oxide (N2O) directly using NAD(P)H as electron donor:
Fatty acid β-hydroxylase P450BSβ from Bacillus subtilis (CYP152A1) and fatty acid α-hydroxylase P450SPα from Pseudomonas paucimobilis (CYP152B1) catalyse the hydroxylation reaction of long-chain fatty acids using hydrogen peroxide (H2O2) as an oxidant. These enzymes do not require any reduction system for catalysis.
Allene oxide synthase (CYP74A; EC 4.2.1.92), fatty acid hydroperoxide lyase (CYP74B), prostacyclin synthase (CYP8; EC 5.3.99.4) and thromboxane synthase (CYP5; EC 5.3.99.5) are examples of P450 enzymes that do not require a reductase or molecular oxygen for their catalytic activity. Substrates for all these enzymes are fatty acid derivatives containing partially reduced dioxygen (either hydroperoxy or epidioxy groups).
== References ==
== External links ==
Directory of P450-containing Systems | Wikipedia/P450-containing_systems |
Macromolecular docking is the computational modelling of the quaternary structure of complexes formed by two or more interacting biological macromolecules. Protein–protein complexes are the most commonly attempted targets of such modelling, followed by protein–nucleic acid complexes.
The ultimate goal of docking is the prediction of the three-dimensional structure of the macromolecular complex of interest as it would occur in a living organism. Docking itself only produces plausible candidate structures. These candidates must be ranked using methods such as scoring functions to identify structures that are most likely to occur in nature.
The term "docking" originated in the late 1970s, with a more restricted meaning; then, "docking" meant refining a model of a complex structure by optimizing the separation between the interactors but keeping their relative orientations fixed. Later, the relative orientations of the interacting partners in the modelling was allowed to vary, but the internal geometry of each of the partners was held fixed. This type of modelling is sometimes referred to as "rigid docking". With further increases in computational power, it became possible to model changes in internal geometry of the interacting partners that may occur when a complex is formed. This type of modelling is referred to as "flexible docking".
== Background ==
The biological roles of most proteins, as characterized by which other macromolecules they interact with, are known at best incompletely. Even those proteins that participate in a well-studied biological process (e.g., the Krebs cycle) may have unexpected interaction partners or functions which are unrelated to that process.
In cases of known protein–protein interactions, other questions arise. Genetic diseases (e.g., cystic fibrosis) are known to be caused by misfolded or mutated proteins, and there is a desire to understand what, if any, anomalous protein–protein interactions a given mutation can cause. In the distant future, proteins may be designed to perform biological functions, and a determination of the potential interactions of such proteins will be essential.
For any given set of proteins, the following questions may be of interest, from the point of view of technology or natural history:
Do these proteins bind in vivo?
If they do bind,
What is the spatial configuration which they adopt in their bound state?
How strong or weak is their interaction?
If they do not bind,
Can they be made to bind by inducing a mutation?
Protein–protein docking is ultimately envisaged to address all these issues. Furthermore, since docking methods can be based on purely physical principles, even proteins of unknown function (or which have been studied relatively little) may be docked. The only prerequisite is that their molecular structure has been either determined experimentally, or can be estimated by a protein structure prediction technique.
Protein–nucleic acid interactions feature prominently in the living cell. Transcription factors, which regulate gene expression, and polymerases, which catalyse replication, are composed of proteins, and the genetic material they interact with is composed of nucleic acids. Modeling protein–nucleic acid complexes presents some unique challenges, as described below.
== History ==
In the 1970s, complex modelling revolved around manually identifying features on the surfaces of the interactors, and interpreting the consequences for binding, function and activity; any computer programmes were typically used at the end of the modelling process, to discriminate between the relatively few configurations which remained after all the heuristic constraints had been imposed. The first use of computers was in a study on hemoglobin interaction in sickle-cell fibres. This was followed in 1978 by work on the trypsin-BPTI complex. Computers discriminated between good and bad models using a scoring function which rewarded large interface area, and pairs of molecules in contact but not occupying the same space. The computer used a simplified representation of the interacting proteins, with one interaction centre for each residue. Favorable electrostatic interactions, including hydrogen bonds, were identified by hand.
In the early 1990s, more structures of complexes were determined, and available computational power had increased substantially. With the emergence of bioinformatics, the focus moved towards developing generalized techniques which could be applied to an arbitrary set of complexes at acceptable computational cost. The new methods were envisaged to apply even in the absence of phylogenetic or experimental clues; any specific prior knowledge could still be introduced at the stage of choosing between the highest ranking output models, or be framed as input if the algorithm catered for it.
1992 saw the publication of the correlation method, an algorithm which used the fast Fourier transform to give a vastly improved scalability for evaluating coarse shape complementarity on rigid-body models. This was extended in 1997 to cover coarse electrostatics.
In 1996 the results of the first blind trial were published, in which six research groups attempted to predict the complexed structure of TEM-1 Beta-lactamase with Beta-lactamase inhibitor protein (BLIP). The exercise brought into focus the necessity of accommodating conformational change and the difficulty of discriminating between conformers. It also served as the prototype for the CAPRI assessment series, which debuted in 2001.
== Rigid-body docking vs. flexible docking ==
If the bond angles, bond lengths and torsion angles of the components are not modified at any stage of complex generation, it is known as rigid body docking. A subject of speculation is whether or not rigid-body docking is sufficiently good for most docking. When substantial conformational change occurs within the components at the time of complex formation, rigid-body docking is inadequate. However, scoring all possible conformational changes is prohibitively expensive in computer time. Docking procedures which permit conformational change, or flexible docking procedures, must intelligently select small subset of possible conformational changes for consideration.
== Methods ==
Successful docking requires two criteria:
Generating a set of configurations which reliably includes at least one nearly correct one.
Reliably distinguishing nearly correct configurations from the others.
For many interactions, the binding site is known on one or more of the proteins to be docked. This is the case for antibodies and for competitive inhibitors. In other cases, a binding site may be strongly suggested by mutagenic or phylogenetic evidence. Configurations where the proteins interpenetrate severely may also be ruled out a priori.
After making exclusions based on prior knowledge or stereochemical clash, the remaining space of possible complexed structures must be sampled exhaustively, evenly and with a sufficient coverage to guarantee a near hit. Each configuration must be scored with a measure that is capable of ranking a nearly correct structure above at least 100,000 alternatives. This is a computationally intensive task, and a variety of strategies have been developed.
=== Reciprocal space methods ===
Each of the proteins may be represented as a simple cubic lattice. Then, for the class of scores which are discrete convolutions, configurations related to each other by translation of one protein by an exact lattice vector can all be scored almost simultaneously by applying the convolution theorem. It is possible to construct reasonable, if approximate, convolution-like scoring functions representing both stereochemical and electrostatic fitness.
Reciprocal space methods have been used extensively for their ability to evaluate enormous numbers of configurations. They lose their speed advantage if torsional changes are introduced. Another drawback is that it is impossible to make efficient use of prior knowledge. The question also remains whether convolutions are too limited a class of scoring function to identify the best complex reliably.
=== Monte Carlo methods ===
In Monte Carlo, an initial configuration is refined by taking random steps which are accepted or rejected based on their induced improvement in score (see the Metropolis criterion), until a certain number of steps have been tried. The assumption is that convergence to the best structure should occur from a large class of initial configurations, only one of which needs to be considered. Initial configurations may be sampled coarsely, and much computation time can be saved. Because of the difficulty of finding a scoring function which is both highly discriminating for the correct configuration and also converges to the correct configuration from a distance, the use of two levels of refinement, with different scoring functions, has been proposed. Torsion can be introduced naturally to Monte Carlo as an additional property of each random move.
Monte Carlo methods are not guaranteed to search exhaustively, so that the best configuration may be missed even using a scoring function which would in theory identify it. How severe a problem this is for docking has not been firmly established.
== Evaluation ==
=== Scoring functions ===
To find a score which forms a consistent basis for selecting the best configuration, studies are carried out on a standard benchmark (see below) of protein–protein interaction cases. Scoring functions are assessed on the rank they assign to the best structure (ideally the best structure should be ranked 1), and on their coverage (the proportion of the benchmark cases for which they achieve an acceptable result).
Types of scores studied include:
Heuristic scores based on residue contacts.
Shape complementarity of molecular surfaces ("stereochemistry").
Free energies, estimated using parameters from molecular mechanics force fields such as CHARMM or AMBER.
Phylogenetic desirability of the interacting regions.
Clustering coefficients.
Information based cues.
It is usual to create hybrid scores by combining one or more categories above in a weighted sum whose weights are optimized on cases from the benchmark. To avoid bias, the benchmark cases used to optimize the weights must not overlap with the cases used to make the final test of the score.
The ultimate goal in protein–protein docking is to select the ideal ranking solution according to a scoring scheme that would also give an insight into the affinity of the complex. Such a development would drive in silico protein engineering, computer-aided drug design and/or high-throughput annotation of which proteins bind or not (annotation of interactome). Several scoring functions have been proposed for binding affinity / free energy prediction. However the correlation between experimentally determined binding affinities and the predictions of nine commonly used scoring functions have been found to be nearly orthogonal (R2 ~ 0). It was also observed that some components of the scoring algorithms may display better correlation to the experimental binding energies than the full score, suggesting that a significantly better performance might be obtained by combining the appropriate contributions from different scoring algorithms. Experimental methods for the determination of binding affinities are: surface plasmon resonance (SPR), Förster resonance energy transfer, radioligand-based techniques, isothermal titration calorimetry (ITC), microscale thermophoresis (MST) or spectroscopic measurements and other fluorescence techniques. Textual information from scientific articles can provide useful cues for scoring.
=== Benchmarks ===
A benchmark of 84 protein–protein interactions with known complexed structures has been developed for testing docking methods. The set is chosen to cover a wide range of interaction types, and to avoid repeated features, such as the profile of interactors' structural families according to the SCOP database. Benchmark elements are classified into three levels of difficulty (the most difficult containing the largest change in backbone conformation). The protein–protein docking benchmark contains examples of enzyme-inhibitor, antigen-antibody and homomultimeric complexes.
The latest version of protein-protein docking benchmark consists of 230 complexes. A protein-DNA docking benchmark consists of 47 test cases. A protein-RNA docking benchmark was curated as a dataset of 45 non-redundant test cases with complexes solved by X-ray crystallography only as well as an extended dataset of 71 test cases with structures derived from homology modelling as well. The protein-RNA benchmark has been updated to include more structures solved by X-ray crystallography and now it consists of 126 test cases. The benchmarks have a combined dataset of 209 complexes.
A binding affinity benchmark has been based on the protein–protein docking benchmark. 81 protein–protein complexes with known experimental affinities are included; these complexes span over 11 orders of magnitude in terms of affinity. Each entry of the benchmark includes several biochemical parameters associated with the experimental data, along with the method used to determine the affinity. This benchmark was used to assess the extent to which scoring functions could also predict affinities of macromolecular complexes.
This Benchmark was post-peer reviewed and significantly expanded. The new set is diverse in terms of the biological functions it represents, with complexes that involve G-proteins and receptor extracellular domains, as well as antigen/antibody, enzyme/inhibitor, and enzyme/substrate complexes. It is also diverse in terms of the partners' affinity for each other, with Kd ranging between 10−5 and 10−14 M. Nine pairs of entries represent closely related complexes that have a similar structure, but a very different affinity, each pair comprising a cognate and a noncognate assembly. The unbound structures of the component proteins being available, conformation changes can be assessed. They are significant in most of the complexes, and large movements or disorder-to-order transitions are frequently observed. The set may be used to benchmark biophysical models aiming to relate affinity to structure in protein–protein interactions, taking into account the reactants and the conformation changes that accompany the association reaction, instead of just the final product.
=== The CAPRI assessment ===
The Critical Assessment of PRediction of Interactions is an ongoing series of events in which researchers throughout the community try to dock the same proteins, as provided by the assessors. Rounds take place approximately every 6 months. Each round contains between one and six target protein–protein complexes whose structures have been recently determined experimentally. The coordinates and are held privately by the assessors, with the cooperation of the structural biologists who determined them. The assessment of submissions is double blind.
CAPRI attracts a high level of participation (37 groups participated worldwide in round seven) and a high level of interest from the biological community in general. Although CAPRI results are of little statistical significance owing to the small number of targets in each round, the role of CAPRI in stimulating discourse is significant. (The CASP assessment is a similar exercise in the field of protein structure prediction).
== See also ==
Biomolecular complex – any biological complex of protein, RNA, DNA (sometimes has lipids and carbohydrates)
Docking (molecular) – small molecule docking to proteins
== References == | Wikipedia/Protein–protein_docking |
Mitochondrial trifunctional protein (MTP) is a protein attached to the inner mitochondrial membrane which catalyzes three out of the four steps in beta oxidation. MTP is a hetero-octamer composed of four alpha and four beta subunits:
HADHA
HADHB
The three functions are 2-enoyl coenzyme A (CoA) hydratase, long-chain 3-hydroxy acyl-coenzyme A dehydrogenase and long-chain 3-ketoacyl CoA thiolase.
== Association with the electron transport chain ==
Fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two major metabolic pathways in the mitochondria. Reducing equivalents from FAO enter OXPHOS at the level of complexes I and III. In 2010, Wang et al. discovered a functional and physical association between MTP and ETC respirasomes. Not only does MTP appear to be bound to Complex I, but it also appears to channel substrates between the two enzymes. This is especially interesting, because up until then it was unknown exactly how MTP was associated with the inner mitochondrial membrane, and this discovery may provide the explanation.
== Hormonal influences ==
Recent research has revealed that MTP can be affected by various hormones, via hormone receptors located in the mitochondria. Chochron et al. (2012) demonstrated that thyroid hormone stimulates mitochondrial metabolism in a pathway mediated by MTP. Zhou et al. (2012) used 2D gel electrophoresis and mass spectrometry to identify MTP as one of the proteins that interacts with ER alpha, a receptor triggered by estrogen.
== Cardiolipin remodeling ==
In 2009, Taylor et al. identified a human mitochondrial protein, monolysocardiolipin acyltransferase (MLCL AT-1), that is identical in amino acid sequence to the 59-kDa C-terminal end of MTP, linking MTP to the remodeling of cardiolipin from monolysocardiolipin. Although MLCL AT-1 and MTP are different proteins, in 2012 the same lab discovered that MTP did indeed have cardiolipin remodeling capabilities. This suggests a possible link between mitochondrial membrane cardiolipin content and beta oxidation.
== Clinical significance ==
Disorders associated with MTP are:
Mitochondrial trifunctional protein deficiency
LCHAD deficiency
Acute fatty liver of pregnancy
== References ==
== External links ==
mitochondrial+trifunctional+protein+TP at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Mitochondrial_trifunctional_protein |
The oxoglutarate dehydrogenase complex (OGDC) or α-ketoglutarate dehydrogenase complex is an enzyme complex, most commonly known for its role in the citric acid cycle.
== Units ==
Much like pyruvate dehydrogenase complex (PDC), this enzyme forms a complex composed of three components:
Three classes of these multienzyme complexes have been characterized: one specific for pyruvate, a second specific for 2-oxoglutarate, and a third specific for branched-chain α-keto acids. The oxoglutarate dehydrogenase complex has the same subunit structure and thus uses the same cofactors as the pyruvate dehydrogenase complex and the branched-chain alpha-keto acid dehydrogenase complex (TPP, CoA, lipoate, FAD and NAD). Only the E3 subunit is shared in common between the three enzymes.
== Properties ==
=== Metabolic pathways ===
This enzyme participates in three different pathways:
Citric acid cycle (KEGG link: MAP00020)
Lysine degradation (KEGG link: MAP00310)
Tryptophan metabolism (KEGG link: MAP00380)
=== Kinetic properties ===
The following values are from Azotobacter vinelandii (1):
KM: 0.14 ± 0.04 mM
Vmax : 9 ± 3 μmol.min−1.mg−1
== Citric acid cycle ==
=== Reaction ===
The reaction catalyzed by this enzyme in the citric acid cycle is:
α-ketoglutarate + NAD+ + CoA → Succinyl CoA + CO2 + NADH
This reaction proceeds in three steps:
decarboxylation of α-ketoglutarate,
reduction of NAD+ to NADH,
and subsequent transfer to CoA, which forms the end product, succinyl CoA.
ΔG°' for this reaction is -7.2 kcal mol−1. The energy needed for this oxidation is conserved in the formation of a thioester bond of succinyl CoA.
=== Regulation ===
Oxoglutarate dehydrogenase is a key control point in the citric acid cycle. It is inhibited by its products, succinyl CoA and NADH. A high energy charge in the cell will also be inhibitive. ADP and calcium ions are allosteric activators of the enzyme.
By controlling the amount of available reducing equivalents generated by the Krebs cycle, Oxoglutarate dehydrogenase has a downstream regulatory effect on oxidative phosphorylation and ATP production. Reducing equivalents (such as NAD+/NADH) supply the electrons that run through the electron transport chain of oxidative phosphorylation. Increased Oxoglutarate dehydrogenase activation levels serve to increase the concentrations of NADH relative to NAD+. High NADH concentrations stimulate an increase in flux through oxidative phosphorylation.
While an increase in flux through this pathway generates ATP for the cell, the pathway also generates free radical species as a side product, which can cause oxidative stress to the cells if left to accumulate.
Oxoglutarate dehydrogenase is considered to be a redox sensor in the mitochondria, and has an ability to change the functioning level of mitochondria to help prevent oxidative damage. In the presence of a high concentration of free radical species, Oxoglutarate dehydrogenase undergoes fully reversible free radical mediated inhibition. In extreme cases, the enzyme can also undergo complete oxidative inhibition.
When mitochondria are treated with excess hydrogen peroxide, flux through the electron transport chain is reduced, and NADH production is halted. Upon consumption and removal of the free radical source, normal mitochondrial function is restored.
It is believed that the temporary inhibition of mitochondrial function stems from the reversible glutathionylation of the E2-lipoac acid domain of Oxoglutarate dehydrogenase. Glutathionylation, a form of post-translational modification, occurs during times of increased concentrations of free radicals, and can be undone after hydrogen peroxide consumption via glutaredoxin. Glutathionylation "protects" the lipoic acid of the E2 domain from undergoing oxidative damage, which helps spare the Oxoglutarate dehydrogenase complex from oxidative stress.
Oxoglutarate dehydrogenase activity is turned off in the presence of free radicals in order to protect the enzyme from damage. Once free radicals are consumed by the cell, the enzyme's activity is turned back on via glutaredoxin. The reduction in activity of the enzyme under times of oxidative stress also serves to slow the flux through the electron transport chain, which slows production of free radicals.
In addition to free radicals and the mitochondrial redox state, Oxoglutarate dehydrogenase activity is also regulated by ATP/ADP ratios, the ratio of Succinyl-CoA to CoA-SH, and the concentrations of various metal ion cofactors (Mg2+, Ca2+). Many of these allosteric regulators act at the E1 domain of the enzyme complex, but all three domains of the enzyme complex can be allosterically controlled. The activity of the enzyme complex is upregulated with high levels of ADP and Pi, Ca2+, and CoA-SH. The enzyme is inhibited by high ATP levels, high NADH levels, and high Succinyl-CoA concentrations.
=== Stress response ===
Oxoglutarate dehydrogenase plays a role in the cellular response to stress. The enzyme complex undergoes a stress-mediated temporary inhibition upon acute exposure to stress. The temporary inhibition period sparks a stronger up-regulation response, allowing an increased level of oxoglutarate dehydrogenase activity to compensate for the acute stress exposure. Acute exposures to stress are usually at lower, tolerable levels for the cell.
Pathophysiologies can arise when the stress becomes cumulative or develops into chronic stress. The up-regulation response that occurs after acute exposure can become exhausted if the inhibition of the enzyme complex becomes too strong. Stress in cells can cause a deregulation in the biosynthesis of the neurotransmitter glutamate. Glutamate toxicity in the brain is caused by a buildup of glutamate under times of stress. If oxoglutarate dehydrogenase activity is dysfunctional (no adaptive stress compensation), the build-up of glutamate cannot be fixed, and brain pathologies can ensue. Dysfunctional oxoglutarate dehydrogenase may also predispose the cell to damage from other toxins that can cause neurodegeneration.
== Pathology ==
2-Oxo-glutarate dehydrogenase is an autoantigen recognized in primary biliary cirrhosis, a form of acute liver failure. These antibodies appear to recognize oxidized protein that has resulted from inflammatory immune responses. Some of these inflammatory responses are explained by gluten sensitivity. Other mitochondrial autoantigens include pyruvate dehydrogenase and branched-chain alpha-keto acid dehydrogenase complex, which are antigens recognized by anti-mitochondrial antibodies.
Activity of the 2-oxoglutarate dehydrogenase complex is decreased in many neurodegenerative diseases. Alzheimer's disease, Parkinson's disease, Huntington disease, and supranuclear palsy are all associated with an increased oxidative stress level in the brain. Specifically for Alzheimer Disease patients, the activity of oxoglutarate dehydrogenase is significantly diminished. This leads to a possibility that the portion of the TCA cycle responsible for causing the build-up of free radical species in the brain of patients is a malfunctioning oxoglutarate dehydrogenase complex. The mechanism for disease-related inhibition of this enzyme complex remains relatively unknown.
In the metabolic disease combined malonic and methylmalonic aciduria (CMAMMA) due to ACSF3 deficiency, mitochondrial fatty acid synthesis (mtFASII) is impaired, which is the precursor reaction of lipoic acid biosynthesis. The result is a reduced lipoylation degree of important mitochondrial enzymes, such as oxoglutarate dehydrogenase complex (OGDC).
== References ==
== Further reading ==
== External links ==
Oxoglutarate+dehydrogenase at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Oxoglutarate_dehydrogenase_complex |
A vaccine is a biological preparation that provides active acquired immunity to a particular infectious or malignant disease. The safety and effectiveness of vaccines has been widely studied and verified. A vaccine typically contains an agent that resembles a disease-causing microorganism and is often made from weakened or killed forms of the microbe, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and recognize further and destroy any of the microorganisms associated with that agent that it may encounter in the future.
Vaccines can be prophylactic (to prevent or alleviate the effects of a future infection by a natural or "wild" pathogen), or therapeutic (to fight a disease that has already occurred, such as cancer). Some vaccines offer full sterilizing immunity, in which infection is prevented.
The administration of vaccines is called vaccination. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the restriction of diseases such as polio, measles, and tetanus from much of the world. The World Health Organization (WHO) reports that licensed vaccines are available for twenty-five different preventable infections.
The first recorded use of inoculation to prevent smallpox (see variolation) occurred in the 16th century in China, with the earliest hints of the practice in China coming during the 10th century. It was also the first disease for which a vaccine was produced. The folk practice of inoculation against smallpox was brought from Turkey to Britain in 1721 by Lady Mary Wortley Montagu.
The terms vaccine and vaccination are derived from Variolae vaccinae (smallpox of the cow), the term devised by Edward Jenner (who both developed the concept of vaccines and created the first vaccine) to denote cowpox. He used the phrase in 1798 for the long title of his Inquiry into the Variolae vaccinae Known as the Cow Pox, in which he described the protective effect of cowpox against smallpox. In 1881, to honor Jenner, Louis Pasteur proposed that the terms should be extended to cover the new protective inoculations then being developed. The science of vaccine development and production is termed vaccinology.
== Effectiveness ==
There is overwhelming scientific consensus that vaccines are a very safe and effective way to fight and eradicate infectious diseases. The immune system recognizes vaccine agents as foreign, destroys them, and "remembers" them. When the virulent version of an agent is encountered, the body recognizes the protein coat on the agent, and thus is prepared to respond, by first neutralizing the target agent before it can enter cells, and secondly by recognizing and destroying infected cells before that agent can multiply to vast numbers.
In 1958, there were 763,094 cases of measles in the United States; 552 deaths resulted. After the introduction of new vaccines, the number of cases dropped to fewer than 150 per year (median of 56). In early 2008, there were 64 suspected cases of measles. Fifty-four of those infections were associated with importation from another country, although only thirteen percent were actually acquired outside the United States; 63 of the 64 individuals either had never been vaccinated against measles or were uncertain whether they had been vaccinated.
The measles vaccine is estimated to prevent a million deaths every year.
Vaccines led to the eradication of smallpox, one of the most contagious and deadly diseases in humans. Other diseases such as rubella, polio, measles, mumps, chickenpox, and typhoid are nowhere near as common as they were a hundred years ago thanks to widespread vaccination programs. As long as the vast majority of people are vaccinated, it is much more difficult for an outbreak of disease to occur, let alone spread. This effect is called herd immunity. Polio, which is transmitted only among humans, is targeted by an extensive eradication campaign that has seen endemic polio restricted to only parts of three countries (Afghanistan, Nigeria, and Pakistan). However, the difficulty of reaching all children, cultural misunderstandings, and disinformation have caused the anticipated eradication date to be missed several times.
Vaccines also help prevent the development of antibiotic resistance. For example, by greatly reducing the incidence of pneumonia caused by Streptococcus pneumoniae, vaccine programs have greatly reduced the prevalence of infections resistant to penicillin or other first-line antibiotics.
=== Limitations ===
Limitations to their effectiveness, nevertheless, exist. Sometimes, protection fails for vaccine-related reasons such as failures in vaccine attenuation, vaccination regimens or administration.
Failure may also occur for host-related reasons if the host's immune system does not respond adequately or at all. Host-related lack of response occurs in an estimated 2-10% of individuals, due to factors including genetics, immune status, age, health and nutritional status. One type of primary immunodeficiency disorder resulting in genetic failure is X-linked agammaglobulinemia, in which the absence of an enzyme essential for B cell development prevents the host's immune system from generating antibodies to a pathogen.
Host–pathogen interactions and responses to infection are dynamic processes involving multiple pathways in the immune system. A host does not develop antibodies instantaneously: while the body's innate immunity may be activated in as little as twelve hours, adaptive immunity can take 1–2 weeks to fully develop. During that time, the host can still become infected.
Once antibodies are produced, they may promote immunity in any of several ways, depending on the class of antibodies involved. Their success in clearing or inactivating a pathogen will depend on the amount of antibodies produced and on the extent to which those antibodies are effective at countering the strain of the pathogen involved, since different strains may be differently susceptible to a given immune reaction.
In some cases vaccines may result in partial immune protection (in which immunity is less than 100% effective but still reduces risk of infection) or in temporary immune protection (in which immunity wanes over time) rather than full or permanent immunity. They can still raise the reinfection threshold for the population as a whole and make a substantial impact. They can also mitigate the severity of infection, resulting in a lower mortality rate, lower morbidity, faster recovery from illness, and a wide range of other effects.
Those who are older often display less of a response than those who are younger, a pattern known as Immunosenescence.
Adjuvants commonly are used to boost immune response, particularly for older people whose immune response to a simple vaccine may have weakened.
The efficacy or performance of the vaccine is dependent on several factors:
the disease itself (for some diseases vaccination performs better than for others)
the strain of vaccine (some vaccines are specific to, or at least most effective against, particular strains of the disease)
whether the vaccination schedule has been properly observed.
idiosyncratic response to vaccination; some individuals are "non-responders" to certain vaccines, meaning that they do not generate antibodies even after being vaccinated correctly.
assorted factors such as ethnicity, age, or genetic predisposition.
If a vaccinated individual does develop the disease vaccinated against (breakthrough infection), the disease is likely to be less severe and less transmissible than in unvaccinated cases.
Important considerations in an effective vaccination program:
careful modeling to anticipate the effect that an immunization campaign will have on the epidemiology of the disease in the medium to long term
ongoing surveillance for the relevant disease following introduction of a new vaccine
maintenance of high immunization rates, even when a disease has become rare
== Safety ==
Vaccinations given to children, adolescents, or adults are generally safe. Adverse effects, if any, are generally mild. The rate of side effects depends on the vaccine in question. Some common side effects include fever, pain around the injection site, and muscle aches. Additionally, some individuals may be allergic to ingredients in the vaccine. The MMR vaccine is rarely associated with febrile seizures.
Host-("vaccinee")-related determinants that render a person susceptible to infection, such as genetics, health status (underlying disease, nutrition, pregnancy, sensitivities or allergies), immune competence, age, and economic impact or cultural environment can be primary or secondary factors affecting the severity of infection and response to a vaccine. Elderly (above age 60), allergen-hypersensitive, and obese people have susceptibility to compromised immunogenicity, which prevents or inhibits vaccine effectiveness, possibly requiring separate vaccine technologies for these specific populations or repetitive booster vaccinations to limit virus transmission.
Severe side effects are extremely rare. Varicella vaccine is rarely associated with complications in immunodeficient individuals, and rotavirus vaccines are moderately associated with intussusception.
At least 19 countries have no-fault compensation programs to provide compensation for those with severe adverse effects of vaccination. The United States' program is known as the National Childhood Vaccine Injury Act, and the United Kingdom employs the Vaccine Damage Payment.
== Types ==
Vaccines typically contain attenuated, inactivated or dead organisms or purified products derived from them. There are several types of vaccines in use. These represent different strategies used to try to reduce the risk of illness while retaining the ability to induce a beneficial immune response.
=== Attenuated ===
Some vaccines contain live, attenuated microorganisms. Many of these are active viruses that have been cultivated under conditions that disable their virulent properties, or that use closely related but less dangerous organisms to produce a broad immune response. Although most attenuated vaccines are viral, some are bacterial in nature. Examples include the viral diseases yellow fever, measles, mumps, and rubella, and the bacterial disease typhoid. The live Mycobacterium tuberculosis vaccine developed by Calmette and Guérin is not made of a contagious strain but contains a virulently modified strain called "BCG" used to elicit an immune response to the vaccine. The live attenuated vaccine containing strain Yersinia pestis EV is used for plague immunization. Attenuated vaccines have some advantages and disadvantages. Attenuated, or live, weakened, vaccines typically provoke more durable immunological responses. Attenuated vaccines also elicit a cellular and humoral response. However, they may not be safe for use in immunocompromised individuals, and on rare occasions mutate to a virulent form and cause disease.
=== Inactivated ===
Some vaccines contain microorganisms that have been killed or inactivated by physical or chemical means. Examples include IPV (polio vaccine), hepatitis A vaccine, rabies vaccine and most influenza vaccines.
=== Toxoid ===
Toxoid vaccines are made from inactivated toxic compounds that cause illness rather than the microorganism. Examples of toxoid-based vaccines include tetanus and diphtheria. Not all toxoids are for microorganisms; for example, Crotalus atrox toxoid is used to vaccinate dogs against rattlesnake bites.
=== Subunit ===
Rather than introducing an inactivated or attenuated microorganism to an immune system (which would constitute a "whole-agent" vaccine), a subunit vaccine uses a fragment of it to create an immune response. One example is the subunit vaccine against hepatitis B, which is composed of only the surface proteins of the virus (previously extracted from the blood serum of chronically infected patients but now produced by recombination of the viral genes into yeast). Other examples include the Gardasil virus-like particle human papillomavirus (HPV) vaccine, the hemagglutinin and neuraminidase subunits of the influenza virus, and edible algae vaccines. A subunit vaccine is being used for plague immunization.
=== Conjugate ===
Certain bacteria have a polysaccharide outer coat that is poorly immunogenic. By linking these outer coats to proteins (e.g., toxins), the immune system can be led to recognize the polysaccharide as if it were a protein antigen. This approach is used in the Haemophilus influenzae type B vaccine.
=== Outer membrane vesicle ===
Outer membrane vesicles (OMVs) are naturally immunogenic and can be manipulated to produce potent vaccines. The best known OMV vaccines are those developed for serotype B meningococcal disease.
=== Heterotypic ===
Heterologous vaccines also known as "Jennerian vaccines", are vaccines that are pathogens of other animals that either do not cause disease or cause mild disease in the organism being treated. The classic example is Jenner's use of cowpox to protect against smallpox. A current example is the use of BCG vaccine made from Mycobacterium bovis to protect against tuberculosis.
=== Genetic vaccine ===
Genetic vaccines are based on the principle of uptake of a nucleic acid into cells, whereupon a protein is produced according to the nucleic acid template. This protein is usually the immunodominant antigen of the pathogen or a surface protein that enables the formation of neutralizing antibodies. The subgroup of genetic vaccines encompass viral vector vaccines, RNA vaccines and DNA vaccines.
==== Viral vector ====
Viral vector vaccines use a safe virus to insert pathogen genes in the body to produce specific antigens, such as surface proteins, to stimulate an immune response. Viruses being researched for use as viral vectors include adenovirus, vaccinia virus, and VSV.
==== RNA ====
An mRNA vaccine (or RNA vaccine) is a novel type of vaccine which is composed of the nucleic acid RNA, packaged within a vector such as lipid nanoparticles. Among the COVID-19 vaccines are a number of RNA vaccines to combat the COVID-19 pandemic and some have been approved or have received emergency use authorization in some countries. For example, the Pfizer-BioNTech vaccine and Moderna mRNA vaccine are approved for use in adults and children in the US.
==== DNA ====
A DNA vaccine uses a DNA plasmid (pDNA)) that encodes for an antigenic protein originating from the pathogen upon which the vaccine will be targeted. pDNA is inexpensive, stable, and relatively safe, making it an excellent option for vaccine delivery.
This approach offers a number of potential advantages over traditional approaches, including the stimulation of both B- and T-cell responses, improved vaccine stability, the absence of any infectious agent and the relative ease of large-scale manufacture.
=== Experimental ===
Many innovative vaccines are also in development and use.
Dendritic cell vaccines combine dendritic cells with antigens to present the antigens to the body's white blood cells, thus stimulating an immune reaction. These vaccines have shown some positive preliminary results for treating brain tumors and are also tested in malignant melanoma.
Recombinant vector – by combining the physiology of one microorganism and the DNA of another, immunity can be created against diseases that have complex infection processes. An example is the RVSV-ZEBOV vaccine licensed to Merck that is being used in 2018 to combat ebola in Congo.
T-cell receptor peptide vaccines are under development for several diseases using models of Valley Fever, stomatitis, and atopic dermatitis. These peptides have been shown to modulate cytokine production and improve cell-mediated immunity.
Targeting of identified bacterial proteins that are involved in complement inhibition would neutralize the key bacterial virulence mechanism.
The use of plasmids has been validated in preclinical studies as a protective vaccine strategy for cancer and infectious diseases. However, in human studies, this approach has failed to provide clinically relevant benefit. The overall efficacy of plasmid DNA immunization depends on increasing the plasmid's immunogenicity while also correcting for factors involved in the specific activation of immune effector cells.
Bacterial vector – Similar in principle to viral vector vaccines, but using bacteria instead.
Antigen-presenting cell
Technologies which may allow rapid vaccine deployment in response to a novel pathogen include the use of virus-like particles or protein nanoparticles.
Inverse vaccines are vaccines that train the immune system to not respond to certain substances.
While most vaccines are created using inactivated or attenuated compounds from microorganisms, synthetic vaccines are composed mainly or wholly of synthetic peptides, carbohydrates, or antigens.
== Valence ==
Vaccines may be monovalent (also called univalent) or multivalent (also called polyvalent). A monovalent vaccine is designed to immunize against a single antigen or single microorganism. A multivalent or polyvalent vaccine is designed to immunize against two or more strains of the same microorganism, or against two or more microorganisms. The valency of a multivalent vaccine may be denoted with a Greek or Latin prefix (e.g., bivalent, trivalent, or tetravalent/quadrivalent). In certain cases, a monovalent vaccine may be preferable for rapidly developing a strong immune response.
=== Interactions ===
When two or more vaccines are mixed in the same formulation, the two vaccines can interfere. This most frequently occurs with live attenuated vaccines, where one of the vaccine components is more robust than the others and suppresses the growth and immune response to the other components.
This phenomenon was noted in the trivalent Sabin polio vaccine, where the relative amount of serotype 2 virus in the vaccine had to be reduced to stop it from interfering with the "take" of the serotype 1 and 3 viruses in the vaccine. To accomplish this, the doses of serotypes 1 and 3 were increased in the vaccine in the early 1960s. It was also noted in a 2001 study to be a problem with dengue vaccines, where the DEN-3 serotype was found to predominate and suppress the response to DEN-1, -2 and -4 serotypes.
== Other contents ==
=== Adjuvants ===
Vaccines typically contain one or more adjuvants, used to boost the immune response. Tetanus toxoid, for instance, is usually adsorbed onto alum. This presents the antigen in such a way as to produce a greater action than the simple aqueous tetanus toxoid. People who have an adverse reaction to adsorbed tetanus toxoid may be given the simple vaccine when the time comes for a booster.
In the preparation for the 1990 Persian Gulf campaign, the whole cell pertussis vaccine was used as an adjuvant for anthrax vaccine. This produces a more rapid immune response than giving only the anthrax vaccine, which is of some benefit if exposure might be imminent.
=== Preservatives ===
Vaccines may also contain preservatives to prevent contamination with bacteria or fungi. Until recent years, the preservative thiomersal (a.k.a. Thimerosal in the US and Japan) was used in many vaccines that did not contain live viruses. As of 2005, the only childhood vaccine in the U.S. that contains thiomersal in greater than trace amounts is the influenza vaccine, which is currently recommended only for children with certain risk factors. Single-dose influenza vaccines supplied in the UK do not list thiomersal in the ingredients. Preservatives may be used at various stages of the production of vaccines, and the most sophisticated methods of measurement might detect traces of them in the finished product, as they may in the environment and population as a whole.
Many vaccines need preservatives to prevent serious adverse effects such as Staphylococcus infection, which in one 1928 incident killed 12 of 21 children inoculated with a diphtheria vaccine that lacked a preservative. Several preservatives are available, including thiomersal, phenoxyethanol, and formaldehyde. Thiomersal is more effective against bacteria, has a better shelf-life, and improves vaccine stability, potency, and safety; however, in the U.S., the European Union, and a few other affluent countries, it is no longer used as a preservative in childhood vaccines, as a precautionary measure due to its mercury content. Although controversial claims have been made that thiomersal contributes to autism, no convincing scientific evidence supports these claims. Furthermore, a 10–11-year study of 657,461 children found that the MMR vaccine does not cause autism and actually reduced the risk of autism by seven percent.
=== Excipients ===
Beside the active vaccine itself, the following excipients and residual manufacturing compounds are present or may be present in vaccine preparations:
Aluminum salts or gels are added as adjuvants. Adjuvants are added to promote an earlier, more potent response, and more persistent immune response to the vaccine; they allow for a lower vaccine dosage.
Antibiotics are added to some vaccines to prevent the growth of bacteria during production and storage of the vaccine.
Egg protein is present in the influenza vaccine and yellow fever vaccine as they are prepared using chicken eggs. Other proteins may be present.
Formaldehyde is used to inactivate bacterial products for toxoid vaccines. Formaldehyde is also used to inactivate unwanted viruses and kill bacteria that might contaminate the vaccine during production.
Monosodium glutamate (MSG) and 2-phenoxyethanol are used as stabilizers in a few vaccines to help the vaccine remain unchanged when the vaccine is exposed to heat, light, acidity, or humidity.
Thiomersal is a mercury-containing antimicrobial that is added to vials of vaccines that contain more than one dose to prevent contamination and growth of potentially harmful bacteria. Due to the controversy surrounding thiomersal, it has been removed from most vaccines except multi-use influenza, where it was reduced to levels so that a single dose contained less than a microgram of mercury, a level similar to eating ten grams of canned tuna.
== Nomenclature ==
Various fairly standardized abbreviations for vaccine names have developed, although the standardization is by no means centralized or global. For example, the vaccine names used in the United States have well-established abbreviations that are also widely known and used elsewhere. An extensive list of them provided in a sortable table and freely accessible is available at a US Centers for Disease Control and Prevention web page. The page explains that "The abbreviations [in] this table (Column 3) were standardized jointly by staff of the Centers for Disease Control and Prevention, ACIP Work Groups, the editor of the Morbidity and Mortality Weekly Report (MMWR), the editor of Epidemiology and Prevention of Vaccine-Preventable Diseases (the Pink Book), ACIP members, and liaison organizations to the ACIP."
Some examples are "DTaP" for diphtheria and tetanus toxoids and acellular pertussis vaccine, "DT" for diphtheria and tetanus toxoids, and "Td" for tetanus and diphtheria toxoids. At its page on tetanus vaccination, the CDC further explains that "Upper-case letters in these abbreviations denote full-strength doses of diphtheria (D) and tetanus (T) toxoids and pertussis (P) vaccine. Lower-case "d" and "p" denote reduced doses of diphtheria and pertussis used in the adolescent/adult-formulations. The 'a' in DTaP and Tdap stands for 'acellular', meaning that the pertussis component contains only a part of the pertussis organism."
Another list of established vaccine abbreviations is at the CDC's page called "Vaccine Acronyms and Abbreviations", with abbreviations used on U.S. immunization records. The United States Adopted Name system has some conventions for the word order of vaccine names, placing head nouns first and adjectives postpositively. This is why the USAN for "OPV" is "poliovirus vaccine live oral" rather than "oral poliovirus vaccine".
== Licensing ==
A vaccine licensure occurs after the successful conclusion of the development cycle and further the clinical trials and other programs involved through Phases I–III demonstrating safety, immunoactivity, immunogenetic safety at a given specific dose, proven effectiveness in preventing infection for target populations, and enduring preventive effect (time endurance or need for revaccination must be estimated). Because preventive vaccines are predominantly evaluated in healthy population cohorts and distributed among the general population, a high standard of safety is required. As part of a multinational licensing of a vaccine, the World Health Organization Expert Committee on Biological Standardization developed guidelines of international standards for manufacturing and quality control of vaccines, a process intended as a platform for national regulatory agencies to apply for their own licensing process. Vaccine manufacturers do not receive licensing until a complete clinical cycle of development and trials proves the vaccine is safe and has long-term effectiveness, following scientific review by a multinational or national regulatory organization, such as the European Medicines Agency (EMA) or the US Food and Drug Administration (FDA).
Upon developing countries adopting WHO guidelines for vaccine development and licensure, each country has its own responsibility to issue a national licensure, and to manage, deploy, and monitor the vaccine throughout its use in each nation. Building trust and acceptance of a licensed vaccine among the public is a task of communication by governments and healthcare personnel to ensure a vaccination campaign proceeds smoothly, saves lives, and enables economic recovery. When a vaccine is licensed, it will initially be in limited supply due to variable manufacturing, distribution, and logistical factors, requiring an allocation plan for the limited supply and which population segments should be prioritized to first receive the vaccine.
=== World Health Organization ===
Vaccines developed for multinational distribution via the United Nations Children's Fund (UNICEF) require pre-qualification by the WHO to ensure international standards of quality, safety, immunogenicity, and efficacy for adoption by numerous countries.
The process requires manufacturing consistency at WHO-contracted laboratories following Good Manufacturing Practice (GMP). When UN agencies are involved in vaccine licensure, individual nations collaborate by 1) issuing marketing authorization and a national license for the vaccine, its manufacturers, and distribution partners; and 2) conducting postmarketing surveillance, including records for adverse events after the vaccination program. The WHO works with national agencies to monitor inspections of manufacturing facilities and distributors for compliance with GMP and regulatory oversight.
Some countries choose to buy vaccines licensed by reputable national organizations, such as EMA, FDA, or national agencies in other affluent countries, but such purchases typically are more expensive and may not have distribution resources suitable to local conditions in developing countries.
=== European Union ===
In the European Union (EU), vaccines for pandemic pathogens, such as seasonal influenza, are licensed EU-wide where all the member states comply ("centralized"), are licensed for only some member states ("decentralized"), or are licensed on an individual national level. Generally, all EU states follow regulatory guidance and clinical programs defined by the European Committee for Medicinal Products for Human Use (CHMP), a scientific panel of the European Medicines Agency (EMA) responsible for vaccine licensure. The CHMP is supported by several expert groups who assess and monitor the progress of a vaccine before and after licensure and distribution.
=== United States ===
Under the FDA, the process of establishing evidence for vaccine clinical safety and efficacy is the same as for the approval process for prescription drugs. If successful through the stages of clinical development, the vaccine licensing process is followed by a Biologics License Application which must provide a scientific review team (from diverse disciplines, such as physicians, statisticians, microbiologists, chemists) and comprehensive documentation for the vaccine candidate having efficacy and safety throughout its development. Also during this stage, the proposed manufacturing facility is examined by expert reviewers for GMP compliance, and the label must have a compliant description to enable health care providers' definition of vaccine-specific use, including its possible risks, to communicate and deliver the vaccine to the public. After licensure, monitoring of the vaccine and its production, including periodic inspections for GMP compliance, continue as long as the manufacturer retains its license, which may include additional submissions to the FDA of tests for potency, safety, and purity for each vaccine manufacturing step.
=== India ===
In India, the Drugs Controller General, the head of department of the Central Drugs Standard Control Organization, India's national regulatory body for cosmetics, pharmaceuticals and medical devices, is responsible for the approval of licences for specified categories of drugs such as vaccines and other medicinal items, such as blood or blood products, IV fluids, and sera.
=== Postmarketing surveillance ===
Until a vaccine is in use amongst the general population, all potential adverse events from the vaccine may not be known, requiring manufacturers to conduct Phase IV studies for postmarketing surveillance of the vaccine while it is used widely in the public. The WHO works with UN member states to implement post-licensing surveillance. The FDA relies on a Vaccine Adverse Event Reporting System to monitor safety concerns about a vaccine throughout its use in the American public.
== Scheduling ==
In order to provide the best protection, children are recommended to receive vaccinations as soon as their immune systems are sufficiently developed to respond to particular vaccines, with additional "booster" shots often required to achieve "full immunity". This has led to the development of complex vaccination schedules. Global recommendations of vaccination schedule are issued by Strategic Advisory Group of Experts and will be further translated by advisory committee at the country level with considering of local factors such as disease epidemiology, acceptability of vaccination, equity in local populations, and programmatic and financial constraint. In the United States, the Advisory Committee on Immunization Practices, which recommends schedule additions for the Centers for Disease Control and Prevention, recommends routine vaccination of children against hepatitis A, hepatitis B, polio, mumps, measles, rubella, diphtheria, pertussis, tetanus, HiB, chickenpox, rotavirus, influenza, meningococcal disease and pneumonia.
The large number of vaccines and boosters recommended (up to 24 injections by age two) has led to problems with achieving full compliance. To combat declining compliance rates, various notification systems have been instituted and many combination injections are now marketed (e.g., Pentavalent vaccine and MMRV vaccine), which protect against multiple diseases.
Besides recommendations for infant vaccinations and boosters, many specific vaccines are recommended for other ages or for repeated injections throughout life – most commonly for measles, tetanus, influenza, and pneumonia. Pregnant women are often screened for continued resistance to rubella. The human papillomavirus vaccine is recommended in the U.S. (as of 2011) and UK (as of 2009). Vaccine recommendations for the elderly concentrate on pneumonia and influenza, which are more deadly to that group. In 2006, a vaccine was introduced against shingles, a disease caused by the chickenpox virus, which usually affects the elderly.
Scheduling and dosing of a vaccination may be tailored to the level of immunocompetence of an individual and to optimize population-wide deployment of a vaccine when its supply is limited, e.g. in the setting of a pandemic.
== Economics of development ==
One challenge in vaccine development is economic: Many of the diseases most demanding a vaccine, including HIV, malaria and tuberculosis, exist principally in poor countries. Pharmaceutical firms and biotechnology companies have little incentive to develop vaccines for these diseases because there is little revenue potential. Even in more affluent countries, financial returns are usually minimal and the financial and other risks are great.
Most vaccine development to date has relied on "push" funding by government, universities and non-profit organizations. Many vaccines have been highly cost effective and beneficial for public health. The number of vaccines actually administered has risen dramatically in recent decades. This increase, particularly in the number of different vaccines administered to children before entry into schools, may be due to government mandates and support, rather than economic incentive.
=== Patents ===
According to the World Health Organization (WHO), the biggest barrier to vaccine production in less developed countries has not been patents, but the substantial financial, infrastructure, and workforce requirements needed for market entry. Vaccines are complex mixtures of biological compounds, and unlike the case for prescription drugs, there are no true generic vaccines. The vaccine produced by a new facility must undergo complete clinical testing for safety and efficacy by the manufacturer. For most vaccines, specific processes in technology are patented. These can be circumvented by alternative manufacturing methods, but this required R&D infrastructure and a suitably skilled workforce. In the case of a few relatively new vaccines, such as the human papillomavirus vaccine, the patents may impose an additional barrier.
When increased production of vaccines was urgently needed during the COVID-19 pandemic in 2021, the World Trade Organization and governments around the world evaluated whether to waive intellectual property rights and patents on COVID-19 vaccines, which would "eliminate all potential barriers to the timely access of affordable COVID-19 medical products, including vaccines and medicines, and scale up the manufacturing and supply of essential medical products".
== Production ==
Vaccine production is fundamentally different from other kinds of manufacturing – including regular pharmaceutical manufacturing – in that vaccines are intended to be administered to millions of people of whom the vast majority are perfectly healthy. This fact drives an extraordinarily rigorous production process with strict compliance requirements that go far beyond what is required of other products.
Depending upon the antigen, it can cost anywhere from US$50 to $500 million to build a vaccine production facility, which requires highly specialized equipment, clean rooms, and containment rooms. There is a global scarcity of personnel with the right combination of skills, expertise, knowledge, competence and personality to staff vaccine production lines. With the notable exceptions of Brazil, China, and India, many developing countries' educational systems are unable to provide enough qualified candidates, and vaccine makers based in such countries must hire expatriate personnel to keep production going.
Vaccine production has several stages. First, the antigen itself is generated. Viruses are grown either on primary cells such as chicken eggs (e.g., for influenza) or on continuous cell lines such as cultured human cells (e.g., for hepatitis A). Bacteria are grown in bioreactors (e.g., Haemophilus influenzae type b). Likewise, a recombinant protein derived from the viruses or bacteria can be generated in yeast, bacteria, or cell cultures.
After the antigen is generated, it is isolated from the cells used to generate it. A virus may need to be inactivated, possibly with no further purification required. Recombinant proteins need many operations involving ultrafiltration and column chromatography. Finally, the vaccine is formulated by adding adjuvant, stabilizers, and preservatives as needed. The adjuvant enhances the immune response to the antigen, stabilizers increase the storage life, and preservatives allow the use of multidose vials. Combination vaccines are harder to develop and produce, because of potential incompatibilities and interactions among the antigens and other ingredients involved.
The final stage in vaccine manufacture before distribution is fill and finish, which is the process of filling vials with vaccines and packaging them for distribution. Although this is a conceptually simple part of the vaccine manufacture process, it is often a bottleneck in the process of distributing and administering vaccines.
Vaccine production techniques are evolving. Cultured mammalian cells are expected to become increasingly important, compared to conventional options such as chicken eggs, due to greater productivity and low incidence of problems with contamination. Recombination technology that produces genetically detoxified vaccines is expected to grow in popularity for the production of bacterial vaccines that use toxoids. Combination vaccines are expected to reduce the quantities of antigens they contain, and thereby decrease undesirable interactions, by using pathogen-associated molecular patterns.
=== Vaccine manufacturers ===
The companies with the highest market share in vaccine production are Merck, Sanofi, GlaxoSmithKline, Pfizer and Novartis, with 70% of vaccine sales concentrated in the EU or US (2013).: 42 Vaccine manufacturing plants require large capital investments ($50 million up to $300 million) and may take between 4 and 6 years to construct, with the full process of vaccine development taking between 10 and 15 years.: 43 Manufacturing in developing countries is playing an increasing role in supplying these countries, specifically with regards to older vaccines and in Brazil, India and China.: 47 The manufacturers in India are the most advanced in the developing world and include the Serum Institute of India, one of the largest producers of vaccines by number of doses and an innovator in processes, recently improving efficiency of producing the measles vaccine by 10 to 20-fold, due to switching to a MRC-5 cell culture instead of chicken eggs.: 48 China's manufacturing capabilities are focused on supplying their own domestic need, with Sinopharm (CNPGC) alone providing over 85% of the doses for 14 different vaccines in China.: 48 Brazil is approaching the point of supplying its own domestic needs using technology transferred from the developed world.: 49
== Delivery systems ==
One of the most common methods of delivering vaccines into the human body is injection.
The development of new delivery systems raises the hope of vaccines that are safer and more efficient to deliver and administer. Lines of research include liposomes and ISCOM (immune stimulating complex).
Notable developments in vaccine delivery technologies have included oral vaccines. Early attempts to apply oral vaccines showed varying degrees of promise, beginning early in the 20th century, at a time when the very possibility of an effective oral antibacterial vaccine was controversial. By the 1930s there was increasing interest in the prophylactic value of an oral typhoid fever vaccine for example.
An oral polio vaccine turned out to be effective when vaccinations were administered by volunteer staff without formal training; the results also demonstrated increased ease and efficiency of administering the vaccines. Effective oral vaccines have many advantages; for example, there is no risk of blood contamination. Vaccines intended for oral administration need not be liquid, and as solids, they commonly are more stable and less prone to damage or spoilage by freezing in transport and storage. Such stability reduces the need for a "cold chain": the resources required to keep vaccines within a restricted temperature range from the manufacturing stage to the point of administration, which, in turn, may decrease costs of vaccines.
A microneedle approach, which is still in stages of development, uses "pointed projections fabricated into arrays that can create vaccine delivery pathways through the skin".
An experimental needle-free vaccine delivery system is undergoing animal testing. A stamp-size patch similar to an adhesive bandage contains about 20,000 microscopic projections per square cm. This dermal administration potentially increases the effectiveness of vaccination, while requiring less vaccine than injection.
== In veterinary medicine ==
Vaccinations of animals are used both to prevent their contracting diseases and to prevent transmission of disease to humans. Both animals kept as pets and animals raised as livestock are routinely vaccinated. In some instances, wild populations may be vaccinated. This is sometimes accomplished with vaccine-laced food spread in a disease-prone area and has been used to attempt to control rabies in raccoons.
Where rabies occurs, rabies vaccination of dogs may be required by law. Other canine vaccines include canine distemper, canine parvovirus, infectious canine hepatitis, adenovirus-2, leptospirosis, Bordetella, canine parainfluenza virus, and Lyme disease, among others.
Cases of veterinary vaccines used in humans have been documented, whether intentional or accidental, with some cases of resultant illness, most notably with brucellosis. However, the reporting of such cases is rare and very little has been studied about the safety and results of such practices. With the advent of aerosol vaccination in veterinary clinics, human exposure to pathogens not naturally carried in humans, such as Bordetella bronchiseptica, has likely increased in recent years. In some cases, most notably rabies, the parallel veterinary vaccine against a pathogen may be as much as orders of magnitude more economical than the human one.
=== DIVA vaccines ===
DIVA (Differentiation of Infected from Vaccinated Animals), also known as SIVA (Segregation of Infected from Vaccinated Animals) vaccines, make it possible to differentiate between infected and vaccinated animals. DIVA vaccines carry at least one epitope less than the equivalent wild microorganism. An accompanying diagnostic test that detects the antibody against that epitope assists in identifying whether the animal has been vaccinated or not.
The first DIVA vaccines (formerly termed marker vaccines and since 1999 coined as DIVA vaccines) and companion diagnostic tests were developed by J. T. van Oirschot and colleagues at the Central Veterinary Institute in Lelystad, The Netherlands. They found that some existing vaccines against pseudorabies (also termed Aujeszky's disease) had deletions in their viral genome (among which was the gE gene). Monoclonal antibodies were produced against that deletion and selected to develop an ELISA that demonstrated antibodies against gE. In addition, novel genetically engineered gE-negative vaccines were constructed. Along the same lines, DIVA vaccines and companion diagnostic tests against bovine herpesvirus 1 infections have been developed.
The DIVA strategy has been applied in various countries to successfully eradicate pseudorabies virus from those countries. Swine populations were intensively vaccinated and monitored by the companion diagnostic test and, subsequently, the infected pigs were removed from the population. Bovine herpesvirus 1 DIVA vaccines are also widely used in practice. Considerable efforts are ongoing to apply the DIVA principle to a wide range of infectious diseases, such as classical swine fever, avian influenza, Actinobacillus pleuropneumonia and Salmonella infections in pigs.
== History ==
Prior to the introduction of vaccination with material from cases of cowpox (heterotypic immunisation), smallpox could be prevented by deliberate variolation with smallpox virus. According to historian Joseph Needham, Taoists in China as far back as the 10th century practiced a form of inoculation and passed it down through oral tradition, though Needham's claim has been criticized since the practice was not written about. The Chinese also practiced the oldest documented use of variolation, dating back to the fifteenth century. They implemented a method of "nasal insufflation" administered by blowing powdered smallpox material, usually scabs, up the nostrils. Various insufflation techniques have been recorded throughout the sixteenth and seventeenth centuries within China.: 60 Two reports on the Chinese practice of inoculation were received by the Royal Society in London in 1700; one by Martin Lister who received a report by an employee of the East India Company stationed in China and another by Clopton Havers. In France, Voltaire reports that the Chinese have practiced variolation "these hundred years".
Mary Wortley Montagu, who had witnessed variolation in Turkey, had her four-year-old daughter variolated in the presence of physicians of the Royal Court in 1721 upon her return to England. Later on that year, Charles Maitland conducted an experimental variolation of six prisoners in Newgate Prison in London. The experiment was a success, and soon variolation was drawing attention from the royal family, who helped promote the procedure. However, in 1783, several days after Prince Octavius of Great Britain was inoculated, he died.
In 1796, the physician Edward Jenner took pus from the hand of a milkmaid with cowpox, scratched it into the arm of an 8-year-old boy, James Phipps, and six weeks later variolated the boy with smallpox, afterwards observing that he did not catch smallpox. Jenner extended his studies and, in 1798, reported that his vaccine was safe in children and adults, and could be transferred from arm-to-arm, which reduced reliance on uncertain supplies from infected cows. In 1804, the Spanish Balmis smallpox vaccination expedition to Spain's colonies Mexico and Philippines used the arm-to-arm transport method to get around the fact the vaccine survived for only 12 days in vitro. They used cowpox. Since vaccination with cowpox was much safer than smallpox inoculation, the latter, though still widely practiced in England, was banned in 1840.
Following on from Jenner's work, the second generation of vaccines was introduced in the 1880s by Louis Pasteur who developed vaccines for chicken cholera and anthrax, and from the late nineteenth century vaccines were considered a matter of national prestige. National vaccination policies were adopted and compulsory vaccination laws were passed. In 1931 Alice Miles Woodruff and Ernest Goodpasture documented that the fowlpox virus could be grown in embryonated chicken egg. Soon scientists began cultivating other viruses in eggs. Eggs were used for virus propagation in the development of a yellow fever vaccine in 1935 and an influenza vaccine in 1945. In 1959 growth media and cell culture replaced eggs as the standard method of virus propagation for vaccines.
Vaccinology flourished in the twentieth century, which saw the introduction of several successful vaccines, including those against diphtheria, measles, mumps, and rubella. Major achievements included the development of the polio vaccine in the 1950s and the eradication of smallpox during the 1960s and 1970s. Maurice Hilleman was the most prolific of the developers of the vaccines in the twentieth century. As vaccines became more common, many people began taking them for granted. However, vaccines remain elusive for many important diseases, including herpes simplex, malaria, gonorrhea, and HIV.
=== Generations of vaccines ===
First generation vaccines are whole-organism vaccines – either live and weakened, or killed forms. Live, attenuated vaccines, such as smallpox and polio vaccines, are able to induce killer T-cell (TC or CTL) responses, helper T-cell (TH) responses and antibody immunity. However, attenuated forms of a pathogen can convert to a dangerous form and may cause disease in immunocompromised vaccine recipients (such as those with AIDS). While killed vaccines do not have this risk, they cannot generate specific killer T-cell responses and may not work at all for some diseases.
Second generation vaccines were developed to reduce the risks from live vaccines. These are subunit vaccines, consisting of specific protein antigens (such as tetanus or diphtheria toxoid) or recombinant protein components (such as the hepatitis B surface antigen). They can generate TH and antibody responses, but not killer T cell responses.
RNA vaccines and DNA vaccines are examples of third generation vaccines. In 2016 a DNA vaccine for the Zika virus began testing at the National Institutes of Health. Separately, Inovio Pharmaceuticals and GeneOne Life Science began tests of a different DNA vaccine against Zika in Miami. Manufacturing the vaccines in volume was unsolved as of 2016. Clinical trials for DNA vaccines to prevent HIV are underway. mRNA vaccines such as BNT162b2 were developed in the year 2020 with the help of Operation Warp Speed and massively deployed to combat the COVID-19 pandemic. In 2021, Katalin Karikó and Drew Weissman received Columbia University's Horwitz Prize for their pioneering research in mRNA vaccine technology.
== Trends ==
Since at least 2013, scientists have been trying to develop synthetic third-generation vaccines by reconstructing the outside structure of a virus; it was hoped that this will help prevent vaccine resistance.
Principles that govern the immune response can now be used in tailor-made vaccines against many noninfectious human diseases, such as cancers and autoimmune disorders. For example, the experimental vaccine CYT006-AngQb has been investigated as a possible treatment for high blood pressure. Factors that affect the trends of vaccine development include progress in translatory medicine, demographics, regulatory science, political, cultural, and social responses.
=== Plants as bioreactors for vaccine production ===
The idea of vaccine production via transgenic plants was identified as early as 2003. Plants such as tobacco, potato, tomato, and banana can have genes inserted that cause them to produce vaccines usable for humans. In 2005, bananas were developed that produce a human vaccine against hepatitis B.
== Vaccine hesitancy ==
Vaccine hesitancy is a delay in acceptance, or refusal of vaccines despite the availability of vaccine services. The term covers outright refusals to vaccinate, delaying vaccines, accepting vaccines but remaining uncertain about their use, or using certain vaccines but not others. There is an overwhelming scientific consensus that vaccines are generally safe and effective. Vaccine hesitancy often results in disease outbreaks and deaths from vaccine-preventable diseases. The World Health Organization therefore characterized vaccine hesitancy as one of the top ten global health threats in 2019.
== References ==
== Further reading ==
Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. (2021). Epidemiology and Prevention of Vaccine-Preventable Diseases (14th ed.). Washington D.C.: U.S. Centers for Disease Control and Prevention (CDC).
== External links ==
Immunization, vaccine preventable diseases and polio transition World Health Organization
WHO Vaccine Position Papers World Health Organization
The History of Vaccines, from the College of Physicians of Philadelphia
This website was highlighted by Genetic Engineering & Biotechnology News in its "Best of the Web" section in January 2015. See: "The History of Vaccines". Best of the Web. Genetic Engineering & Biotechnology News. Vol. 35, no. 2. 15 January 2015. p. 38. | Wikipedia/Vaccines |
Gain-of-function research (GoF research or GoFR) is medical research that genetically alters an organism in a way that may enhance the biological functions of gene products. This may include an altered pathogenesis, transmissibility, or host range, i.e., the types of hosts that a microorganism can infect. This research is intended to reveal targets to better predict emerging infectious diseases and to develop vaccines and therapeutics. For example, influenza B can infect only humans and harbor seals. Introducing a mutation that would allow influenza B to infect rabbits in a controlled laboratory situation would be considered a gain-of-function experiment, as the virus did not previously have that function. That type of experiment could then help reveal which parts of the virus's genome correspond to the species that it can infect, enabling the creation of antiviral medicines which block this function.
In virology, gain-of-function research is usually employed with the intention of better understanding current and future pandemics. In vaccine development, gain-of-function research is conducted in the hope of gaining a head start on a virus and being able to develop a vaccine or therapeutic before it emerges. The term "gain of function" is sometimes applied more narrowly to refer to "research which could enable a pandemic-potential pathogen to replicate more quickly or cause more harm in humans or other closely-related mammals."
Some forms of gain-of-function research (specifically work which involves certain select agent pathogens) carry inherent biosafety and biosecurity risks, and are thus also referred to as dual use research of concern (DURC). To mitigate these risks while allowing the benefits of such research, various governments have mandated that DURC experiments be regulated under additional oversight by institutions (so-called institutional "DURC" committees) and government agencies (such as the NIH's recombinant DNA advisory committee). A mirrored approach can be seen in the European Union's Dual Use Coordination Group (DUCG).
Importantly, regulations in the United States and European Union both mandate that at least one unaffiliated member of the public should be an active participant in the oversight process. Significant debate has taken place in the scientific community on how to assess the risks and benefit of gain-of-function research, how to publish such research responsibly, and how to engage the public in an open and honest review. In January 2020, the National Science Advisory Board for Biosecurity convened an expert panel to revisit the rules for gain-of-function research and provide more clarity in how such experiments are approved, and when they should be disclosed to the public.
== Experiments that have been referred to as "gain-of-function" ==
In early 2011, two groups were investigating how flu viruses specific to birds could possibly cross over and create pandemics in humans: one led by Yoshihiro Kawaoka at the University of Wisconsin–Madison in Madison, Wisconsin, and another led by Ron Fouchier at Erasmus University Medical Center in the Netherlands. Both groups had serially passaged the H5N1 avian influenza in ferrets, manually taking the virus from one ferret to another, until it was capable of spreading via respiratory droplets. The normally bird-specific virus, through replication over time in the ferrets' lungs, had adopted several amino acid changes that enabled it to replicate in the mammalian lungs, which are notably colder than those found in birds. This small change also allowed the virus to transmit via droplets in the air made when the ferrets coughed or sneezed.
Proponents of the Kawaoka and Fouchier experiments cited several benefits: these answered the question of how a virus like H5N1 could possibly become airborne in humans, allowed other researchers to develop vaccines and therapeutics which specifically targeted these amino acid changes, and also demonstrated that there was a linkage in avian viruses between transmissibility and lethality: while the virus had become more transmissible, it had also become significantly less deadly. Various critics of the research (including members of Congress) responded to the publications with alarm. Others called the experiments an "engineered doomsday". Questions were raised by other scientists including Marc Lipsitch of the T. H. Chan School of Public Health at Harvard University about the relative risks and benefits of this research.
At an international technical consultation convened by the WHO, it was concluded that this work was an important contribution to public health surveillance of H5N1 viruses and to a better understanding of the properties of these viruses, but that broader global discussions were needed. The European Academies of Science Advisory Council (EASAC) concluded that all required laws, rules, regulations, and codes of conduct are in place in several EU countries to continue this type of work responsibly. In the US, where regulations were previously less strict than in the EU, a new governmental policy and review mechanism was launched for "Potential Pandemic Pathogen Care and Oversight" (P3CO).
In May 2013, a group led by Hualan Chen, director of China's National Avian Influenza Reference Laboratory, published several experiments they had conducted at the BSL3+ laboratory of the Harbin Veterinary Research Institute, investigating what would happen if a 2009 H1N1 circulating in humans infected the same cell as an avian influenza H5N1. Importantly, the experiments had been conducted before a research pause on H5N1 experiments had been agreed upon by the broader virologist community. They used these experiments to determine that certain genes, if reassorted in such a dual-infection scenario in the wild, would allow transmission of the H5N1 virus more easily in mammals (notably guinea pigs as a model organism for rodent species), proving that certain agricultural scenarios carry the risk of allowing H5N1 to cross over into mammals. As in the Fouchier and Kawaoka experiments above, the viruses in this study were also significantly less lethal after the modification.
Critics of the 2013 Chen group study (including Simon Wain-Hobson of the Pasteur Institute and former Royal Society President Robert May) decried this as an unsafe experiment that was unnecessary to prove the intended conclusions, calling Chen's work "appallingly irresponsible" and also raising concerns about the biosafety of the laboratory itself. Others (including the director of the WHO Collaborating Centre on Influenza in Tokyo, Masato Tashiro) praised Chen's laboratory as "state of the art". Jeremy Farrar, director of the Oxford University Clinical Research Unit in Ho Chi Minh City, described the work as "remarkable" and said that it demonstrated the "very real threat" that "continued circulation of H5N1 strains in Asia and Egypt" posed.
A preprint by Boston University researchers, published on 14 October 2022, described their experiments splicing the SARS-CoV-2 BA.1 Omicron's spike protein into an ancestral SARS-CoV-2 variant isolated in the early days of the pandemic, creating a new chimeric version of the virus. All of the six mice exposed to the ancestral variant died; eight of the ten mice exposed to the chimeric variant died; and none of the ten mice exposed to Omicron died. This suggests that "mutations outside of spike are major determinants of the attenuated pathogenicity of Omicron in K18-hACE2 mice". According to the preprint, the work was supported by grants from various branches of the NIH, but the NIH later denied funding the experiments and the researchers stated the NIH did not fund the experiments directly. On 17 October, the Daily Mail ran the headline "Boston University CREATES a new COVID strain that has an 80% kill rate—echoing dangerous experiments feared to have started the pandemic". The headline was later flagged "as part of Facebook's efforts to combat false news and misinformation". PolitiFact noted the "lab leak" theory was unproven, and also stated "citing the 80% figure alone leaves out key context, including that the resulting strain was less fatal than the original, which killed 100% of mice. Experts say this kind of research is not unusual and the experiment was conducted in accordance with accepted safety procedures." All research funded by the NIH that can make COVID more virulent or transmissible must undergo an extra gain-of-function review. Critics charged that, because the chimera could have combined Omicron's high transmissibility with the ancestral strain's lethality, the experiment should have undergone the extra review. The researchers denied that the experiment qualified as gain-of-function in the first place.
== Gain-of-function research of concern ==
Significant debate has taken place in the scientific community on how to assess the risks and benefits of gain-of-function research, and how to engage the public in deliberations for policymaking. These concerns encompass biosafety, relating to the accidental release of a pathogen into the population, biosecurity relating to the intentional release of a pathogen into the population, and bioethics, the principles of biorisk management and research review procedures.
== Academic symposia ==
=== Gain-of-Function Research: A Symposium ===
In December 2014, the National Research Council and the Institute of Medicine organized a two-day symposium to discuss the potential risks and benefits of gain-of-function research. The event was attended by scientists from around the world, including George Gao, Gabriel Leung and Michael Selgelid, Baruch Fischhoff, Alta Charo, Harvey Fineberg, Jonathan Moreno, Ralph Cicerone, Margaret Hamburg, Jo Handelsman, Samuel Stanley, Kenneth Berns, Ralph Baric, Robert Lamb, Silja Vöneky, Keiji Fukuda, David Relman, and Marc Lipsitch. Shortly thereafter, the US government granted exceptions to the GoFR moratorium to 7 out of 18 research projects that had been affected.
=== Gain-of-Function Research: A Second Symposium ===
On March 10–11, 2016, the National Academies of Sciences, Engineering, and Medicine held its second public symposium to discuss potential U.S. government policies for the oversight of gain-of-function research. The symposium was held at the request of the U.S. government to provide a mechanism to engage the life sciences community and the broader public and solicit feedback on optimal approaches to ensure effective federal oversight of GoFR as part of a broader U.S. government deliberative process.
== Academic advocacy groups ==
=== Cambridge Working Group ===
The Cambridge Working Group was formed by Harvard epidemiologist Marc Lipsitch with fellow scientists at a meeting held in Cambridge, Massachusetts, following a "trifecta" of biosecurity incidents involving the CDC, including the accidental exposure of viable anthrax to personnel at CDC's Roybal Campus, the discovery of six vials containing viable smallpox from the 1950s, labeled as Variola but in a box with other samples poorly labeled, at the FDA's White Oak campus, and the accidental shipping of H9N2 vials contaminated with H5N1 from the CDC lab to a USDA lab.
On July 14, 2014, the group published a Consensus Statement authored by 18 founding members, including Amir Attaran, Barry Bloom, Arturo Casadevall, Richard H. Ebright, Alison Galvani, Edward Hammond, Thomas Inglesby, Michael Osterholm, David Relman, Richard Roberts, Marcel Salathé and Silja Vöneky. Since its initial publication, over 300 scientists, academics, and physicians have added their signature.
The statement advocates for all work involving potential pandemic pathogens to be halted until a quantitative and objective assessment of the risks has been undertaken. It then argues that alternative approaches that do not involve such risks should be used instead.
The group engaged in public advocacy, influencing the US government's decision in December 2014 to suspend funding of research that would create certain types of novel potential pandemic pathogens.
=== Scientists for Science ===
Shortly after the Cambridge Working Group released its position statement, Scientists for Science was formed by 37 signatories taking an alternative position, that "biomedical research on potentially dangerous pathogens can be performed safely and is essential for a comprehensive understanding of microbial disease pathogenesis, prevention and treatment." Since its publication, the SfS statement has received 200+ signatures from working scientists, academics, and biosafety professionals.
One of the group's founding members, University of Pittsburgh virologist W. Paul Duprex, has argued (c. 2014) that the then-recent few events were exceptions to an overall good record of lab safety, and that these exceptions should not have been a reason for shutting down experiments that may have been of tangible benefit to public health. He and other SfS signatories have argued that these pathogens are already subject to extensive regulations and that it would be more advantageous and effective to focus on improving lab safety and oversight, ensuring that experiments are conducted in the public interest.
Notable signatories are Constance Cepko, Dickson Despommier, Erica Ollmann Saphire, Geoffrey Smith, Karla Kirkegaard, Sean Whelan, Vincent Racaniello and Yoshihiro Kawaoka. Columbia University virologist Ian Lipkin, who signed both statements, said "there has to be a coming together of what should be done".
Founders of both groups published a series of letters detailing their discussions and viewpoints. All authors, however, agreed that more education of the public and open discussion of the risks and benefits was necessary. Several also wrote that sensationalized headlines and framings of the ongoing process as a "debate" with "opposing sides" had negatively affected the process, while the reality is much more collegial.
== International policies and regulations ==
International outlook and engagement on gain-of-function research policy and regulation vary by country and region. Due to the potential effect on the global community at large, the ethical acceptability of such experiments depends on the extent to which it is accepted internationally. In 2010, the World Health Organization developed a non-binding guidance document for DURC, summarizing the positions of many different nations as "self-governing" and others as strictly following oversight based on the International Health Regulations, the Biological and Toxin Weapons Convention (BTWC), and the Center for International Security Studies' Biological Research Security System. The document also recommended the aforementioned as potential resources for countries to develop their own policies and procedures for DURC.
=== European Union ===
The European Academies Science Advisory Council has formed a working group to examine the issues raised by gain-of-function research and to make recommendations for the management of such research and its outputs. The possibility for developing common approaches between the United States and Europe has been explored.
In May 2014, the German National Ethics Council presented a report to the Bundestag on proposed guidance for governance of GoFR. The report called for national legislation on DURC. As of May 2021, the German government has not passed the endorsed legislation. The NEC also proposed a national code-of-conduct for researchers to consent, endorsing which experiments qualify as misconduct and which do not, based on founding principles of public benefit. The German Research Foundation and German National Academy of Sciences made a joint suggestion to expand the role of existing research ethics committees to also evaluate proposals of DURC.
=== United States ===
==== Gain-of-function research moratorium ====
From 2014 to 2017, the White House Office of Science and Technology Policy and the Department of Health and Human Services instituted a gain-of-function research moratorium and funding pause on any dual-use research into specific pandemic-potential pathogens (influenza, MERS, and SARS) while the regulatory environment and review process were reconsidered and overhauled. Under the moratorium, any laboratory who conducted such research would put their future funding (for any project, not just the indicated pathogens) in jeopardy. The NIH has said 18 studies were affected by the moratorium.
The moratorium was a response to laboratory biosecurity incidents that occurred in 2014, including not properly inactivating anthrax samples, the discovery of unlogged smallpox samples, and injecting a chicken with the wrong strain of influenza. These incidents were not related to gain-of-function research. One of the goals of the moratorium was to reduce the handling of dangerous pathogens by all laboratories until safety procedures were evaluated and improved.
Subsequently, symposia and expert panels were convened by the National Science Advisory Board for Biosecurity (NSABB) and National Research Council (NRC). In May 2016, the NSABB published "Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research". On 9 January 2017, the HHS published the "Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight" (P3CO). This report sets out how "pandemic potential pathogens" should be regulated, funded, stored, and researched to minimize threats to public health and safety.
On 19 December 2017, the NIH lifted the moratorium because gain-of-function research was deemed "important in helping us identify, understand, and develop strategies and effective countermeasures against rapidly evolving pathogens that pose a threat to public health."
== COVID-19 pandemic ==
During the COVID-19 pandemic a number of conspiracy theories emerged about the origin of the SARS-CoV-2 virus and links to gain-of-function research. In January 2021, University of Saskatchewan virologist Angela Rasmussen wrote that one version of the information invoked previous gain-of-function work on coronaviruses to promulgate the idea that the virus was of laboratory origin. Rasmussen stated that this was unlikely, due to the intense scrutiny and government oversight to which GoFR is subject, and it is improbable that research on hard-to-obtain coronaviruses could occur under the radar.
In a congressional hearing on May 11, 2021, about Anthony Fauci's role as the Chief Medical Advisor to the United States Office of the President, senator Rand Paul stated that "the U.S. has been collaborating with Shi Zhengli of the Wuhan Virology Institute, sharing discoveries about how to create super viruses. This gain-of-function research has been funded by the NIH." Fauci responded "with all due respect, you are entirely and completely incorrect...the NIH has not ever and does not now fund gain-of-function research [conducted at] the Wuhan Institute of Virology." The Washington Post fact-checking team later rated Paul's statements as containing "significant omissions and/or exaggerations". NIH funding to the EcoHealth Alliance and later sub-contracted to the Wuhan Institute of Virology was not to support gain-of-function experiments, but instead to enable the collection of bat samples in the wild. EcoHealth Alliance spokesperson Robert Kessler has also categorically denied the accusation.
The Washington Post also quoted Rutgers University biosecurity expert Richard Ebright's dissenting opinion about Fauci's testimony, demonstrating that there is disagreement about what qualifies as "gain of function" research. Ebright asserted that experiments conducted under the EcoHealth grant "met the definition for gain-of-function research of concern under the 2014 Pause." MIT molecular biologist Alina Chan has argued that these experiments would not have been affected by the 2014 moratorium, because the experiments involved "naturally-occurring viruses" adding that the moratorium had "no teeth".
Several scientists have criticized the US government's GoFR regulations as having serious shortcomings (especially with regard to the NIH's funding of the EcoHealth Alliance grant proposal). Ebright has remarked that the process is not applied to all the experiments covered by the government's policies, while virologists David Relman and Angela Rasmussen have cited a worrying lack of transparency from oversight panels.
== See also ==
Biotechnology risk
Directed evolution
Dual-use technology
Global Virome Project
== References ==
== Further reading ==
European Academies' Science Advisory Council: Gain of function: experimental applications relating to potentially pandemic pathogens (Report)
Lowen, Anice; Lakdawala, Seema (8 May 2023). "Gain-of-function research is more than just tweaking risky viruses – it's a routine and essential tool in all biology research". The Conversation. | Wikipedia/Gain-of-function_research_moratorium |
The Lancet is a weekly peer-reviewed general medical journal, founded in England in 1823. It is one of the world's highest-impact academic journals and also one of the oldest medical journals still in publication.
The journal publishes original research articles, review articles ("seminars" and "reviews"), editorials, book reviews, correspondence, as well as news features and case reports. The Lancet has been owned by Elsevier since 1991, and its editor-in-chief since 1995 has been Richard Horton. The journal has editorial offices in London, New York City, and Beijing.
== History ==
The Lancet was founded in 1823 by Thomas Wakley, an English surgeon who named it after the surgical instrument called a lancet (scalpel). According to BBC, the journal was initially considered to be radical following its founding.
Members of the Wakley family retained editorship of the journal until 1908. In 1921, The Lancet was acquired by Hodder & Stoughton. Elsevier acquired The Lancet from Hodder & Stoughton in 1991.
== Impact ==
According to Journal Citation Reports, the journal had a 2023 impact factor of 98.4, ranking it first above The New England Journal of Medicine in the category "Medicine, General & Internal". According to BMJ Open in 2017, The Lancet was more frequently cited in general newspapers around the world than The BMJ, NEJM and JAMA.
== Journal ranking summary ==
The Lancet is consistently ranked among the top journals in general medicine based on major citation indexes.
Journal ranking summary (2023)
== Specialty journals ==
The Lancet also publishes several specialty journals: The Lancet Neurology (neurology), The Lancet Oncology (oncology), The Lancet Infectious Diseases (infectious diseases), The Lancet Respiratory Medicine (respiratory medicine), The Lancet Psychiatry (psychiatry), The Lancet Diabetes and Endocrinology (endocrinology), and The Lancet Gastroenterology & Hepatology (gastroenterology) all of which publish original research and reviews. In 2013, The Lancet Global Health (global health) became the group's first fully open access journal. In 2014, The Lancet Haematology (haematology) and The Lancet HIV (infectious diseases) were launched, both as online only research titles. The Lancet Child & Adolescent Health (paediatrics) launched in 2017. According to the Journal Citation Reports, The Lancet Oncology had a 2021 impact factor of 54.433, The Lancet Neurology had 59.935, and The Lancet Infectious Diseases had 71.421. There is also an online website for students entitled The Lancet Student in blog format, launched in 2007.
Since July 2018, The Lancet has also published two open access journals as part of The Lancet Discovery Science, dedicated to essential early evidence: eBioMedicine (translational research), a journal initially launched in 2014 by parent publisher Elsevier, since 2015 supported by Cell Press and The Lancet, and eventually (July 2018) incorporated in The Lancet family journals together with its newly incepted sister journal eClinicalMedicine (clinical research and public health research). In May 2019, The Lancet Digital Health published its first issue.
=== Specialty journal commissions ===
Occasionally, the editors of the specialty journals will feel name commissions about a certain particular issue of concern to a wide sub-audience of their readers. One example of this type of commission is the Lancet Infectious Diseases Commission on "Preparedness for emerging epidemic threats", which reported on its mandate in January 2020.
== Volume renumbering ==
Prior to 1990, The Lancet had volume numbering that reset every year. Issues in January to June were in volume i, with the rest in volume ii. In 1990, the journal moved to a sequential volume numbering scheme, with two volumes per year. Volumes were retro-actively assigned to the years prior to 1990, with the first issue of 1990 being assigned volume 335, and the last issue of 1989 assigned volume 334. The table of contents listing on ScienceDirect uses this newer numbering scheme.
== Editorial controversies ==
The Lancet includes editorial content and letters in addition to scientific papers, which have at times been controversial. For example, it called for a ban on tobacco in the United Kingdom in 2003, expressed support for Gaza during the 2014 Israel-Gaza conflict, and issued an apology for sexist language.
=== Tobacco ban proposal (2003) ===
A December 2003 editorial by the journal, titled "How do you sleep at night, Mr Blair?", called for tobacco use to be completely banned in the United Kingdom.
The Royal College of Physicians rejected their argument. John Britton, chairman of the college's tobacco advisory group, praised the journal for discussing the health problem, but concluded that a "ban on tobacco would be a nightmare." Amanda Sandford, spokesperson for the anti-tobacco group Action on Smoking and Health, stated that criminalising a behaviour 26% of the population commit "is ludicrous." She also said: "We can't turn the clock back. If tobacco were banned we would have 13 million people desperately craving a drug that they would not be able to get." The deputy editor of The Lancet responded to the criticism by arguing that no other measures besides a total ban would likely be able to reduce tobacco use.
The smokers' rights group FOREST stated that the editorial gave them "amusement and disbelief". Director Simon Clark called the journal "fascist," and argued that it is hypocritical to ban tobacco while allowing unhealthy junk foods, alcohol consumption, and participation in extreme sports. Health Secretary John Reid reiterated that his government was committed to helping people give up smoking. He added: "Despite the fact that this is a serious problem, it is a little bit extreme for us in Britain to start locking people up because they have an ounce of tobacco somewhere."
=== Open letter for the people of Gaza (2014) ===
In August 2014 and during the 2014 Israel–Gaza conflict, The Lancet published an "Open letter for the people of Gaza" in their correspondence section. As reported in The Daily Telegraph, the letter "condemned Israel in the strongest possible terms, but strikingly made no mention of Hamas' atrocities." According to Haaretz, the authors of the letter include doctors who "are apparently sympathetic to the views of David Duke, a white supremacist and former Ku Klux Klan Grand Wizard." One of the doctors responded by saying that the letter was a legitimate exercise in freedom of expression, while a second one stated that he had no knowledge about David Duke or the Ku Klux Klan.
The editor of The Lancet, Richard Horton, said: "I have no plans to retract the letter, and I would not retract the letter even if it was found to be substantiated." However, Horton subsequently came to Israel's Rambam Hospital for a visit and said that he "deeply, deeply regret[ted] the completely unnecessary polarization that publication of the letter by Dr Paola Manduca caused."
Mark Pepys, a member of the Jewish Medical Association, criticised the letter as being a "partisan political diatribe" which was inappropriate for a serious publication. In addition, Pepys accused Richard Horton personally for allowing the publication of such political views.
=== February 2020 letter dismissing Covid lab-leak theory ===
On 19 February 2020, The Lancet published a letter signed by 27 scientists that stated: "We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin ... [Scientists] overwhelmingly conclude that this coronavirus originated in wildlife," adding: "Conspiracy theories do nothing but create fear, rumours, and prejudice that jeopardise our global collaboration in the fight against this virus." The letter has been criticized for having a chilling effect on scientific research and the scientific community, by implying that scientists who "bring up the lab-leak theory... are doing the work of conspiracy theorists"; the statement was deemed to have "effectively ended the debate over COVID-19's origins before it began". Further criticism of the letter was focused on the fact that, according to emails obtained through the Freedom of Information Act, members involved in producing the letter concealed their involvement "to creat[e] the impression of scientific unanimity" and failed to disclose conflicts of interest.
After having published letters supporting only the natural origins theory, The Lancet published a letter in September 2021 from a group of 16 virologists, biologists, and biosecurity specialists saying that "Research-related hypotheses are not misinformation or conjecture" and that "Scientific journals should open their columns to in-depth analyses of all hypotheses." The Times of India described The Lancet's decision to publish the letter as a "u-turn".
In June 2024, The Lancet wrote an op-ed stating that "SARS-CoV-2 is a natural virus that found its way into humans through mundane contact with infected wildlife" and that "doubling down on flawed assumptions in the face of growing evidence calls motivations into question."
=== "Bodies with vaginas" controversy ===
The 25 September 2021 edition of The Lancet included a review of an exhibition about the history of menstruation at the Vagina Museum. The journal's cover displayed a quotation from the review that referred to women as "bodies with vaginas". The quotation drew strong criticism on Twitter accusing The Lancet of sexism, arguing that this language was "dehumanising" and an "unhelpful" attempt at inclusivity. Horton later issued an apology on the journal's website.
=== Gaza death count report (2024) ===
On 5 July 2024, The Lancet published in its Correspondence section a letter with an estimate of the number of direct and indirect deaths that may be caused in the coming months and years by the Gaza war. Using other conflicts, where the number of indirect deaths was 3 to 15 times higher than the number of direct deaths, the authors estimated the total number of conflict-related deaths by multiplying the reported deaths by five, and argued that in the coming months and years "it is not implausible to estimate that up to 186,000 or even more deaths could be attributable to the current conflict in Gaza".
The estimate quickly gained traction in both international and regional media, with some of the outlets misrepresenting the 186,000 figure as the actual number of deaths, rather than long-term cumulative estimate. As a result, three days after the publication, one of the letter's authors, Martin McKee, wrote that the letter “has been greatly misquoted and misinterpreted” and clarified that the 186,000 figure was “purely illustrative”.
The letter has been criticized by the Chair of "Every Casualty Counts" network Michael Spagat, who wrote that the estimate "lacks a solid foundation and is implausible". Peter A. Singer, former Special Adviser to the Director-General of WHO, characterized the letter's methods as "take one unreliable number and multiply by another unreliable number to get a bigger unreliable number”.
Consequently, American Jewish Committee called upon The Lancet to "remove the letter from its website and, moving forward, exercise greater caution in selecting the claims it amplifies".
== Scientific controversies ==
=== Andrew Wakefield and the MMR vaccine (1998) ===
The Lancet was criticised after it published a paper in 1998 in which the authors suggested a link between the MMR vaccine and autism spectrum disorder. In February 2004, The Lancet published a statement by 10 of the paper's 13 coauthors repudiating the possibility that MMR could cause autism. The editor-in-chief, Richard Horton, went on the record to say the paper had "fatal conflicts of interest" because the study's lead author, Andrew Wakefield, had a serious conflict of interest that he had not declared to The Lancet. The journal completely retracted the paper on 2 February 2010, after Wakefield was found to have acted unethically in conducting the research.
The Lancet's six editors, including the editor-in-chief, were also criticised in 2011 because they had "covered up" the "Wakefield concocted fear of MMR" with an "avalanche of denials" in 2004.
=== Iraq War death toll estimates (2004–2006) ===
The Lancet also published an estimate of the Iraq War's Iraqi death toll—around 100,000—in 2004. In 2006, a follow-up study by the same team suggested that the violent death rate in Iraq was not only consistent with the earlier estimate, but had increased considerably in the intervening period (see Lancet surveys of casualties of the Iraq War). The second survey estimated that there had been 654,965 excess Iraqi deaths as a consequence of the war. The 95% confidence interval was 392,979 to 942,636. 1,849 households that contained 12,801 people were surveyed.
=== PACE study (2011) ===
In 2011, The Lancet published a study by the UK-based "PACE trial management group", which reported success with graded exercise therapy and cognitive behavioural therapy for Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS); a follow-up study was published in Lancet Psychiatry in 2015. The studies attracted criticism from some patients and researchers, especially with regard to conclusions from data analysis that was different from that described in the original protocol. In a 2015 Slate article, biostatistician Bruce Levin of Columbia University was quoted saying "The Lancet needs to stop circling the wagons and be open", and that "one of the tenets of good science is transparency"; while Ronald Davis of Stanford University said: "the Lancet should step up to the plate and pull that paper". Horton defended The Lancet's publication of the trial and called the critics: "a fairly small, but highly organized, very vocal and very damaging group of individuals who have, I would say, actually hijacked this agenda and distorted the debate so that it actually harms the overwhelming majority of patients."
Starting in 2011, critics of the studies filed Freedom of Information Act requests to get access to the authors' primary data, in order to learn what the trial's results would have been under the original protocol. In 2016, some of the data was released, which allowed calculation of results based on the original protocol and found that additional treatment led to no significant improvement in recovery rates over the control group.
The results from the PACE trial have been used to promote graded exercise therapy; however, these recommendations are now viewed by most public health bodies as outdated and highly harmful to ME/CFS patients.
=== Metastudy on the use of hydroxychloroquine and chloroquine (2020) ===
In May 2020, The Lancet published a metastudy by Mandeep R. Mehra of the Harvard Medical School and Sapan S. Desai of Surgisphere Corporation, which concluded that the malaria drugs hydroxychloroquine and chloroquine did not improve the condition of COVID-19 patients, and may have harmed some of them.
In response to concerns raised by members of the scientific community and the media about the veracity of the data and analyses, The Lancet decided to launch an independent third party investigation of Surgisphere and the metastudy. Specifically, The Lancet editors wanted to "evaluate the origination of the database elements, to confirm the completeness of the database, and to replicate the analyses presented in the paper." The independent peer reviewers in charge of the investigation notified The Lancet that Surgisphere would not provide the requested data and documentation. The authors of the metastudy then asked The Lancet to retract the article, which was done on June 3, 2020.
As a step to increase quality control, the editors of The Lancet Group announced changes to the editorial policy in a comment titled "Learning from a retraction" which was published on September 22, 2020.
=== Covid Commission head pushed US lab origin conspiracy theory (2022) ===
In September 2022, The Lancet published the report of their "COVID-19 Commission" which was headed by Jeffrey Sachs, an economist with no medical background, who has pushed the conspiracy theory that Covid came from a US "biotechnology" lab.
Before the report's release, Sachs appeared on the podcast of Robert F. Kennedy Jr., who has previously spread vaccine conspiracy theories. On the podcast episode, Sachs claimed that "Government officials such as Anthony Fauci "are not being honest" about the virus's origins". The published report included claims that "'independent researchers have not yet investigated' US labs, and said the National Institutes of Health has 'resisted disclosing details' of its work."
Virologist Angela Rasmussen commented that this may have been "one of The Lancet's most shameful moments regarding its role as a steward and leader in communicating crucial findings about science and medicine".
David Robertson from the University of Glasgow's Centre for Virus Research said that "It's really disappointing to see such a potentially influential report contributing to further misinformation on such an important topic" and "It's true we've details to understand on the side of natural origins, for example the exact intermediate species involved, but that doesn't mean there's... any basis to the wild speculation that US labs were involved".
=== Tissue-engineered trachea transplant (2023) ===
In October 2023, The Lancet retracted two papers from 2008 and 2014 by surgeon Paolo Macchiarini. These papers, which discussed the first tissue-engineered trachea transplant, were found to contain fabricated information following an investigation by the Swedish National Board for Assessment of Research Misconduct.
Before the 2023 retractions, in September 2015, The Lancet published an editorial titled, "Paolo Macchiarini is not guilty of scientific misconduct."
== List of editors ==
The following persons have been editors-in-chief of the journal:
== See also ==
List of medical journals
List of healthcare journals
== References ==
== External links ==
Official website | Wikipedia/The_Lancet_Infectious_Diseases |
Disease Models & Mechanisms (DMM) is a monthly peer-reviewed Open Access biomedical journal published by The Company of Biologists that launched in 2008. DMM is partnered with Publons, is part of the Review Commons initiative and has two-way integration with bioRxiv.
== Scope and content ==
DMM publishes original research, resources and reviews that focus on the use of model systems to better understand, diagnose and treat human disease.
Model systems of interest include:
Vertebrates such as mice, zebrafish, frogs, rats and other mammals
Invertebrates such as Drosophila melanogaster and Caenorhabditis elegans
Unique in vitro or ex vivo models, such as stem-cell-based models, organoids and systems based on patient material
Microorganisms such as yeast and Dictyostelium
Other biological systems with relevance to human disease research
Disease areas of interest include:
Cancer
Neurodegenerative and neurological diseases
Psychiatric disorders
Metabolic disorders, including diabetes and obesity
Cardiovascular diseases, stroke and hypertension
Gastrointestinal diseases
Infectious diseases
Autoimmunity and inflammation
Developmental diseases
Musculoskeletal disorders
Renal or liver disease
Eye disorders
Drug and biomarker discovery/screening
Stem cell therapies in regenerative medicine
The journal operates on a continuous publication model. The final version of record is immediately released online as soon as it is ready.
All papers are published as Open Access articles under the CC-BY licence.
== Abstracting and indexing ==
The journal is abstracted and/or indexed by:
BIOBASE
CAB abstracts
Cambridge Scientific Abstracts
Clarivate Analytics Web of Science
EMBASE
Medline
Scopus
It is a member of OASPA (Open Access Scholarly Publishers Association) and is indexed in the DOAJ (Directory of Open Access Journals).
Disease Models & Mechanisms is a signatory of the San Francisco Declaration on Research Assessment (DORA).
== Management ==
The founding editor-in-chief was Vivian Siegel (2008-2013), followed by Ross Cagan (2013-2016) and Monica J. Justice (2016-2020).
Elizabeth Patton was appointed Editor-in-Chief in December 2020, with Elaine Mardis as Deputy Editor-in-Chief.
== References ==
== External links ==
Official website
The Company of Biologists | Wikipedia/Disease_Models_&_Mechanisms |
An emerging infectious disease (EID) refer to infectious diseases that have either newly appeared in a population or have existed but are rapidly increasing in incidence, geographic range, or severity due to factors such as environmental changes, antimicrobial resistance, and human-animal interactions. The minority that are capable of developing efficient transmission between humans can become major public and global concerns as potential causes of epidemics or pandemics. Their many impacts can be economic and societal, as well as clinical. EIDs have been increasing steadily since at least 1940.
For every decade since 1940, there has been a consistent increase in the number of EID events from wildlife-related zoonosis. Human activity is the primary driver of this increase, with loss of biodiversity a leading mechanism.
Emerging infections account for at least 12% of all human pathogens. EIDs can be caused by newly identified microbes, including novel species or strains of virus (e.g. novel coronaviruses, ebolaviruses, HIV). Some EIDs evolve from a known pathogen, as occurs with new strains of influenza. EIDs may also result from spread of an existing disease to a new population in a different geographic region, as occurs with West Nile fever outbreaks. Some known diseases can also emerge in areas undergoing ecologic transformation (as in the case of Lyme disease). Others can experience a resurgence as a re-emerging infectious disease, like tuberculosis (following drug resistance) or measles. Nosocomial (hospital-acquired) infections, such as methicillin-resistant Staphylococcus aureus are emerging in hospitals, and are extremely problematic in that they are resistant to many antibiotics. Of growing concern are adverse synergistic interactions between emerging diseases and other infectious and non-infectious conditions leading to the development of novel syndemics.
Many EID are zoonotic, deriving from pathogens present in animals, with only occasional cross-species transmission into human populations. For instance, most emergent viruses are zoonotic (whereas other novel viruses may have been circulating in the species without being recognized, as occurred with hepatitis C).
== History of the concept of emerging infectious diseases ==
The French doctor Charles Anglada (1809–1878) wrote a book in 1869 on extinct and new diseases. He did not distinguish infectious diseases from others (he uses the terms reactive and affective diseases, to mean diseases with an external or internal cause, more or less meaning diseases with or without an observable external cause). He writes in the introduction:A widely held opinion among physicians admits the invariability of pathologies. All the illnesses which have existed or which have an outbreak around us are categorized according to arrested and preconceived types, and must enter one way or the other into the frameworks established by the nosologists. History and observation protest wildly against this prejudice, and this is what they teach: Diseases which have disappeared and whose traces are confined to the archives of science, are followed by other diseases, unknown to the contemporary generation, and which come for the first time to assert their rights. In other words, there are extinct and new diseases.Charles Nicolle, laureate of the Nobel Prize in Physiology or Medicine elaborated the concept of emergence of diseases in his 1930 book Naissance, vie et mort des maladies infectieuses (Birth, Life and Death of Infectious Diseases), and later in Destin des maladies infectieuses (Fate of Infectious Diseases) published in 1933 which served as lecture notes for his teaching of a second year course at the Collège de France. In the introduction of the book he sets out the program of the lectures:It is this historical existence, this destiny that will be the subject of our talks. I will have to answer, to the extent that our current knowledge allows, questions that you have asked yourself, that every thoughtful or simply curious mind asks: have the infectious diseases that we observe today always existed? Or have some of them appeared in the course of history? Can we assume that new ones will appear? Can we assume that some of these diseases will disappear? Have some of them already disappeared? Finally, what will become of humanity and domestic animals if, as a result of more and more frequent contacts between people, the number of infectious diseases continues to increase?The term emerging disease has been in use in scientific publications since the beginning of the 1960s at least and is used in the modern sense by David Sencer in his 1971 article "Emerging Diseases of Man and Animals" where in the first sentence of the introduction he implicitly defines emerging diseases as "infectious diseases of man and animals currently emerging as public health problems" and as a consequence also includes re-emerging diseases:Infectious diseases of man and animals currently emerging as public health problems include some old acquaintances and some that are new in respect to identity or concept.He also notes that some infectious agents are newly considered as diseases because of changing medical technologies:But there are also many familiar organisms formerly considered nonpathogenic that are now associated with nosocomial infections, use of artificial kidneys, and the acceptance or rejection of organ transplants, for example.He concludes the introduction with a word of caution:And so infectious disease, one of man's oldest enemies, survives as an adversary that calls forth our best efforts.However, to many people in the 1960s and 1970s the emergence of new diseases appeared as a marginal problem, as illustrated by the introduction to the 1962 edition of Natural History of Infectious Disease by Macfarlane Burnet:to write about infectious disease is almost to write of something that has passed into historyas well as the epilogue of the 1972 edition:On the basis of what has happened in the last thirty years, can we forecast any likely developments for the 1970s? If for the present we retain a basic optimism and assume no major catastrophes occur [...] the most likely forecast about the future of infectious disease is that it will be very dull. There may be some wholly unexpected emergence of a new and dangerous infectious disease, but nothing of the sort has marked the past fifty years.
The concept gained more interest at the end of the 1980s as a reaction to the AIDS epidemic. On the side of epistemology, Mirko Grmek worked on the concept of emerging diseases while writing his book on the history of AIDS and later in 1993 published an article about the concept of emerging disease as a more precise notion than the term "new disease" that was mostly used in France at that time to qualify AIDS among others.
Also under the shock of the emergence of AIDS, epidemiologists wanted to take a more active approach to anticipate and prevent the emergence of new diseases. Stephen S. Morse from The Rockefeller University in New York was chair and principal organizer of the NIAID/NIH Conference "Emerging Viruses: The Evolution of Viruses and Viral Diseases" held 1–3 May 1989 in Washington, DC. In the article summarizing the conference the authors write:Challenged by the sudden appearance of AIDS as a major public health crisis [...] jointly sponsored the conference "Emerging Viruses: The Evolution of Viruses and Viral Diseases" [...] It was convened to consider the mechanisms of viral emergence and possible strategies for anticipating, detecting, and preventing the emergence of new viral diseases in the future. They further note:Surprisingly, most emergent viruses are zoonotic, with natural animal reservoirs a more frequent source of new viruses than is the sudden evolution of a new entity. The most frequent factor in emergence is human behavior that increases the probability of transfer of viruses from their endogenous animal hosts to man.In a 1991 paper Morse underlines how the emergence of new infectious diseases (of which the public became aware through the AIDS epidemic) is the opposite of the then generally expected retreat of these diseases:The striking successes achieved with antibiotics, together with widespread application of vaccines for many previously feared viral diseases, made it appear to many physicians and the public that infectious diseases were retreating and would in time be fully conquered. Although this view was disputed by virologists and many specialists in infectious diseases, it had become a commonplace to suggest that infectious diseases were about to become a thing of the past [...].As a direct consequence of the 1989 conference on emerging viruses, the Institute Of Medicine convened in February 1991 the 19-member multidisciplinary Committee on Emerging Microbial Threats to Health, co-chaired by Joshua Lederberg and Robert Shope, to conduct an 18-month study. According to the report produced by the committee in 1992, its charge "was to identify significant emerging infectious diseases, determine what might be done to deal with them, and recommend how similar future threats might be confronted to lessen their impact on public health." The report recommended setting up a surveillance program to recognize emerging diseases and proposed methods of intervention in case an emergent disease was discovered.A well-designed, well-implemented surveillance program can detect unusual clusters of disease, document the geographic and demographic spread of an outbreak, and estimate the magnitude of the problem. It can also help to describe the natural history of a disease, identify factors responsible for emergence, facilitate laboratory and epidemiological research, and assess the success of specific intervention efforts.The proposed interventions were based on the following: the U.S. public health system, research and training, vaccine and drug development, vector control, public education and behavioral change. A few years after the 1989 Emerging Viruses conference and the 1992 IOM report, the Program for Monitoring Emerging Diseases (ProMED) was formed by a group of scientists as a follow-up in 1994 and the Centres for Disease Control (CDC) launched the Emerging Infectious Diseases journal in 1995.
A decade later the IOM convened the Committee on Emerging Microbial Threats to Health in the 21st Century which published its conclusions in 2003.
In April 2000 the WHO organized a meeting on Global Outbreak Alert and Response, which was the founding act of the Global Outbreak Alert and Response Network.
In 2014, the Western African Ebola virus epidemic demonstrated how ill-prepared the world was to handle such an epidemic. In response, the Coalition for Epidemic Preparedness Innovation was launched at the World Economic Forum in 2017 with the objective of accelerating the development of vaccines against emerging infectious diseases to be able to offer them to affected populations during outbreaks. CEPI promotes the idea that a proactive approach is required to "create a world in which epidemics are no longer a threat to humanity".
== Classification ==
One way to classify emerging infections diseases is by time and how humans were involved in the emergence:
Newly emerging infectious diseases – diseases that were not previously described in humans, such as SARS-CoV-2 (COVID-19) and MERS
Re-emerging infectious diseases – diseases that have spread to new places or which previous treatments no longer control, such as methicillin-resistant Staphylococcus aureus, tuberculosis (due to drug resistance, measles (due to declining vaccination rates), and cholera (due to climate-related factors)
Deliberately emerging infectious diseases – diseases created by humans for bioterrorism, such as bioterrorism-related agents like anthrax and smallpox
Accidentally emerging infectious diseases – diseases created or spread unintentionally by humans, such as vaccine-derived poliovirus
== Contributing factors ==
The 1992 IOM report distinguished 6 factors contributing to emergence of new diseases (Microbial adaptation and change; Economic development and land use; Human demographics and behavior; International travel and commerce; Technology and industry; Breakdown of public health measures) which were extended to 13 factors in the 2003 report (Chapter 3 of the report detailing each of them)
Microbial adaptation and change
Human susceptibility to infection
Climate and weather
Changing ecosystems
Human demographics and behavior
Economic development and land use
International travel and commerce
Technology and industry
Breakdown of public health measures
Poverty and social inequality
War and famine
Lack of political will
Intent to harm
Their classification serves as a basis for many others. The following table gives examples for different factors:
== Emerging Infectious Diseases between Humans and Animals ==
Emerging infectious diseases between human, animal have become a significant concern in recent years, playing a crucial role in the occurrence and spread of diseases. Human population growth, increased proximity to wildlife, and climate change have created favorable conditions for the transmission of zoonotic diseases, leading to outbreaks such as Zika, Ebola, and COVID-19. The One Health approach, which integrates animal, human, and environmental health, has emerged as a crucial tool for monitoring and mitigating the spread of infectious diseases.
Zoonotic diseases, originating from animal sources, pose a significant threat to human health. Up to 75% of emerging infectious diseases are zoonotic, originating from viruses and other pathogens that are transmitted from animals to humans. Understanding the mechanisms of transmission, the role of wildlife trade, and the importance of surveillance and early detection is crucial for mitigating the impact of zoonotic diseases on human health. Surveillance efforts involving wastewater have been identified as valuable tools for detecting early warning signs of disease emergence and providing timely interventions.
== List ==
=== NIAID list of Biodefense and Emerging Infectious Diseases ===
The U.S. National Institute of Allergy and Infectious Diseases (NIAID) maintains a list of Biodefense and Emerging Infectious Diseases. The list is categorized by biodefense risk, which is mostly based on biological warfare and bioterrorism considerations. As of 2004, it recognized the following emerging and re-emerging diseases.
=== WHO list of most important emerging infectious diseases ===
In December 2015, the World Health Organization held a workshop on prioritization of pathogens "for accelerated R&D for severe emerging diseases with potential to generate a public health emergency, and for which no, or insufficient, preventive and curative solutions exist." The result was a list containing the following six diseases:
Crimean–Congo hemorrhagic fever
Filovirus diseases (Ebola virus disease and Marburg virus disease)
Highly pathogenic emerging Coronaviruses relevant to humans (MERS and SARS)
Lassa fever
Nipah virus infection
Rift Valley fever
These were selected based on the following measures:
Human transmissibility (including population immunity, behavioural factors, etc.)
Severity or case fatality rate
Spillover potential
Evolutionary potential
Available countermeasures
Difficulty of detection or control
Public health context of the affected area(s)
Potential scope of outbreak (risk of international spread)
Potential societal impacts
=== Newly reported infectious diseases ===
In 2007 Mark Woolhouse and Eleanor Gaunt established a list of 87 human pathogens first reported in the period between 1980 and 2005. These were classified according to their types.
=== Major outbreaks ===
The following table summarizes the major outbreaks since 1998 caused by emerging or re-emerging infectious diseases.
== Methicillin-resistant Staphylococcus aureus ==
Methicillin-resistant Staphylococcus aureus (MRSA) evolved from methicillin-susceptible Staphylococcus aureus (MSSA), otherwise known as common S. aureus. Many people are natural carriers of S. aureus, without being affected in any way. Infections occur in healthcare settings (Healthcare acquired-MRSA) and in the community (Community acquired-MRSA), often leading to severe skin infections, pneumonia, and bloodstream infections. Community-acquired MRSA, is increasingly found in healthy individuals such as athletes, prisoners, and schoolchildren outside of hospital settings. MSSA was treatable with the antibiotic methicillin until it acquired the gene for antibiotic resistance. MRSA is a major public health threat due to its resistance to beta-lactam antibiotics. Through genetic mapping of various strains of MRSA, scientists have found that MSSA acquired the mecA gene in the 1960s, which accounts for its pathogenicity, before this it had a predominantly commensal relationship with humans. It is theorized that when this S. aureus strain that had acquired the mecA gene was introduced into hospitals, it came into contact with other hospital bacteria that had already been exposed to high levels of antibiotics. When exposed to such high levels of antibiotics, the hospital bacteria suddenly found themselves in an environment that had a high level of selection for antibiotic resistance, and thus resistance to multiple antibiotics formed within these hospital populations. When S. aureus came into contact with these populations, the multiple genes that code for antibiotic resistance to different drugs were then acquired by MRSA, making it nearly impossible to control. It is thought that MSSA acquired the resistance gene through the horizontal gene transfer, a method in which genetic information can be passed within a generation, and spread rapidly through its own population as was illustrated in multiple studies. Horizontal gene transfer speeds the process of genetic transfer since there is no need to wait an entire generation time for gene to be passed on. Since most antibiotics do not work on MRSA, physicians have to turn to alternative methods based in Darwinian medicine. Efforts to combat MRSA include: Antibiotic stewardship programs to limit unnecessary antibiotic use, enhanced hospital hygiene protocols to reduce healthcare-associated infections, and development of new antimicrobial agents and alternative therapies, such as bacteriophage therapy. However, prevention is the most preferred method of avoiding antibiotic resistance. By reducing unnecessary antibiotic use in human and animal populations, antibiotics resistance can be slowed.
== Scientific Advisory Group for Origins of Novel Pathogens ==
On 16 July 2021, the Director-General of WHO announced the formation of the Scientific Advisory Group for Origins of Novel Pathogens (SAGO), which is to be a permanent advisory body of the organisation. The Group was formed with a broad objective to examine emerging infectious diseases, including COVID-19. The group's primary objective is to provide scientific guidance on identifying the origins of emerging pathogens, including SARS-CoV-2, and to establish a global framework for preventing future pandemics by examining high-risk virus families such as coronaviruses, filoviruses, and paramyxoviruses. The group has also recommended enhanced global surveillance systems, particularly in regions with a history of emerging zoonotic diseases. According to the WHO Director-General, "SAGO will play a vital role in the next phase of studies into the origins of SARS-CoV-2, as well as the origins of future new pathogens."
== See also ==
Disease X
Epidemiological transition
Globalization and disease
Pandemic prevention
== References ==
== Further reading ==
Nathan Wolfe (2012). The Viral Storm: The Dawn of a New Pandemic Age. St. Martin's Griffin. ISBN 978-1250012210.
== External links ==
Website of Emerging Infectious Diseases, an open-access, peer-review journal published by the Centers for Disease Control and Prevention (CDC) | Wikipedia/Emerging_infectious_disease |
Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. Proteins responsible for detecting stimuli are generally termed receptors, although in some cases the term sensor is used. The changes elicited by ligand binding (or signal sensing) in a receptor give rise to a biochemical cascade, which is a chain of biochemical events known as a signaling pathway.
When signaling pathways interact with one another they form networks, which allow cellular responses to be coordinated, often by combinatorial signaling events. At the molecular level, such responses include changes in the transcription or translation of genes, and post-translational and conformational changes in proteins, as well as changes in their location. These molecular events are the basic mechanisms controlling cell growth, proliferation, metabolism and many other processes. In multicellular organisms, signal transduction pathways regulate cell communication in a wide variety of ways.
Each component (or node) of a signaling pathway is classified according to the role it plays with respect to the initial stimulus. Ligands are termed first messengers, while receptors are the signal transducers, which then activate primary effectors. Such effectors are typically proteins and are often linked to second messengers, which can activate secondary effectors, and so on. Depending on the efficiency of the nodes, a signal can be amplified (a concept known as signal gain), so that one signaling molecule can generate a response involving hundreds to millions of molecules. As with other signals, the transduction of biological signals is characterised by delay, noise, signal feedback and feedforward and interference, which can range from negligible to pathological. With the advent of computational biology, the analysis of signaling pathways and networks has become an essential tool to understand cellular functions and disease, including signaling rewiring mechanisms underlying responses to acquired drug resistance.
== Stimuli ==
The basis for signal transduction is the transformation of a certain stimulus into a biochemical signal. The nature of such stimuli can vary widely, ranging from extracellular cues, such as the presence of EGF, to intracellular events, such as the DNA damage resulting from replicative telomere attrition. Traditionally, signals that reach the central nervous system are classified as senses. These are transmitted from neuron to neuron in a process called synaptic transmission. Many other intercellular signal relay mechanisms exist in multicellular organisms, such as those that govern embryonic development.
=== Ligands ===
The majority of signal transduction pathways involve the binding of signaling molecules, known as ligands, to receptors that trigger events inside the cell. The binding of a signaling molecule with a receptor causes a change in the conformation of the receptor, known as receptor activation. Most ligands are soluble molecules from the extracellular medium which bind to cell surface receptors. These include growth factors, cytokines and neurotransmitters. Components of the extracellular matrix such as fibronectin and hyaluronan can also bind to such receptors (integrins and CD44, respectively). In addition, some molecules such as steroid hormones are lipid-soluble and thus cross the plasma membrane to reach cytoplasmic or nuclear receptors. In the case of steroid hormone receptors, their stimulation leads to binding to the promoter region of steroid-responsive genes.
Not all classifications of signaling molecules take into account the molecular nature of each class member. For example, odorants belong to a wide range of molecular classes, as do neurotransmitters, which range in size from small molecules such as dopamine to neuropeptides such as endorphins. Moreover, some molecules may fit into more than one class, e.g. epinephrine is a neurotransmitter when secreted by the central nervous system and a hormone when secreted by the adrenal medulla.
Some receptors such as HER2 are capable of ligand-independent activation when overexpressed or mutated. This leads to constitutive activation of the pathway, which may or may not be overturned by compensation mechanisms. In the case of HER2, which acts as a dimerization partner of other EGFRs, constitutive activation leads to hyperproliferation and cancer.
=== Mechanical forces ===
The prevalence of basement membranes in the tissues of Eumetazoans means that most cell types require attachment to survive. This requirement has led to the development of complex mechanotransduction pathways, allowing cells to sense the stiffness of the substratum. Such signaling is mainly orchestrated in focal adhesions, regions where the integrin-bound actin cytoskeleton detects changes and transmits them downstream through YAP1. Calcium-dependent cell adhesion molecules such as cadherins and selectins can also mediate mechanotransduction. Specialised forms of mechanotransduction within the nervous system are responsible for mechanosensation: hearing, touch, proprioception and balance.
=== Osmolarity ===
Cellular and systemic control of osmotic pressure (the difference in osmolarity between the cytosol and the extracellular medium) is critical for homeostasis. There are three ways in which cells can detect osmotic stimuli: as changes in macromolecular crowding, ionic strength, and changes in the properties of the plasma membrane or cytoskeleton (the latter being a form of mechanotransduction). These changes are detected by proteins known as osmosensors or osmoreceptors. In humans, the best characterised osmosensors are transient receptor potential channels present in the primary cilium of human cells. In yeast, the HOG pathway has been extensively characterised.
=== Temperature ===
The sensing of temperature in cells is known as thermoception and is primarily mediated by transient receptor potential channels. Additionally, animal cells contain a conserved mechanism to prevent high temperatures from causing cellular damage, the heat-shock response. Such response is triggered when high temperatures cause the dissociation of inactive HSF1 from complexes with heat shock proteins Hsp40/Hsp70 and Hsp90. With help from the ncRNA hsr1, HSF1 then trimerizes, becoming active and upregulating the expression of its target genes. Many other thermosensory mechanisms exist in both prokaryotes and eukaryotes.
=== Light ===
In mammals, light controls the sense of sight and the circadian clock by activating light-sensitive proteins in photoreceptor cells in the eye's retina. In the case of vision, light is detected by rhodopsin in rod and cone cells. In the case of the circadian clock, a different photopigment, melanopsin, is responsible for detecting light in intrinsically photosensitive retinal ganglion cells.
== Receptors ==
Receptors can be roughly divided into two major classes: intracellular and extracellular receptors.
=== Extracellular receptors ===
Extracellular receptors are integral transmembrane proteins and make up most receptors. They span the plasma membrane of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside region of the receptor (the ligand does not pass through the membrane). Ligand-receptor binding induces a change in the conformation of the inside part of the receptor, a process sometimes called "receptor activation". This results in either the activation of an enzyme domain of the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm.
In eukaryotic cells, most intracellular proteins activated by a ligand/receptor interaction possess an enzymatic activity; examples include tyrosine kinase and phosphatases. Often such enzymes are covalently linked to the receptor. Some of them create second messengers such as cyclic AMP and IP3, the latter controlling the release of intracellular calcium stores into the cytoplasm. Other activated proteins interact with adaptor proteins that facilitate signaling protein interactions and coordination of signaling complexes necessary to respond to a particular stimulus. Enzymes and adaptor proteins are both responsive to various second messenger molecules.
Many adaptor proteins and enzymes activated as part of signal transduction possess specialized protein domains that bind to specific secondary messenger molecules. For example, calcium ions bind to the EF hand domains of calmodulin, allowing it to bind and activate calmodulin-dependent kinase. PIP3 and other phosphoinositides do the same thing to the Pleckstrin homology domains of proteins such as the kinase protein AKT.
==== G protein–coupled receptors ====
G protein–coupled receptors (GPCRs) are a family of integral transmembrane proteins that possess seven transmembrane domains and are linked to a heterotrimeric G protein. With nearly 800 members, this is the largest family of membrane proteins and receptors in mammals. Counting all animal species, they add up to over 5000. Mammalian GPCRs are classified into 5 major families: rhodopsin-like, secretin-like, metabotropic glutamate, adhesion and frizzled/smoothened, with a few GPCR groups being difficult to classify due to low sequence similarity, e.g. vomeronasal receptors. Other classes exist in eukaryotes, such as the Dictyostelium cyclic AMP receptors and fungal mating pheromone receptors.
Signal transduction by a GPCR begins with an inactive G protein coupled to the receptor; the G protein exists as a heterotrimer consisting of Gα, Gβ, and Gγ subunits. Once the GPCR recognizes a ligand, the conformation of the receptor changes to activate the G protein, causing Gα to bind a molecule of GTP and dissociate from the other two G-protein subunits. The dissociation exposes sites on the subunits that can interact with other molecules. The activated G protein subunits detach from the receptor and initiate signaling from many downstream effector proteins such as phospholipases and ion channels, the latter permitting the release of second messenger molecules. The total strength of signal amplification by a GPCR is determined by the lifetimes of the ligand-receptor complex and receptor-effector protein complex and the deactivation time of the activated receptor and effectors through intrinsic enzymatic activity; e.g. via protein kinase phosphorylation or b-arrestin-dependent internalization.
A study was conducted where a point mutation was inserted into the gene encoding the chemokine receptor CXCR2; mutated cells underwent a malignant transformation due to the expression of CXCR2 in an active conformation despite the absence of chemokine-binding. This meant that chemokine receptors can contribute to cancer development.
==== Tyrosine, Ser/Thr and Histidine-specific protein kinases ====
Receptor tyrosine kinases (RTKs) are transmembrane proteins with an intracellular kinase domain and an extracellular domain that binds ligands; examples include growth factor receptors such as the insulin receptor. To perform signal transduction, RTKs need to form dimers in the plasma membrane; the dimer is stabilized by ligands binding to the receptor. The interaction between the cytoplasmic domains stimulates the autophosphorylation of tyrosine residues within the intracellular kinase domains of the RTKs, causing conformational changes. Subsequent to this, the receptors' kinase domains are activated, initiating phosphorylation signaling cascades of downstream cytoplasmic molecules that facilitate various cellular processes such as cell differentiation and metabolism. Many Ser/Thr and dual-specificity protein kinases are important for signal transduction, either acting downstream of [receptor tyrosine kinases], or as membrane-embedded or cell-soluble versions in their own right. The process of signal transduction involves around 560 known protein kinases and pseudokinases, encoded by the human kinome
As is the case with GPCRs, proteins that bind GTP play a major role in signal transduction from the activated RTK into the cell. In this case, the G proteins are members of the Ras, Rho, and Raf families, referred to collectively as small G proteins. They act as molecular switches usually tethered to membranes by isoprenyl groups linked to their carboxyl ends. Upon activation, they assign proteins to specific membrane subdomains where they participate in signaling. Activated RTKs in turn activate small G proteins that activate guanine nucleotide exchange factors such as SOS1. Once activated, these exchange factors can activate more small G proteins, thus amplifying the receptor's initial signal. The mutation of certain RTK genes, as with that of GPCRs, can result in the expression of receptors that exist in a constitutively activated state; such mutated genes may act as oncogenes.
Histidine-specific protein kinases are structurally distinct from other protein kinases and are found in prokaryotes, fungi, and plants as part of a two-component signal transduction mechanism: a phosphate group from ATP is first added to a histidine residue within the kinase, then transferred to an aspartate residue on a receiver domain on a different protein or the kinase itself, thus activating the aspartate residue.
==== Integrins ====
Integrins are produced by a wide variety of cells; they play a role in cell attachment to other cells and the extracellular matrix and in the transduction of signals from extracellular matrix components such as fibronectin and collagen. Ligand binding to the extracellular domain of integrins changes the protein's conformation, clustering it at the cell membrane to initiate signal transduction. Integrins lack kinase activity; hence, integrin-mediated signal transduction is achieved through a variety of intracellular protein kinases and adaptor molecules, the main coordinator being integrin-linked kinase. As shown in the adjacent picture, cooperative integrin-RTK signaling determines the timing of cellular survival, apoptosis, proliferation, and differentiation.
Important differences exist between integrin-signaling in circulating blood cells and non-circulating cells such as epithelial cells; integrins of circulating cells are normally inactive. For example, cell membrane integrins on circulating leukocytes are maintained in an inactive state to avoid epithelial cell attachment; they are activated only in response to stimuli such as those received at the site of an inflammatory response. In a similar manner, integrins at the cell membrane of circulating platelets are normally kept inactive to avoid thrombosis. Epithelial cells (which are non-circulating) normally have active integrins at their cell membrane, helping maintain their stable adhesion to underlying stromal cells that provide signals to maintain normal functioning.
In plants, there are no bona fide integrin receptors identified to date; nevertheless, several integrin-like proteins were proposed based on structural homology with the metazoan receptors. Plants contain integrin-linked kinases that are very similar in their primary structure with the animal ILKs. In the experimental model plant Arabidopsis thaliana, one of the integrin-linked kinase genes, ILK1, has been shown to be a critical element in the plant immune response to signal molecules from bacterial pathogens and plant sensitivity to salt and osmotic stress. ILK1 protein interacts with the high-affinity potassium transporter HAK5 and with the calcium sensor CML9.
==== Toll-like receptors ====
When activated, toll-like receptors (TLRs) take adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adaptor molecules are known to be involved in signaling, which are Myd88, TIRAP, TRIF, and TRAM. These adapters activate other intracellular molecules such as IRAK1, IRAK4, TBK1, and IKKi that amplify the signal, eventually leading to the induction or suppression of genes that cause certain responses. Thousands of genes are activated by TLR signaling, implying that this method constitutes an important gateway for gene modulation.
==== Ligand-gated ion channels ====
A ligand-gated ion channel, upon binding with a ligand, changes conformation to open a channel in the cell membrane through which ions relaying signals can pass. An example of this mechanism is found in the receiving cell of a neural synapse. The influx of ions that occurs in response to the opening of these channels induces action potentials, such as those that travel along nerves, by depolarizing the membrane of post-synaptic cells, resulting in the opening of voltage-gated ion channels.
An example of an ion allowed into the cell during a ligand-gated ion channel opening is Ca2+; it acts as a second messenger initiating signal transduction cascades and altering the physiology of the responding cell. This results in amplification of the synapse response between synaptic cells by remodelling the dendritic spines involved in the synapse.
=== Intracellular receptors ===
Intracellular receptors, such as nuclear receptors and cytoplasmic receptors, are soluble proteins localized within their respective areas. The typical ligands for nuclear receptors are non-polar hormones like the steroid hormones testosterone and progesterone and derivatives of vitamins A and D. To initiate signal transduction, the ligand must pass through the plasma membrane by passive diffusion. On binding with the receptor, the ligands pass through the nuclear membrane into the nucleus, altering gene expression.
Activated nuclear receptors attach to the DNA at receptor-specific hormone-responsive element (HRE) sequences, located in the promoter region of the genes activated by the hormone-receptor complex. Due to their enabling gene transcription, they are alternatively called inductors of gene expression. All hormones that act by regulation of gene expression have two consequences in their mechanism of action; their effects are produced after a characteristically long period of time and their effects persist for another long period of time, even after their concentration has been reduced to zero, due to a relatively slow turnover of most enzymes and proteins that would either deactivate or terminate ligand binding onto the receptor.
Nucleic receptors have DNA-binding domains containing zinc fingers and a ligand-binding domain; the zinc fingers stabilize DNA binding by holding its phosphate backbone. DNA sequences that match the receptor are usually hexameric repeats of any kind; the sequences are similar but their orientation and distance differentiate them. The ligand-binding domain is additionally responsible for dimerization of nucleic receptors prior to binding and providing structures for transactivation used for communication with the translational apparatus.
Steroid receptors are a subclass of nuclear receptors located primarily within the cytosol. In the absence of steroids, they associate in an aporeceptor complex containing chaperone or heatshock proteins (HSPs). The HSPs are necessary to activate the receptor by assisting the protein to fold in a way such that the signal sequence enabling its passage into the nucleus is accessible. Steroid receptors, on the other hand, may be repressive on gene expression when their transactivation domain is hidden. Receptor activity can be enhanced by phosphorylation of serine residues at their N-terminal as a result of another signal transduction pathway, a process called crosstalk.
Retinoic acid receptors are another subset of nuclear receptors. They can be activated by an endocrine-synthesized ligand that entered the cell by diffusion, a ligand synthesised from a precursor like retinol brought to the cell through the bloodstream or a completely intracellularly synthesised ligand like prostaglandin. These receptors are located in the nucleus and are not accompanied by HSPs. They repress their gene by binding to their specific DNA sequence when no ligand binds to them, and vice versa.
Certain intracellular receptors of the immune system are cytoplasmic receptors; recently identified NOD-like receptors (NLRs) reside in the cytoplasm of some eukaryotic cells and interact with ligands using a leucine-rich repeat (LRR) motif similar to TLRs. Some of these molecules like NOD2 interact with RIP2 kinase that activates NF-κB signaling, whereas others like NALP3 interact with inflammatory caspases and initiate processing of particular cytokines like interleukin-1β.
== Second messengers ==
First messengers are the signaling molecules (hormones, neurotransmitters, and paracrine/autocrine agents) that reach the cell from the extracellular fluid and bind to their specific receptors. Second messengers are the substances that enter the cytoplasm and act within the cell to trigger a response. In essence, second messengers serve as chemical relays from the plasma membrane to the cytoplasm, thus carrying out intracellular signal transduction.
=== Calcium ===
The release of calcium ions from the endoplasmic reticulum into the cytosol results in its binding to signaling proteins that are then activated; it is then sequestered in the smooth endoplasmic reticulum and the mitochondria. Two combined receptor/ion channel proteins control the transport of calcium: the InsP3-receptor that transports calcium upon interaction with inositol triphosphate on its cytosolic side; and the ryanodine receptor named after the alkaloid ryanodine, similar to the InsP3 receptor but having a feedback mechanism that releases more calcium upon binding with it. The nature of calcium in the cytosol means that it is active for only a very short time, meaning its free state concentration is very low and is mostly bound to organelle molecules like calreticulin when inactive.
Calcium is used in many processes including muscle contraction, neurotransmitter release from nerve endings, and cell migration. The three main pathways that lead to its activation are GPCR pathways, RTK pathways, and gated ion channels; it regulates proteins either directly or by binding to an enzyme.
=== Lipid messengers ===
Lipophilic second messenger molecules are derived from lipids residing in cellular membranes; enzymes stimulated by activated receptors activate the lipids by modifying them. Examples include diacylglycerol and ceramide, the former required for the activation of protein kinase C.
=== Nitric oxide ===
Nitric oxide (NO) acts as a second messenger because it is a free radical that can diffuse through the plasma membrane and affect nearby cells. It is synthesised from arginine and oxygen by the NO synthase and works through activation of soluble guanylyl cyclase, which when activated produces another second messenger, cGMP. NO can also act through covalent modification of proteins or their metal co-factors; some have a redox mechanism and are reversible. It is toxic in high concentrations and causes damage during stroke, but is the cause of many other functions like the relaxation of blood vessels, apoptosis, and penile erections.
=== Redox signaling ===
In addition to nitric oxide, other electronically activated species are also signal-transducing agents in a process called redox signaling. Examples include superoxide, hydrogen peroxide, carbon monoxide, and hydrogen sulfide. Redox signaling also includes active modulation of electronic flows in semiconductive biological macromolecules.
== Cellular responses ==
Gene activations and metabolism alterations are examples of cellular responses to extracellular stimulation that require signal transduction. Gene activation leads to further cellular effects, since the products of responding genes include instigators of activation; transcription factors produced as a result of a signal transduction cascade can activate even more genes. Hence, an initial stimulus can trigger the expression of a large number of genes, leading to physiological events like the increased uptake of glucose from the blood stream and the migration of neutrophils to sites of infection. The set of genes and their activation order to certain stimuli is referred to as a genetic program.
Mammalian cells require stimulation for cell division and survival; in the absence of growth factor, apoptosis ensues. Such requirements for extracellular stimulation are necessary for controlling cell behavior in unicellular and multicellular organisms; signal transduction pathways are perceived to be so central to biological processes that a large number of diseases are attributed to their dysregulation.
Three basic signals determine cellular growth:
Stimulatory (growth factors)
Transcription dependent responseFor example, steroids act directly as transcription factor (gives slow response, as transcription factor must bind DNA, which needs to be transcribed. Produced mRNA needs to be translated, and the produced protein/peptide can undergo posttranslational modification (PTM))
Transcription independent responseFor example, epidermal growth factor (EGF) binds the epidermal growth factor receptor (EGFR), which causes dimerization and autophosphorylation of the EGFR, which in turn activates the intracellular signaling pathway .
Inhibitory (cell-cell contact)
Permissive (cell-matrix interactions)
The combination of these signals is integrated into altered cytoplasmic machinery which leads to altered cell behaviour.
== Major pathways ==
Following are some major signaling pathways, demonstrating how ligands binding to their receptors can affect second messengers and eventually result in altered cellular responses.
MAPK/ERK pathway: A pathway that couples intracellular responses to the binding of growth factors to cell surface receptors. This pathway is very complex and includes many protein components. In many cell types, activation of this pathway promotes cell division, and many forms of cancer are associated with aberrations in it.
cAMP-dependent pathway: In humans, cAMP works by activating protein kinase A (PKA, cAMP-dependent protein kinase) (see picture), and, thus, further effects depend mainly on cAMP-dependent protein kinase, which vary based on the type of cell.
IP3/DAG pathway: PLC cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2), yielding diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3). DAG remains bound to the membrane, and IP3 is released as a soluble structure into the cytosol. IP3 then diffuses through the cytosol to bind to IP3 receptors, particular calcium channels in the endoplasmic reticulum (ER). These channels are specific to calcium and allow the passage of only calcium to move through. This causes the cytosolic concentration of Calcium to increase, causing a cascade of intracellular changes and activity. In addition, calcium and DAG together works to activate PKC, which goes on to phosphorylate other molecules, leading to altered cellular activity. End-effects include taste, manic depression, tumor promotion, etc.
== History ==
The earliest notion of signal transduction can be traced back to 1855, when Claude Bernard proposed that ductless glands such as the spleen, the thyroid and adrenal glands, were responsible for the release of "internal secretions" with physiological effects. Bernard's "secretions" were later named "hormones" by Ernest Starling in 1905. Together with William Bayliss, Starling had discovered secretin in 1902. Although many other hormones, most notably insulin, were discovered in the following years, the mechanisms remained largely unknown.
The discovery of nerve growth factor by Rita Levi-Montalcini in 1954, and epidermal growth factor by Stanley Cohen in 1962, led to more detailed insights into the molecular basis of cell signaling, in particular growth factors. Their work, together with Earl Wilbur Sutherland's discovery of cyclic AMP in 1956, prompted the redefinition of endocrine signaling to include only signaling from glands, while the terms autocrine and paracrine began to be used. Sutherland was awarded the 1971 Nobel Prize in Physiology or Medicine, while Levi-Montalcini and Cohen shared it in 1986.
In 1970, Martin Rodbell examined the effects of glucagon on a rat's liver cell membrane receptor. He noted that guanosine triphosphate disassociated glucagon from this receptor and stimulated the G-protein, which strongly influenced the cell's metabolism. Thus, he deduced that the G-protein is a transducer that accepts glucagon molecules and affects the cell. For this, he shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman. Thus, the characterization of RTKs and GPCRs led to the formulation of the concept of "signal transduction", a word first used in 1972. Some early articles used the terms signal transmission and sensory transduction. In 2007, a total of 48,377 scientific papers—including 11,211 review papers—were published on the subject. The term first appeared in a paper's title in 1979. Widespread use of the term has been traced to a 1980 review article by Rodbell: Research papers focusing on signal transduction first appeared in large numbers in the late 1980s and early 1990s.
=== Signal transduction in Immunology ===
The purpose of this section is to briefly describe some developments in immunology in the 1960s and 1970s, relevant to the initial stages of transmembrane signal transduction, and how they impacted our understanding of immunology, and ultimately of other areas of cell biology.
The relevant events begin with the sequencing of myeloma protein light chains, which are found in abundance in the urine of individuals with multiple myeloma. Biochemical experiments revealed that these so-called Bence Jones proteins consisted of 2 discrete domains –one that varied from one molecule to the next (the V domain) and one that did not (the Fc domain or the Fragment crystallizable region). An analysis of multiple V region sequences by Wu and Kabat identified locations within the V region that were hypervariable and which, they hypothesized, combined in the folded protein to form the antigen recognition site. Thus, within a relatively short time a plausible model was developed for the molecular basis of immunological specificity, and for mediation of biological function through the Fc domain. Crystallization of an IgG molecule soon followed ) confirming the inferences based on sequencing, and providing an understanding of immunological specificity at the highest level of resolution.
The biological significance of these developments was encapsulated in the theory of clonal selection which holds that a B cell has on its surface immunoglobulin receptors whose antigen-binding site is identical to that of antibodies that are secreted by the cell when it encounters an antigen, and more specifically a particular B cell clone secretes antibodies with identical sequences. The final piece of the story, the Fluid mosaic model of the plasma membrane provided all the ingredients for a new model for the initiation of signal transduction; viz, receptor dimerization.
The first hints of this were obtained by Becker et al who demonstrated that the extent to which human basophils—for which bivalent Immunoglobulin E (IgE) functions as a surface receptor – degranulate, depends on the concentration of anti IgE antibodies to which they are exposed, and results in a redistribution of surface molecules, which is absent when monovalent ligand is used. The latter observation was consistent with earlier findings by Fanger et al. These observations tied a biological response to events and structural details of molecules on the cell surface. A preponderance of evidence soon developed that receptor dimerization initiates responses (reviewed in ) in a variety of cell types, including B cells.
Such observations led to a number of theoretical (mathematical) developments. The first of these was a simple model proposed by Bell which resolved an apparent paradox: clustering forms stable networks; i.e. binding is essentially irreversible, whereas the affinities of antibodies secreted by B cells increase as the immune response progresses. A theory of the dynamics of cell surface clustering on lymphocyte membranes was developed by DeLisi and Perelson who found the size distribution of clusters as a function of time, and its dependence on the affinity and valence of the ligand. Subsequent theories for basophils and mast cells were developed by Goldstein and Sobotka and their collaborators, all aimed at the analysis of dose-response patterns of immune cells and their biological correlates. For a recent review of clustering in immunological systems see.
Ligand binding to cell surface receptors is also critical to motility, a phenomenon that is best understood in single-celled organisms. An example is a detection and response to concentration gradients by bacteria -–the classic mathematical theory appearing in. A recent account can be found in
== See also ==
Adaptor protein
Scaffold protein
Biosemiotics
Cell signaling
Gene regulatory network
Hormonal imprinting
Metabolic pathway
Protein–protein interaction
Two-component regulatory system
== References ==
== External links ==
Netpath - A curated resource of signal transduction pathways in humans Archived 2012-09-20 at the Wayback Machine
Signal Transduction - The Virtual Library of Biochemistry, Molecular Biology and Cell Biology
TRANSPATH(R) - A database about signal transduction pathways
Science's STKE - Signal Transduction Knowledge Environment, from the journal Science, published by AAAS.
Signal+Transduction at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
UCSD-Nature Signaling Gateway Archived 2013-02-12 at the Wayback Machine, from Nature Publishing Group
LitInspector Archived 2019-05-11 at the Wayback Machine - Signal transduction pathway mining in PubMed abstracts
Huaxian Chen, et al. A Cell Based Immunocytochemical Assay For Monitoring Kinase Signaling Pathways And Drug Efficacy (PDF) Archived 2012-02-22 at the Wayback Machine Analytical Biochemistry 338 (2005) 136-142
www.Redoxsignaling.com
Signaling PAthway Database Archived 2012-09-17 at the Wayback Machine - Kyushu University
Cell cycle - Homo sapiens (human) Archived 2012-10-23 at the Wayback Machine - KEGG PATHWAY [1]
Pathway Interaction Database - NCI
Literature-curated human signaling network, the largest human signaling network database | Wikipedia/Intracellular_signaling_peptides_and_proteins |
The protein kinase domain is a structurally conserved protein domain containing the catalytic function of protein kinases. Protein kinases are a group of enzymes that move a phosphate group onto proteins, in a process called phosphorylation. This functions as an on/off switch for many cellular processes, including metabolism, transcription, cell cycle progression, cytoskeletal rearrangement and cell movement, apoptosis, and differentiation. They also function in embryonic development, physiological responses, and in the nervous and immune system. Abnormal phosphorylation causes many human diseases, including cancer, and drugs that affect phosphorylation can treat those diseases.
Protein kinases possess a catalytic subunit which transfers the gamma phosphate from nucleoside triphosphates (almost always ATP) to the side chain of an amino acid in a protein, resulting in a conformational and/or dynamic changes affecting protein function. These enzymes fall into two broad classes, characterised with respect to substrate specificity: serine/threonine specific and tyrosine specific.
== Function ==
Protein kinase function has been evolutionarily conserved from Escherichia coli to Homo sapiens. Protein kinases play a role in a multitude of cellular processes, including division, proliferation, apoptosis, and differentiation. Phosphorylation usually results in a functional change of the target protein by changing structure, dynamics, enzyme activity, cellular location, or association with other proteins.
== Structure ==
The catalytic subunits of protein kinases are highly conserved, and the structures of over 280 of the approximately 494 kinase domains from 481 human genes have been determined, leading to large screens to develop kinase-specific inhibitors for the treatments of a number of diseases. Humans have only 437 kinase domains that have catalytic activity; the rest are pseudokinases or catalyze other reactions.
Eukaryotic protein kinases are enzymes that belong to a very extensive family of proteins which share a conserved catalytic core common with both serine/threonine and tyrosine protein kinases. The domain consists of two sub-domains referred to as the N- and C-terminal domains. The N-terminal domain consists of five beta sheet strands and an alpha helix called the C-helix, and the C-terminal domain usually consists of six alpha helices (labeled D, E, F, G, H, and I). The C-terminal domain contains two long loops, called the catalytic loop and the activation loop, which are essential for catalytic activity. The catalytic loop includes the "HRD motif" (for the amino acid sequence His-Arg-Asp), whose aspartic acid residue interacts directly with the hydroxyl group of the target serine, threonine, or tyrosine residue that is phosphorylated.
The activation loop starts with the DFG motif (for the amino acid sequence Asp-Phe-Gly), which helps to bind ATP and magnesium in the active site. Broadly, the state or conformation of the kinase may be classified as DFGin or DFGout, depending on whether the Asp residue of the DFG motif is in or out of the active site. In the active form, the first few residues of the activation loop adopt a specific form of the DFGin conformation. Some inactive structures may adopt one of several other DFGin conformations, while other inactive structures are DFGout.
== Examples ==
The following is a list of human proteins containing the protein kinase domain:
AAK1 ; AATK ; ABL1 ; ABL2 ; ACVR1 ; ACVR1B ; ACVR1C ; ACVR2A ; ACVR2B ; ACVRL1 ; AKT1 ; AKT2 ; AKT3 ; ALK ; AMHR2 ; ANKK1 ; ARAF ; AURKA ; AURKB ; AURKC ; AXL ; BLK ; BMP2K ; BMPR1A ; BMPR1B ; BMPR2 ; BMX ; BRAF ; BRSK1 ; BRSK2 ; BTK ; BUB1 ; BUB1B ; CAMK1 ; CAMK1D ; CAMK1G ; CAMK2A ; CAMK2B ; CAMK2D ; CAMK2G ; CAMK4 ; CAMKK1 ; CAMKK2 ; CAMKV ; CASK ; CDC42BPA ; CDC42BPB ; CDC42BPG ; CDC7 ; CDK1 ; CDK10 ; CDK11A ; CDK11B ; CDK12 ; CDK13 ; CDK14 ; CDK15 ; CDK16 ; CDK17 ; CDK18 ; CDK19 ; CDK2 ; CDK20 ; CDK3 ; CDK4 ; CDK5 ; CDK6 ; CDK7 ; CDK8 ; CDK9 ; CDKL1 ; CDKL2 ; CDKL3 ; CDKL4 ; CDKL5 ; CHEK1 ; CHEK2 ; CHUK ; CIT ; CLK1 ; CLK2 ; CLK3 ; CLK4 ; CSF1R ; CSK ; CSNK1A1 ; CSNK1A1L ; CSNK1D ; CSNK1E ; CSNK1G1 ; CSNK1G2 ; CSNK1G3 ; CSNK2A1 ; CSNK2A2 ; CSNK2A3 ; DAPK1 ; DAPK2 ; DAPK3 ; DCLK1 ; DCLK2 ; DCLK3 ; DDR1 ; DDR2 ; DMPK ; DSTYK ; DYRK1A ; DYRK1B ; DYRK2 ; DYRK3 ; DYRK4 ; EGFR ; EIF2AK1 ; EIF2AK2 ; EIF2AK3 ; EIF2AK4 ; EPHA1 ; EPHA10 ; EPHA2 ; EPHA3 ; EPHA4 ; EPHA5 ; EPHA6 ; EPHA7 ; EPHA8 ; EPHB1 ; EPHB2 ; EPHB3 ; EPHB4 ; EPHB6 ; ERBB2 ; ERBB3 ; ERBB4 ; ERN1 ; ERN2 ; FER ; FES ; FGFR1 ; FGFR2 ; FGFR3 ; FGFR4 ; FGR ; FLT1 ; FLT3 ; FLT4 ; FRK ; FYN ; GAK ; GRK1 ; GRK2 ; GRK3 ; GRK4 ; GRK5 ; GRK6 ; GRK7 ; GSG2 ; GSK3A ; GSK3B ; GUCY2C ; GUCY2D ; GUCY2F ; HCK ; HIPK1 ; HIPK2 ; HIPK3 ; HIPK4 ; HUNK ; ICK ; IGF1R ; IKBKB ; IKBKE ; ILK ; INSR ; INSRR ; IRAK1 ; IRAK2 ; IRAK3 ; IRAK4 ; ITK ; JAK1 ; JAK2 ; JAK3 ; KALRN ; KDR ; KIT ; KSR1 ; KSR2 ; LATS1 ; LATS2 ; LCK ; LIMK1 ; LIMK2 ; LMTK2 ; LMTK3 ; LRRK1 ; LRRK2 ; LTK ; LYN ; MAK ; MAP2K1 ; MAP2K2 ; MAP2K3 ; MAP2K4 ; MAP2K5 ; MAP2K6 ; MAP2K7 ; MAP3K1 ; MAP3K10 ; MAP3K11 ; MAP3K12 ; MAP3K13 ; MAP3K14 ; MAP3K15 ; MAP3K19 ; MAP3K2 ; MAP3K20 ; MAP3K21 ; MAP3K3 ; MAP3K4 ; MAP3K5 ; MAP3K6 ; MAP3K7 ; MAP3K8 ; MAP3K9 ; MAP4K1 ; MAP4K2 ; MAP4K3 ; MAP4K4 ; MAP4K5 ; MAPK1 ; MAPK10 ; MAPK11 ; MAPK12 ; MAPK13 ; MAPK14 ; MAPK15 ; MAPK3 ; MAPK4 ; MAPK6 ; MAPK7 ; MAPK8 ; MAPK9 ; MAPKAPK2 ; MAPKAPK3 ; MAPKAPK5 ; MARK1 ; MARK2 ; MARK3 ; MARK4 ; MAST1 ; MAST2 ; MAST3 ; MAST4 ; MASTL ; MATK ; MELK ; MERTK ; MET ; MINK1 ; MKNK1 ; MKNK2 ; MLKL ; MOK ; MOS ; MST1R ; MUSK ; MYLK ; MYLK2 ; MYLK3 ; MYLK4 ; MYO3A ; MYO3B ; NEK1 ; NEK10 ; NEK11 ; NEK2 ; NEK3 ; NEK4 ; NEK5 ; NEK6 ; NEK7 ; NEK8 ; NEK9 ; NIM1K ; NLK ; NPR1 ; NPR2 ; NRBP1 ; NRBP2 ; NRK ; NTRK1 ; NTRK2 ; NTRK3 ; NUAK1 ; NUAK2 ; OBSCN ; OXSR1 ; PAK1 ; PAK2 ; PAK3 ; PAK4 ; PAK5 ; PAK6 ; PAN3 ; PASK ; PBK ; PDGFRA ; PDGFRB ; PDIK1L ; PDPK1 ; PDPK2P ; PEAK1 ; PEAK3 ; PHKG1 ; PHKG2 ; PIK3R4 ; PIM1 ; PIM2 ; PIM3 ; PINK1 ; PKDCC ; PKMYT1 ; PKN1 ; PKN2 ; PKN3 ; PLK1 ; PLK2 ; PLK3 ; PLK4 ; PLK5 ; PNCK ; POMK ; PRKAA1 ; PRKAA2 ; PRKACA ; PRKACB ; PRKACG ; PRKCA ; PRKCB ; PRKCD ; PRKCE ; PRKCG ; PRKCH ; PRKCI ; PRKCQ ; PRKCZ ; PRKD1 ; PRKD2 ; PRKD3 ; PRKG1 ; PRKG2 ; PRKX ; PRKY ; PRPF4B ; PSKH1 ; PSKH2 ; PTK2 ; PTK2B ; PTK6 ; PTK7 ; PXK ; RAF1 ; RET ; RIOK1 ; RIOK2 ; RIOK3 ; RIPK1 ; RIPK2 ; RIPK3 ; RIPK4 ; RNASEL ; ROCK1 ; ROCK2 ; ROR1 ; ROR2 ; ROS1 ; RPS6KA1 ; RPS6KA2 ; RPS6KA3 ; RPS6KA4 ; RPS6KA5 ; RPS6KA6 ; RPS6KB1 ; RPS6KB2 ; RPS6KC1 ; RPS6KL1 ; RSKR ; RYK ; SBK1 ; SBK2 ; SBK3 ; SCYL1 ; SCYL2 ; SCYL3 ; SGK1 ; SGK2 ; SGK223 ; SGK3 ; SIK1 ; SIK1B ; SIK2 ; SIK3 ; SLK ; SNRK ; SPEG ; SRC ; SRMS ; SRPK1 ; SRPK2 ; SRPK3 ; STK10 ; STK11 ; STK16 ; STK17A ; STK17B ; STK24 ; STK25 ; STK26 ; STK3 ; STK31 ; STK32A ; STK32B ; STK32C ; STK33 ; STK35 ; STK36 ; STK38 ; STK38L ; STK39 ; STK4 ; STK40 ; STKLD1 ; STRADA ; STRADB ; STYK1 ; SYK ; TAOK1 ; TAOK2 ; TAOK3 ; TBCK ; TBK1 ; TEC ; TEK ; TESK1 ; TESK2 ; TEX14 ; TGFBR1 ; TGFBR2 ; TIE1 ; TLK1 ; TLK2 ; TNIK ; TNK1 ; TNK2 ; TNNI3K ; TP53RK ; TRIB1 ; TRIB2 ; TRIB3 ; TRIO ; TSSK1B ; TSSK2 ; TSSK3 ; TSSK4 ; TSSK6 ; TTBK1 ; TTBK2 ; TTK ; TTN ; TXK ; TYK2 ; TYRO3 ; UHMK1 ; ULK1 ; ULK2 ; ULK3 ; ULK4 ; VRK1 ; VRK2 ; VRK3 ; WEE1 ; WEE2 ; WNK1 ; WNK2 ; WNK3 ; WNK4 ; YES1 ; ZAP70
== References == | Wikipedia/Protein_kinase_domain |
Members of the signal transducer and activator of transcription (STAT) protein family are intracellular transcription factors that mediate many aspects of cellular immunity, proliferation, apoptosis and differentiation. They are primarily activated by membrane receptor-associated Janus kinases (JAK). Dysregulation of this pathway is frequently observed in primary tumors and leads to increased angiogenesis which enhances the survival of tumors and immunosuppression. Gene knockout studies have provided evidence that STAT proteins are involved in the development and function of the immune system and play a role in maintaining immune tolerance and tumor surveillance.
== STAT family ==
The first two STAT proteins were identified in the interferon system. There are seven mammalian STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6.
STAT1 homodimers are involved in type II interferon signalling, and bind to the GAS (Interferon-Gamma Activated Sequence) promoter to induce expression of interferon stimulated genes (ISG). In type I interferon signaling, STAT1-STAT2 heterodimer combines with IRF9 (Interferon Response Factor) to form ISGF3 (Interferon Stimulated Gene Factor), which binds to the ISRE (Interferon-Stimulated Response Element) promoter to induce ISG expression.
== Structure ==
All seven STAT proteins share a common structural motif consisting of an N-terminal domain followed by a coiled-coil, DNA-binding domain, linker, Src homology 2 (SH2), and a C-terminal transactivation domain. Much research has focused on elucidating the roles each of these domains play in regulating different STAT isoforms. Both the N-terminal and SH2 domains mediate homo or heterodimer formation, while the coiled-coil domain functions partially as a nuclear localization signal (NLS). Transcriptional activity and DNA association are determined by the transactivation and DNA-binding domains, respectively.
== Activation ==
Extracellular binding of cytokines or growth factors induce activation of receptor-associated Janus kinases, which phosphorylate a specific tyrosine residue within the STAT protein promoting dimerization via their SH2 domains. The phosphorylated dimer is then actively transported to the nucleus via an importin α/β ternary complex. Originally, STAT proteins were described as latent cytoplasmic transcription factors as phosphorylation was thought to be required for nuclear retention. However, unphosphorylated STAT proteins also shuttle between the cytosol and nucleus, and play a role in gene expression. Once STAT reaches the nucleus, it binds to a consensus DNA-recognition motif called gamma-activated sites (GAS) in the promoter region of cytokine-inducible genes and activates transcription. The STAT protein can be dephosphorylated by nuclear phosphatases, which leads to inactivation of STAT and subsequent transport out of the nucleus by an exportin-RanGTP complex.
== See also ==
JAK-STAT pathway
DNA-binding protein
STAT Inhibitors
== Additional images ==
== References ==
== External links ==
STAT+Transcription+Factors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Drosophila Signal-transducer and activator of transcription protein at 92E - The Interactive Fly | Wikipedia/STAT_protein |
cGMP-dependent protein kinase or protein kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle relaxation, platelet function, sperm metabolism, cell division, and nucleic acid synthesis.
== Genes and proteins ==
PKG are serine/threonine kinases that are present in a variety of eukaryotes ranging from the unicellular organism Paramecium to humans. Two PKG genes, coding for PKG type I (PKG-I) and type II (PKG-II), have been identified in mammals. The N-terminus of PKG-I is encoded by two alternatively spliced exons that specify for the PKG-Iα and PKG-Iβ isoforms. PKG-Iβ is activated at ~10-fold higher cGMP concentrations than PKG-Iα. The PKG-I and PKG-II are homodimers of two identical subunits (~75 kDa and ~85 kDa, respectively) and share common structural features.
Each subunit is composed of three functional domains:
(1) an N-terminal domain that mediates homodimerization, suppression of the kinase activity in the absence of cGMP, and interactions with other proteins including protein substrates
(2) a regulatory domain that contains two non-identical cGMP-binding sites
(3) a kinase domain that catalyzes the phosphate transfer from ATP to the hydroxyl group of a serine/threonine side chain of the target protein
Binding of cGMP to the regulatory domain induces a conformational change which stops the inhibition of the catalytic core by the N-terminus and allows the phosphorylation of substrate proteins. Whereas PKG-I is predominantly localized in the cytoplasm, PKG-II is anchored to the plasma membrane by N-terminal myristoylation.
== Tissue distribution ==
In general, PKG-I and PKG-II are expressed in different cell types.
PKG-I has been detected at high concentrations (above 0.1 μmol/L) in all types of smooth muscle cells (SMCs) including vascular SMCs and in platelets. Lower levels are present in vascular endothelium and cardiomyocytes. The enzyme is also expressed in fibroblasts, certain types of renal cells and leukocytes, and in specific regions of the nervous system, for example in the hippocampus, in cerebellar Purkinje cells, and in dorsal root ganglia. Neurons express either the PKG-Iα or the PKG-Iβ isoform, platelets predominantly Iβ, and both isoforms are present in smooth muscle.
PKG-II has been detected in renal cells, zona glomerulosa cells of the adrenal cortex, club cells in distal airways, intestinal mucosa, pancreatic ducts, parotid and submandibular glands, chondrocytes, and several brain nuclei, but not in cardiac and vascular myocytes.
Specifically, in smooth muscle tissue, PKG promotes the opening of calcium-activated potassium channels, leading to cell hyperpolarization and relaxation, and blocks agonist activity of phospholipase C, reducing liberation of stored calcium ions by inositol triphosphate.
== Role in cancer ==
Cancerous colon cells stop producing PKG, which apparently limits beta-catenin, thus allowing the VEGF enzyme to solicit angiogenesis.
== Behavioral genetics in Drosophila melanogaster ==
In Drosophila melanogaster the foraging (for) gene is a polymorphic trait that underlies differences in food-seeking behaviors. The for locus is made up of Rover (forR) and Sitter (forS) alleles, with the Rover allele being dominant. Rover individuals typically travel greater distances when foraging for food, while Sitter individuals travel less distance to forage for food. Both Rover and Sitter phenotypes are considered wild-type, as fruit fly populations typically exhibit a 70:30 Rover-to-Sitter ratio. The Rover and Sitter alleles are located within the 24A3-5 region of the Drosophila melanogaster polytene chromosome, a region which contains the PKG d2g gene. PKG expression levels account for differences in forR and forS allele frequency and therefore behavior as Rover individuals show higher PKG expression than Sitter individuals, and the Sitter phenotype can be converted to Rover by over-expression of the dg2 gene.
== See also ==
cAMP-dependent protein kinase (PKA)
== References ==
== External links ==
EC 2.7.11.12
Cyclic GMP-Dependent Protein Kinases and the Cardiovascular System
cGMP-Dependent+Protein+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/CGMP-dependent_protein_kinase |
Signal transducing adaptor proteins (STAPs) are proteins that are accessory to main proteins in a signal transduction pathway. Adaptor proteins contain a variety of protein-binding modules that link protein-binding partners together and facilitate the creation of larger signaling complexes. These proteins tend to lack any intrinsic enzymatic activity themselves, instead mediating specific protein–protein interactions that drive the formation of protein complexes. Examples of adaptor proteins include MYD88, Grb2 and SHC1.
== Signaling components ==
Much of the specificity of signal transduction depends on the recruitment of several signalling components such as protein kinases and G-protein GTPases into short-lived active complexes in response to an activating signal such as a growth factor binding to its receptor.
== Domains ==
Adaptor proteins usually contain several domains within their structure (e.g., Src homology 2 (SH2) and SH3 domains) that allow specific interactions with several other specific proteins. SH2 domains recognise specific amino acid sequences within proteins containing phosphotyrosine residues and SH3 domains recognise proline-rich sequences within specific peptide sequence contexts of proteins.
There are many other types of interaction domains found within adaptor and other signalling proteins that allow a rich diversity of specific and coordinated protein–protein interactions to occur within the cell during signal transduction.
== Examples of adaptor proteins ==
Adaptor proteins include:
BCAR3 – Breast cancer anti-estrogen resistance protein 3
CBL – Casitas B-lineage Lymphoma
FRS2 – Fibroblast growth factor receptor substrate 2
GAB2 – GRB2-associated binding protein 2
GRAP – GRB2-related adaptor protein
GRAP2 – GRB2-related adaptor protein 2
GRB2 – Growth factor receptor-bound protein 2
IRS1 – Insulin receptor substrate 1
LDLRAP1 – low-density lipoprotein receptor adaptor protein 1
MYD88 - Myeloid differentiation primary response gene 88
NCDN - Neurochondrin
NCK1 – NCK adaptor protein 1
NCK2 – NCK adaptor protein 2
NOS1AP – nitric oxide synthase 1 (neuronal) adaptor protein
PIK3AP1 – phosphoinositide-3-kinase adaptor protein 1
SH2B1 – SH2B adaptor protein 1
SH2B2 – SH2B adaptor protein 2
SH2B3 – SH2B adaptor protein 3
SH2D3A -SH2 domain containing 3A
SH2D3C – SH2 domain containing 3C
SNTA1 – Syntrophin, alpha 1
SHB – Src homology 2 domain containing adaptor protein B
SLC4A1AP – solute carrier family 4 (anion exchanger), member 1, adaptor protein
== See also ==
Wikipedia:MeSH D12.776#MeSH D12.776.157.057 --- adaptor proteins.2C signal transducing
Wikipedia:MeSH D12.776#MeSH D12.776.543.990.150 --- adaptor proteins.2C vesicular transport
== References ==
== Further reading ==
TAB2 is an adaptor protein involved in the IL-1 signal transduction pathway: Takaesu G, Kishida S, Hiyama A, Yamaguchi K, Shibuya H, Irie K, Ninomiya-Tsuji J, Matsumoto K (April 2000). "TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway". Molecular Cell. 5 (4): 649–58. doi:10.1016/S1097-2765(00)80244-0. PMID 10882101.
Good article about adaptor proteins involved in protein kinase C-mediated signal transduction: Schechtman D, Mochly-Rosen D (October 2001). "Adaptor proteins in protein kinase C-mediated signal transduction". Oncogene. 20 (44): 6339–47. doi:10.1038/sj.onc.1204778. PMID 11607837.
A good article regarding the role of adaptor proteins involved with the T-cell antigen receptor: Samelson LE (2002). "Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins". Annual Review of Immunology. 20 (1): 371–94. doi:10.1146/annurev.immunol.20.092601.111357. PMID 11861607.
Signalling discussed with regards to adaptor proteins: Pawson, T. (1997). "Signaling Through Scaffold, Anchoring, and Adaptor Proteins". Science. 278 (5346): 2075–2080. Bibcode:1997Sci...278.2075P. doi:10.1126/science.278.5346.2075. ISSN 0036-8075. PMID 9405336. | Wikipedia/Signal_transducing_adaptor_protein |
Rho-associated protein kinase or Rho-associated coiled-coil kinase (ROCK) is a kinase belonging to the AGC (PKA/ PKG/PKC) family of serine-threonine specific protein kinases. It is involved mainly in regulating the shape and movement of cells by acting on the cytoskeleton.
ROCKs (ROCK1 and ROCK2) occur in mammals (human, rat, mouse, cow), zebrafish, Xenopus, invertebrates (C. elegans, mosquito, Drosophila) and chicken. Human ROCK1 has a molecular mass of 158 kDa and is a major downstream effector of the small GTPase RhoA. Mammalian ROCK consists of a kinase domain, a coiled-coil region and a Pleckstrin homology (PH) domain, which reduces the kinase activity of ROCKs by an autoinhibitory intramolecular fold if RhoA-GTP is not present.
Rat ROCKs were discovered as the first effectors of Rho and they induce the formation of stress fibers and focal adhesions by phosphorylating MLC (myosin light chain).
Due to this phosphorylation, the actin binding of myosin II and, thus, the contractility increases. Two mouse ROCK isoforms ROCK1 and ROCK2 have been identified. ROCK1 is mainly expressed in the lung, liver, spleen, kidney and testis. However, ROCK2 is distributed mostly in the brain and heart.
Protein kinase C and Rho-associated protein kinase are involved in regulating calcium ion intake; these calcium ions, in turn stimulate a myosin light chain kinase, forcing a contraction. Rho-associated protein kinase are serine or threonine kinases that determine the calcium sensitivity in smooth muscle cells.
== Function ==
ROCK plays a role in a wide range of different cellular phenomena, as ROCK is a downstream effector protein of the small GTPase Rho, which is one of the major regulators of the cytoskeleton.
1. ROCK is a key regulator of actin organization and thus a regulator of cell migration as follows:
Different substrates can be phosphorylated by ROCKs, including LIM kinase, myosin light chain (MLC) and MLC phosphatase. These substrates, once phosphorylated, regulate actin filament organization and contractility as follows:
Amount of actin filaments
ROCK inhibits the depolymerization of actin filaments indirectly: ROCK phosphorylates and activates LIM kinase, which in turn phosphorylates ADF/cofilin, thereby inactivating its actin-depolymerization activity. This results in the stabilization of actin filaments and an increase in their numbers. Thus, over time actin monomers that are needed to continue actin polymerization for migration become limited. The increased stable actin filaments and the loss of actin monomers contribute to a reduction of cell migration.
Cellular contractility
ROCK also regulates cell migration by promoting cellular contraction and thus cell-substratum contacts. ROCK increases the activity of the motor protein myosin II by two different mechanisms:
Firstly, phosphorylation of the myosin light chain (MLC) increases the myosin II ATPase activity. Thus several bundled and active myosins, which are asynchronously active on several actin filaments, move actin filaments against each other, resulting in the net shortenting of actin fibres.
Secondly, ROCK inactivates MLC phosphatase, leading to increased levels of phosphorylated MLC.
Thus in both cases, ROCK activation by Rho induces the formation of actin stress fibers, actin filament bundles of opposing polarity, containing myosin II, tropomyosin, caldesmon and MLC-kinase, and consequently of focal contacts, which are immature integrin-based adhesion points with the extracellular substrate.
2. Other functions and targets
RhoA-GTP stimulates the phospholipid phosphatase activity of PTEN (phosphatase and tensin homologue), a human tumor suppressor protein. This stimulation seems to depend on ROCK. In this way, PTEN is important to prevent uncontrolled cell division as is exhibited in cancer cells.
ROCK plays an important role in cell cycle control, it seems to inhibit the premature separation of the two centrioles in G1, and is proposed to be required for contraction of the cleavage furrow, which is necessary for the completion of cytokinesis.
ROCKs also seem to antagonize the insulin signaling pathway, resulting in a reduction of cell size and influence cell fate.
ROCKS play a role in membrane blebbing, a morphological change seen in cells committed to apoptosis. The pro-apoptotic protease, caspase 3, activates ROCK kinase activity by cleaving the C-terminal PH domain. As a result, the autoinhibitory intramolecular fold of ROCK is abolished. ROCK also regulates MLC phosphorylation and actomyosin contractility, which regulate membrane blebbing.
ROCKs contribute to neurite retraction by inducing growth cone collapse by activating actomyosin contractility. It is also possible that phosphorylation of collapsin response mediator protein-2 (CRMP2) by ROCK inhibits CRPM2 function of promoting axon outgrowth, resulting in growth cone collapse.
ROCKs regulate cell-cell adhesion: Loss of ROCK activity seems to lead to loss of tight junction integrity in endothelial cells. In epithelial cells inhibition of ROCK seems to decrease tight junction integrity. Active ROCK in these cells seems to stimulate the disruption of E-Cadherin-mediated cell-cell contacts by activating actomyosin contractility.
3. Other ROCK targets
NHE1 (a sodium hydrogen exchanger, involved in focal adhesions and actin organisation)
intermediate filament proteins: Vimentin, GFAP (glial fibrillaric acidic protein), NF-L (neurofilament L protein)
F-actin binding proteins: Adducin, EF-1&alpha (elongation factor, translation co-factor), MARCKS (myristylated alanine-rich C kinase substrate), Caponin (unknown function), and ERM (involved in linkage of the actin cytoskelton to the plasma membrane).
== Homologues ==
The two mouse ROCK isoforms, ROCK1 and ROCK2, have high homology. They have 65% amino acid sequences in common and 92% homology within their kinase domains.
ROCKs are homologous to other metazoan kinases such as myotonic dystrophy kinase (DMPK), DMPK-related cell division control protein 42 (Cdc42)-binding kinases (MRCK) and citron kinase. All of these kinases are composed of a N-terminal kinase domain, a coiled-coil structure and other functional motifs at the C-terminus
== Regulation ==
ROCK is a downstream effector molecule of the Rho GTPase Rho that increases ROCK kinase activity when bound to it.
=== Autoinhibition ===
ROCK activity is regulated by the disruption of an intramolecular autoinhibition. In general, the structure of ROCK proteins consists of an N-terminal kinase domain, a coiled-coiled region and a PH domain containing a cystein-rich domain (CRD) at the C-terminal. A Rho-binding domain (RBD) is located in close proximity just in front of the PH domain.
The kinase activity is inhibited by the intramolecular binding between the C-terminal cluster of RBD domain and the PH domain to the N-terminal kinase domain of ROCK. Thus, the kinase activity is off when ROCK is intramolecularly folded. The kinase activity is switched on when Rho-GTP binds to the Rho-binding domain of ROCK, disrupting the autoinhibitory interaction within ROCK, which liberates the kinase domain because ROCK is then no longer intramolecularly folded.
=== Other regulators ===
It has also been shown that Rho is not the only activator of ROCK. ROCK can also be regulated by lipids, in particular arachidonic acid, and protein oligomerization, which induces N-terminal transphosphorylation.
== Inhibitors ==
== Disease ==
Research over the past two decades has shown that ROCK signaling plays an important role in many diseases including cardiovascular disease, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and cancer. For example, ROCK has been hypothesized to play an important role in the pleiotropic effects of statins. ROCK1/2 along with MRCKα/β kinases have been implicated in the plasticity of cancer cell migration, the phenomenon which bestows survival advantage to the cancer cells during drug treatments (drug resistance).
Researchers are developing ROCK inhibitors such as RKI-1447 for treating various diseases including cancer. For example, such drugs have potential to prevent cancer from spreading by blocking cell migration, stopping cancer cells from spreading into neighboring tissue.
== See also ==
ROCK1
== References == | Wikipedia/Rho-associated_protein_kinase |
The SH2 (Src Homology 2) domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins. SH2 domains bind to phosphorylated tyrosine residues on other proteins, modifying the function or activity of the SH2-containing protein. The SH2 domain may be considered the prototypical modular protein-protein interaction domain, allowing the transmission of signals controlling a variety of cellular functions. SH2 domains are especially common in adaptor proteins that aid in the signal transduction of receptor tyrosine kinase pathways.
== Structure and interactions ==
SH2 domains contain about 100 amino acid residues and exhibit a central antiparallel β-sheet centered between two α-helices. Binding to phosphotyrosine-containing peptides involves a strictly-conserved Arg residue that pairs with the negatively-charged phosphate on the phosphotyrosine, and a surrounding pocket that recognizes flanking sequences on the target peptide. Compared to other signaling proteins, SH2 domains exhibit only a moderate degree of specificity for their target peptides, due to the relative weakness of the interactions with the flanking sequences.
Over 100 human proteins are known to contain SH2 domains. A variety of tyrosine-containing sequences have been found to bind SH2 domains and are conserved across a wide range of organisms, performing similar functions. Binding of a phosphotyrosine-containing protein to an SH2 domain may lead to either activation or inactivation of the SH2-containing protein, depending on the types of interactions formed between the SH2 domain and other domains of the enzyme. Mutations that disrupt the structural stability of the SH2 domain, or that affect the binding of the phosphotyrosine peptide of the target, are involved in a range of diseases including X-linked agammaglobulinemia and severe combined immunodeficiency.
== Diversity ==
SH2 domains are not present in yeast and appear at the boundary between protozoa and animalia in organisms such as the social amoeba Dictyostelium discoideum.
A detailed bioinformatic examination of SH2 domains of human and mouse reveals 120 SH2 domains contained within 115 proteins encoded by the human genome, representing a rapid rate of evolutionary expansion among the SH2 domains.
A large number of SH2 domain structures have been solved and many SH2 proteins have been knocked out in mice.
== Applications ==
SH2 domains, and other binding domains, have been used in protein engineering to create protein assemblies. Protein assemblies are formed when several proteins bind to one another to create a larger structure (called a supramolecular assembly). Using molecular biology techniques, fusion proteins of specific enzymes and SH2 domains have been created, which can bind to each other to form protein assemblies.
Since SH2 domains require phosphorylation in order for binding to occur, the use of kinase and phosphatase enzymes gives researchers control over whether protein assemblies will form or not. High affinity engineered SH2 domains have been developed and utilized for protein assembly applications.
The goal of most protein assembly formation is to increase the efficiency of metabolic pathways via enzymatic co-localization. Other applications of SH2 domain mediated protein assemblies have been in the formation of high density fractal-like structures, which have extensive molecular trapping properties.
== Examples ==
Human proteins containing this domain include:
ABL1; ABL2
BCAR3; BLK; BLNK; BMX; BTK
CHN2; CISH; CRK; CRKL; CSK
DAPP1
FER; FES; FGR; FRK; FYN
GRAP; GRAP2; GRB10; GRB14; GRB2; GRB7
HCK; HSH2D
INPP5D; INPPL1; ITK; JAK2; LCK; LCP2; LYN
MATK; NCK1; NCK2
PIK3R1; PIK3R2; PIK3R3; PLCG1; PLCG2; PTK6; PTPN11; PTPN6; RASA1
SH2B1; SH2B2; SH2B3; SH2D1A; SH2D1B; SH2D2A; SH2D3A; SH2D3C; SH2D4A; SH2D4B; SH2D5; SH2D6; SH3BP2; SHB; SHC1; SHC3; SHC4; SHD; SHE
SLA; SLA2
SOCS1; SOCS2; SOCS3; SOCS4; SOCS5; SOCS6; SOCS7
SRC; SRMS
STAT1; STAT2; STAT3; STAT4; STAT5A; STAT5B; STAT6
SUPT6H; SYK
TEC; TENC1; TNS; TNS1; TNS3; TNS4; TXK
VAV1; VAV2; VAV3
YES1; ZAP70
== See also ==
Phosphotyrosine-binding domains also bind phosphorylated tyrosines
Anthony Pawson, discoverer of the SH2 Domain
== References ==
== External links ==
SH2 Domain website created by lab of Dr. Piers Nash | Wikipedia/Sh2_domain-containing_protein_tyrosine_phosphatase |
Heterotrimeric G protein, also sometimes referred to as the "large" G proteins (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structural difference between heterotrimeric and monomeric G protein is that heterotrimeric proteins bind to their cell-surface receptors, called G protein-coupled receptors (GPCR), directly. These G proteins are made up of alpha (α), beta (β) and gamma (γ) subunits. The alpha subunit is attached to either a GTP or GDP, which serves as an on-off switch for the activation of G-protein.
When ligands bind a GPCR, the GPCR acquires GEF (guanine nucleotide exchange factor) ability, which activates the G-protein by exchanging the GDP on the alpha subunit to GTP. The binding of GTP to the alpha subunit results in a structural change and its dissociation from the rest of the G-protein. Generally, the alpha subunit binds membrane-bound effector proteins for the downstream signaling cascade, but the beta-gamma complex can carry out this function also. G-proteins are involved in pathways such as the cAMP/PKA pathway, ion channels, MAPK, PI3K.
There are four main families of G proteins: Gi/Go, Gq, Gs, and G12/13.
== Alpha subunits ==
Reconstitution experiments carried out in the early 1980s showed that purified Gα subunits can directly activate effector enzymes. The GTP form of the α subunit of transducin (Gt) activates the cyclic GMP phosphodiesterase from retinal rod outer segments, and the GTP form of the α subunit of the stimulatory G protein (Gs) activates hormone-sensitive adenylate cyclase. More than one type of G protein co-exist in the same tissue. For example, in adipose tissues, two different G-proteins with interchangeable beta-gamma complexes are used to activate or inhibit adenylyl cyclase. The alpha subunit of a stimulatory G protein activated by receptors for stimulatory hormones could stimulate adenylyl cyclase, which activates cAMP used for downstream signal cascades. While on the other hand, the alpha subunit of an inhibitory G protein activated by receptors of inhibitory hormones could inhibit adenylyl cyclase, which blocks downstream signal cascades.
Gα subunits consist of two domains, the GTPase domain, and the alpha-helical domain.
There exist at least 20 different Gα subunits, which are separated into four main groups. This nomenclature is based on their sequence homologies:
== G beta-gamma complex ==
The β and γ subunits are closely bound to one another and are referred to as the G beta-gamma complex. Both beta and gamma subunits have different isoforms, and some combination of isoforms result in dimerization while other combinations do not. For example, beta1 binds both gamma subunits while beta3 binds neither. Upon activation of the GPCR, the Gβγ complex is released from the Gα subunit after its GDP-GTP exchange.
=== Function ===
The free Gβγ complex can act as a signaling molecule itself, by activating other second messengers or by gating ion channels directly.
For example, the Gβγ complex, when bound to histamine receptors, can activate phospholipase A2. Gβγ complexes bound to muscarinic acetylcholine receptors, on the other hand, directly open G protein-coupled inward rectifying potassium channels (GIRKs). When acetylcholine is the extracellular ligand in the pathway, the heart cell hyperpolarizes normally to decrease heart muscle contraction. When substances such as muscarine act as ligands, the dangerous amount of hyperpolarization leads to hallucination. Therefore, proper functioning of Gβγ plays a key role in our physiological well-being. The last function is activating L-type calcium channels, as in H3 receptor pharmacology.
=== Heterotrimeric G-proteins in plants ===
Heterotrimeric G-protein signaling in plants deviates from the metazoan model at various levels. For example, the presence of extra-Large G alpha, loss of G alpha and Regulator of G-protein signaling (RGS) in many plant lineages. In addition, the G-proteins are not essential for the survival in dicotyledonous plants, while they are essential for the survival of monocotyledonous plants.
== References ==
== External links ==
Heterotrimeric+G-Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
EC 3.6.5.1 | Wikipedia/Heterotrimeric_G_protein |
A cyclin-dependent kinase inhibitor protein (also known as CKIs, CDIs, or CDKIs) is a protein that inhibits the enzyme cyclin-dependent kinase (CDK) and Cyclin activity by stopping the cell cycle if there are unfavorable conditions, therefore, acting as tumor suppressors. Cell cycle progression is stopped by Cyclin-dependent kinase inhibitor protein at the G1 phase. CKIs are vital proteins within the control system that point out whether the processes of DNA synthesis, mitosis, and cytokines control one another. When a malfunction hinders the successful completion of DNA synthesis in the G1 phase, it triggers a signal that delays or halts the progression to the S phase. Cyclin-dependent kinase inhibitor proteins are essential in the regulation of the cell cycle. If cell mutations surpass the cell cycle checkpoints during cell cycle regulation, it can result in various types of cancer.
== CKI Inactivation Process ==
Cyclin-dependent kinase inhibitor proteins work by inactivating the CDKs through degradation. The typical inactivation mechanism of the CDK/Cyclin complex is based on binding a CDK inhibitor to the CDK cyclin complex and a partial conformational rotation of the CDK. The cyclin is thus forced to release the T loop and detach from the CDK. Then, the CDK inhibitor initiates a small helix into the cleft, blocking the cleft and blocking the active site of the CDK. Eventually, it releases the ATP out of the aperture of the CDK and deactivates it. Cyclin-dependent kinase inhibitor proteins use ATP as a phosphate contributor to phosphorylate serine and threonine residues.
Human cells contain many different cyclins that bind to different CDKs. CDKs and cyclins appear and activate at specific cell cycle phases. Seven cyclin-dependent kinase inhibitor proteins have been identified. They are p15, p16, p18, p19, p21, p27, and p57. These cyclin-dependent kinase inhibitor proteins emerge only in their specific cell cycle phase. Each Cyclin/CDK complex is specific to the part of the cell cycle phase. Each CDK and cyclin can be identified based on the location of the cell cycle. CKIs fall into two categories; those that inhibit CDK1, CDK2, and CDK5 and those that inhibit CDK4 and CDK6. These checkpoints' cell cycle blocks at both the G1/S and G2/M checkpoints are consistent with the inhibition profiles of the enzymes.
=== Discovery ===
The discovery of Cyclin-dependent kinase inhibitor proteins in 1990 opened the door in how we think about cell cycle control. It has steered to various other fields of study such as developmental biology, cell biology and cancer research. The discovery of the first CKIs in yeast (Far1) and P21 in mammals has led to research on family of molecules. Further research has demonstrates that Cdks, cyclins and CKIs play essential roles in processes such as transcription, epigenetic regulation, metabolism, stem cell self-renewal, neuronal functions and spermatogenesis.
In mammals, p27, a cyclin-dependent kinase inhibitor protein, helps control CDK activity in G1. Also, the INK4 proteins help stop the G1-CDK activity when they encounter anti-proliferative signals within the environment. CKIs help promote the specific inhibitory signals that contain the cell from entering the S phase. In budding yeast, SIC 1 and Roughex, RUX, in Drosophila possess the same contributions that contribute to the stability of G1 cells. They are expressed in higher numbers in G1 cells to make sure that no S or M CDKs are in the cell.
== Structure ==
In the cyclin-dependent kinase (CDK) family, or CDK, Cyclin, and CKIs, serine/threonine kinases play an integral role in regulating the eukaryotic cell cycle. The structure of CDK2-CyclinA and p27 is determined by crystallography, demonstrating that the inhibitor of p27 stretches at the top of the Cyclin-CDK complex. The amino terminal of p27 has an RXL motif exhibiting a hydrophobic patch of cyclin A. The carboxyl-terminal end of the p27 fragment interacts with the beta sheet of CDKs, causing interference with the structure; p27 slides into the ATP-binding site of CDK2 and inhibits ATP binding.
=== Clinical significance ===
Role in cancer: Cyclin-dependent kinase inhibitor (CKI) mutants are frequent in human cancers. The function of CKI is to stop cell growth when there are mistakes due to DNA damage. Once a cell is stopped at a checkpoint due to DNA damage, either the damage is repaired or the cell is induced to perform apoptosis. However, if CKI’s mutations don’t stop the cell, Cyclin D is transcribed. It moves into the cytoplasm and eventually activates a specific cyclin-dependent kinase (CDK). The active cyclin/CDK complex then phosphorylates proteins, activates them, and sends the cell into the next phase of the cell cycle. Since the cell with damaged DNA is not stopped, the cell eventually moves out of the G1 checkpoint and prepares for DNA synthesis. When there is uncontrolled cell growth, it can lead to cancer cells due to the inactivation of the CKIs.
== Associated gene and target ==
== References ==
== External links ==
Cyclin-Dependent+Kinase+Inhibitor+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Cyclin-dependent_kinase_inhibitor_protein |
The Rab family of proteins is a member of the Ras superfamily of small G proteins. Approximately 70 types of Rabs have now been identified in humans. Rab proteins generally possess a GTPase fold, which consists of a six-stranded beta sheet which is flanked by five alpha helices.
Rab GTPases regulate many steps of membrane trafficking, including vesicle formation, vesicle movement along actin and tubulin networks, and membrane fusion. These processes make up the route through which cell surface proteins are trafficked from the Golgi to the plasma membrane and are recycled. Surface protein recycling returns proteins to the surface whose function involves carrying another protein or substance inside the cell, such as the transferrin receptor, or serves as a means of regulating the number of a certain type of protein molecules on the surface.
== Function ==
Rab proteins are peripheral membrane proteins, anchored to a membrane via a lipid group covalently linked to an amino acid. Specifically, Rabs are anchored via prenyl groups on two cysteines in the C-terminus. Rab escort proteins (REPs) deliver newly synthesized and prenylated Rab to its destination membrane by binding the hydrophobic, insoluble prenyl groups and carrying Rab through the cytoplasm. The lipid prenyl groups can then insert into the membrane, anchoring Rab at the cytoplasmic face of a vesicle or the plasma membrane. Because Rab proteins are anchored to the membrane through a flexible C-terminal region, they can be thought of as a 'balloon on a string'.
Rabs switch between two conformations, an inactive form bound to GDP (guanosine diphosphate), and an active form bound to GTP (guanosine triphosphate). A guanine nucleotide exchange factor (GEF) catalyzes the conversion from GDP-bound to GTP-bound form, thereby activating the Rab. The inherent GTP hydrolysis of Rabs can be enhanced by a GTPase-activating protein (GAP) leading to Rab inactivation. REPs carry only the GDP-bound form of Rab, and Rab effectors, proteins with which Rab interacts and through which it functions, only bind the GTP-bound form of Rab. Rab effectors are very heterogeneous, and each Rab isoform has many effectors through which it carries out multiple functions. The specific binding of the effector to the Rab protein allows the Rab protein to be effective, and conversely, the conformation shift of the Rab protein to the inactive state leads to effector dissociation from the Rab protein.
Effector proteins have one of four different functions.
Cargo budding, selection, and coating
Vesicle transport
Vesicle uncoating and tethering
Vesicle fusion
After membrane fusion and effector dissociation, Rab is recycled back to its membrane of origin. A GDP dissociation inhibitor (GDI) binds the prenyl groups of the inactive, GDP-bound form of Rab, inhibits the exchange of GDP for GTP (which would reactivate the Rab) and delivers Rab to its original membrane.
== Clinical significance ==
Rab proteins and their functions are essential to proper organelle function, and as such, when any deviation is introduced to the Rab protein cycle, physiological disease states ensue.
=== Choroideremia ===
Choroideremia is caused by a loss-of-function mutation in the CHM gene which codes for Rab escort protein (REP-1). REP-1 and REP-2 (a REP-1 like protein) both help with the prenylation and transport of Rab proteins. Rab27 has been found to preferentially depend on REP-1 for prenylation, which could be the underlying cause of choroideremia.
=== Intellectual disability ===
Mutations in the GDI1 gene, which encodes a guanosine nucleotide dissociation inhibitor, have been shown to lead to X-linked nonspecific intellectual disability. In a study done on mice, carriers for a deletion of the GDI1 gene have shown marked abnormalities in short-term memory formation and social interaction patterns. It is noted that the social and behavioral patterns exhibited in mice that are carriers of the GDI1 protein are similar to those observed in humans with the same deletion. The loss of the GDI1 gene has been shown through brain extracts of the mutant mice to lead to the accumulation of the Rab4 and Rab5 proteins, thus inhibiting their function.
=== Cancer/carcinogenesis ===
Evidence shows that overexpression of Rab GTPases have a striking relationship with carcinogenesis, such as in prostate cancer. There are many mechanisms by which Rab protein dysfunction has been shown to cause cancer. To name a few, elevated expression of the oncogenic Rab1, along with Rab1A proteins, promote the growth of tumors, often with a poor prognosis. The overexpression of Rab23 has been linked to gastric cancer. In addition to directly causing cancer, dysregulation of Rab proteins has also been linked to progression of already existent tumors, and contributing to their malignancy.
=== Parkinson's disease ===
Mutations of the Rab39b protein have been linked to X-linked intellectual disability and also to a rare form of Parkinson's disease.
== Types of Rab proteins ==
There are approximately 70 different Rabs that have been identified in humans thus far. They are mostly involved in vesicle trafficking. Their complexity can be understood if thought of as address labels for vesicle trafficking, defining the identity and routing of vesicles. Shown in parentheses are the equivalent names in the model organisms Saccharomyces cerevisiae and Aspergillus nidulans.
=== Other Rab proteins ===
RABIF
== References ==
== External links ==
rab+G-Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Rab_(G-protein) |
A biological membrane, biomembrane or cell membrane is a selectively permeable membrane that separates the interior of a cell from the external environment or creates intracellular compartments by serving as a boundary between one part of the cell and another. Biological membranes, in the form of eukaryotic cell membranes, consist of a phospholipid bilayer with embedded, integral and peripheral proteins used in communication and transportation of chemicals and ions. The bulk of lipids in a cell membrane provides a fluid matrix for proteins to rotate and laterally diffuse for physiological functioning. Proteins are adapted to high membrane fluidity environment of the lipid bilayer with the presence of an annular lipid shell, consisting of lipid molecules bound tightly to the surface of integral membrane proteins. The cell membranes are different from the isolating tissues formed by layers of cells, such as mucous membranes, basement membranes, and serous membranes.
== Composition ==
=== Asymmetry ===
The lipid bilayer consists of two layers- an outer leaflet and an inner leaflet. The components of bilayers are distributed unequally between the two surfaces to create asymmetry between the outer and inner surfaces. This asymmetric organization is important for cell functions such as cell signaling. The asymmetry of the biological membrane reflects the different functions of the two leaflets of the membrane. As seen in the fluid membrane model of the phospholipid bilayer, the outer leaflet and inner leaflet of the membrane are asymmetrical in their composition. Certain proteins and lipids rest only on one surface of the membrane and not the other.
Both the plasma membrane and internal membranes have cytosolic and exoplasmic faces.
This orientation is maintained during membrane trafficking – proteins, lipids, glycoconjugates facing the lumen of the ER and Golgi get expressed on the extracellular side of the plasma membrane. In eukaryotic cells, new phospholipids are manufactured by enzymes bound to the part of the endoplasmic reticulum membrane that faces the cytosol. These enzymes, which use free fatty acids as substrates, deposit all newly made phospholipids into the cytosolic half of the bilayer. To enable the membrane as a whole to grow evenly, half of the new phospholipid molecules then have to be transferred to the opposite monolayer. This transfer is catalyzed by enzymes called flippases. In the plasma membrane, flippases transfer specific phospholipids selectively, so that different types become concentrated in each monolayer.
Using selective flippases is not the only way to produce asymmetry in lipid bilayers, however. In particular, a different mechanism operates for glycolipids—the lipids that show the most striking and consistent asymmetric distribution in animal cells.
=== Lipids ===
The biological membrane is made up of lipids with hydrophobic tails and hydrophilic heads. The hydrophobic tails are hydrocarbon tails whose length and saturation is important in characterizing the cell. Lipid rafts occur when lipid species and proteins aggregate in domains in the membrane. These help organize membrane components into localized areas that are involved in specific processes, such as signal transduction.
Red blood cells, or erythrocytes, have a unique lipid composition. The bilayer of red blood cells is composed of cholesterol and phospholipids in equal proportions by weight. Erythrocyte membrane plays a crucial role in blood clotting. In the bilayer of red blood cells is phosphatidylserine. This is usually in the cytoplasmic side of the membrane. However, it is flipped to the outer membrane to be used during blood clotting.
=== Proteins ===
Phospholipid bilayers contain different proteins. These membrane proteins have various functions and characteristics and catalyze different chemical reactions. Integral proteins span the membranes with different domains on either side. Integral proteins hold strong association with the lipid bilayer and cannot easily become detached. They will dissociate only with chemical treatment that breaks the membrane. Peripheral proteins are unlike integral proteins in that they hold weak interactions with the surface of the bilayer and can easily become dissociated from the membrane. Peripheral proteins are located on only one face of a membrane and create membrane asymmetry.
=== Oligosaccharides ===
Oligosaccharides are sugar containing polymers. In the membrane, they can be covalently bound to lipids to form glycolipids or covalently bound to proteins to form glycoproteins. Membranes contain sugar-containing lipid molecules known as glycolipids. In the bilayer, the sugar groups of glycolipids are exposed at the cell surface, where they can form hydrogen bonds. Glycolipids provide the most extreme example of asymmetry in the lipid bilayer. Glycolipids perform a vast number of functions in the biological membrane that are mainly communicative, including cell recognition and cell-cell adhesion. Glycoproteins are integral proteins. They play an important role in the immune response and protection.
== Formation ==
The phospholipid bilayer is formed due to the aggregation of membrane lipids in aqueous solutions. Aggregation is caused by the hydrophobic effect, where hydrophobic ends come into contact with each other and are sequestered away from water. This arrangement maximises hydrogen bonding between hydrophilic heads and water while minimising unfavorable contact between hydrophobic tails and water. The increase in available hydrogen bonding increases the entropy of the system, creating a spontaneous process.
== Function ==
Biological molecules are amphiphilic or amphipathic, i.e. are simultaneously hydrophobic and hydrophilic. The phospholipid bilayer contains charged hydrophilic headgroups, which interact with polar water. The layers also contain hydrophobic tails, which meet with the hydrophobic tails of the complementary layer. The hydrophobic tails are usually fatty acids that differ in lengths. The interactions of lipids, especially the hydrophobic tails, determine the lipid bilayer physical properties such as fluidity.
Membranes in cells typically define enclosed spaces or compartments in which cells may maintain a chemical or biochemical environment that differs from the outside. For example, the membrane around peroxisomes shields the rest of the cell from peroxides, chemicals that can be toxic to the cell, and the cell membrane separates a cell from its surrounding medium. Peroxisomes are one form of vacuole found in the cell that contain by-products of chemical reactions within the cell. Most organelles are defined by such membranes, and are called membrane-bound organelles.
=== Selective permeability ===
Probably the most important feature of a biomembrane is that it is a selectively permeable structure. This means that the size, charge, and other chemical properties of the atoms and molecules attempting to cross it will determine whether they succeed in doing so. Selective permeability is essential for effective separation of a cell or organelle from its surroundings. Biological membranes also have certain mechanical or elastic properties that allow them to change shape and move as required.
Generally, small hydrophobic molecules can readily cross phospholipid bilayers by simple diffusion.
Particles that are required for cellular function but are unable to diffuse freely across a membrane enter through a membrane transport protein or are taken in by means of endocytosis, where the membrane allows for a vacuole to join onto it and push its contents into the cell. Many types of specialized plasma membranes can separate cell from external environment: apical, basolateral, presynaptic and postsynaptic ones, membranes of flagella, cilia, microvillus, filopodia and lamellipodia, the sarcolemma of muscle cells, as well as specialized myelin and dendritic spine membranes of neurons. Plasma membranes can also form different types of "supramembrane" structures such as caveolae, postsynaptic density, podosome, invadopodium, desmosome, hemidesmosome, focal adhesion, and cell junctions. These types of membranes differ in lipid and protein composition.
Distinct types of membranes also create intracellular organelles: endosome; smooth and rough endoplasmic reticulum; sarcoplasmic reticulum; Golgi apparatus; lysosome; mitochondrion (inner and outer membranes); nucleus (inner and outer membranes); peroxisome; vacuole; cytoplasmic granules; cell vesicles (phagosome, autophagosome, clathrin-coated vesicles, COPI-coated and COPII-coated vesicles) and secretory vesicles (including synaptosome, acrosomes, melanosomes, and chromaffin granules).
Different types of biological membranes have diverse lipid and protein compositions. The content of membranes defines their physical and biological properties. Some components of membranes play a key role in medicine, such as the efflux pumps that pump drugs out of a cell.
=== Fluidity ===
The hydrophobic core of the phospholipid bilayer is constantly in motion because of rotations around the bonds of lipid tails. Hydrophobic tails of a bilayer bend and lock together. However, because of hydrogen bonding with water, the hydrophilic head groups exhibit less movement as their rotation and mobility are constrained. This results in increasing viscosity of the lipid bilayer closer to the hydrophilic heads.
Below a transition temperature, a lipid bilayer loses fluidity when the highly mobile lipids exhibits less movement becoming a gel-like solid. The transition temperature depends on such components of the lipid bilayer as the hydrocarbon chain length and the saturation of its fatty acids. Temperature-dependence fluidity constitutes an important physiological attribute for bacteria and cold-blooded organisms. These organisms maintain a constant fluidity by modifying membrane lipid fatty acid composition in accordance with differing temperatures.
In animal cells, membrane fluidity is modulated by the inclusion of the sterol cholesterol. This molecule is present in especially large amounts in the plasma membrane, where it constitutes approximately 20% of the lipids in the membrane by weight. Because cholesterol molecules are short and rigid, they fill the spaces between neighboring phospholipid molecules left by the kinks in their unsaturated hydrocarbon tails. In this way, cholesterol tends to stiffen the bilayer, making it more rigid and less permeable.
For all cells, membrane fluidity is important for many reasons. It enables membrane proteins to diffuse rapidly in the plane of the bilayer and to interact with one another, as is crucial, for example, in cell signaling. It permits membrane lipids and proteins to diffuse from sites where they are inserted into the bilayer after their synthesis to other regions of the cell. It allows membranes to fuse with one another and mix their molecules, and it ensures that membrane molecules are distributed evenly between daughter cells when a cell divides. If biological membranes were not fluid, it is hard to imagine how cells could live, grow, and reproduce.
The fluidity property is at the center of the Helfrich model which allows for calculating the energy cost of an elastic deformation to the membrane.
== See also ==
Collodion bag
Fluid mosaic model
Osmosis
Membrane biology
Soft matter
== References ==
== External links ==
Media related to Biological membranes at Wikimedia Commons
Membranes at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Phosphatidylethanolamine_binding_protein |
5' AMP-activated protein kinase or AMPK or 5' adenosine monophosphate-activated protein kinase is an enzyme (EC 2.7.11.31) that plays a role in cellular energy homeostasis, largely to activate glucose and fatty acid uptake and oxidation when cellular energy is low. It belongs to a highly conserved eukaryotic protein family and its orthologues are SNF1 in yeast, and SnRK1 in plants. It consists of three proteins (subunits) that together make a functional enzyme, conserved from yeast to humans. It is expressed in a number of tissues, including the liver, brain, and skeletal muscle. In response to binding AMP and ADP, the net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipogenesis, inhibition of adipocyte lipolysis, and modulation of insulin secretion by pancreatic β-cells.
It should not be confused with cyclic AMP-activated protein kinase (protein kinase A).
== Structure ==
AMPK is a heterotrimeric protein complex that is formed by α, β, and γ subunits. Each of these three subunits takes on a specific role in both the stability and activity of AMPK. Specifically, the γ subunit includes four particular Cystathionine-β-synthase (CBS) domains, giving AMPK its ability to sensitively detect shifts in the AMP/ATP ratio. AMPK is deactivated upon AMP displacement by ATP at CBS site 3, suggesting CBS3 to be the primary allosteric regulatory site. The four CBS domains create two binding sites for AMP commonly referred to as Bateman domains. Binding of one AMP to a Bateman domain cooperatively increases the binding affinity of the second AMP to the other Bateman domain. As AMP binds both Bateman domains the γ subunit undergoes a conformational change which exposes the catalytic domain found on the α subunit. It is in this catalytic domain where AMPK becomes activated when phosphorylation takes place at threonine-172 (on α1 isoform) or Thr-174 (on α2 isoform) by an upstream AMPK kinase (AMPKK). The α, β, and γ subunits can also be found in different isoforms: the γ subunit can exist as either the γ1, γ2 or γ3 isoform; the β subunit can exist as either the β1 or β2 isoform; and the α subunit can exist as either the α1 or α2 isoform. Although the most common isoforms expressed in most cells are the α1, β1, and γ1 isoforms, it has been demonstrated that the α2, β2, γ2, and γ3 isoforms are also expressed in cardiac and skeletal muscle.
The following human genes encode AMPK subunits:
α – PRKAA1, PRKAA2
β – PRKAB1, PRKAB2
γ – PRKAG1, PRKAG2, PRKAG3
The crystal structure of mammalian AMPK regulatory core domain (α C terminal, β C terminal, γ) has been solved in complex with AMP, ADP or ATP.
== Regulation ==
Due to the presence of isoforms of its components, there are 12 versions of AMPK in mammals, each of which can have different tissue localizations, and different functions under different conditions. AMPK is regulated allosterically and by post-translational modification, which work together.
If residue Thr-172 of AMPK's α1-subunit (or Thr-174 of AMPK's α2-subunit) is phosphorylated, AMPK is activated around 100-fold; access to that residue by phosphatases is blocked if AMP or ADP can block access for and ATP can displace AMP and ADP. That residue is phosphorylated by at least three kinases (liver kinase B1 (LKB1), which works in a complex with STRAD and MO25, Calcium/calmodulin-dependent protein kinase kinase II-(CAMKK2), and TGFβ-activated kinase 1 (TAK1)) and is dephosphorylated by three phosphatases (protein phosphatase 2A (PP2A); protein phosphatase 2C (PP2C) and Mg2+-/Mn2+-dependent protein phosphatase 1E (PPM1E)).
Regulation of AMPK by CaMKK2 requires a direct interaction of these two proteins via their kinase domains. The interaction of CaMKK2 with AMPK only involves the α and β subunits of AMPK (AMPK γ is absent from the CaMKK2 complex), thus rendering regulation of AMPK in this context to changes in calcium levels but not AMP or ADP.
AMPK is regulated allosterically mostly by competitive binding to the CBS sites on its γ subunit between ATP (which allows phosphatase access to Thr-172) and AMP or ADP (each of which blocks access to phosphatases). It thus appears that AMPK is a sensor of AMP/ATP or ADP/ATP ratios and thus cell energy level. AMPK undergoes a large conformational change upon ATP binding. A region on the α subunit known as the kinase domain (KD) dissociates from its active-state conformation and loosely associates with the γ subunit ~100Å away. The KD also rotates ~180° in the conformational change. Upon KD dissociation, the active loop (AL) of the α subunit which contains the critical phosphorylated Thr residue is fully exposed to upstream phosphatases. This conformational change represents a plausible mechanism for AMPK modulation. When cellular energy states are low (high AMP/ATP or ADP/ATP levels), AMPK adopts the KD-associated conformation and AMPK is protected from dephosphorylation and remains activated. When cellular energy states are high, AMPK adopts the KD-displaced conformation, the AL is exposed to upstream phosphatases, and AMPK is deactivated.
The pharmacological compounds Merck Compound 991 and Abbott A769662 bind to the allosteric drug and metabolism site (ADaM) on the β subunit and have been shown to activate AMPK up to 10-fold. ADaM site binding may have roles in AMPK activation as well as protection against dephosphorylation.
There are other mechanisms by which AMPK is inhibited or activated by insulin, leptin, and diacylglycerol by inducing various other phosphorylations.
AMPK may be inhibited or activated by various tissue-specific ubiquitinations.
It is also regulated by several protein-protein interactions, and may either be activated or inhibited by oxidative factors; the role of oxidation in regulating AMPK was controversial as of 2016.
== Function ==
When AMPK phosphorylates acetyl-CoA carboxylase 1 (ACC1) or sterol regulatory element-binding protein 1c (SREBP1c), it inhibits synthesis of fatty acids, cholesterol, and triglycerides, and activates fatty acid uptake and β-oxidation.
AMPK stimulates glucose uptake in skeletal muscle by phosphorylating Rab-GTPase-activating protein TBC1D1, which ultimately induces fusion of GLUT4 vesicles with the plasma membrane. AMPK stimulates glycolysis by activating phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2/3 and activating phosphorylation of glycogen phosphorylase, and it inhibits glycogen synthesis through inhibitory phosphorylation of glycogen synthase. In the liver, AMPK inhibits gluconeogenesis by inhibiting transcription factors including hepatocyte nuclear factor 4 (HNF4) and CREB regulated transcription coactivator 2 (CRTC2).
AMPK inhibits the energy-intensive protein biosynthesis process and can also force a switch from cap-dependent translation to cap-independent translation, which requires less energy, by phosphorylation of TSC2, RPTOR, transcription initiation factor 1A.66, and eEF2K. When TSC2 is activated it inhibits mTORC1. As a result of inhibition of mTORC1 by AMPK, protein synthesis comes to a halt. Activation of AMPK signifies low energy within the cell, so all of the energy consuming pathways like protein synthesis are inhibited, and pathways that generate energy are activated to restore appropriate energy levels in the cell.
AMPK activates autophagy by directly and indirectly activating ULK1. AMPK also appears to stimulate mitochondrial biogenesis by regulating PGC-1α which in turn promotes gene transcription in mitochondria. AMPK also activates anti-oxidant defenses.
== Clinical significance ==
=== Exercise/training ===
Many biochemical adaptations of skeletal muscle that take place during a single bout of exercise or an extended duration of training, such as increased mitochondrial biogenesis and capacity, increased muscle glycogen, and an increase in enzymes which specialize in glucose uptake in cells such as GLUT4 and hexokinase II are thought to be mediated in part by AMPK when it is activated. Additionally, recent discoveries can conceivably suggest a direct AMPK role in increasing blood supply to exercised/trained muscle cells by stimulating and stabilizing both vasculogenesis and angiogenesis. Taken together, these adaptations most likely transpire as a result of both temporary and maintained increases in AMPK activity brought about by increases in the AMP:ATP ratio during single bouts of exercise and long-term training.
During a single acute exercise bout, AMPK allows the contracting muscle cells to adapt to the energy challenges by increasing expression of hexokinase II, translocation of GLUT4 to the plasma membrane, for glucose uptake, and by stimulating glycolysis. If bouts of exercise continue through a long-term training regimen, AMPK and other signals will facilitate contracting muscle adaptations by escorting muscle cell activity to a metabolic transition resulting in a fatty-acid oxidation approach to ATP generation as opposed to a glycolytic approach. AMPK accomplishes this transition to the oxidative mode of metabolism by upregulating and activating oxidative enzymes such as hexokinase II, PPAR-α, PPAR-δ, PGC-1, UCP-3, cytochrome C and TFAM.
Mutations in the skeletal muscle calcium release channel (RYR1) underlies a life- threatening response to heat in patients with malignant hyperthermia susceptibility (MHS). Upon acute exposure to heat, these mutations cause uncontrolled Ca2+ release from the sarcoplasmic reticulum, leading to sustained muscle contractures, severe hyperthermia, and sudden death. At basal conditions, the temperature-dependent Ca2+ leak also leads to increased energy demand and activation of energy sensing AMP kinase (AMPK) in skeletal muscle. The activated AMPK increases muscle metabolic activity, including glycolysis, which leads to marked elevation of circulating lactate.
AMPK activity increases with exercise and the LKB1/MO25/STRAD complex is considered to be the major upstream AMPKK of the 5’-AMP-activated protein kinase phosphorylating the α subunit of AMPK at Thr-172. This fact is puzzling considering that although AMPK protein abundance has been shown to increase in skeletal tissue with endurance training, its level of activity has been shown to decrease with endurance training in both trained and untrained tissue. Currently, the activity of AMPK immediately following a 2 hour bout of exercise of an endurance trained rat is unclear. It is possible that a direct link exists between the observed decrease in AMPK activity in endurance trained skeletal muscle and the apparent decrease in the AMPK response to exercise with endurance training.
Although AMPKα2 activation has been thought to be important for mitochondrial adaptations to exercise training, a recent study investigating the response to exercise training in AMPKα2 knockout mice opposes this idea. Their study compared the response to exercise training of several proteins and enzymes in wild type and AMPKα2 knockout mice. And even though the knockout mice had lower basal markers of mitochondrial density (COX-1, CS, and HAD), these markers increased similarly to the wild type mice after exercise training. These findings are supported by another study also showing no difference in mitochondrial adaptations to exercise training between wild type and knockout mice.
=== Maximum life span ===
The C. elegans homologue of AMPK, aak-2, has been shown by Michael Ristow and colleagues to be required for extension of life span in states of glucose restriction mediating a process named mitohormesis.
=== Lipid metabolism ===
One of the effects of exercise is an increase in fatty acid metabolism, which provides more energy for the cell. One of the key pathways in AMPK's regulation of fatty acid oxidation is the phosphorylation and inactivation of acetyl-CoA carboxylase. Acetyl-CoA carboxylase (ACC) converts acetyl-CoA to malonyl-CoA, an inhibitor of carnitine palmitoyltransferase 1 (CPT-1). CPT-1 transports fatty acids into the mitochondria for oxidation. Inactivation of ACC, therefore, results in increased fatty acid transport and subsequent oxidation. It is also thought that the decrease in malonyl-CoA occurs as a result of malonyl-CoA decarboxylase (MCD), which may be regulated by AMPK. MCD is an antagonist to ACC, decarboxylating malonyl-CoA to acetyl-CoA, resulting in decreased malonyl-CoA and increased CPT-1 and fatty acid oxidation.
AMPK also plays an important role in lipid metabolism in the liver. It has long been known that hepatic ACC has been regulated in the liver by phosphorylation. AMPK also phosphorylates and inactivates 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), a key enzyme in cholesterol synthesis. HMGR converts 3-hydroxy-3-methylglutaryl-CoA, which is made from acetyl-CoA, into mevalonic acid, which then travels down several more metabolic steps to become cholesterol. AMPK, therefore, helps regulate fatty acid oxidation and cholesterol synthesis.
=== Glucose transport ===
Insulin is a hormone which helps regulate glucose levels in the body. When blood glucose is high, insulin is released from the Islets of Langerhans. Insulin, among other things, will then facilitate the uptake of glucose into cells via increased expression and translocation of glucose transporter GLUT-4. Under conditions of exercise, however, blood sugar levels are not necessarily high, and insulin is not necessarily activated, yet muscles are still able to bring in glucose. AMPK seems to be responsible in part for this exercise-induced glucose uptake. Goodyear et al. observed that with exercise, the concentration of GLUT-4 was increased in the plasma membrane, but decreased in the microsomal membranes, suggesting that exercise facilitates the translocation of vesicular GLUT-4 to the plasma membrane. While acute exercise increases GLUT-4 translocation, endurance training will increase the total amount of GLUT-4 protein available. It has been shown that both electrical contraction and AICA ribonucleotide (AICAR) treatment increase AMPK activation, glucose uptake, and GLUT-4 translocation in perfused rat hindlimb muscle, linking exercise-induced glucose uptake to AMPK. Chronic AICAR injections, simulating some of the effects of endurance training, also increase the total amount of GLUT-4 protein in the muscle cell.
Two proteins are essential for the regulation of GLUT-4 expression at a transcriptional level – myocyte enhancer factor 2 (MEF2) and GLUT4 enhancer factor (GEF). Mutations in the DNA binding regions for either of these proteins results in ablation of transgene GLUT-4 expression. These results prompted a study in 2005 which showed that AMPK directly phosphorylates GEF, but it doesn't seem to directly activate MEF2. AICAR treatment has been shown, however, to increase transport of both proteins into the nucleus, as well as increase the binding of both to the GLUT-4 promoter region.
There is another protein involved in carbohydrate metabolism that is worthy of mention along with GLUT-4. The enzyme hexokinase phosphorylates a six-carbon sugar, most notably glucose, which is the first step in glycolysis. When glucose is transported into the cell it is phosphorylated by hexokinase. This phosphorylation keeps glucose from leaving the cell, and by changing the structure of glucose through phosphorylation, it decreases the concentration of glucose molecules, maintaining a gradient for more glucose to be transported into the cell. Hexokinase II transcription is increased in both red and white skeletal muscle upon treatment with AICAR. With chronic injections of AICAR, total protein content of hexokinase II increases in rat skeletal muscle.
=== Mitochondria ===
Mitochondrial enzymes, such as cytochrome c, succinate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase, and citrate synthase, increase in expression and activity in response to exercise. AICAR stimulation of AMPK increases cytochrome c and δ-aminolevulinate synthase (ALAS), a rate-limiting enzyme involved in the production of heme. Malate dehydrogenase and succinate dehydrogenase also increase, as well as citrate synthase activity, in rats treated with AICAR injections. Conversely, in LKB1 knockout mice, there are decreases in cytochrome c and citrate synthase activity, even if the mice are "trained" by voluntary exercise.
AMPK is required for increased peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression in skeletal muscle in response to creatine depletion. PGC-1α is a transcriptional regulator for genes involved in fatty acid oxidation, gluconeogenesis, and is considered the master regulator for mitochondrial biogenesis.
To do this, it enhances the activity of transcription factors like nuclear respiratory factor 1 (NRF-1), myocyte enhancer factor 2 (MEF2), host cell factor (HCF), and others. It also has a positive feedback loop, enhancing its own expression. Both MEF2 and cAMP response element (CRE) are essential for contraction-induced PGC-1α promoter activity. LKB1 knockout mice show a decrease in PGC-1α, as well as mitochondrial proteins.
=== Thyroid hormone ===
AMPK and thyroid hormone regulate some similar processes. Knowing these similarities, Winder and Hardie et al. designed an experiment to see if AMPK was influenced by thyroid hormone. They found that all of the subunits of AMPK were increased in skeletal muscle, especially in the soleus and red quadriceps, with thyroid hormone treatment. There was also an increase in phospho-ACC, a marker of AMPK activity.
=== Glucose sensing systems ===
Loss of AMPK has been reported to alter the sensitivity of glucose sensing cells, through poorly defined mechanisms. Loss of the AMPKα2 subunit in pancreatic β-cells and hypothalamic neurons decreases the sensitivity of these cells to changes in extracellular glucose concentration. Moreover, exposure of rats to recurrent bouts of insulin induced hypoglycemia/glucopenia, reduces the activation of AMPK within the hypothalamus, whilst also suppressing the counterregulatory response to hypoglycemia.
Pharmacological activation of AMPK by delivery of AMPK activating drug AICAR, directly into the hypothalamus can increase the counterregulatory response to hypoglycaemia.
=== Lysosomal damage, inflammatory diseases, and metformin ===
AMPK is recruited to lysosomes and regulated at the lysosomes via several systems of clinical significance. This includes the AXIN - LKB1 complex, acting in response to glucose limitations functioning independently of AMP sensing, which detects low glucose as absence of fructose-1,6-bisphosphate via a dynamic set of interactions between lysosomally localized V-ATPase-aldolase in contact with the endoplasmic reticulum localized TRPV. A second AMPK-control system localized to lysosomes depends on the Galectin-9-TAK1 system and ubiquitination responses at controlled by deubiquitinating enzymes such as USP9X leading to AMPK activation in response to lysosomal damage, a condition that can occur biochemically, physically via protein aggregates such as proteopathic tau in Alzheimer's disease, crystalline silica causing silicosis, cholesterol crystals causing inflammation via NLRP3 inflammasome and rupture of atherosclerotic lesions, urate crystals associated with gout, or during microbial invasion such as Mycobacterium tuberculosis or coronaviruses causing SARS. Both of the above lysosomally localized systems controlling AMPK activate it in response to metformin, a widely prescribed anti-diabetic drug.
=== Tumor suppression and promotion ===
Some evidence indicates that AMPK may have a role in tumor suppression. Studies have found that AMPK may exert most, or even all of, the tumor suppressing properties of liver kinase B1 (LKB1). Additionally, studies where the AMPK activator metformin was used to treat diabetes found a correlation with a reduced risk of cancer, compared to other medications. Gene knockout and knockdown studies with mice found that mice without the gene to express AMPK had greater risks of developing lymphomas, though as the gene was knocked out globally instead of just in B cells, it was impossible to conclude that AMP knockout had cell-autonomous effects within tumor progenitor cells.
In contrast, some studies have linked AMPK with a role as a tumor promoter by protecting cancer cells from stress. Thus, once cancerous cells have formed in an organism, AMPK may swap from protecting against cancer to protecting the cancer itself. Studies have found that tumor cells with AMPK knockout are more susceptible to death by glucose starvation or extracellular matrix detachment, which may indicate AMPK has a role in preventing these two outcomes. A recent study on pancreatic cancer suggests that AMPKα may play a role in the metastatic cascade and the phenotype of cancer cells. Mechanistically, the authors propose that in the absence of AMPKα, pancreatic cancer cells are more vulnerable to oxidative stress, supporting a tumor-promoting function of AMPKα.
== Controversy over role in adaption to exercise/training ==
A seemingly paradoxical role of AMPK occurs when we take a closer look at the energy-sensing enzyme in relation to exercise and long-term training. Similar to short-term acute training scale, long-term endurance training studies also reveal increases in oxidative metabolic enzymes, GLUT-4, mitochondrial size and quantity, and an increased dependency on the oxidation of fatty acids; however, Winder et al. reported in 2002 that despite observing these increased oxidative biochemical adaptations to long-term endurance training (similar to those mentioned above), the AMPK response (activation of AMPK with the onset of exercise) to acute bouts of exercise decreased in red quadriceps (RQ) with training (3 – see Fig.1). Conversely, the study did not observe the same results in white quadriceps (WQ) and soleus (SOL) muscles that they did in RQ. The trained rats used for that endurance study ran on treadmills 5 days/wk in two 1-h sessions, morning and afternoon. The rats were also running up to 31m/min (grade 15%). Finally, following training, the rats were sacrificed either at rest or following 10 minutes of exercise.
Because the AMPK response to exercise decreases with increased training duration, many questions arise that would challenge the AMPK role with respect to biochemical adaptations to exercise and endurance training. This is due in part to the marked increases in the mitochondrial biogenesis, upregulation of GLUT-4, UCP-3, Hexokinase II along with other metabolic and mitochondrial enzymes despite decreases in AMPK activity with training. Questions also arise because skeletal muscle cells which express these decreases in AMPK activity in response to endurance training also seem to be maintaining an oxidative dependent approach to metabolism, which is likewise thought to be regulated to some extent by AMPK activity.
If the AMPK response to exercise is responsible in part for biochemical adaptations to training, how then can these adaptations to training be maintained if the AMPK response to exercise is being attenuated with training? It is hypothesized that these adaptive roles to training are maintained by AMPK activity and that the increases in AMPK activity in response to exercise in trained skeletal muscle have not yet been observed due to biochemical adaptations that the training itself stimulated in the muscle tissue to reduce the metabolic need for AMPK activation. In other words, due to previous adaptations to training, AMPK will not be activated, and further adaptation will not occur, until the intracellular ATP levels become depleted from an even higher intensity energy challenge than prior to those previous adaptations.
== See also ==
Salicylic acid
Aspirin
Salsalate
== Notes ==
== References ==
== External links ==
AMP-activated+protein+kinase at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
EC 2.7.11.31 | Wikipedia/AMP-activated_protein_kinase |
Protein phosphatase 2 (PP2), also known as PP2A, is an enzyme that in humans is encoded by the PPP2CA gene. The PP2A heterotrimeric protein phosphatase is ubiquitously expressed, accounting for a large fraction of phosphatase activity in eukaryotic cells. Its serine/threonine phosphatase activity has a broad substrate specificity and diverse cellular functions. Among the targets of PP2A are proteins of oncogenic signaling cascades, such as Raf, MEK, and AKT, where PP2A may act as a tumor suppressor.
== Structure and function ==
PP2A consists of a dimeric core enzyme composed of the structural A and catalytic C subunits, and a regulatory B subunit. When the PP2A catalytic C subunit associates with the A and B subunits several species of holoenzymes are produced with distinct functions and characteristics. The A subunit, a founding member of the HEAT repeat protein family (huntingtin, EF3, PP2A, TOR1), is the scaffold required for the formation of the heterotrimeric complex. When the A subunit binds it alters the enzymatic activity of the catalytic subunit, even if the B subunit is absent. While C and A subunit sequences show remarkable sequence conservation throughout eukaryotes, regulatory B subunits are more heterogeneous and are believed to play key roles in controlling the localization and specific activity of different holoenzymes. Multicellular eukaryotes express four classes of variable regulatory subunits: B (PR55), B′ (B56 or PR61), B″ (PR72), and B‴ (PR93/PR110), with at least 16 members in these subfamilies. In addition, accessory proteins and post-translational modifications (such as methylation) control PP2A subunit associations and activities.
The two catalytic metal ions located in PP2A's active site are manganese.
== Drug discovery ==
PP2 has been identified as a potential biological target to discover drugs to treat Parkinson's disease and Alzheimer's disease, however as of 2014 it was unclear which isoforms would be most beneficial to target, and also whether activation or inhibition would be most therapeutic.
PP2 has also been identified as a tumor suppressor for blood cancers, and as of 2015 programs were underway to identify compounds that could either directly activate it, or that could inhibit other proteins that suppress its activity.
== References ==
== Further reading ==
== External links ==
PPP2CA+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Rubratoxin | Wikipedia/Protein_phosphatase_2 |
GTP-binding protein regulators regulate G proteins in several different ways. Small GTPases act as molecular switches in signaling pathways, which act to regulate functions of other proteins. They are active or 'ON' when it is bound to GTP and inactive or 'OFF' when bound to GDP. Activation and deactivation of small GTPases can be regarded as occurring in a cycle, between the GTP-bound and GDP-bound form, regulated by other regulatory proteins.
== Exchangers ==
The inactive form of GTPases (GDP-form) are activated by a class of proteins called Guanosine nucleotide exchange factors (GEFs). GEFs catalyse nucleotide exchange by encouraging the release of GDP from the small GTPase (by displacement of the small GTPase-associated Mg2+ ion) and GDP's replacement by GTP (which is in at least a 10-fold excess within the cell) . Inactivation of the active small GTPase is achieved through hydrolysis of the GTP by the small GTPase's intrinsic GTP hydrolytic activity.
== Stimulators ==
The rate of GTP hydrolysis for small GTPases is generally too slow to create physiologically relevant transient signals, and thus requires another class of regulatory proteins to accelerate this activity, the GTPase activating proteins (GAPs).
== Inhibitors ==
Another class of regulatory proteins, the Guanosine nucleotide dissociation inhibitors (GDIs), bind to the GDP-bound form of Rho and Rab small GTPases and not only prevent exchange (maintaining the small GTPase in an off-state), but also prevent the small GTPase from localizing at the membrane, which is their place of action.
== References ==
== External links ==
GTP-Binding+Protein+Regulators at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/GTP-binding_protein_regulators |
In molecular biology, olfactory marker protein is a protein involved in signal transduction.
It is a highly expressed, cytoplasmic protein found in mature olfactory sensory receptor neurons of all vertebrates. OMP is a modulator of the olfactory signal transduction cascade. The crystal structure of OMP reveals a beta sandwich consisting of eight strands in two sheets with a jelly-roll topology. Three highly conserved regions have been identified as possible protein–protein interaction sites in OMP, indicating a possible role for OMP in modulating such interactions, thereby acting as a molecular switch.
== External links ==
Olfactory+marker+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
== References == | Wikipedia/Olfactory_marker_protein |
Rap GTP-binding protein also known as Ras-related proteins or simply RAP is a type of small GTPase, similar in structure to Ras.
These proteins share approximately 50% amino acid identity with the classical RAS proteins and have numerous structural features in common. The most striking difference between RAP proteins and RAS proteins resides in their 61st amino acid: glutamine in RAS is replaced by threonine in RAP proteins. RAP counteracts the mitogenic function of RAS because it can interact with RAS GAPs and RAF in a competitive manner.
== Family members ==
Human genes that encode Ras-related proteins include:
RAP1A, RAP1B
RAP2A, RAP2B, RAP2C
RAB5C
== References ==
== External links ==
rap+GTP-Binding+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain. | Wikipedia/Rap_GTP-binding_protein |
A protein kinase inhibitor (PKI) is a type of enzyme inhibitor that blocks the action of one or more protein kinases. Protein kinases are enzymes that phosphorylate (add a phosphate, or PO4, group) to a protein and can modulate its function.
The phosphate groups are usually added to serine, threonine, or tyrosine amino acids on the protein. Most kinases act on both serine and threonine, the tyrosine kinases act on tyrosine, and a number (dual-specificity kinases) act on all three. There are also protein kinases that phosphorylate other amino acids, including histidine kinases that phosphorylate histidine residues.
Phosphorylation regulates many biological processes, and protein kinase inhibitors can be used to treat diseases due to hyperactive protein kinases (including mutant or overexpressed kinases in cancer) or to modulate cell functions to overcome other disease drivers.
== Clinical use ==
Kinase inhibitors such as dasatinib are often used in the treatment of cancer and inflammation.
Some of the kinase inhibitors used in treating cancer are inhibitors of tyrosine kinases.
The effectiveness of kinase inhibitors on various cancers can vary from patient to patient.
== Examples ==
There are several drugs launched or in development that target protein kinases and the receptors that activate them:
== Comparison of available agents ==
Note:
AD = Approval date.
MS = Myelosuppression.
D = Diarrhoea.
FR = Fluid retention.
As far as myelosuppression, diarrhoea and fluid retention goes: +++ means >70% of patients exhibit clinically significant myelosuppression. ++ means 30-70% of patients exhibit significant myelosuppression. + means 10-30% of patients exhibit significant myelosuppression. - means 0-10% of patients exhibit this side effect.
General references templates are given, which refer the reader to the respective drug database.
== See also ==
Tyrosine kinase inhibitor
== References ==
== Further reading ==
Attwood, Misty M.; Fabbro, Doriano; Sokolov, Aleksandr V.; Knapp, Stefan; Schiöth, Helgi B. (November 2021). "Trends in kinase drug discovery: targets, indications and inhibitor design". Nature Reviews Drug Discovery. 20 (11): 839–861. doi:10.1038/s41573-021-00252-y. PMID 34354255. S2CID 236935403.
Ayala-Aguilera, Cecilia C.; Valero, Teresa; Lorente-Macías, Álvaro; Baillache, Daniel J.; Croke, Stephen; Unciti-Broceta, Asier (27 January 2022). "Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis" (PDF). Journal of Medicinal Chemistry. 65 (2): 1047–1131. doi:10.1021/acs.jmedchem.1c00963. PMID 34624192. S2CID 238528289.
Carles, Fabrice; Bourg, Stéphane; Meyer, Christophe; Bonnet, Pascal (15 April 2018). "PKIDB: A Curated, Annotated and Updated Database of Protein Kinase Inhibitors in Clinical Trials". Molecules. 23 (4): 908. doi:10.3390/molecules23040908. PMC 6017449. PMID 29662024.
Jänne, Pasi A.; Gray, Nathanael; Settleman, Jeff (September 2009). "Factors underlying sensitivity of cancers to small-molecule kinase inhibitors". Nature Reviews Drug Discovery. 8 (9): 709–723. doi:10.1038/nrd2871. PMID 19629074. S2CID 7817325.
Roskoski, Robert (March 2021). "Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update". Pharmacological Research. 165: 105463. doi:10.1016/j.phrs.2021.105463. PMID 33513356. S2CID 231770008.
== External links ==
Protein+kinase+inhibitors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
PKIDB: A searchable database of kinase inhibitors in clinical trials containing physicochemical properties and structures, protein kinase targets, therapeutic indications, year of first approval, and trade names
A list of US FDA-approved small molecule protein kinase inhibitors, their protein kinase targets, therapeutic indications, and links to the FDA label are provided at the Blue Ridge Institute for Medical Research web site. | Wikipedia/Protein_kinase_inhibitor |
Ras, from "Rat sarcoma virus", is a family of related proteins that are expressed in all animal cell lineages and organs. All Ras protein family members belong to a class of protein called small GTPase, and are involved in transmitting signals within cells (cellular signal transduction). Ras is the prototypical member of the Ras superfamily of proteins, which are all related in three-dimensional structure and regulate diverse cell behaviours.
When Ras is 'switched on' by incoming signals, it subsequently switches on other proteins, which ultimately turn on genes involved in cell growth, differentiation, and survival. Mutations in Ras genes can lead to the production of permanently activated Ras proteins, which can cause unintended and overactive signaling inside the cell, even in the absence of incoming signals.
Because these signals result in cell growth and division, overactive Ras signaling can ultimately lead to cancer. The three Ras genes in humans (HRAS, KRAS, and NRAS) are the most common oncogenes in human cancer; mutations that permanently activate Ras are found in 20 to 25% of all human tumors and up to 90% in certain types of cancer (e.g., pancreatic cancer). For this reason, Ras inhibitors are being studied as a treatment for cancer and other diseases with Ras overexpression.
== History ==
The first two Ras genes, HRAS and KRAS, were identified from studies of two cancer-causing viruses, the Harvey sarcoma virus and Kirsten sarcoma virus, by Edward M. Scolnick and colleagues at the National Institutes of Health (NIH). These viruses were discovered originally in rats during the 1960s by Jennifer Harvey and Werner H. Kirsten, respectively, hence the name Rat sarcoma. In 1982, activated and transforming human ras genes were discovered in human cancer cells by Geoffrey M. Cooper at Harvard, Mariano Barbacid and Stuart A. Aaronson at the NIH, Robert Weinberg at MIT, and Michael Wigler at Cold Spring Harbor Laboratory. A third ras gene was subsequently discovered by researchers in the group of Robin Weiss at the Institute of Cancer Research, and Michael Wigler at Cold Spring Harbor Laboratory, named NRAS, for its initial identification in human neuroblastoma cells.
The three human ras genes encode extremely similar proteins made up of chains of 188 to 189 amino acids. Their gene symbols are HRAS, NRAS and KRAS, the latter of which produces the K-Ras4A and K-Ras4B isoforms from alternative splicing.
== Structure ==
Ras contains six beta strands and five alpha helices.
It consists of two domains: a G domain of 166 amino acids (about 20 kDa) that binds guanosine nucleotides, and a C-terminal membrane targeting region (CAAX-COOH, also known as CAAX box), which is lipid-modified by farnesyl transferase, RCE1, and ICMT.
The G domain contains five G motifs that bind GDP/GTP directly.
The G1 motif, or the P-loop, binds the beta phosphate of GDP and GTP.
The G2 motif, also called Switch I or SW1, contains threonine35, which binds the terminal phosphate (γ-phosphate) of GTP and the divalent magnesium ion bound in the active site.
The G3 motif, also called Switch II or SW2, has a DXXGQ motif. The D is aspartate57, which is specific for guanine versus adenine binding, and Q is glutamine61, the crucial residue that activates a catalytic water molecule for hydrolysis of GTP to GDP.
The G4 motif contains a LVGNKxDL motif, and provides specific interaction to guanine.
The G5 motif contains a SAK consensus sequence. The A is alanine146, which provides specificity for guanine rather than adenine.
The two switch motifs, G2 (SW1) and G3 (SW2), are the main parts of the protein that move when GTP is hydrolyzed into GDP. This conformational change by the two switch motifs is what mediates the basic functionality as a molecular switch protein. This GTP-bound state of Ras is the "on" state, and the GDP-bound state is the "off" state. The two switch motifs have a number of conformations when binding GTP or GDP or no nucleotide (when bound to SOS1, which releases the nucleotide).
Ras also binds a magnesium ion which helps to coordinate nucleotide binding.
== Function ==
Ras proteins function as binary molecular switches that control intracellular signaling networks. Ras-regulated signal pathways control such processes as actin cytoskeletal integrity, cell proliferation, cell differentiation, cell adhesion, apoptosis, and cell migration. Ras and Ras-related proteins are often deregulated in cancers, leading to increased invasion and metastasis, and decreased apoptosis.
Ras activates several pathways, of which the mitogen-activated protein (MAP) kinase cascade has been well-studied. This cascade transmits signals downstream and results in the transcription of genes involved in cell growth and division. Another Ras-activated signaling pathway is the PI3K/AKT/mTOR pathway, which stimulates protein synthesis, cellular migration and growth, and inhibits apoptosis.
=== Activation and deactivation ===
Ras is a guanosine-nucleotide-binding protein. Specifically, it is a single-subunit small GTPase, which is related in structure to the Gα subunit of heterotrimeric G proteins (large GTPases). G proteins function as binary signaling switches with "on" and "off" states. In the "off" state it is bound to the nucleotide guanosine diphosphate (GDP), while in the "on" state, Ras is bound to guanosine triphosphate (GTP), which has an extra phosphate group as compared to GDP. This extra phosphate holds the two switch regions in a "loaded-spring" configuration (specifically the Thr-35 and Gly-60). When released, the switch regions relax which causes a conformational change into the inactive state. Hence, activation and deactivation of Ras and other small G proteins are controlled by cycling between the active GTP-bound and inactive GDP-bound forms.
The process of exchanging the bound nucleotide is facilitated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). As per its classification, Ras has an intrinsic GTPase activity, which means that the protein on its own will hydrolyze a bound GTP molecule into GDP. However this process is too slow for efficient function, and hence the GAP for Ras, RasGAP, may bind to and stabilize the catalytic machinery of Ras, supplying additional catalytic residues ("arginine finger") such that a water molecule is optimally positioned for nucleophilic attack on the gamma-phosphate of GTP. An inorganic phosphate is released and the Ras molecule is now bound to a GDP. Since the GDP-bound form is "off" or "inactive" for signaling, GTPase Activating Protein inactivates Ras by activating its GTPase activity. Thus, GAPs accelerate Ras inactivation.
GEFs catalyze a "push and pull" reaction which releases GDP from Ras. They insert close to the P-loop and magnesium cation binding site and inhibit the interaction of these with the gamma phosphate anion. Acidic (negative) residues in switch II "pull" a lysine in the P-loop away from the GDP which "pushes" switch I away from the guanine. The contacts holding GDP in place are broken and it is released into the cytoplasm. Because intracellular GTP is abundant relative to GDP (approximately 10 fold more) GTP predominantly re-enters the nucleotide binding pocket of Ras and reloads the spring. Thus GEFs facilitate Ras activation. Well known GEFs include Son of Sevenless (Sos) and cdc25 which include the RasGEF domain.
The balance between GEF and GAP activity determines the guanine nucleotide status of Ras, thereby regulating Ras activity.
In the GTP-bound conformation, Ras has a high affinity for numerous effectors which allow it to carry out its functions. These include PI3K. Other small GTPases may bind adaptors such as arfaptin or second messenger systems such as adenylyl cyclase. The Ras binding domain is found in many effectors and invariably binds to one of the switch regions, because these change conformation between the active and inactive forms. However, they may also bind to the rest of the protein surface.
Other proteins exist that may change the activity of Ras family proteins. One example is GDI (GDP Disassociation Inhibitor). These function by slowing the exchange of GDP for GTP, thus prolonging the inactive state of Ras family members. Other proteins that augment this cycle may exist.
=== Membrane attachment ===
Ras is attached to the cell membrane owing to its prenylation and palmitoylation (HRAS and NRAS) or the combination of prenylation and a polybasic sequence adjacent to the prenylation site (KRAS). The C-terminal CaaX box of Ras first gets farnesylated at its Cys residue in the cytosol, allowing Ras to loosely insert into the membrane of the endoplasmatic reticulum and other cellular membranes. The Tripeptide (aaX) is then cleaved from the C-terminus by a specific prenyl-protein specific endoprotease and the new C-terminus is methylated by a methyltransferase. KRas processing is completed at this stage. Dynamic electrostatic interactions between its positively charged basic sequence with negative charges at the inner leaflet of the plasma membrane account for its predominant localization at the cell surface at steady-state. NRAS and HRAS are further processed on the surface of the Golgi apparatus by palmitoylation of one or two Cys residues, respectively, adjacent to the CaaX box. The proteins thereby become stably membrane anchored (lipid-rafts) and are transported to the plasma membrane on vesicles of the secretory pathway. Depalmitoylation by acyl-protein thioesterases eventually releases the proteins from the membrane, allowing them to enter another cycle of palmitoylation and depalmitoylation. This cycle is believed to prevent the leakage of NRAS and HRAS to other membranes over time and to maintain their steady-state localization along the Golgi apparatus, secretory pathway, plasma membrane and inter-linked endocytosis pathway.
== Members ==
The clinically most notable members of the Ras subfamily are HRAS, KRAS and NRAS, mainly for being implicated in many types of cancer.
However, there are many other members of this subfamily as well:
DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASD1; RASD2; RASL10A; RASL10B; RASL11A; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS; RRAS2
== Ras in cancer ==
Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumors. It is reasonable to speculate that a pharmacological approach that curtails Ras activity may represent a possible method to inhibit certain cancer types. Ras point mutations are the single most common abnormality of human proto-oncogenes.
Ras inhibitor trans-farnesylthiosalicylic acid (FTS, Salirasib) exhibits profound anti-oncogenic effects in many cancer cell lines.
=== Inappropriate activation ===
Inappropriate activation of the gene has been shown to play a key role in improper signal transduction, proliferation and malignant transformation.
Mutations in a number of different genes as well as RAS itself can have this effect. Oncogenes such as p210BCR-ABL or the growth receptor erbB are upstream of Ras, so if they are constitutively activated their signals will transduce through Ras.
The tumour suppressor gene NF1 encodes a Ras-GAP – its mutation in neurofibromatosis will mean that Ras is less likely to be inactivated. Ras can also be amplified, although this only occurs occasionally in tumours.
Finally, Ras oncogenes can be activated by point mutations so that the GTPase reaction can no longer be stimulated by GAP – this increases the half life of active Ras-GTP mutants.
=== Constitutively active Ras ===
Constitutively active Ras (RasD) is one which contains mutations that prevent GTP hydrolysis, thus locking Ras in a permanently 'On' state.
The most common mutations are found at residue G12 in the P-loop and the catalytic residue Q61.
The glycine to valine mutation at residue 12 renders the GTPase domain of Ras insensitive to inactivation by GAP and thus stuck in the "on state". Ras requires a GAP for inactivation as it is a relatively poor catalyst on its own, as opposed to other G-domain-containing proteins such as the alpha subunit of heterotrimeric G proteins.
Residue 61 is responsible for stabilizing the transition state for GTP hydrolysis. Because enzyme catalysis in general is achieved by lowering the energy barrier between substrate and product, mutation of Q61 to K (Glutamine to Lysine) necessarily reduces the rate of intrinsic Ras GTP hydrolysis to physiologically meaningless levels.
See also "dominant negative" mutants such as S17N and D119N.
=== Ras-targeted cancer treatments ===
Reovirus was noted to be a potential cancer therapeutic when studies suggested it reproduces well in certain cancer cell lines. It replicates specifically in cells that have an activated Ras pathway (a cellular signaling pathway that is involved in cell growth and differentiation). Reovirus replicates in and eventually kills Ras-activated tumour cells and as cell death occurs, progeny virus particles are free to infect surrounding cancer cells. This cycle of infection, replication and cell death is believed to be repeated until all tumour cells carrying an activated Ras pathway are destroyed.
Another tumor-lysing virus that specifically targets tumor cells with an activated Ras pathway is a type II herpes simplex virus (HSV-2) based agent, designated FusOn-H2. Activating mutations of the Ras protein and upstream elements of the Ras protein may play a role in more than two-thirds of all human cancers, including most metastatic disease. Reolysin, a formulation of reovirus, and FusOn-H2 are currently in clinical trials or under development for the treatment of various cancers. In addition, a treatment based on siRNA anti-mutated K-RAS (G12D) called siG12D LODER is currently in clinical trials for the treatment of locally advanced pancreatic cancer (NCT01188785, NCT01676259).
In glioblastoma mouse models SHP2 levels were heightened in cancerous brain cells. Inhibiting SHP2 in turn inhibited Ras dephosphorylation. This reduced tumor sizes and accompanying rise in survival rates.
Other strategies have attempted to manipulate the regulation of the above-mentioned localization of Ras. Farnesyltransferase inhibitors have been developed to stop the farnesylation of Ras and therefore weaken its affinity to membranes. Other inhibitors are targeting the palmitoylation cycle of Ras through inhibiting depalmitoylation by acyl-protein thioesterases, potentially leading to a destabilization of the Ras cycle.
A novel inhibitor finding strategy for mutated Ras molecules was described in. The Ras mutations in the 12th residue position inhibit the bound of the regulatory GAP molecule to the mutated Ras, causing uncontrolled cell growth. The novel strategy proposes finding small glue molecules, which attach the mutated Ras to the GAP, prohibiting uncontrolled cell growth and restoring the normal function. For this goal a theoretical Ras-GAP conformation was designed with a several Å gap between the molecules, and a high-throughput in silico docking was performed for finding gluing agents. As a proof of concept, two novel molecules were described with satisfying biological activity.
== In other species ==
In most of the cell types of most species, most Ras is the GDP type. This is true for Xenopus oocytes and mouse fibroblasts.
=== Xenopus laevis ===
As mentioned above most X. oocyte Ras is the GDP conjugate. Mammal Ras induces meiosis in X. laevis oocytes almost certainly by potentiating insulin-induced meiosis, but not progesterone-induced. Protein synthesis does not seem to be a part of this step. Injection increases synthesis of diacylglycerol from phosphatidylcholine. Some meiosis effects are antagonized by rap1 (and by a Ras modified to dock incorrectly). Both rap1 and the modified Ras are co-antagonists with p120Ras GAP in this pathway.
=== Drosophila melanogaster ===
Expressed in all tissues of Drosophila melanogaster but mostly in neural cells. Overexpression is somewhat lethal and, during development, produces eye and wing abnormalities. (This parallels - and may be the reason for - similar abnormalities due to mutated receptor tyrosine kinases.) The D. genes for rases in mammals produce abnormalities.
=== Aplysia ===
Most expression in Aplysia spp. is in neural cells.
=== Caenorhabditis elegans ===
The gene in C. elegans is let 60. Also appears to play a role in receptor tyrosine kinase formation in this model. Overexpression yields a multivulval development due to its involvement in that region's normal development; overexpression in effector sites in lethal.
=== Dictyostelium discoideum ===
Essential in Dictyostelium discoideum. This is evidenced by severe developmental failure in deficient ras expression and by significant impairment of various life activities when artificially expressed, such as: increased concentration of inositol phosphates; likely reduction of cAMP binding to chemotaxis receptors; and that is likely the reason cGMP synthesis is impaired. Adenylate cyclase activity is unaffected by ras.
== References ==
== Further reading ==
== External links ==
"Brain tumour findings offer hope of new strategy Canadian Cancer Society says" at ncic.cancer.ca
"Novel cancer treatment gets NCI support" at arstechnica.com
ras+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
ras+Genes at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Drosophila Ras oncogene at 85D - The Interactive Fly
"Animation of ras activation by EGFR"
"Rascore: A tool for analyzing RAS protein structures" | Wikipedia/Ras_protein |
The enzyme protein serine/threonine phosphatase (EC 3.1.3.16; systematic name protein-serine/threonine-phosphate phosphohydrolase) is a form of phosphoprotein phosphatase that acts upon phosphorylated serine/threonine residues:
[a protein]-serine/threonine phosphate + H2O = [a protein]-serine/threonine + phosphate
Serine and threonine phosphates are stable under physiological conditions, so a phosphatase enzyme has to remove the phosphate to reverse the regulation signal. Ser/Thr-specific protein phosphatases are regulated partly by their location within the cell and by specific inhibitor proteins.
Serine and threonine are amino acids which have similar side-chain compositions that contain a hydroxyl group and thus can be phosphorylated by enzymes called serine/threonine protein kinases. The addition of the phosphate group can be reversed by enzymes called serine/threonine phosphatases. The addition and removal of phosphate groups regulates many cellular pathways involved in cell proliferation, programmed cell death (apoptosis), embryonic development, and cell differentiation.
== Examples ==
There are several known groups with numerous members in each:
PPP1 (α, β, γ1, γ2)
PPP2 (formerly 2A)
PPP3 (formerly 2b, also known as calcineurin)
PPP2C
PPP4
PPP5
PPP6
(links are to the catalytic subunit)
== References ==
== External links ==
EC 3.1.3.16 | Wikipedia/Protein_serine/threonine_phosphatase |
In cell biology, protein kinase A (PKA) is a family of serine-threonine kinases whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (EC 2.7.11.11). PKA has several functions in the cell, including regulation of glycogen, sugar, and lipid metabolism. It should not be confused with 5'-AMP-activated protein kinase (AMP-activated protein kinase).
== History ==
Protein kinase A, more precisely known as adenosine 3',5'-monophosphate (cyclic AMP)-dependent protein kinase, abbreviated to PKA, was discovered by chemists Edmond H. Fischer and Edwin G. Krebs in 1968. They won the Nobel Prize in Physiology or Medicine in 1992 for their work on phosphorylation and dephosphorylation and how it relates to PKA activity.
PKA is one of the most widely researched protein kinases, in part because of its uniqueness; out of 540 different protein kinase genes that make up the human kinome, only one other protein kinase, casein kinase 2, is known to exist in a physiological tetrameric complex, meaning it consists of four subunits.
The diversity of mammalian PKA subunits was realized after Dr. Stan McKnight and others identified four possible catalytic subunit genes and four regulatory subunit genes. In 1991, Susan Taylor and colleagues crystallized the PKA Cα subunit, which revealed the bi-lobe structure of the protein kinase core for the very first time, providing a blueprint for all the other protein kinases in a genome (the kinome).
== Structure ==
When inactive, the PKA apoenzyme exists as a tetramer which consists of two regulatory subunits and two catalytic subunits. The catalytic subunit contains the active site, a series of canonical residues found in protein kinases that bind and hydrolyse ATP, and a domain to bind the regulatory subunit. The regulatory subunit has domains to bind to cyclic AMP, a domain that interacts with catalytic subunit, and an auto inhibitory domain. There are two major forms of regulatory subunit; RI and RII.
Mammalian cells have at least two types of PKAs: type I is mainly in the cytosol, whereas type II is bound via its regulatory subunits and special anchoring proteins, described in the anchorage section, to the plasma membrane, nuclear membrane, mitochondrial outer membrane, and microtubules. In both types, once the catalytic subunits are freed and active, they can migrate into the nucleus (where they can phosphorylate transcription regulatory proteins), while the regulatory subunits remain in the cytoplasm.
The following human genes encode PKA subunits:
catalytic subunit – PRKACA, PRKACB, PRKACG
regulatory subunit type I - PRKAR1A, PRKAR1B
regulatory subunit type II - PRKAR2A, PRKAR2B
== Mechanism ==
=== Activation ===
PKA is also commonly known as cAMP-dependent protein kinase, because it has traditionally been thought to be activated through release of the catalytic subunits when levels of the second messenger called cyclic adenosine monophosphate, or cAMP, rise in response to a variety of signals. However, recent studies evaluating the intact holoenzyme complexes, including regulatory AKAP-bound signalling complexes, have suggested that the local sub cellular activation of the catalytic activity of PKA might proceed without physical separation of the regulatory and catalytic components, especially at physiological concentrations of cAMP. In contrast, experimentally induced supra physiological concentrations of cAMP, meaning higher than normally observed in cells, are able to cause separation of the holoenzymes, and release of the catalytic subunits.
Extracellular hormones, such as glucagon and epinephrine, begin an intracellular signalling cascade that triggers protein kinase A activation by first binding to a G protein–coupled receptor (GPCR) on the target cell. When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellular heterotrimeric G protein complex by protein domain dynamics. The Gs alpha subunit of the stimulated G protein complex exchanges GDP for GTP in a reaction catalyzed by the GPCR and is released from the complex. The activated Gs alpha subunit binds to and activates an enzyme called adenylyl cyclase, which, in turn, catalyzes the conversion of ATP into cAMP, directly increasing the cAMP level. Four cAMP molecules are able to bind to the two regulatory subunits. This is done by two cAMP molecules binding to each of the two cAMP binding sites (CNB-B and CNB-A) which induces a conformational change in the regulatory subunits of PKA, causing the subunits to detach and unleash the two, now activated, catalytic subunits.
Once released from inhibitory regulatory subunit, the catalytic subunits can go on to phosphorylate a number of other proteins in the minimal substrate context Arg-Arg-X-Ser/Thr., although they are still subject to other layers of regulation, including modulation by the heat stable pseudosubstrate inhibitor of PKA, termed PKI.
Below is a list of the steps involved in PKA activation:
Cytosolic cAMP increases
Two cAMP molecules bind to each PKA regulatory subunit
The regulatory subunits move out of the active sites of the catalytic subunits and the R2C2 complex dissociates
The free catalytic subunits interact with proteins to phosphorylate Ser or Thr residues.
=== Catalysis ===
The liberated catalytic subunits can then catalyze the transfer of ATP terminal phosphates to protein substrates at serine, or threonine residues. This phosphorylation usually results in a change in activity of the substrate. Since PKAs are present in a variety of cells and act on different substrates, PKA regulation and cAMP regulation are involved in many different pathways.
The mechanisms of further effects may be divided into direct protein phosphorylation and protein synthesis:
In direct protein phosphorylation, PKA directly either increases or decreases the activity of a protein.
In protein synthesis, PKA first directly activates CREB, which binds the cAMP response element (CRE), altering the transcription and therefore the synthesis of the protein. In general, this mechanism takes more time (hours to days).
=== Phosphorylation mechanism ===
The Serine/Threonine residue of the substrate peptide is orientated in such a way that the hydroxyl group faces the gamma phosphate group of the bound ATP molecule. Both the substrate, ATP, and two Mg2+ ions form intensive contacts with the catalytic subunit of PKA. In the active conformation, the C helix packs against the N-terminal lobe and the Aspartate residue of the conserved DFG motif chelates the Mg2+ ions, assisting in positioning the ATP substrate. The triphosphate group of ATP points out of the adenosine pocket for the transfer of gamma-phosphate to the Serine/Threonine of the peptide substrate. There are several conserved residues, include Glutamate (E) 91 and Lysine (K) 72, that mediate the positioning of alpha- and beta-phosphate groups. The hydroxyl group of the peptide substrate's Serine/Threonine attacks the gamma phosphate group at the phosphorus via an SN2 nucleophilic reaction, which results in the transfer of the terminal phosphate to the peptide substrate and cleavage of the phosphodiester bond between the beta-phosphate and the gamma-phosphate groups. PKA acts as a model for understanding protein kinase biology, with the position of the conserved residues helping to distinguish the active protein kinase and inactive pseudokinase members of the human kinome.
=== Inactivation ===
Downregulation of protein kinase A occurs by a feedback mechanism and uses a number of cAMP hydrolyzing phosphodiesterase (PDE) enzymes, which belong to the substrates activated by PKA. Phosphodiesterase quickly converts cAMP to AMP, thus reducing the amount of cAMP that can activate protein kinase A. PKA is also regulated by a complex series of phosphorylation events, which can include modification by autophosphorylation and phosphorylation by regulatory kinases, such as PDK1.
Thus, PKA is controlled, in part, by the levels of cAMP. Also, the catalytic subunit itself can be down-regulated by phosphorylation.
=== Anchorage ===
The regulatory subunit dimer of PKA is important for localizing the kinase inside the cell. The dimerization and docking (D/D) domain of the dimer binds to the A-kinase binding (AKB) domain of A-kinase anchor protein (AKAP). The AKAPs localize PKA to various locations (e.g., plasma membrane, mitochondria, etc.) within the cell.
AKAPs bind many other signaling proteins, creating a very efficient signaling hub at a certain location within the cell. For example, an AKAP located near the nucleus of a heart muscle cell would bind both PKA and phosphodiesterase (hydrolyzes cAMP), which allows the cell to limit the productivity of PKA, since the catalytic subunit is activated once cAMP binds to the regulatory subunits.
== Function ==
PKA phosphorylates proteins that have the motif Arginine-Arginine-X-Serine exposed, in turn (de)activating the proteins. Many possible substrates of PKA exist; a list of such substrates is available and maintained by the NIH.
As protein expression varies from cell type to cell type, the proteins that are available for phosphorylation will depend upon the cell in which PKA is present. Thus, the effects of PKA activation vary with cell type:
=== Overview table ===
=== In adipocytes and hepatocytes ===
Epinephrine and glucagon affect the activity of protein kinase A by changing the levels of cAMP in a cell via the G-protein mechanism, using adenylate cyclase. Protein kinase A acts to phosphorylate many enzymes important in metabolism. For example, protein kinase A phosphorylates acetyl-CoA carboxylase and pyruvate dehydrogenase. Such covalent modification has an inhibitory effect on these enzymes, thus inhibiting lipogenesis and promoting net gluconeogenesis. Insulin, on the other hand, decreases the level of phosphorylation of these enzymes, which instead promotes lipogenesis. Recall that gluconeogenesis does not occur in myocytes.
=== In nucleus accumbens neurons ===
PKA helps transfer/translate the dopamine signal into cells in the nucleus accumbens, which mediates reward, motivation, and task salience. The vast majority of reward perception involves neuronal activation in the nucleus accumbens, some examples of which include sex, recreational drugs, and food. Protein Kinase A signal transduction pathway helps in modulation of ethanol consumption and its sedative effects. A mouse study reports that mice with genetically reduced cAMP-PKA signalling results into less consumption of ethanol and are more sensitive to its sedative effects.
=== In skeletal muscle ===
PKA is directed to specific sub-cellular locations after tethering to AKAPs. Ryanodine receptor (RyR) co-localizes with the muscle AKAP and RyR phosphorylation and efflux of Ca2+ is increased by localization of PKA at RyR by AKAPs.
=== In cardiac muscle ===
In a cascade mediated by a GPCR known as β1 adrenoceptor, activated by catecholamines (notably norepinephrine), PKA gets activated and phosphorylates numerous targets, namely: L-type calcium channels, phospholamban, troponin I, myosin binding protein C, and potassium channels. This increases inotropy as well as lusitropy, increasing contraction force as well as enabling the muscles to relax faster.
=== In memory formation ===
PKA has always been considered important in formation of a memory. In the fruit fly, reductions in expression activity of DCO (PKA catalytic subunit encoding gene) can cause severe learning disabilities, middle term memory and short term memory. Long term memory is dependent on the CREB transcription factor, regulated by PKA. A study done on drosophila reported that an increase in PKA activity can affect short term memory. However, a decrease in PKA activity by 24% inhibited learning abilities and a decrease by 16% affected both learning ability and memory retention. Formation of a normal memory is highly sensitive to PKA levels.
== See also ==
Protein kinase
Signal transduction
G protein-coupled receptor
Serine/threonine-specific protein kinase
Myosin light-chain kinase
cAMP-dependent pathway
== References ==
== External links ==
Cyclic+AMP-Dependent+Protein+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Drosophila cAMP-dependent protein kinase 1 - The Interactive Fly
cAMP-dependent protein kinase: PDB Molecule of the Month
Overview of all the structural information available in the PDB for UniProt: P25321 (cAMP-dependent protein kinase catalytic subunit alpha) at the PDBe-KB.
== Notes == | Wikipedia/Protein_kinase_A |
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.
There are two classes of G proteins. The first function as monomeric small GTPases (small G-proteins), while the second function as heterotrimeric G protein complexes. The latter class of complexes is made up of alpha (Gα), beta (Gβ) and gamma (Gγ) subunits. In addition, the beta and gamma subunits can form a stable dimeric complex referred to as the beta-gamma complex
.
Heterotrimeric G proteins located within the cell are activated by G protein-coupled receptors (GPCRs) that span the cell membrane. Signaling molecules bind to a domain of the GPCR located outside the cell, and an intracellular GPCR domain then in turn activates a particular G protein. Some active-state GPCRs have also been shown to be "pre-coupled" with G proteins, whereas in other cases a collision coupling mechanism is thought to occur. The G protein triggers a cascade of further signaling events that finally results in a change in cell function. G protein-coupled receptors and G proteins working together transmit signals from many hormones, neurotransmitters, and other signaling factors. G proteins regulate metabolic enzymes, ion channels, transporter proteins, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate diverse systemic functions such as embryonic development, learning and memory, and homeostasis.
== History ==
G proteins were discovered in 1980 when Alfred G. Gilman and Martin Rodbell investigated stimulation of cells by adrenaline. They found that when adrenaline binds to a receptor, the receptor does not stimulate enzymes (inside the cell) directly. Instead, the receptor stimulates a G protein, which then stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cyclic AMP. For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine.
Nobel prizes have been awarded for many aspects of signaling by G proteins and GPCRs. These include receptor antagonists, neurotransmitters, neurotransmitter reuptake, G protein-coupled receptors, G proteins, second messengers, the enzymes that trigger protein phosphorylation in response to cAMP, and consequent metabolic processes such as glycogenolysis.
Prominent examples include (in chronological order of awarding):
The 1947 Nobel Prize in Physiology or Medicine to Carl Cori, Gerty Cori and Bernardo Houssay, for their discovery of how glycogen is broken down to glucose and resynthesized in the body, for use as a store and source of energy. Glycogenolysis is stimulated by numerous hormones and neurotransmitters including adrenaline.
The 1970 Nobel Prize in Physiology or Medicine to Julius Axelrod, Bernard Katz and Ulf von Euler for their work on the release and reuptake of neurotransmitters.
The 1971 Nobel Prize in Physiology or Medicine to Earl Sutherland for discovering the key role of adenylate cyclase, which produces the second messenger cyclic AMP.
The 1988 Nobel Prize in Physiology or Medicine to George H. Hitchings, Sir James Black and Gertrude Elion "for their discoveries of important principles for drug treatment" targeting GPCRs.
The 1992 Nobel Prize in Physiology or Medicine to Edwin G. Krebs and Edmond H. Fischer for describing how reversible phosphorylation works as a switch to activate proteins, and to regulate various cellular processes including glycogenolysis.
The 1994 Nobel Prize in Physiology or Medicine to Alfred G. Gilman and Martin Rodbell for their discovery of "G-proteins and the role of these proteins in signal transduction in cells".
The 2000 Nobel Prize in Physiology or Medicine to Eric Kandel, Arvid Carlsson and Paul Greengard, for research on neurotransmitters such as dopamine, which act via GPCRs.
The 2004 Nobel Prize in Physiology or Medicine to Richard Axel and Linda B. Buck for their work on G protein-coupled olfactory receptors.
The 2012 Nobel Prize in Chemistry to Brian Kobilka and Robert Lefkowitz for their work on GPCR function.
== Function ==
G proteins are important signal transducing molecules in cells. "Malfunction of GPCR [G Protein-Coupled Receptor] signaling pathways are involved in many diseases, such as diabetes, blindness, allergies, depression, cardiovascular defects, and certain forms of cancer. It is estimated that about 30% of the modern drugs' cellular targets are GPCRs." The human genome encodes roughly 800 G protein-coupled receptors, which detect photons of light, hormones, growth factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome still have unknown functions.
Whereas G proteins are activated by G protein-coupled receptors, they are inactivated by RGS proteins (for "Regulator of G protein signalling"). Receptors stimulate GTP binding (turning the G protein on). RGS proteins stimulate GTP hydrolysis (creating GDP, thus turning the G protein off).
== Diversity ==
All eukaryotes use G proteins for signaling and have evolved a large diversity of G proteins. For instance, humans encode 18 different Gα proteins, 5 Gβ proteins, and 12 Gγ proteins.
== Signaling ==
G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins, are activated by G protein-coupled receptors and are made up of alpha (α), beta (β), and gamma (γ) subunits. "Small" G proteins (20-25kDa) belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha (α) subunit found in heterotrimers, but are in fact monomeric, consisting of only a single unit. However, like their larger relatives, they also bind GTP and GDP and are involved in signal transduction.
=== Heterotrimeric ===
Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to a conformational change in the GPCR, exchanging GDP for GTP, and dissociating in order to activate other proteins in a particular signal transduction pathway. The specific mechanisms, however, differ between protein types.
=== Mechanism ===
Receptor-activated G proteins are bound to the inner surface of the cell membrane. They consist of the Gα and the tightly associated Gβγ subunits.
There are four main families of Gα subunits: Gαs (G stimulatory), Gαi (G inhibitory), Gαq/11, and Gα12/13. They behave differently in the recognition of the effector molecule, but share a similar mechanism of activation.
==== Activation ====
When a ligand activates the G protein-coupled receptor, it induces a conformational change in the receptor that allows the receptor to function as a guanine nucleotide exchange factor (GEF) that exchanges GDP for GTP. The GTP (or GDP) is bound to the Gα subunit in the traditional view of heterotrimeric GPCR activation. This exchange triggers the dissociation of the Gα subunit (which is bound to GTP) from the Gβγ dimer and the receptor as a whole. However, models which suggest molecular rearrangement, reorganization, and pre-complexing of effector molecules are beginning to be accepted. Both Gα-GTP and Gβγ can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein.
==== Termination ====
The Gα subunit will eventually hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to re-associate with Gβγ and starting a new cycle. A group of proteins called Regulator of G protein signalling (RGSs), act as GTPase-activating proteins (GAPs), are specific for Gα subunits. These proteins accelerate the hydrolysis of GTP to GDP, thus terminating the transduced signal. In some cases, the effector itself may possess intrinsic GAP activity, which then can help deactivate the pathway. This is true in the case of phospholipase C-beta, which possesses GAP activity within its C-terminal region. This is an alternate form of regulation for the Gα subunit. Such Gα GAPs do not have catalytic residues (specific amino acid sequences) to activate the Gα protein. They work instead by lowering the required activation energy for the reaction to take place.
==== Specific mechanisms ====
===== Gαs =====
Gαs activates the cAMP-dependent pathway by stimulating the production of cyclic AMP (cAMP) from ATP. This is accomplished by direct stimulation of the membrane-associated enzyme adenylate cyclase. cAMP can then act as a second messenger that goes on to interact with and activate protein kinase A (PKA). PKA can phosphorylate a myriad downstream targets.
The cAMP-dependent pathway is used as a signal transduction pathway for many hormones including:
ADH – Promotes water retention by the kidneys (created by the magnocellular neurosecretory cells of the posterior pituitary)
GHRH – Stimulates the synthesis and release of GH (somatotropic cells of the anterior pituitary)
GHIH – Inhibits the synthesis and release of GH (somatotropic cells of anterior pituitary)
CRH – Stimulates the synthesis and release of ACTH (anterior pituitary)
ACTH – Stimulates the synthesis and release of cortisol (zona fasciculata of the adrenal cortex in the adrenal glands)
TSH – Stimulates the synthesis and release of a majority of T4 (thyroid gland)
LH – Stimulates follicular maturation and ovulation in women; or testosterone production and spermatogenesis in men
FSH – Stimulates follicular development in women; or spermatogenesis in men
PTH – Increases blood calcium levels. This is accomplished via the parathyroid hormone 1 receptor (PTH1) in the kidneys and bones, or via the parathyroid hormone 2 receptor (PTH2) in the central nervous system and brain, as well as the bones and kidneys.
Calcitonin – Decreases blood calcium levels (via the calcitonin receptor in the intestines, bones, kidneys, and brain)
Glucagon – Stimulates glycogen breakdown in the liver
hCG – Promotes cellular differentiation, and is potentially involved in apoptosis.
Epinephrine – released by the adrenal medulla during the fasting state, when body is under metabolic duress. It stimulates glycogenolysis, in addition to the actions of glucagon.
===== Gαi =====
Gαi inhibits the production of cAMP from ATP.
e.g. somatostatin, prostaglandins
===== Gαq/11 =====
Gαq/11 stimulates the membrane-bound phospholipase C beta, which then cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces calcium release from the endoplasmic reticulum. DAG activates protein kinase C.
The Inositol Phospholipid Dependent Pathway is used as a signal transduction pathway for many hormones including:
Epinephrine
ADH (Vasopressin/AVP) – Induces the synthesis and release of glucocorticoids (Zona fasciculata of adrenal cortex); Induces vasoconstriction (V1 Cells of Posterior pituitary)
TRH – Induces the synthesis and release of TSH (Anterior pituitary gland)
TSH – Induces the synthesis and release of a small amount of T4 (Thyroid Gland)
Angiotensin II – Induces Aldosterone synthesis and release (zona glomerulosa of adrenal cortex in kidney)
GnRH – Induces the synthesis and release of FSH and LH (Anterior Pituitary)
===== Gα12/13 =====
Gα12/13 are involved in Rho family GTPase signaling (see Rho family of GTPases). This is through the RhoGEF superfamily involving the RhoGEF domain of the proteins' structures). These are involved in control of cell cytoskeleton remodeling, and thus in regulating cell migration.
===== Gβ, Gγ =====
The Gβγ complexes sometimes also have active functions. Examples include coupling to and activating G protein-coupled inwardly-rectifying potassium channels.
=== Small GTPases ===
Small GTPases, also known as small G-proteins, bind GTP and GDP likewise, and are involved in signal transduction. These proteins are homologous to the alpha (α) subunit found in heterotrimers, but exist as monomers. They are small (20-kDa to 25-kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to the Ras GTPases and is also called the Ras superfamily GTPases.
== Lipidation ==
In order to associate with the inner leaflet of the plasma membrane, many G proteins and small GTPases are lipidated, that is, covalently modified with lipid extensions. They may be myristoylated, palmitoylated or prenylated.
== References ==
== External links ==
GTP-Binding Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/G_protein |
CAMK, also written as CaMK or CCaMK, is an abbreviation for the Ca2+/calmodulin-dependent protein kinase class of enzymes. CAMKs are activated by increases in the concentration of intracellular calcium ions (Ca2+) and calmodulin. When activated, the enzymes transfer phosphates from ATP to defined serine or threonine residues in other proteins, so they are serine/threonine-specific protein kinases. Activated CAMK is involved in the phosphorylation of transcription factors and therefore, in the regulation of expression of responding genes. CAMK also works to regulate the cell life cycle (i.e. programmed cell death), rearrangement of the cell's cytoskeletal network, and mechanisms involved in the learning and memory of an organism.
== Types ==
There are 2 common types of CAM Kinase proteins: specialized and multi-functional CAM kinases.
Substrate-specific CAM Kinases
only have one target that they can phosphorylate, such as myosin light chain kinases. This group of proteins includes CAMK III. More on CAMKIII can be found following this link.
Multi-functional CAM Kinases
have multiple targets they can phosphorylate and are found in processes including the secretion of neurotransmitters, metabolism of glycogen, and the regulation of various transcription factors. CAMK II is the main protein in this subset. More on CAMKII can be found following this link.
== Substrate phosphorylation ==
Once calcium concentrations in the cell rise, CAM kinases become saturated and bind the maximum of four calcium molecules. This calcium saturation activates the kinase and allows it to undergo a conformational change which permits the kinase to bind to its phosphorylation target sites. CAMK removes a phosphate group from ATP, most typically using a Mg2+ ion, and adds it to the CAM protein, rendering it active. The CAM Kinase contains a highly concentrated glycine loop where the gamma phosphate from the donor ATP molecule is easily able to bind to the enzyme which then utilizes the metal ion to facilitate a smooth phosphate transfer to the target protein. This phosphate transfer then activates the kinase's target and completes the phosphorylation cycle.
Figure 1 shows how the presence of calcium or calmodulin allows for the activation of CAM kinases (CAMK II).
== Structure ==
All kinases have a common structure of a catalytic core including an ATP binding site along with a larger substrate binding site. The catalytic core is typically composed of β-strands with the substrate binding site composed of α-helices. Most all CAM kinases includes a variety of domains, including: a catalytic domain, a regulatory domain, an association domain, and a calcium/calmodulin binding domain.
CAMK I
as shown in Figure 2, has a double-lobed structure, consisting of a catalytic, substrate-binding domain and an autoinhibitory domain. For the autoinhibitory domain to become functional, it must cause the protein to conform in such a way that this domain completely blocks the substrate domain from taking in new targets. Figure 2 goes into detail showing the structure and domains of CAMK I.
CAMK II
has a variety of different forms, with CAMK 2A being the most common, as shown in Figure 3. CAMK 2A has a ring-like crystalline structure, composed of smaller functional groups. These groups allow for the CaM-dependent phosphorylation of targets, but also allows the structure to autophosphorylate itself and become CaM-independent, as seen in Figure 1. This means once the CAMK 2A protein is initially activated by calcium or calmodulin, it can, in turn, further activate itself, so it doesn't become inactive even when it is without calcium or calmodulin.
== Family members ==
Members of the CAMK enzyme class include, but are not limited to:
CAMKI
CAMKIα (CAMK1)
CAMKIβ (PNCK)
CAMKIδ
CAMKIγ (CAMK1G)
CAMKII
CAMKIIα
CAMKIIβ
CAMKIIδ
CAMKIIγ
CAMKIII
CAMKIV
CAMKV CaM kinase like vesicle associated
SCAMK
Ca2+/calmodulin-dependent protein kinase kinase
CAMKK1
CAMKK2
== Pseudokinases ==
Pseudokinases are pseudoenzymes, proteins that resemble enzymes structurally, but lack catalytic activity.
Some of these pseudokinases that are related to the CAMK family include:
Tribbles subfamily
TRIB1
TRIB2
TRIB3
== References == | Wikipedia/Ca2+/calmodulin-dependent_protein_kinase |
A serine/threonine protein kinase (EC 2.7.11.-) is a kinase enzyme, in particular a protein kinase, that phosphorylates the OH group of the amino-acid residues serine or threonine, which have similar side chains. At least 350 of the 500+ human protein kinases are serine/threonine kinases (STK).
In enzymology, the term serine/threonine protein kinase describes a class of enzymes in the family of transferases, that transfer phosphates to the oxygen atom of a serine or threonine side chain in proteins. This process is called phosphorylation. Protein phosphorylation in particular plays a significant role in a wide range of cellular processes and is a very important post-translational modification.
The chemical reaction performed by these enzymes can be written as
ATP + a protein
⇌
{\displaystyle \rightleftharpoons }
ADP + a phosphoprotein
Thus, the two substrates of this enzyme are ATP and a protein, whereas its two products are ADP and phosphoprotein.
The systematic name of this enzyme class is ATP:protein phosphotransferase (non-specific).
== Function ==
Serine/threonine kinases play a role in the regulation of cell proliferation, programmed cell death (apoptosis), cell differentiation, and embryonic development.
== Selectivity ==
While serine/threonine kinases all phosphorylate serine or threonine residues in their substrates, they select specific residues to phosphorylate on the basis of residues that flank the phosphoacceptor site, which together comprise the consensus sequence. Since the consensus sequence residues of a target substrate only make contact with several key amino acids within the catalytic cleft of the kinase (usually through hydrophobic forces and ionic bonds), a kinase is usually not specific to a single substrate, but instead can phosphorylate a whole "substrate family" which share common recognition sequences. While the catalytic domain of these kinases is highly conserved, the sequence variation that is observed in the kinome (the subset of genes in the genome that encode kinases) provides for recognition of distinct substrates. Many kinases are inhibited by a pseudosubstrate that binds to the kinase like a real substrate but lacks the amino acid to be phosphorylated. When the pseudosubstrate is removed, the kinase can perform its normal function.
== EC numbers ==
Many serine/threonine protein kinases do not have their own individual EC numbers and use 2.7.11.1, "non-specific serine/threonine protein kinase". This entry is for any enzyme that phosphorylates proteins while converting ATP to ADP (i.e., ATP:protein phosphotransferases.) 2.7.11.37 "protein kinase" was the former generic placeholder and was split into several entries (including 2.7.11.1) in 2005. 2.7.11.70 "protamine kinase" was merged into 2.7.11.1 in 2004.
2.7.11.- is the generic level where all serine/threonine kinases should sit in.
== Types ==
Types include those acting directly as membrane-bound receptors (Receptor protein serine/threonine kinase) and intracellular kinases participating in Signal transduction. Of the latter, types include:
== Clinical significance ==
Serine/threonine kinase (STK) expression is altered in many types of cancer. Limited benefit of serine/threonine kinase inhibitors has been demonstrated in ovarian cancer but studies are ongoing to evaluate their safety and efficacy.
Serine/threonine protein kinase p90-kDa ribosomal S6 kinase (RSK) is in involved in development of some prostate cancers.
Raf inhibition has become the target for new anti-metastatic cancer drugs as they inhibit the MAPK cascade and reduce cell proliferation.
== See also ==
Protein serine/threonine phosphatase, enzyme for reverse process.
Pseudokinase, a protein without enzyme activity (pseudoenzyme). It can be related to proteins of this class.
ATM serine/threonine kinase, responsible for the disorder ataxia–telangiectasia.
== References ==
== External links ==
protein-serine-threonine+kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
KinCore (Kinase Conformational Resource) | Wikipedia/Serine/threonine-specific_protein_kinases |
G protein-coupled receptor kinases (GPCRKs, GRKs) are a family of protein kinases within the AGC (protein kinase A, protein kinase G, protein kinase C) group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.
== Types of GRKs ==
== GRK activity and regulation ==
GRKs reside normally in an inactive state, but their kinase activity is stimulated by binding to a ligand-activated GPCR (rather than by regulatory phosphorylation as is common in other AGC kinases). Because there are only seven GRKs (only 4 of which are widely expressed throughout the body) but over 800 human GPCRs, GRKs appear to have limited phosphorylation site selectivity and are regulated primarily by the GPCR active state.
G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an arrestin protein to the receptor. Phosphorylated serine and threonine residues in GPCRs act as binding sites for and activators of arrestin proteins. Arrestin binding to phosphorylated, active receptors prevents receptor stimulation of heterotrimeric G protein transducer proteins, blocking their cellular signaling and resulting in receptor desensitization. Arrestin binding also directs receptors to specific cellular internalization pathways, removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors.
GRKs can be regulated by signaling events in cells, both in direct feedback mechanisms where receptor signals alter GRK activity over time, and due to signals emanating from distinct pathways from a particular GPCR/GRK system of interest. For example, GRK1 is regulated by the calcium sensor protein recoverin: calcium-bound recoverin binds directly to GRK1 to inhibit its ability to phosphorylate and desensitize rhodopsin, the visual GPCR in the retina, in light-activated retinal rod cells since light activation raises intracellular calcium in these cells, whereas in dark-adapted eyes, calcium levels are low in rod cells and GRK1 is not inhibited by recoverin. The non-visual GRKs are inhibited instead by the calcium-binding protein calmodulin. GRK2 and GRK3 share a carboxyl terminal pleckstrin homology (PH) domain that binds to G protein beta/gamma subunits, and GPCR activation of heterotrimeric G proteins releases this free beta/gamma complex that binds to GRK2/3 to recruit these kinases to the cell membrane precisely at the location of the activated receptor, augmenting GRK activity to regulate the activated receptor. GRK2 activity can be modulated by its phosphorylation by protein kinase A or protein kinase C, and by post-translational modification of cysteines by S-nitrosylation.
== GRK Structures ==
X-ray crystal structures have been obtained for several GRKs (GRK1, GRK2, GRK4, GRK5 and GRK6), alone or bound to ligands. Overall, GRKs share sequence homology and domain organization in which the central protein kinase catalytic domain is preceded by a domain with homology to the active domain of Regulator of G protein Signaling proteins, RGS proteins (the RGS-homology – RH – domain) and is followed by a variable carboxyl terminal tail regulatory region. In the folded proteins, the kinase domain forms a typical bi-lobe kinase structure with a central ATP-binding active site. The RH domain is composed of alpha-helical region formed from the amino terminal sequence plus a short stretch of sequence following the kinase domain that provides 2 additional helices, and makes extensive contacts with one side of the kinase domain. Modeling and mutagenesis suggests that the RH domain senses GPCR activation to open the kinase active site.
== GRK physiological functions ==
GRK1 is involved with rhodopsin phosphorylation and deactivation in vision, together with arrestin-1, also known as S-antigen. Defects in GRK1 result in Oguchi stationary night blindness. GRK7 similarly regulates cone opsin phosphorylation and deactivation in color vision, together with cone arrestin, also known as arrestin-4 or X-arrestin.
GRK2 was first identified as an enzyme that phosphorylated the beta-2 adrenergic receptor, and was originally called the beta adrenergic receptor kinase (βARK, or ββARK1). GRK2 is overexpressed in heart failure, and GRK2 inhibition could be used to treat heart failure in the future.
Polymorphisms in the GRK4 gene have been linked to both genetic and acquired hypertension, acting in part through kidney dopamine receptors. GRK4 is the most highly expressed GRK at the mRNA level, in maturing spermatids, but mice lacking GRK4 remain fertile so its role in these cells remains unknown.
In humans, a GRK5 sequence polymorphism at residue 41 (leucine rather than glutamine) that is most common in individuals with African ancestry leads to elevated GRK5-mediated desensitization of airway beta2-adrenergic receptors, a drug target in asthma. In zebrafish and in humans, loss of GRK5 function has been associated with heart defects due to heterotaxy, a series of developmental defects arising from improper left-right laterality during organogenesis.
In the mouse, GRK6 regulation of D2 dopamine receptors in the striatum region of the brain alters sensitivity to psychostimulant drugs that act through dopamine, and GRK6 has been implicated in Parkinson's disease and in the dyskinesia side effects of anti-parkinson therapy with the drug L-DOPA.
== Non-GPCR functions of GRKs ==
GRKs also phosphorylate non-GPCR substrates. GRK2 and GRK5 can phosphorylate some tyrosine kinase receptors, including the receptor for platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF).
GRKs also regulate cellular responses independent of their kinase activity. In particular, G protein-coupled receptor kinase 2 is known to interact with a diverse repertoire of non-GPCR partner proteins, but other GRKs also have non-GPCR partners. The RGS-homology (RH) domain of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family, but despite these RH domains being unable to act as GTPase-activating proteins like traditional RGS proteins to turn off G protein signaling, this binding reduces Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta.
== See also ==
Downregulation and upregulation
Desensitization
G protein-coupled receptor
Phosphorylation
Protein kinase
== References ==
== Further reading == | Wikipedia/G_protein-coupled_receptor_kinase |
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have unique functions. A set of protein isoforms may be formed from alternative splicings, variable promoter usage, or other post-transcriptional modifications of a single gene; post-translational modifications are generally not considered. (For that, see Proteoforms.) Through RNA splicing mechanisms, mRNA has the ability to select different protein-coding segments (exons) of a gene, or even different parts of exons from RNA to form different mRNA sequences. Each unique sequence produces a specific form of a protein.
The discovery of isoforms could explain the discrepancy between the small number of protein coding regions of genes revealed by the human genome project and the large diversity of proteins seen in an organism: different proteins encoded by the same gene could increase the diversity of the proteome. Isoforms at the RNA level are readily characterized by cDNA transcript studies. Many human genes possess confirmed alternative splicing isoforms. It has been estimated that ~100,000 expressed sequence tags (ESTs) can be identified in humans. Isoforms at the protein level can manifest in the deletion of whole domains or shorter loops, usually located on the surface of the protein.
== Definition ==
One single gene has the ability to produce multiple proteins that differ both in structure and composition; this process is regulated by the alternative splicing of mRNA, though it is not clear to what extent such a process affects the diversity of the human proteome, as the abundance of mRNA transcript isoforms does not necessarily correlate with the abundance of protein isoforms. Three-dimensional protein structure comparisons can be used to help determine which, if any, isoforms represent functional protein products, and the structure of most isoforms in the human proteome has been predicted by AlphaFold and publicly released at isoform.io. The specificity of translated isoforms is derived by the protein's structure/function, as well as the cell type and developmental stage during which they are produced. Determining specificity becomes more complicated when a protein has multiple subunits and each subunit has multiple isoforms.
For example, the 5' AMP-activated protein kinase (AMPK), an enzyme, which performs different roles in human cells, has 3 subunits:
α, catalytic domain, has two isoforms: α1 and α2 which are encoded from PRKAA1 and PRKAA2
β, regulatory domain, has two isoforms: β1 and β2 which are encoded from PRKAB1 and PRKAB2
γ, regulatory domain, has three isoforms: γ1, γ2, and γ3 which are encoded from PRKAG1, PRKAG2, and PRKAG3
In human skeletal muscle, the preferred form is α2β2γ1. But in the human liver, the most abundant form is α1β2γ1.
== Mechanism ==
The primary mechanisms that produce protein isoforms are alternative splicing and variable promoter usage, though modifications due to genetic changes, such as mutations and polymorphisms are sometimes also considered distinct isoforms.
Alternative splicing is the main post-transcriptional modification process that produces mRNA transcript isoforms, and is a major molecular mechanism that may contribute to protein diversity. The spliceosome, a large ribonucleoprotein, is the molecular machine inside the nucleus responsible for RNA cleavage and ligation, removing non-protein coding segments (introns).
Because splicing is a process that occurs between transcription and translation, its primary effects have mainly been studied through genomics techniques—for example, microarray analyses and RNA sequencing have been used to identify alternatively spliced transcripts and measure their abundances. Transcript abundance is often used as a proxy for the abundance of protein isoforms, though proteomics experiments using gel electrophoresis and mass spectrometry have demonstrated that the correlation between transcript and protein counts is often low, and that one protein isoform is usually dominant. One 2015 study states that the cause of this discrepancy likely occurs after translation, though the mechanism is essentially unknown. Consequently, although alternative splicing has been implicated as an important link between variation and disease, there is no conclusive evidence that it acts primarily by producing novel protein isoforms.
Alternative splicing generally describes a tightly regulated process in which alternative transcripts are intentionally generated by the splicing machinery. However, such transcripts are also produced by splicing errors in a process called "noisy splicing," and are also potentially translated into protein isoforms. Although ~95% of multi-exonic genes are thought to be alternatively spliced, one study on noisy splicing observed that most of the different low-abundance transcripts are noise, and predicts that most alternative transcript and protein isoforms present in a cell are not functionally relevant.
Other transcriptional and post-transcriptional regulatory steps can also produce different protein isoforms. Variable promoter usage occurs when the transcriptional machinery of a cell (RNA polymerase, transcription factors, and other enzymes) begin transcription at different promoters—the region of DNA near a gene that serves as an initial binding site—resulting in slightly modified transcripts and protein isoforms.
== Characteristics ==
Generally, one protein isoform is labeled as the canonical sequence based on criteria such as its prevalence and similarity to orthologous—or functionally analogous—sequences in other species. Isoforms are assumed to have similar functional properties, as most have similar sequences, and share some to most exons with the canonical sequence. However, some isoforms show much greater divergence (for example, through trans-splicing), and can share few to no exons with the canonical sequence. In addition, they can have different biological effects—for example, in an extreme case, the function of one isoform can promote cell survival, while another promotes cell death—or can have similar basic functions but differ in their sub-cellular localization. A 2016 study, however, functionally characterized all the isoforms of 1,492 genes and determined that most isoforms behave as "functional alloforms." The authors came to the conclusion that isoforms behave like distinct proteins after observing that the functional of most isoforms did not overlap. Because the study was conducted on cells in vitro, it is not known if the isoforms in the expressed human proteome share these characteristics. Additionally, because the function of each isoform must generally be determined separately, most identified and predicted isoforms still have unknown functions.
== Related concepts ==
=== Glycoform ===
A glycoform is an isoform of a protein that differs only with respect to the number or type of attached glycan. Glycoproteins often consist of a number of different glycoforms, with alterations in the attached saccharide or oligosaccharide. These modifications may result from differences in biosynthesis during the process of glycosylation, or due to the action of glycosidases or glycosyltransferases. Glycoforms may be detected through detailed chemical analysis of separated glycoforms, but more conveniently detected through differential reaction with lectins, as in lectin affinity chromatography and lectin affinity electrophoresis. Typical examples of glycoproteins consisting of glycoforms are the blood proteins as orosomucoid, antitrypsin, and haptoglobin. An unusual glycoform variation is seen in neuronal cell adhesion molecule, NCAM involving polysialic acids, PSA.
== Examples ==
G-actin: despite its conserved nature, it has a varying number of isoforms (at least six in mammals).
Creatine kinase, the presence of which in the blood can be used as an aid in the diagnosis of myocardial infarction, exists in 3 isoforms.
Hyaluronan synthase, the enzyme responsible for the production of hyaluronan, has three isoforms in mammalian cells.
UDP-glucuronosyltransferase, an enzyme superfamily responsible for the detoxification pathway of many drugs, environmental pollutants, and toxic endogenous compounds has 16 known isoforms encoded in the human genome.
G6PDA: normal ratio of active isoforms in cells of any tissue is 1:1 shared with G6PDG. This is precisely the normal isoform ratio in hyperplasia. Only one of these isoforms is found during neoplasia.
Monoamine oxidase, a family of enzymes that catalyze the oxidation of monoamines, exists in two isoforms, MAO-A and MAO-B.
== See also ==
Gene isoform
== References ==
== External links ==
MeSH entry protein isoforms
Definitions Isoform | Wikipedia/Protein_isoform |
G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their activity is regulated by factors that control their ability to bind to and hydrolyze guanosine triphosphate (GTP) to guanosine diphosphate (GDP). When they are bound to GTP, they are 'on', and, when they are bound to GDP, they are 'off'. G proteins belong to the larger group of enzymes called GTPases.
There are two classes of G proteins. The first function as monomeric small GTPases (small G-proteins), while the second function as heterotrimeric G protein complexes. The latter class of complexes is made up of alpha (Gα), beta (Gβ) and gamma (Gγ) subunits. In addition, the beta and gamma subunits can form a stable dimeric complex referred to as the beta-gamma complex
.
Heterotrimeric G proteins located within the cell are activated by G protein-coupled receptors (GPCRs) that span the cell membrane. Signaling molecules bind to a domain of the GPCR located outside the cell, and an intracellular GPCR domain then in turn activates a particular G protein. Some active-state GPCRs have also been shown to be "pre-coupled" with G proteins, whereas in other cases a collision coupling mechanism is thought to occur. The G protein triggers a cascade of further signaling events that finally results in a change in cell function. G protein-coupled receptors and G proteins working together transmit signals from many hormones, neurotransmitters, and other signaling factors. G proteins regulate metabolic enzymes, ion channels, transporter proteins, and other parts of the cell machinery, controlling transcription, motility, contractility, and secretion, which in turn regulate diverse systemic functions such as embryonic development, learning and memory, and homeostasis.
== History ==
G proteins were discovered in 1980 when Alfred G. Gilman and Martin Rodbell investigated stimulation of cells by adrenaline. They found that when adrenaline binds to a receptor, the receptor does not stimulate enzymes (inside the cell) directly. Instead, the receptor stimulates a G protein, which then stimulates an enzyme. An example is adenylate cyclase, which produces the second messenger cyclic AMP. For this discovery, they won the 1994 Nobel Prize in Physiology or Medicine.
Nobel prizes have been awarded for many aspects of signaling by G proteins and GPCRs. These include receptor antagonists, neurotransmitters, neurotransmitter reuptake, G protein-coupled receptors, G proteins, second messengers, the enzymes that trigger protein phosphorylation in response to cAMP, and consequent metabolic processes such as glycogenolysis.
Prominent examples include (in chronological order of awarding):
The 1947 Nobel Prize in Physiology or Medicine to Carl Cori, Gerty Cori and Bernardo Houssay, for their discovery of how glycogen is broken down to glucose and resynthesized in the body, for use as a store and source of energy. Glycogenolysis is stimulated by numerous hormones and neurotransmitters including adrenaline.
The 1970 Nobel Prize in Physiology or Medicine to Julius Axelrod, Bernard Katz and Ulf von Euler for their work on the release and reuptake of neurotransmitters.
The 1971 Nobel Prize in Physiology or Medicine to Earl Sutherland for discovering the key role of adenylate cyclase, which produces the second messenger cyclic AMP.
The 1988 Nobel Prize in Physiology or Medicine to George H. Hitchings, Sir James Black and Gertrude Elion "for their discoveries of important principles for drug treatment" targeting GPCRs.
The 1992 Nobel Prize in Physiology or Medicine to Edwin G. Krebs and Edmond H. Fischer for describing how reversible phosphorylation works as a switch to activate proteins, and to regulate various cellular processes including glycogenolysis.
The 1994 Nobel Prize in Physiology or Medicine to Alfred G. Gilman and Martin Rodbell for their discovery of "G-proteins and the role of these proteins in signal transduction in cells".
The 2000 Nobel Prize in Physiology or Medicine to Eric Kandel, Arvid Carlsson and Paul Greengard, for research on neurotransmitters such as dopamine, which act via GPCRs.
The 2004 Nobel Prize in Physiology or Medicine to Richard Axel and Linda B. Buck for their work on G protein-coupled olfactory receptors.
The 2012 Nobel Prize in Chemistry to Brian Kobilka and Robert Lefkowitz for their work on GPCR function.
== Function ==
G proteins are important signal transducing molecules in cells. "Malfunction of GPCR [G Protein-Coupled Receptor] signaling pathways are involved in many diseases, such as diabetes, blindness, allergies, depression, cardiovascular defects, and certain forms of cancer. It is estimated that about 30% of the modern drugs' cellular targets are GPCRs." The human genome encodes roughly 800 G protein-coupled receptors, which detect photons of light, hormones, growth factors, drugs, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome still have unknown functions.
Whereas G proteins are activated by G protein-coupled receptors, they are inactivated by RGS proteins (for "Regulator of G protein signalling"). Receptors stimulate GTP binding (turning the G protein on). RGS proteins stimulate GTP hydrolysis (creating GDP, thus turning the G protein off).
== Diversity ==
All eukaryotes use G proteins for signaling and have evolved a large diversity of G proteins. For instance, humans encode 18 different Gα proteins, 5 Gβ proteins, and 12 Gγ proteins.
== Signaling ==
G protein can refer to two distinct families of proteins. Heterotrimeric G proteins, sometimes referred to as the "large" G proteins, are activated by G protein-coupled receptors and are made up of alpha (α), beta (β), and gamma (γ) subunits. "Small" G proteins (20-25kDa) belong to the Ras superfamily of small GTPases. These proteins are homologous to the alpha (α) subunit found in heterotrimers, but are in fact monomeric, consisting of only a single unit. However, like their larger relatives, they also bind GTP and GDP and are involved in signal transduction.
=== Heterotrimeric ===
Different types of heterotrimeric G proteins share a common mechanism. They are activated in response to a conformational change in the GPCR, exchanging GDP for GTP, and dissociating in order to activate other proteins in a particular signal transduction pathway. The specific mechanisms, however, differ between protein types.
=== Mechanism ===
Receptor-activated G proteins are bound to the inner surface of the cell membrane. They consist of the Gα and the tightly associated Gβγ subunits.
There are four main families of Gα subunits: Gαs (G stimulatory), Gαi (G inhibitory), Gαq/11, and Gα12/13. They behave differently in the recognition of the effector molecule, but share a similar mechanism of activation.
==== Activation ====
When a ligand activates the G protein-coupled receptor, it induces a conformational change in the receptor that allows the receptor to function as a guanine nucleotide exchange factor (GEF) that exchanges GDP for GTP. The GTP (or GDP) is bound to the Gα subunit in the traditional view of heterotrimeric GPCR activation. This exchange triggers the dissociation of the Gα subunit (which is bound to GTP) from the Gβγ dimer and the receptor as a whole. However, models which suggest molecular rearrangement, reorganization, and pre-complexing of effector molecules are beginning to be accepted. Both Gα-GTP and Gβγ can then activate different signaling cascades (or second messenger pathways) and effector proteins, while the receptor is able to activate the next G protein.
==== Termination ====
The Gα subunit will eventually hydrolyze the attached GTP to GDP by its inherent enzymatic activity, allowing it to re-associate with Gβγ and starting a new cycle. A group of proteins called Regulator of G protein signalling (RGSs), act as GTPase-activating proteins (GAPs), are specific for Gα subunits. These proteins accelerate the hydrolysis of GTP to GDP, thus terminating the transduced signal. In some cases, the effector itself may possess intrinsic GAP activity, which then can help deactivate the pathway. This is true in the case of phospholipase C-beta, which possesses GAP activity within its C-terminal region. This is an alternate form of regulation for the Gα subunit. Such Gα GAPs do not have catalytic residues (specific amino acid sequences) to activate the Gα protein. They work instead by lowering the required activation energy for the reaction to take place.
==== Specific mechanisms ====
===== Gαs =====
Gαs activates the cAMP-dependent pathway by stimulating the production of cyclic AMP (cAMP) from ATP. This is accomplished by direct stimulation of the membrane-associated enzyme adenylate cyclase. cAMP can then act as a second messenger that goes on to interact with and activate protein kinase A (PKA). PKA can phosphorylate a myriad downstream targets.
The cAMP-dependent pathway is used as a signal transduction pathway for many hormones including:
ADH – Promotes water retention by the kidneys (created by the magnocellular neurosecretory cells of the posterior pituitary)
GHRH – Stimulates the synthesis and release of GH (somatotropic cells of the anterior pituitary)
GHIH – Inhibits the synthesis and release of GH (somatotropic cells of anterior pituitary)
CRH – Stimulates the synthesis and release of ACTH (anterior pituitary)
ACTH – Stimulates the synthesis and release of cortisol (zona fasciculata of the adrenal cortex in the adrenal glands)
TSH – Stimulates the synthesis and release of a majority of T4 (thyroid gland)
LH – Stimulates follicular maturation and ovulation in women; or testosterone production and spermatogenesis in men
FSH – Stimulates follicular development in women; or spermatogenesis in men
PTH – Increases blood calcium levels. This is accomplished via the parathyroid hormone 1 receptor (PTH1) in the kidneys and bones, or via the parathyroid hormone 2 receptor (PTH2) in the central nervous system and brain, as well as the bones and kidneys.
Calcitonin – Decreases blood calcium levels (via the calcitonin receptor in the intestines, bones, kidneys, and brain)
Glucagon – Stimulates glycogen breakdown in the liver
hCG – Promotes cellular differentiation, and is potentially involved in apoptosis.
Epinephrine – released by the adrenal medulla during the fasting state, when body is under metabolic duress. It stimulates glycogenolysis, in addition to the actions of glucagon.
===== Gαi =====
Gαi inhibits the production of cAMP from ATP.
e.g. somatostatin, prostaglandins
===== Gαq/11 =====
Gαq/11 stimulates the membrane-bound phospholipase C beta, which then cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers, inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 induces calcium release from the endoplasmic reticulum. DAG activates protein kinase C.
The Inositol Phospholipid Dependent Pathway is used as a signal transduction pathway for many hormones including:
Epinephrine
ADH (Vasopressin/AVP) – Induces the synthesis and release of glucocorticoids (Zona fasciculata of adrenal cortex); Induces vasoconstriction (V1 Cells of Posterior pituitary)
TRH – Induces the synthesis and release of TSH (Anterior pituitary gland)
TSH – Induces the synthesis and release of a small amount of T4 (Thyroid Gland)
Angiotensin II – Induces Aldosterone synthesis and release (zona glomerulosa of adrenal cortex in kidney)
GnRH – Induces the synthesis and release of FSH and LH (Anterior Pituitary)
===== Gα12/13 =====
Gα12/13 are involved in Rho family GTPase signaling (see Rho family of GTPases). This is through the RhoGEF superfamily involving the RhoGEF domain of the proteins' structures). These are involved in control of cell cytoskeleton remodeling, and thus in regulating cell migration.
===== Gβ, Gγ =====
The Gβγ complexes sometimes also have active functions. Examples include coupling to and activating G protein-coupled inwardly-rectifying potassium channels.
=== Small GTPases ===
Small GTPases, also known as small G-proteins, bind GTP and GDP likewise, and are involved in signal transduction. These proteins are homologous to the alpha (α) subunit found in heterotrimers, but exist as monomers. They are small (20-kDa to 25-kDa) proteins that bind to guanosine triphosphate (GTP). This family of proteins is homologous to the Ras GTPases and is also called the Ras superfamily GTPases.
== Lipidation ==
In order to associate with the inner leaflet of the plasma membrane, many G proteins and small GTPases are lipidated, that is, covalently modified with lipid extensions. They may be myristoylated, palmitoylated or prenylated.
== References ==
== External links ==
GTP-Binding Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/G-proteins |
RPE-retinal G protein-coupled receptor also known as RGR-opsin is a protein that in humans is encoded by the RGR gene. RGR-opsin is a member of the rhodopsin-like receptor subfamily of GPCR. Like other opsins which bind retinaldehyde, it contains a conserved lysine residue in the seventh transmembrane domain. RGR-opsin comes in different isoforms produced by alternative splicing.
== Function ==
RGR-opsin preferentially binds all-trans-retinal, which is the dominant form in the dark adapted retina, upon light exposure it is isomerized to 11-cis-retinal. Therefore, RGR-opsin presumably acts as a photoisomerase to convert all-trans-retinal to 11-cis-retinal, similar to retinochrome in invertebrates. 11-cis-retinal is isomerized back within rhodopsin and the iodopsins in the rods and cones of the retina. RGR-opsin is exclusively expressed in tissue close to the rods and cones, the retinal pigment epithelium (RPE) and Müller cells.
== Phylogeny ==
The RGR-opsins are restricted to the echinoderms, the hemichordates the craniates. The craniates are the taxon that contains mammals and with them humans. The RGR-opsins are one of the seven subgroups of the chromopsins. The other groups are the peropsins, the retinochromes, the nemopsins, the astropsins, the varropsins, and the gluopsins. The chromopsins are one of three subgroups of the tetraopsins (also known as RGR/Go or Group 4 opsins). The other groups are the neuropsins and the Go-opsins. The tetraopsins are one of the five major groups of the animal opsins, also known as type 2 opsins). The other groups are the ciliary opsins (c-opsins, cilopsins), the rhabdomeric opsins (r-opsins, rhabopsins), the xenopsins, and the nessopsins. Four of these subclades occur in Bilateria (all but the nessopsins). However, the bilaterian clades constitute a paraphyletic taxon without the opsins from the cnidarians.
In the phylogeny above, Each clade contains sequences from opsins and other G protein-coupled receptors. The number of sequences and two pie charts are shown next to the clade. The first pie chart shows the percentage of a certain amino acid at the position in the sequences corresponding to position 296 in cattle rhodopsin. The amino acids are color-coded. The colors are red for lysine (K), purple for glutamic acid (E), orange for arginine (R), dark and mid-gray for other amino acids, and light gray for sequences that have no data at that position. The second pie chart gives the taxon composition for each clade, green stands for craniates, dark green for cephalochordates, mid green for echinoderms, brown for nematodes, pale pink for annelids, dark blue for arthropods, light blue for mollusks, and purple for cnidarians. The branches to the clades have pie charts, which give support values for the branches. The values are from right to left SH-aLRT/aBayes/UFBoot. The branches are considered supported when SH-aLRT ≥ 80%, aBayes ≥ 0.95, and UFBoot ≥ 95%. If a support value is above its threshold the pie chart is black otherwise gray.
== Clinical significance ==
RGR-opsin may be associated with autosomal recessive and autosomal dominant retinitis pigmentosa (arRP and adRP, respectively).
== Interactions ==
RGR-opsin has been shown to interact with KIAA1279.
== References ==
== Further reading ==
This article incorporates text from the United States National Library of Medicine, which is in the public domain. | Wikipedia/Retinal_G_protein_coupled_receptor |
In biochemistry, a protein trimer is a macromolecular complex formed by three, usually non-covalently bound, macromolecules like proteins or nucleic acids. A protein trimer often occurs from the assembly of a protein's quaternary structure. The non-covalent interactions between the hydrophobic and hydrophilic regions on the polypeptides units help to stabilize the quaternary structure. Since a protein trimer is composed of multiple polypeptide subunits, it is considered an oligomer.
A homotrimer would be formed by three identical molecules. A heterotrimer would be formed by three different macromolecules. Type II Collagen is an example of homotrimeric protein, while Type I collagen is an AAB-type heterotrimeric protein. An example of viral protein homotrimeric protein is mammarenavirus of Z matrix protein.
Porins usually arrange themselves in membranes as trimers.
== Bacteriophage T4 tail fiber ==
Multiple copies of a polypeptide encoded by a gene often can form an aggregate referred to as a multimer. When a multimer is formed from polypeptides produced by two different mutant alleles of a particular gene, the mixed multimer may exhibit greater functional activity than the unmixed multimers formed by each of the mutants alone. When a mixed multimer displays increased functionality relative to the unmixed multimers, the phenomenon is referred to as intragenic complementation. The distal portion of each of the bacteriophage T4 tail fibers is encoded by gene 37 and mutants defective in this gene undergo intragenic complementation. This finding indicated that the distal tail fibers are a multimer of the gene 37 encoded polypeptide. An analysis of the complementation data further indicated that the polypeptides making up the multimer were folded back on themselves in the form of a hairpin. A further high-resolution crystal structure analysis of the distal tail fiber indicated that the gene 37 polypeptides are present as a trimer and that each polypeptide of the trimer is folded back on itself in a hairpin configuration.
== See also ==
Spike protein (coronavirus)
Hemagglutinin (influenza)
Oligomer
Protein quaternary structure
Trimer (chemistry)
== References == | Wikipedia/Protein_trimer |
Adhesion G protein-coupled receptors (adhesion GPCRs) are a class of 33 human protein receptors with a broad distribution in embryonic and larval cells, cells of the reproductive tract, neurons, leukocytes, and a variety of tumours. Adhesion GPCRs are found throughout metazoans and are also found in single-celled colony forming choanoflagellates such as Monosiga brevicollis and unicellular organisms such as Filasterea. The defining feature of adhesion GPCRs that distinguishes them from other GPCRs is their hybrid molecular structure. The extracellular region of adhesion GPCRs can be exceptionally long and contain a variety of structural domains that are known for the ability to facilitate cell and matrix interactions. Their extracellular region contains the membrane proximal GAIN (GPCR-Autoproteolsis INducing) domain. Crystallographic and experimental data has shown this structurally conserved domain to mediate autocatalytic processing at a GPCR-proteolytic site (GPS) proximal to the first transmembrane helix. Autocatalytic processing gives rise to an extracellular (α) and a membrane-spanning (β) subunit, which are associated non-covalently, resulting in expression of a heterodimeric receptor at the cell surface.
Ligand profiles and in vitro studies have indicated a role for adhesion GPCRs in cell adhesion and migration. Work utilizing genetic models confined this concept by demonstrating that the primary function of adhesion GPCRs may relate to the proper positioning of cells in a variety of organ systems. Moreover, growing evidence implies a role of adhesion GPCRs in tumour cell metastasis. Formal G protein-coupled signalling has been demonstrated for a number for adhesion GPCRs, however, the orphan receptor status of many of the receptors still hampers full characterisation of potential signal transduction pathways. In 2011, the adhesion GPCR consortium was established to facilitate research of the physiological and pathological functions of adhesion GPCRs.
== Classification ==
The GPCR superfamily is the largest gene family in the human genome containing approximately 800 genes. As the vertebrate superfamily can be phylogenetically grouped into five main families, the GRAFS classification system has been proposed, which includes the glutamate, rhodopsin, adhesion, Frizzled/Taste2, and secretin GPCR families.
There are 33 human adhesion GPCRs that can be broken down into eight groups, with two independent receptors. Group I consists of LPHN1, LPHN2, LPHN3, and ETL. Group II consists of CD97, EMR1, EMR2, EMR3, and EMR4. Group III consists of GPR123, GPR124, and GPR125. Group IV consists of CELSR1, CELSR2, and CELSR3. Group V consists of GPR133 and GPR144. Group VI consists of GPR110, GPR111, GPR113, GPR115, and GPR116. Group VII consists of BAI1, BAI2, and BAI3. Group VIII consists of GPR56, GPR97, GPR112, GPR114, GPR126, and GPR64. Two additional adhesion GPCRs do not fit into these groups: VLGR1 and GPR128.
== Non-humans and evolution ==
Adhesion GPCRs are found in fungi. They are believed to have evolved from the cAMP receptor family, arising approximately 1275 million years ago before the split of Unikonts from a common ancestor. Several fungi have novel adhesion GPCRs that have both short, 2–66 amino acid residues, and long, 312–4202 amino acid residues. Analysis of fungi showed that there were no secretin receptor family GPCRs, which suggests that they evolved from adhesion GPCRs in a later organism.
Genome analysis of the Teleost Takifugu rubripes has revealed that it has only two adhesion GPCRs that showed homology to Ig-hepta/GPR116. While the Fugu genome is relatively compact and limited with the number of adhesion GPCRs, Tetraodon nigroviridis, another species of puffer fish, has considerably more, totaling 29 adhesion GPCRs.
== Ligands ==
A majority of the adhesion GPCRs are orphan receptors and work is underway to de-orphanize many of these receptors. Adhesion GPCRs get their name from their N-terminal domains that have adhesion-like domains, such as EGF, and the belief that they interact cell to cell and cell to extra cellular matrix. While ligands for many receptors are still not known, researchers are utilizing drug libraries to investigate compounds that can activate GPCRs and using these data for future ligand research.
One adhesion GPCR, GPR56, has a known ligand, collagen III, which is involved in neural migration inhibition. GPR56 has been shown to be the cause of polymicrogyria in humans and may play a role in cancer metastasis. The binding of collagen III to GPR56 occurs on the N-terminus and has been narrowed down to a short stretch of amino acids. The N-terminus of GPR56 is naturally glycosylated, but this glycosylation is not necessary for collagen III binding. Collagen III, results in GPR56 to signal through Gα12/13 activating RhoA.
== Signaling ==
Adhesion GPCRs appear capable to follow standard GPCR signaling modes and signal through Gαs, Gαq, Gαi, and Gα12/13. As of today, many of the adhesion GPCRs are still orphan receptors and their signalling pathways have not been identified. Research groups are working to elucidate the downstream signaling molecules utilizing several methods, including chemical screens and analysis of second messenger levels in over-expressed cells. Adding drugs in vitro, while the cells are over-expressing an adhesion GPCR, has allowed the identification of the molecules activating the GPCR and the second messengers being utilized.
GPR133 signals through Gαs to activate adenylyl cyclase. It has been shown that overexpressing GPCRs in vitro can result in receptor activation in the absence of a ligand or agonist. By over expressing GPR133 in vitro, an elevation in reporter genes and cAMP was observed. Signaling of the overexpressed GPR133 did not require an N-terminus or GPS cleavage. Missense mutations in the 7TM region resulted in loss of signalling.
The latrophilin homolog LPHN1 was shown in C. elegans to require a GPS for signaling, but cleavage at the GPS site was not necessary. Furthermore, having a shortened 7 transmembrane domain, but with an intact GPS domain, resulted in a loss of signaling. This suggests that having both the GPS and 7 transmembrane domain intact is involved in signaling and that the GPS site could act as or be a necessary part of an endogenous ligand.
GPR56 has been shown to be cleaved at the GPS site and then remain associated with the 7TM domain. In a study where the N-terminus was removed up to N342 (the start of the GPS), the receptor became constitutively active and an up regulation of Gα12/13 was seen. When receptors are active, they are ubiquitinated and GPR56 lacking an N-terminus was highly ubiquitinated.
== Cleavage ==
Many adhesion GPCRs undergo proteolytic events posttranslationally at highly conserved Cys-rich motifs known as GPCR proteolysis sites (GPS), located next to the first transmembrane region. This site is called the HL-S(T) site. Once this protein is cleaved, the pieces are expressed at the cell surface as a heterodimer. This cleavage is thought to happen from within the protein itself, through the conserved GAIN domain. This process seems to be similar to those found in other auto-proteolytic proteins such as the Ntn hydrolases and hedgehog proteins.
== Domains ==
One characteristic of adhesion GPCRs is their extended extracellular region. This region is modular in nature, often possessing a variety of structurally defined protein domains and a membrane proximal GAIN domain. In the aptly named Very Large G protein-coupled Receptor 1 VLGR1 the extracellular region extends up to almost 6000 amino acids. Human adhesion GPCRs possess domains including EGF-like (Pfam PF00053), Cadherin (Pfam PF00028), thrombospondin (Pfam PF00090), Immunoglobulin (Pfam PF00047), Pentraxin (Pfam PF00354), Calx-beta (Pfam PF03160) and Leucine-rich repeats (Pfam PF00560). In non-vertebrate species multiple other structural motifs including Kringle, Somatomedin B (Pfam PF01033), SRCR (Pfam PF00530) may be contained with the extracellular region. Since many of these domains have been demonstrated to mediate protein-protein interactions within other proteins, they are believed to play the same role in adhesion GPCRs. Indeed, many ligands have been discovered for adhesion GPCRs (see ligands section). Many of the adhesion GPCR possess long stretches of amino acids with little homology to known protein domains suggesting the possibility of new structural domains being elucidated within their extracellular regions.
== Roles ==
=== Immune system ===
A number of adhesion GPCRs may have important roles within the immune system. In particular, members the EGF-TM7 subfamily which possess N-terminal EGF-like domains are predominantly restricted to leukocytes suggesting a putative role in immune function. The human EGF‑TM7 family is composed of CD97, EMR1 (F4/80 receptor orthologue) EMR2, EMR3 and EMR4 (a probable pseudogene in humans). The human-restricted EMR2 receptor, is expressed by myeloid cells including monocytes, dendritic cells and neutrophils has been shown to be involved in the activation and migration of human neutrophils and upregulated in patients with systemic inflammatory response syndrome (SIRS). Details of EMR1, CD97 needed. The adhesion‑GPCR brain angiogenesis inhibitor 1 (BAI1) acts as a phosphatidylserine receptor playing a potential role in the binding and clearance of apoptotic cells, and the phagocytosis of Gram-negative bacteria. GPR56 has been shown to a marker for inflammatory NK cell subsets and to be expressed by cytotoxic lymphocytes.
=== Neuronal development ===
GPR126 is necessary for Schwann cell myelination. Knockouts of this adhesion GPCR in both Danio rerio and Mus musculus result in an arrest at the promyelinating stage. Schwann cells arise from the neural crest, which migrates to peripheral nerves to form either myelinating or non-myelinating cells. In GPR126 knockouts, these precursor cells develop to the promyelinating stage, where they have wrapped approximately 1.5 times. Myelination is arrested at the promyelinating stage and in fish no myelin basic protein can be detected. In fish this can be rescued by adding forskolin during development, which rescues myelin basic protein expression.
=== Bone marrow and hematapoietic stem cells ===
GPR56 may play a role in the interactions between bone marrow and hematopoietic stem cells.
=== Disease ===
Loss of function mutations have been shown in a number of adhesion GPCRs, including GPR56, GPR126 and VLRG1. Many mutations affect function via decreased cell surface expression or inhibition of autoproteolysis within the GAIN domain.
Mutations in GPR56 result in bilateral frontoparietal polymicrogyria in humans, characterized by abnormal neuronal migration and surface ectopias., Variants of GPR126 have been associated with adolescent idiopathic scoliosis, as well as being responsible for severe arthrogryposis multiplex congenita. Gain of function mutations within the GAIN domain of EMR2 have been shown to result in excessive degranulation by mast cells resulting in vibratory urticaria.
== References == | Wikipedia/Adhesion_G_protein-coupled_receptor |
Functional selectivity (or agonist trafficking, biased agonism, biased signaling, ligand bias, and differential engagement) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the endogenous hormone or peptide) at the same receptor. Functional selectivity can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor. Functional selectivity, or biased signaling, is most extensively characterized at G protein coupled receptors (GPCRs). A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics or antiproliferative drugs, or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and respiratory depression. Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.
== Functional vs. traditional selectivity ==
Functional selectivity has been proposed to broaden conventional definitions of pharmacology.
Traditional pharmacology posits that a ligand can be either classified as an agonist (full or partial), antagonist or more recently an inverse agonist through a specific receptor subtype, and that this characteristic will be consistent with all effector (second messenger) systems coupled to that receptor. While this dogma has been the backbone of ligand-receptor interactions for decades now, more recent data indicates that this classic definition of ligand-protein associations does not hold true for a number of compounds; such compounds may be termed as mixed agonist-antagonists.
Functional selectivity posits that a ligand may inherently produce a mix of the classic characteristics through a single receptor isoform depending on the effector pathway coupled to that receptor. For instance, a ligand can not easily be classified as an agonist or antagonist, because it can be a little of both, depending on its preferred signal transduction pathways. Thus, such ligands must instead be classified on the basis of their individual effects in the cell, instead of being either an agonist or antagonist to a receptor.
These observations were made in a number of different expression systems, and therefore functional selectivity is not just an epiphenomenon of one particular expression system.
== Examples ==
One notable example of functional selectivity occurs with the 5-HT2A receptor, as well as the 5-HT2C receptor. Serotonin, the main endogenous ligand of 5-HT receptors, is a functionally selective agonist at this receptor, activating phospholipase C (which leads to inositol triphosphate accumulation), but does not activate phospholipase A2, which would result in arachidonic acid signaling. However, the other endogenous compound dimethyltryptamine activates arachidonic acid signaling at the 5-HT2A receptor, as do many exogenous hallucinogens such as DOB and lysergic acid diethylamide (LSD). Notably, LSD does not activate IP3 signaling through this receptor to any significant extent. (Conversely, LSD, unlike serotonin, has negligible affinity for the 5-HT2C-VGV isoform, is unable to promote calcium release, and is, thus, functionally selective at 5-HT2C.) Oligomers, specifically 5-HT2A–mGluR2Tooltip metabotropic glutamate receptor 2 heteromers, mediate this effect. This may explain why some direct 5-HT2 receptor agonists have psychedelic effects, whereas compounds that indirectly increase serotonin signaling at the 5-HT2 receptors generally do not, for example: selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and medications using 5HT2A receptor agonists that do not have constitutive activity at the mGluR2 dimer, such as lisuride.
Tianeptine, an atypical antidepressant, is thought to exhibit functional selectivity at the μ-opioid receptor to mediate its antidepressant effects.
Oliceridine is a μ-opioid receptor agonist that has been described to be functionally selective towards G protein and away from β-arrestin2 pathways. However, recent reports highlight that, rather than functional selectivity or 'G protein bias', this agonist has low intrinsic efficacy. In vivo, it has been reported to mediate pain relief without tolerance nor gastrointestinal side effects.
The delta opioid receptor agonists SNC80 and ARM390 demonstrate functional selectivity that is thought to be due to their differing capacity to cause receptor internalization. While SNC80 causes delta opioid receptors to internalize, ARM390 causes very little receptor internalization. Functionally, that means that the effects of SNC80 (e.g. analgesia) do not occur when a subsequent dose follows the first, whereas the effects of ARM390 persist. However, tolerance to ARM390's analgesia still occurs eventually after multiple doses, though through a mechanism that does not involve receptor internalization. Interestingly, the other effects of ARM390 (e.g. decreased anxiety) persist after tolerance to its analgesic effects has occurred.
An example of functional selectivity to bias metabolism was demonstrated for an electron transfer protein cytochrome P450 reductase (POR) with binding of small molecule ligands shown to alter the protein conformation and interaction with various redox partner proteins of POR.
== See also ==
Signal transduction
Second messenger system
== References ==
== Further reading == | Wikipedia/Functional_selectivity |
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_phosphatases |
Regulators of G protein signaling (RGS) are protein structural domains or the proteins that contain these domains, that function to activate the GTPase activity of heterotrimeric G-protein α-subunits.
RGS proteins are multi-functional, GTPase-accelerating proteins that promote GTP hydrolysis by the α-subunit of heterotrimeric G proteins, thereby inactivating the G protein and rapidly switching off G protein-coupled receptor signaling pathways. Upon activation by receptors, G proteins exchange GDP for GTP, are released from the receptor, and dissociate into a free, active GTP-bound α-subunit and βγ-dimer, both of which activate downstream effectors. The response is terminated upon GTP hydrolysis by the α-subunit (InterPro: IPR001019), which can then re-bind the βγ-dimer (InterPro: IPR001632 InterPro: IPR001770) and the receptor. RGS proteins markedly reduce the lifespan of GTP-bound α-subunits by stabilising the G protein transition state. Whereas receptors stimulate GTP binding, RGS proteins stimulate GTP hydrolysis.
RGS proteins have been conserved in evolution. The first to be identified was Sst2 ("SuperSensiTivity to pheromone") in yeast (Saccharomyces cerevisiae). All RGS proteins contain an RGS-box (or RGS domain), which is required for activity. Some small RGS proteins such as RGS1 and RGS4 are little more than an RGS domain, while others also contain additional domains that confer further functionality.
RGS domains in the G protein-coupled receptor kinases are able to bind to Gq family α-subunits, but do not accelerate their GTP hydrolysis. Instead, GRKs appear to reduce Gq signaling by sequestering the active α-subunits away from effectors such as phospholipase C-β.
Plants have RGS proteins but do not have canonical G protein-coupled receptors. Thus G proteins and GTPase accelerating proteins appear to have evolved before any known G protein activator.
RGS domains can be found within the same protein in combination with a variety of other domains, including: DEP for membrane targeting (InterPro: IPR000591), PDZ for binding to GPCRs (InterPro: IPR001478), PTB for phosphotyrosine-binding (InterPro: IPR006020), RBD for Ras-binding (InterPro: IPR003116), GoLoco for guanine nucleotide inhibitor activity (InterPro: IPR003109), PX for phosphoinositide-binding (InterPro: IPR001683), PXA that is associated with PX (InterPro: IPR003114), PH for phosphatidylinositol-binding (InterPro: IPR001849), and GGL (G protein gamma subunit-like) for binding G protein beta subunits (InterPro: IPR001770 Those RGS proteins that contain GGL domains can interact with G protein beta subunits to form novel dimers that prevent G protein gamma subunit binding and G protein alpha subunit association, thereby preventing heterotrimer formation.
== Examples ==
Human proteins containing this domain include:
AXIN1, AXIN2
GRK1, GRK2, GRK3, GRK4, GRK5, GRK6, GRK7
RGS1, RGS2, RGS3, RGS4, RGS5, RGS6, RGS7, RGS8, RGS9, RGS10, RGS11, RGS12, RGS13, RGS14, RGS16, RGS17, RGS18, RGS19, RGS20, RGS21
SNX13
== See also ==
GTP-binding protein regulators:
GEF
GAP
== References ==
== Further reading ==
== External links ==
[1] in PROSITE | Wikipedia/Regulator_of_G_protein_signaling |
Receptor theory is the application of receptor models to explain drug behavior. Pharmacological receptor models preceded accurate knowledge of receptors by many years. John Newport Langley and Paul Ehrlich introduced the concept that receptors can mediate drug action at the beginning of the 20th century. Alfred Joseph Clark was the first to quantify drug-induced biological responses (specifically, f-mediated receptor activation). So far, nearly all of the quantitative theoretical modelling of receptor function has centred on ligand-gated ion channels and G protein-coupled receptors.
== History ==
=== The receptor concept ===
In 1901, Langley challenged the dominant hypothesis that drugs act at nerve endings by demonstrating that nicotine acted at sympathetic ganglia even after the degeneration of the severed preganglionic nerve endings. In 1905 he introduced the concept of a receptive substance on the surface of skeletal muscle that mediated the action of a drug. Langley postulated that these receptive substances were different in different species (citing the fact that nicotine-induced muscle paralysis in mammals was absent in crayfish). Around the same time, Ehrlich was trying to understand the basis of selectivity of agents. He theorized that selectivity was the basis of a preferential distribution of lead and dyes in different body tissues. However, he later modified the theory in order to explain immune reactions and the selectivity of the immune response. Thinking that selectivity was derived from interaction with the tissues themselves, Ehrlich envisaged molecules extending from cells that the body could use to distinguish and mount an immune response to foreign objects. However, it was only after Ahlquist demonstrated the differential effects of adrenaline on two distinct receptor populations, that the theory of receptor-mediated drug interactions gained acceptance.
=== Nature of receptor–drug interactions ===
==== Receptor occupancy model ====
The receptor occupancy model, which describes agonist and competitive antagonists, was built on the work of Langley, Hill, and Clark. The occupancy model was the first model put forward by Clark to explain the activity of drugs at receptors and quantified the relationship between drug concentration and observed effect. It is based on mass-action kinetics and attempts to link the action of a drug to the proportion of receptors occupied by that drug at equilibrium. In particular, the magnitude of the response is directly proportional to the amount of drug bound, and the maximum response would be elicited once all receptors were occupied at equilibrium. He applied mathematical approaches used in enzyme kinetics systematically to the effects of chemicals on tissues.
He showed that for many drugs, the relationship between drug concentration and biological effect corresponded to a hyperbolic curve, similar to that representing the adsorption of a gas onto a metal surface and fitted the Hill–Langmuir equation. Clark, together with Gaddum, was the first to introduce the log concentration–effect curve and described the now-familiar 'parallel shift' of the log concentration–effect curve produced by a competitive antagonist. Attempts to separate the binding phenomenon and activation phenomenon were made by Ariëns in 1954 and by Stephenson in 1956 to account for the intrinsic activity (efficacy) of a drug (that is, its ability to induce an effect after binding). Classic occupational models of receptor activation failed to provide evidence to directly support the idea that receptor occupancy follows a Langmuir curve as the model assumed leading to the development of alternative models to explain drug behaviour.
===== Competitive inhibition models =====
The development of the classic theory of drug antagonism by Gaddum, Schild and Arunlakshana built on the work of Langley, Hill and Clark. Gaddum described a model for the competitive binding of two ligands to the same receptor in short communication to The Physiological Society in 1937. The description referred only to binding, it was not immediately useful for the analysis of experimental measurements of the effects of antagonists on the response to agonists. It was Heinz Otto Schild who made measurement of the equilibrium constant for the binding of an antagonist possible. He developed the Schild equation to determine a dose ratio, a measure of the potency of a drug. In Schild regression, the change in the dose ratio, the ratio of the EC50 of an agonist alone compared to the EC50 in the presence of a competitive antagonist as determined on a dose response curve used to determine the affinity of an antagonist for its receptor.
===== Agonist models =====
The flaw in Clark's receptor-occupancy model was that it was insufficient to explain the concept of a partial agonist. This led to the development of agonist models of drug action by Ariens in 1954 and by Stephenson in 1956 to account for the intrinsic activity (efficacy) of a drug (that is, its ability to induce an effect after binding).
=== Two-state receptor theory ===
The two-state model is a simple linear model to describe the interaction between a ligand and its receptor, but also the active receptor (R*). The model uses an equilibrium dissociation constant to describe the interaction between ligand and receptor. It proposes that ligand binding results in a change in receptor state from an inactive to an active state based on the receptor's conformation. A receptor in its active state will ultimately elicit its biological response. It was first described by Black and Leff in 1983 as an alternative model of receptor activation. Similar to the receptor occupancy model, the theory originated from earlier work by del Castillo & Katz on observations relating to ligand-gated ion channels. In this model, agonists and inverse agonists are thought to have selective binding affinity for the pre-existing resting and active states or can induce a conformational change to a different receptor state. Whereas antagonists have no preference in their affinity for a receptor state. The fact that receptor conformation (state) would affect binding affinity of a ligand was used to explain a mechanism of partial agonism of receptors by del Castillo & Katz in 1957 was based on their work on the action of acetylcholine at the motor endplate build on similar work by Wyman & Allen in 1951 on conformational-induced changes in hemoglobin's oxygen binding affinity occurring as a result of oxygen binding. The del Castillo-Katz mechanism divorces the binding step (that can be made by agonists as well as antagonists) from the receptor activation step (that can be only exerted by agonists), describing them as two independent events.
=== Ternary complex model ===
The original Ternary complex model was used to describe ligand, receptor, and G-protein interactions. It uses equilibrium dissociation constants for the interactions between the receptor and each ligand (Ka for ligand A; Kb for ligand B), as well as a cooperativity factor (α) that denotes the mutual effect of the two ligands on each other's affinity for the receptor. An α > 1.0 refers to positive allosteric modulation, an α < 1.0 refers to negative allosteric modulation, and an α = 1.0 means that binding of either ligand to the receptor does not alter the affinity of the other ligand for the receptor (i.e., a neutral modulator). Further, the α parameter can be added as a subtle but highly useful extension to the ATCM in order to include effects of an allosteric modulator on the efficacy (as distinct from the affinity) of another ligand that binds the receptor, such as the orthosteric agonist. Some ligands can reduce the efficacy but increase the affinity of the orthosteric agonist for the receptor.
Although it is a simple assumption that the proportional amount of an active receptor state should correlate with the biological response, the experimental evidence for receptor overexpression and spare receptors suggests that the calculation of the net change in the active receptor state is a much better measure for response than is the fractional or proportional change. This is demonstrated by the effects of agonist/ antagonist combinations on the desensitization of receptors. This is also demonstrated by receptors that are activated by overexpression, since this requires a change between R and R* that is difficult to understand in terms of a proportional rather than a net change, and for the molecular model that fits with the mathematical model.
== Postulates of receptor theory ==
Receptors must possess structural and steric specificity.
Receptors are saturable and finite (limited number of binding sites)
Receptors must possess high affinity for its endogenous ligand at physiological concentrations
Once the endogenous ligand binds to the receptor, some early recognizable chemical event must occur
== References == | Wikipedia/Receptor_theory |
The G protein-coupled inwardly rectifying potassium channels (GIRKs) are a family of lipid-gated inward-rectifier potassium ion channels which are activated (opened) by the signaling lipid PIP2 and a signal transduction cascade starting with ligand-stimulated G protein-coupled receptors (GPCRs). GPCRs in turn release activated G-protein βγ- subunits (Gβγ) from inactive heterotrimeric G protein complexes (Gαβγ). Finally, the Gβγ dimeric protein interacts with GIRK channels to open them so that they become permeable to potassium ions, resulting in hyperpolarization of the cell membrane. G protein-coupled inwardly rectifying potassium channels are a type of G protein-gated ion channels because of this direct interaction of G protein subunits with GIRK channels. The activation likely works by increasing the affinity of the channel for PIP2. In high concentration PIP2 activates the channel absent G-protein, but G-protein does not activate the channel absent PIP2.
GIRK1 to GIRK3 are distributed broadly in the central nervous system, where their distributions overlap. GIRK4, instead, is found primarily in the heart.
== Subtypes ==
== Examples ==
A wide variety of G protein-coupled receptors activate GIRKs, including the M2-muscarinic, A1-adenosine, α2-adrenergic, D2-dopamine, μ- δ-, and κ-opioid, 5-HT1A serotonin, somatostatin, galanin, m-Glu, GABAB, TAAR1, CB1 and CB2, and sphingosine-1-phosphate receptors.
Examples of GIRKs include a subset of potassium channels in the heart, which, when activated by parasympathetic signals such as acetylcholine through M2 muscarinic receptors, causes an outward current of potassium, which slows down the heart rate. These are called muscarinic potassium channels (IKACh) and are heterotetramers composed of two GIRK1 and two GIRK4 subunits.
== References ==
== External links ==
G+Protein-Coupled+Inwardly-Rectifying+Potassium+Channels at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/G_protein-coupled_inwardly-rectifying_potassium_channel |
The Retinoic Acid-Inducible orphan G-protein-coupled receptors (RAIG) are a group of four closely related G protein-coupled receptors whose expression is induced by retinoic acid.
The exact function of these proteins has not been determined but they may provide a mechanism by which retinoic acid can influence G protein signal transduction cascades. In addition, RAIG receptors interact with members of the frizzled class of G protein-coupled receptors and appear to activate the Wnt signaling pathway.
== References ==
== External links ==
"GPRC5 (RAIG) Receptors". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2007-10-25.
GPRC5A+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GPRC5B+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GPRC5C+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/Retinoic_acid-inducible_orphan_G_protein-coupled_receptor |
The GPCRdb database is the main repository of curated data for G protein-coupled receptors (GPCRs). It integrates various web tools and diagrams for GPCR analysis and stores manual annotations of all GPCR crystal structures made available through the PDB (Protein Data Bank), has the largest collections of receptor mutants and reference sequence alignments. A series of tools made available in the homepage for the GPCRdb can be run in the web browser to analyze structures, sequence similarities, receptor relationships, homology models, drug trends, genetic variants and ligand target profiles. Diagrams illustrate receptor sequences (using snake-plots and helix box diagrams) and relationships (phylogenetic trees).
== Background and development ==
According to Gert Vriend, one of the creators of the GPCRdb, the resource began in the following way: "The GPCRdb was started in the early 90’s when Bob Bywater, Ad IJzerman, Friedrich Rippmann, and Gert Vriend organized a series of small GPCR workshops at the EMBL. Before the introduction of the first browsers, the GPCRdb worked as an automatic Email answering system that could send sequences, alignments, and homology models to the users.
In 1994 the internet was firmly established in its present form, and money was obtained from the fourth EU framework to set up the GPCRdb. Florence Horn joined us to do this project. When she left us at the end of a four-year post-doc period the GPCRdb was firmly established as the prime source of information for GPCR data." Over two decades, the GPCRdb evolved to be a comprehensive information system storing and analyzing data. In 2013, the stewardship of the GPCRdb was transferred to David Gloriam's group at the University of Copenhagen, backed up by an international team of contributors and developers from a EU COST Action called ‘GLISTEN’. The GPCRdb offers reference data and easy-to-use web tools and diagrams for a multidisciplinary audience investigating GPCR function, drug design or evolution and is actively involved in the European Research Network on Signal Transduction (‘ERNEST’).
== Content and features ==
A visual overview of the main features of the GPCRdb can be glimpsed at gpcrdb.org.
The GPCRdb browsing system is structured on most relevant categories which are:
GPCRdb
Receptors
G Proteins
B-Arrestins
Biased Signaling
Ligands
Drugs
Structure Constructs
Tutorials, workshops and documentation of use.
Under the categories one can find subsections for specialized data and tools.
== Future directions ==
As part of two orphan GPCR projects Archived 2016-03-06 at the Wayback Machine funded by the European Research Commission and the Lundbeck Foundation, respectively, the GPCRdb will deposit data and develop computational tools for identification of endogenous and surrogate GPCR ligands. The GPCRdb aims to grow from and enable new progress in GPCR structure, function and ligand design. It crosslinks to the GuideToPharmacology database and has adopted the official NC-IUPHAR receptor naming nomenclature, has exchange with GPCR servers Archived 2015-09-08 at the Wayback Machine, and has also recently become part of the GPCR Consortium set out to generate an unprecedented number of crystal structures. Academic and industrial groups are welcome and encouraged to contact the GPCRdb with suggestions for joint development or data deposition.
== See also ==
G protein-coupled receptors
== References ==
== External links ==
GPCRdb GPCR database
GLISTEN EU COST Action for GPCRs
GPCR-HGmod Predicted structure models of all GPCRs in human genome
GPCR-EXP Database for all experimentally solved GPCR structures | Wikipedia/G_protein-coupled_receptors_database |
G protein-coupled receptor kinases (GPCRKs, GRKs) are a family of protein kinases within the AGC (protein kinase A, protein kinase G, protein kinase C) group of kinases. Like all AGC kinases, GRKs use ATP to add phosphate to Serine and Threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways.
== Types of GRKs ==
== GRK activity and regulation ==
GRKs reside normally in an inactive state, but their kinase activity is stimulated by binding to a ligand-activated GPCR (rather than by regulatory phosphorylation as is common in other AGC kinases). Because there are only seven GRKs (only 4 of which are widely expressed throughout the body) but over 800 human GPCRs, GRKs appear to have limited phosphorylation site selectivity and are regulated primarily by the GPCR active state.
G protein-coupled receptor kinases phosphorylate activated G protein-coupled receptors, which promotes the binding of an arrestin protein to the receptor. Phosphorylated serine and threonine residues in GPCRs act as binding sites for and activators of arrestin proteins. Arrestin binding to phosphorylated, active receptors prevents receptor stimulation of heterotrimeric G protein transducer proteins, blocking their cellular signaling and resulting in receptor desensitization. Arrestin binding also directs receptors to specific cellular internalization pathways, removing the receptors from the cell surface and also preventing additional activation. Arrestin binding to phosphorylated, active receptor also enables receptor signaling through arrestin partner proteins. Thus the GRK/arrestin system serves as a complex signaling switch for G protein-coupled receptors.
GRKs can be regulated by signaling events in cells, both in direct feedback mechanisms where receptor signals alter GRK activity over time, and due to signals emanating from distinct pathways from a particular GPCR/GRK system of interest. For example, GRK1 is regulated by the calcium sensor protein recoverin: calcium-bound recoverin binds directly to GRK1 to inhibit its ability to phosphorylate and desensitize rhodopsin, the visual GPCR in the retina, in light-activated retinal rod cells since light activation raises intracellular calcium in these cells, whereas in dark-adapted eyes, calcium levels are low in rod cells and GRK1 is not inhibited by recoverin. The non-visual GRKs are inhibited instead by the calcium-binding protein calmodulin. GRK2 and GRK3 share a carboxyl terminal pleckstrin homology (PH) domain that binds to G protein beta/gamma subunits, and GPCR activation of heterotrimeric G proteins releases this free beta/gamma complex that binds to GRK2/3 to recruit these kinases to the cell membrane precisely at the location of the activated receptor, augmenting GRK activity to regulate the activated receptor. GRK2 activity can be modulated by its phosphorylation by protein kinase A or protein kinase C, and by post-translational modification of cysteines by S-nitrosylation.
== GRK Structures ==
X-ray crystal structures have been obtained for several GRKs (GRK1, GRK2, GRK4, GRK5 and GRK6), alone or bound to ligands. Overall, GRKs share sequence homology and domain organization in which the central protein kinase catalytic domain is preceded by a domain with homology to the active domain of Regulator of G protein Signaling proteins, RGS proteins (the RGS-homology – RH – domain) and is followed by a variable carboxyl terminal tail regulatory region. In the folded proteins, the kinase domain forms a typical bi-lobe kinase structure with a central ATP-binding active site. The RH domain is composed of alpha-helical region formed from the amino terminal sequence plus a short stretch of sequence following the kinase domain that provides 2 additional helices, and makes extensive contacts with one side of the kinase domain. Modeling and mutagenesis suggests that the RH domain senses GPCR activation to open the kinase active site.
== GRK physiological functions ==
GRK1 is involved with rhodopsin phosphorylation and deactivation in vision, together with arrestin-1, also known as S-antigen. Defects in GRK1 result in Oguchi stationary night blindness. GRK7 similarly regulates cone opsin phosphorylation and deactivation in color vision, together with cone arrestin, also known as arrestin-4 or X-arrestin.
GRK2 was first identified as an enzyme that phosphorylated the beta-2 adrenergic receptor, and was originally called the beta adrenergic receptor kinase (βARK, or ββARK1). GRK2 is overexpressed in heart failure, and GRK2 inhibition could be used to treat heart failure in the future.
Polymorphisms in the GRK4 gene have been linked to both genetic and acquired hypertension, acting in part through kidney dopamine receptors. GRK4 is the most highly expressed GRK at the mRNA level, in maturing spermatids, but mice lacking GRK4 remain fertile so its role in these cells remains unknown.
In humans, a GRK5 sequence polymorphism at residue 41 (leucine rather than glutamine) that is most common in individuals with African ancestry leads to elevated GRK5-mediated desensitization of airway beta2-adrenergic receptors, a drug target in asthma. In zebrafish and in humans, loss of GRK5 function has been associated with heart defects due to heterotaxy, a series of developmental defects arising from improper left-right laterality during organogenesis.
In the mouse, GRK6 regulation of D2 dopamine receptors in the striatum region of the brain alters sensitivity to psychostimulant drugs that act through dopamine, and GRK6 has been implicated in Parkinson's disease and in the dyskinesia side effects of anti-parkinson therapy with the drug L-DOPA.
== Non-GPCR functions of GRKs ==
GRKs also phosphorylate non-GPCR substrates. GRK2 and GRK5 can phosphorylate some tyrosine kinase receptors, including the receptor for platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF).
GRKs also regulate cellular responses independent of their kinase activity. In particular, G protein-coupled receptor kinase 2 is known to interact with a diverse repertoire of non-GPCR partner proteins, but other GRKs also have non-GPCR partners. The RGS-homology (RH) domain of GRK2 and GRK3 binds to heterotrimeric G protein subunits of the Gq family, but despite these RH domains being unable to act as GTPase-activating proteins like traditional RGS proteins to turn off G protein signaling, this binding reduces Gq signaling by sequestering active G proteins away from their effector proteins such as phospholipase C-beta.
== See also ==
Downregulation and upregulation
Desensitization
G protein-coupled receptor
Phosphorylation
Protein kinase
== References ==
== Further reading == | Wikipedia/G_protein-coupled_receptor_kinases |
Heterotrimeric G protein, also sometimes referred to as the "large" G proteins (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a heterotrimeric complex. The biggest non-structural difference between heterotrimeric and monomeric G protein is that heterotrimeric proteins bind to their cell-surface receptors, called G protein-coupled receptors (GPCR), directly. These G proteins are made up of alpha (α), beta (β) and gamma (γ) subunits. The alpha subunit is attached to either a GTP or GDP, which serves as an on-off switch for the activation of G-protein.
When ligands bind a GPCR, the GPCR acquires GEF (guanine nucleotide exchange factor) ability, which activates the G-protein by exchanging the GDP on the alpha subunit to GTP. The binding of GTP to the alpha subunit results in a structural change and its dissociation from the rest of the G-protein. Generally, the alpha subunit binds membrane-bound effector proteins for the downstream signaling cascade, but the beta-gamma complex can carry out this function also. G-proteins are involved in pathways such as the cAMP/PKA pathway, ion channels, MAPK, PI3K.
There are four main families of G proteins: Gi/Go, Gq, Gs, and G12/13.
== Alpha subunits ==
Reconstitution experiments carried out in the early 1980s showed that purified Gα subunits can directly activate effector enzymes. The GTP form of the α subunit of transducin (Gt) activates the cyclic GMP phosphodiesterase from retinal rod outer segments, and the GTP form of the α subunit of the stimulatory G protein (Gs) activates hormone-sensitive adenylate cyclase. More than one type of G protein co-exist in the same tissue. For example, in adipose tissues, two different G-proteins with interchangeable beta-gamma complexes are used to activate or inhibit adenylyl cyclase. The alpha subunit of a stimulatory G protein activated by receptors for stimulatory hormones could stimulate adenylyl cyclase, which activates cAMP used for downstream signal cascades. While on the other hand, the alpha subunit of an inhibitory G protein activated by receptors of inhibitory hormones could inhibit adenylyl cyclase, which blocks downstream signal cascades.
Gα subunits consist of two domains, the GTPase domain, and the alpha-helical domain.
There exist at least 20 different Gα subunits, which are separated into four main groups. This nomenclature is based on their sequence homologies:
== G beta-gamma complex ==
The β and γ subunits are closely bound to one another and are referred to as the G beta-gamma complex. Both beta and gamma subunits have different isoforms, and some combination of isoforms result in dimerization while other combinations do not. For example, beta1 binds both gamma subunits while beta3 binds neither. Upon activation of the GPCR, the Gβγ complex is released from the Gα subunit after its GDP-GTP exchange.
=== Function ===
The free Gβγ complex can act as a signaling molecule itself, by activating other second messengers or by gating ion channels directly.
For example, the Gβγ complex, when bound to histamine receptors, can activate phospholipase A2. Gβγ complexes bound to muscarinic acetylcholine receptors, on the other hand, directly open G protein-coupled inward rectifying potassium channels (GIRKs). When acetylcholine is the extracellular ligand in the pathway, the heart cell hyperpolarizes normally to decrease heart muscle contraction. When substances such as muscarine act as ligands, the dangerous amount of hyperpolarization leads to hallucination. Therefore, proper functioning of Gβγ plays a key role in our physiological well-being. The last function is activating L-type calcium channels, as in H3 receptor pharmacology.
=== Heterotrimeric G-proteins in plants ===
Heterotrimeric G-protein signaling in plants deviates from the metazoan model at various levels. For example, the presence of extra-Large G alpha, loss of G alpha and Regulator of G-protein signaling (RGS) in many plant lineages. In addition, the G-proteins are not essential for the survival in dicotyledonous plants, while they are essential for the survival of monocotyledonous plants.
== References ==
== External links ==
Heterotrimeric+G-Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
EC 3.6.5.1 | Wikipedia/Heterotrimeric_G-protein |
Flamingo is a member of the adhesion-GPCR family of proteins. Flamingo has sequence homology to cadherins and G protein-coupled receptors (GPCR). Flamingo was originally identified as a Drosophila protein involved in planar cell polarity. Mammals have three flamingo homologs, CELSR1, CELSR2, CELSR3. In mice, all three have distinct expression patterns in organs such as the kidney, skin, and lungs, as well as the brain.
== Protein structure ==
Flamingo is an atypical cadherin, with a cadherin-like extracellular domain, composed of cadherin and EGF adhesive repeats, that can bind to other Flamingo proteins expressed on neighboring cells. The transmembrane domain, however, is a 7-pass membrane domain most structurally similar to that of a G protein-coupled receptor, though it is not known to interact with G protein.
== Planar cell polarity ==
Flamingo is one of the core proteins in the planar cell polarity (PCP) pathway, which is required for successful body elongation during gastrulation in early development, as well as the formation of developing organs such as the brain, inner ear, and kidney. It has been extensively studied for its role in patterning developmental tissues in a wide range of species. CELSR1 is the primary flamingo homolog involved in PCP in vertebrates. In humans, CELSR1 mutations are correlated with severe birth defects, including brain, hearing, and kidney defects, due to incorrect establishment of planar polarity in those organs.
== Function in neurons ==
In Drosophila, flamingo mutants were found to have abnormal dendrite branching, outgrowth and routing. Kimura et al. proposed that flamingo regulates dendrite branch elongation and prevents the dendritic trees of adjacent Drosophila sensory neurons from having overlap of dendritic arbors.
A study of mammalian flamingo homolog CELSR2 found that it is involved in the regulation of dendrite growth. RNAi was used to alter CELSR2 expression in cortical and cerebral brain slice cultures. The dendrites of pyramidal neurons in cortical cultures and Purkinje neurons in cerebellar cultures were simplified when CELSR2 expression was reduced. Mice that lack CELSR3 have altered bundling of axons to form fascicles.
== References == | Wikipedia/Flamingo_(protein) |
GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are also known as RGS protein, or RGS proteins, and these proteins are crucial in controlling the activity of G proteins. Regulation of G proteins is important because these proteins are involved in a variety of important cellular processes. The large G proteins, for example, are involved in transduction of signaling from the G protein-coupled receptor for a variety of signaling processes like hormonal signaling, and small G proteins are involved in processes like cellular trafficking and cell cycling. GAP's role in this function is to turn the G protein's activity off. In this sense, GAPs function is opposite to that of guanine nucleotide exchange factors (GEFs), which serve to enhance G protein signaling.
== Mechanism ==
GAP are heavily linked to the G-protein linked receptor family. The activity of G proteins comes from their ability to bind guanosine triphosphate (GTP). Binding of GTP inherently changes the activity of the G proteins and increases their activity, through the loss of inhibitory subunits. In this more active state, G proteins can bind other proteins and turn on downstream signalling targets. This whole process is regulated by GAPs, which can down regulate the activity of G proteins.
G proteins can weakly hydrolyse GTP, breaking a phosphate bond to make GDP. In the GDP-bound state, the G proteins are subsequently inactivated and can no longer bind their targets. This hydrolysis reaction, however, occurs very slowly, meaning G proteins have a built-in timer for their activity. G proteins have a window of activity followed by slow hydrolysis, which turns them off. GAP accelerates this G protein timer by increasing the hydrolytic GTPase activity of the G proteins, hence the name GTPase-activating protein.
It is thought that GAPs serve to make GTP on the G protein a better substrate for nucleophilic attack and lower the transition state energy for the hydrolysis reaction. For example, many GAPs of the small G proteins have a conserved finger-like domain, usually an arginine finger, which changes the conformation of the GTP-bound G protein to orient the GTP for better nucleophilic attack by water. This makes the GTP a better substrate for the reaction. Similarly, GAPs seem to induce a GDP-like charge distribution in the bound GTP. Because the change in charge distribution makes the GTP substrate more like the products of the reaction, GDP and monophosphate, this, along with opening the molecule for nucleophilic attack, lowers the transition state energy barrier of the reaction and allows GTP to be hydrolyzed more readily. GAPs, then, work to enhance the GTP hydrolysis reaction of the G proteins. By doing so, they accelerate the G protein's built-in timer, which inactivates the G proteins more quickly, and along with the inactivation of GEFs, this keeps the G protein signal off. GAPs, then, are critical in the regulation of G proteins.
== Specificity to G proteins ==
In general, GAPs tend to be pretty specific for their target G proteins. The exact mechanism of target specificity is not fully known, but it is likely that this specificity comes from a variety of factors. At the most basic level, GAP-to-G protein specificity may come simply from the timing and location of protein expression. RGS9-1, for example, is specifically expressed in the rod and cone photoreceptors in the eye retina, and is the only one to interact with G proteins involved in phototransduction in this area. A certain GAP and a certain G protein happen to be expressed in the same time and place, and that is how the cell ensures specificity. Meanwhile, scaffold proteins can also sequester the proper GAP to its G protein and enhance the proper binding interactions. These binding interactions may be specific for a particular GAP and G protein. Also, GAPs may have particular amino acid domains that recognize only a particular G protein. Binding to other G proteins may not have the same favorable interactions, and they therefore do not interact. GAPs can, therefore, regulate specific G proteins.
== Examples and classification ==
EIF5 is a GTPase-activating protein. Furthermore, YopE is a protein domain that is a Rho GTPase-activating protein (GAP), which targets small GTPases such as RhoA, Rac1, and Rac2.
=== Monomeric ===
The GAPs that act on small GTP-binding proteins of the Ras superfamily have conserved structures and use similar mechanisms,
An example of a GTPase is the monomer Ran, which is found in the cytosol as well as the nucleus. Hydrolysis of GTP by Ran is thought to provide the energy needed to transport nuclear proteins into the cell. Ran is turned on and off by GEFs and GAPs, respectively.
=== Heterotrimeric ===
Most GAPs that act on alpha subunits of heterotrimeric G proteins belong to a distinct family, the RGS protein family.
== Regulation ==
While GAPs serve to regulate the G proteins, there is also some level of regulation of the GAPs themselves. Many GAPs have allosteric sites that serve as interfaces with downstream targets of the particular path that they regulate. For example, RGS9-1, the GAP in the photoreceptors from above, interacts with cGMP phosphodiesterase (cGMP PDE), a downstream component of phototransduction in the retina. Upon binding with cGMP PDE, RGS9-1 GAP activity is enhanced. In other words, a downstream target of photoreceptor-induced signaling binds and activates the inhibitor of signaling, GAP. This positive regulatory binding of downstream targets to GAP serves as a negative feedback loop that eventually turns off the signaling that was originally activated. GAPs are regulated by targets of the G protein that they regulate.
There are also examples of negative regulatory mechanisms, where downstream targets of G protein signaling inhibit the GAPs. In G protein-gated potassium channels, phosphatidylinositol 3, 4, 5-triphosphate (PIP3) is a downstream target of G protein signaling. PIP3 binds and inhibits the RGS4 GAP. Such inhibition of GAP may perhaps "prime" the signaling pathway for activation. This creates a window of activity for the G proteins once activated because the GAP is temporarily inhibited. When the potassium channel is activated, Ca2+ gets released and binds calmodulin. Together, they displace PIP3 from GAP by binding competitively to the same site, and by doing so, they reactivate GAP to turn G protein signaling off. This particular process demonstrates both inhibition and activation of GAP by its regulators. There is cross-talk between GAP and other components of the signaling pathway that regulate the activity of GAP.
There have been some findings suggesting the possibility of crosstalk between GAPs. A recent study showed that the p120Ras GAP could bind the DLC1 Rho GAP at its catalytic domain. The binding of the Ras GAP to the Rho GAP inhibits the activity of the Rho GAP, thereby activating the Rho G protein. One GAP serves as a negative regulator of another GAP. The reasons for such cross-regulation across GAPs are yet unclear, but one possible hypothesis is that this cross-talk across GAPs attenuates the "off" signal of all the GAPs. Although the p120Ras GAP is active, therefore inhibiting that particular pathway, other cellular processes can still continue because it inhibits other GAPs. This may ensure that the whole system does not shut down from a single off signal. GAP activity is highly dynamic, interacting with many other components of signaling pathways.
== Disease associations and clinical relevance ==
The importance of GAPs comes from its regulation of the crucial G proteins. Many of these G proteins are involved in cell cycling, and as such are known proto-oncogenes. The Ras superfamily of G proteins, for example, has been associated with many cancers because Ras is a common downstream target of many growth factors like FGF, or fibroblast growth factor. Under normal conditions, this signaling ultimately induces regulated cell growth and proliferation. However, in the cancer state, such growth is no longer regulated and results in the formation of tumors. Often, this oncogenic behavior is due to a loss of function of GAPs associated with those G proteins or a loss of the G protein's ability to respond to its GAP. With the former, G proteins are unable to hydrolyze GTP quickly, resulting in sustained expression of the active form of G proteins. Although the G proteins have weak hydrolytic activity, in the presence of functional GEFs, the inactivated G proteins are constantly replaced with activated ones because the GEFs exchange GDP for GTP in these proteins. With no GAPs to curb the G protein's activity, this results in constitutively active G proteins, unregulated cell growth, and the cancerous state. In the case of the latter, a loss of the G protein's ability to respond to GAP, the G proteins have lost their ability to hydrolyze GTP. With a nonfunctional G protein enzyme, GAPs cannot activate the GTPase activity, and the G protein is constitutively on. This also results in unregulated cell growth and cancer.
Examples of GAP malfunction are ubiquitous clinically. Some cases involve a decreased expression of the GAP gene. For example, some recently characterized cases of papillary thyroid cancer cells in patients show a decreased expression of Rap1GAP, and this expression is seemingly caused by a decreased expression of the GAP mRNA, shown by qRT-PCR experiments. In this case, there appears to be a loss of proper Rap1GAP gene expression. In another case, expression of the Ras GAP is lost in several cancers due to improper epigenetic silencing of the gene. These cells have CpG methylations near the gene that, in effect, silence gene transcription. Regulation of G proteins is lost because the regulator is absent, resulting in cancer.
Other cancers show a loss of sensitivity of the G protein to the GAPs. These G proteins acquire missense mutations that disrupt the inherent GTPase activity of the proteins. The mutant G proteins are still bound by GAPs, but enhancing GTPase activity by the GAPs is meaningless when GTPase activity of the G protein itself is lost. GAP works to activate a nonfunctional hydrolytic enzyme. T24 bladder cancer cells, for example, were shown to have a missense mutation, G12V, resulting in constitutively active Ras protein. Despite the presence of the G protein regulator, regulation is lost due to a loss of function in the G protein itself. This loss of function also manifests itself in cancer. GAPs and their interaction with G proteins are, therefore, highly important clinically and are potential targets for cancer therapies.
== References ==
== External links ==
GTPase-Activating+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/GTPase_activating_protein |
GTPase-activating proteins or GTPase-accelerating proteins (GAPs) are a family of regulatory proteins whose members can bind to activated G proteins and stimulate their GTPase activity, with the result of terminating the signaling event. GAPs are also known as RGS protein, or RGS proteins, and these proteins are crucial in controlling the activity of G proteins. Regulation of G proteins is important because these proteins are involved in a variety of important cellular processes. The large G proteins, for example, are involved in transduction of signaling from the G protein-coupled receptor for a variety of signaling processes like hormonal signaling, and small G proteins are involved in processes like cellular trafficking and cell cycling. GAP's role in this function is to turn the G protein's activity off. In this sense, GAPs function is opposite to that of guanine nucleotide exchange factors (GEFs), which serve to enhance G protein signaling.
== Mechanism ==
GAP are heavily linked to the G-protein linked receptor family. The activity of G proteins comes from their ability to bind guanosine triphosphate (GTP). Binding of GTP inherently changes the activity of the G proteins and increases their activity, through the loss of inhibitory subunits. In this more active state, G proteins can bind other proteins and turn on downstream signalling targets. This whole process is regulated by GAPs, which can down regulate the activity of G proteins.
G proteins can weakly hydrolyse GTP, breaking a phosphate bond to make GDP. In the GDP-bound state, the G proteins are subsequently inactivated and can no longer bind their targets. This hydrolysis reaction, however, occurs very slowly, meaning G proteins have a built-in timer for their activity. G proteins have a window of activity followed by slow hydrolysis, which turns them off. GAP accelerates this G protein timer by increasing the hydrolytic GTPase activity of the G proteins, hence the name GTPase-activating protein.
It is thought that GAPs serve to make GTP on the G protein a better substrate for nucleophilic attack and lower the transition state energy for the hydrolysis reaction. For example, many GAPs of the small G proteins have a conserved finger-like domain, usually an arginine finger, which changes the conformation of the GTP-bound G protein to orient the GTP for better nucleophilic attack by water. This makes the GTP a better substrate for the reaction. Similarly, GAPs seem to induce a GDP-like charge distribution in the bound GTP. Because the change in charge distribution makes the GTP substrate more like the products of the reaction, GDP and monophosphate, this, along with opening the molecule for nucleophilic attack, lowers the transition state energy barrier of the reaction and allows GTP to be hydrolyzed more readily. GAPs, then, work to enhance the GTP hydrolysis reaction of the G proteins. By doing so, they accelerate the G protein's built-in timer, which inactivates the G proteins more quickly, and along with the inactivation of GEFs, this keeps the G protein signal off. GAPs, then, are critical in the regulation of G proteins.
== Specificity to G proteins ==
In general, GAPs tend to be pretty specific for their target G proteins. The exact mechanism of target specificity is not fully known, but it is likely that this specificity comes from a variety of factors. At the most basic level, GAP-to-G protein specificity may come simply from the timing and location of protein expression. RGS9-1, for example, is specifically expressed in the rod and cone photoreceptors in the eye retina, and is the only one to interact with G proteins involved in phototransduction in this area. A certain GAP and a certain G protein happen to be expressed in the same time and place, and that is how the cell ensures specificity. Meanwhile, scaffold proteins can also sequester the proper GAP to its G protein and enhance the proper binding interactions. These binding interactions may be specific for a particular GAP and G protein. Also, GAPs may have particular amino acid domains that recognize only a particular G protein. Binding to other G proteins may not have the same favorable interactions, and they therefore do not interact. GAPs can, therefore, regulate specific G proteins.
== Examples and classification ==
EIF5 is a GTPase-activating protein. Furthermore, YopE is a protein domain that is a Rho GTPase-activating protein (GAP), which targets small GTPases such as RhoA, Rac1, and Rac2.
=== Monomeric ===
The GAPs that act on small GTP-binding proteins of the Ras superfamily have conserved structures and use similar mechanisms,
An example of a GTPase is the monomer Ran, which is found in the cytosol as well as the nucleus. Hydrolysis of GTP by Ran is thought to provide the energy needed to transport nuclear proteins into the cell. Ran is turned on and off by GEFs and GAPs, respectively.
=== Heterotrimeric ===
Most GAPs that act on alpha subunits of heterotrimeric G proteins belong to a distinct family, the RGS protein family.
== Regulation ==
While GAPs serve to regulate the G proteins, there is also some level of regulation of the GAPs themselves. Many GAPs have allosteric sites that serve as interfaces with downstream targets of the particular path that they regulate. For example, RGS9-1, the GAP in the photoreceptors from above, interacts with cGMP phosphodiesterase (cGMP PDE), a downstream component of phototransduction in the retina. Upon binding with cGMP PDE, RGS9-1 GAP activity is enhanced. In other words, a downstream target of photoreceptor-induced signaling binds and activates the inhibitor of signaling, GAP. This positive regulatory binding of downstream targets to GAP serves as a negative feedback loop that eventually turns off the signaling that was originally activated. GAPs are regulated by targets of the G protein that they regulate.
There are also examples of negative regulatory mechanisms, where downstream targets of G protein signaling inhibit the GAPs. In G protein-gated potassium channels, phosphatidylinositol 3, 4, 5-triphosphate (PIP3) is a downstream target of G protein signaling. PIP3 binds and inhibits the RGS4 GAP. Such inhibition of GAP may perhaps "prime" the signaling pathway for activation. This creates a window of activity for the G proteins once activated because the GAP is temporarily inhibited. When the potassium channel is activated, Ca2+ gets released and binds calmodulin. Together, they displace PIP3 from GAP by binding competitively to the same site, and by doing so, they reactivate GAP to turn G protein signaling off. This particular process demonstrates both inhibition and activation of GAP by its regulators. There is cross-talk between GAP and other components of the signaling pathway that regulate the activity of GAP.
There have been some findings suggesting the possibility of crosstalk between GAPs. A recent study showed that the p120Ras GAP could bind the DLC1 Rho GAP at its catalytic domain. The binding of the Ras GAP to the Rho GAP inhibits the activity of the Rho GAP, thereby activating the Rho G protein. One GAP serves as a negative regulator of another GAP. The reasons for such cross-regulation across GAPs are yet unclear, but one possible hypothesis is that this cross-talk across GAPs attenuates the "off" signal of all the GAPs. Although the p120Ras GAP is active, therefore inhibiting that particular pathway, other cellular processes can still continue because it inhibits other GAPs. This may ensure that the whole system does not shut down from a single off signal. GAP activity is highly dynamic, interacting with many other components of signaling pathways.
== Disease associations and clinical relevance ==
The importance of GAPs comes from its regulation of the crucial G proteins. Many of these G proteins are involved in cell cycling, and as such are known proto-oncogenes. The Ras superfamily of G proteins, for example, has been associated with many cancers because Ras is a common downstream target of many growth factors like FGF, or fibroblast growth factor. Under normal conditions, this signaling ultimately induces regulated cell growth and proliferation. However, in the cancer state, such growth is no longer regulated and results in the formation of tumors. Often, this oncogenic behavior is due to a loss of function of GAPs associated with those G proteins or a loss of the G protein's ability to respond to its GAP. With the former, G proteins are unable to hydrolyze GTP quickly, resulting in sustained expression of the active form of G proteins. Although the G proteins have weak hydrolytic activity, in the presence of functional GEFs, the inactivated G proteins are constantly replaced with activated ones because the GEFs exchange GDP for GTP in these proteins. With no GAPs to curb the G protein's activity, this results in constitutively active G proteins, unregulated cell growth, and the cancerous state. In the case of the latter, a loss of the G protein's ability to respond to GAP, the G proteins have lost their ability to hydrolyze GTP. With a nonfunctional G protein enzyme, GAPs cannot activate the GTPase activity, and the G protein is constitutively on. This also results in unregulated cell growth and cancer.
Examples of GAP malfunction are ubiquitous clinically. Some cases involve a decreased expression of the GAP gene. For example, some recently characterized cases of papillary thyroid cancer cells in patients show a decreased expression of Rap1GAP, and this expression is seemingly caused by a decreased expression of the GAP mRNA, shown by qRT-PCR experiments. In this case, there appears to be a loss of proper Rap1GAP gene expression. In another case, expression of the Ras GAP is lost in several cancers due to improper epigenetic silencing of the gene. These cells have CpG methylations near the gene that, in effect, silence gene transcription. Regulation of G proteins is lost because the regulator is absent, resulting in cancer.
Other cancers show a loss of sensitivity of the G protein to the GAPs. These G proteins acquire missense mutations that disrupt the inherent GTPase activity of the proteins. The mutant G proteins are still bound by GAPs, but enhancing GTPase activity by the GAPs is meaningless when GTPase activity of the G protein itself is lost. GAP works to activate a nonfunctional hydrolytic enzyme. T24 bladder cancer cells, for example, were shown to have a missense mutation, G12V, resulting in constitutively active Ras protein. Despite the presence of the G protein regulator, regulation is lost due to a loss of function in the G protein itself. This loss of function also manifests itself in cancer. GAPs and their interaction with G proteins are, therefore, highly important clinically and are potential targets for cancer therapies.
== References ==
== External links ==
GTPase-Activating+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH) | Wikipedia/GTPase-activating_protein |
A mitogen-activated protein kinase (MAPK or MAP kinase) is a type of serine/threonine-specific protein kinases involved in directing cellular responses to a diverse array of stimuli, such as mitogens, osmotic stress, heat shock and proinflammatory cytokines. They regulate cell functions including proliferation, gene expression, differentiation, mitosis, cell survival, and apoptosis.
MAP kinases are found in eukaryotes only, but they are fairly diverse and encountered in all animals, fungi and plants, and even in an array of unicellular eukaryotes.
MAPKs belong to the CMGC (CDK/MAPK/GSK3/CLK) kinase group. The closest relatives of MAPKs are the cyclin-dependent kinases (CDKs).
== Discovery ==
The first mitogen-activated protein kinase to be discovered was ERK1 (MAPK3) in mammals. Since ERK1 and its close relative ERK2 (MAPK1) are both involved in growth factor signaling, the family was termed "mitogen-activated". With the discovery of other members, even from distant organisms (e.g. plants), it has become increasingly clear that the name is a misnomer, since most MAPKs are actually involved in the response to potentially harmful, abiotic stress stimuli (hyperosmosis, oxidative stress, DNA damage, low osmolarity, infection, etc.). Because plants cannot "flee" from stress, terrestrial plants have the highest number of MAPK genes per organism ever found. Thus the role of mammalian ERK1/2 kinases as regulators of cell proliferation is not a generic, but a highly specialized function.
== Types ==
Most MAPKs have a number of shared characteristics, such as the activation dependent on two phosphorylation events, a three-tiered pathway architecture and similar substrate recognition sites. These are the "classical" MAP kinases. But there are also some ancient outliers from the group as sketched above, that do not have dual phosphorylation sites, only form two-tiered pathways, and lack the features required by other MAPKs for substrate binding. These are usually referred to as "atypical" MAPKs. It is yet unclear if the atypical MAPKs form a single group as opposed to the classical ones.
The mammalian MAPK family of kinases includes three subfamilies:
Extracellular signal-regulated kinases (ERKs)
c-Jun N-terminal kinases (JNKs)
p38 mitogen-activated protein kinases (p38s)
Generally, ERKs are activated by growth factors and mitogens, whereas cellular stresses and inflammatory cytokines activate JNKs and p38s.
== Activation ==
Mitogen-activated protein kinases are catalytically inactive in their base form. In order to become active, they require (potentially multiple) phosphorylation events in their activation loops. This is conducted by specialized enzymes of the STE protein kinase group. In this way protein dynamics can induce a conformational change in the structure of the protein via long-range allostery.
In the case of classical MAP kinases, the activation loop contains a characteristic TxY (threonine-x-tyrosine) motif (TEY in mammalian ERK1 and ERK2, TDY in ERK5, TPY in JNKs, TGY in p38 kinases) that needs to be phosphorylated on both the threonine and the tyrosine residues in order to lock the kinase domain in a catalytically competent conformation. In vivo and in vitro, phosphorylation of tyrosine oftentimes precedes phosphorylation of threonine, although phosphorylation of either residue can occur in the absence of the other.
This tandem activation loop phosphorylation (that was proposed to be either distributive or processive, dependent on the cellular environment) is performed by members of the Ste7 protein kinase family, also known as MAP2 kinases. MAP2 kinases in turn, are also activated by phosphorylation, by a number of different upstream serine-threonine kinases (MAP3 kinases). Because MAP2 kinases display very little activity on substrates other than their cognate MAPK, classical MAPK pathways form multi-tiered, but relatively linear pathways. These pathways can effectively convey stimuli from the cell membrane (where many MAP3Ks are activated) to the nucleus (where only MAPKs may enter) or to many other subcellular targets.
In comparison to the three-tiered classical MAPK pathways, some atypical MAP kinases appear to have a more ancient, two-tiered system. ERK3 (MAPK6) and ERK4 (MAPK4) were recently shown to be directly phosphorylated and thus activated by PAK kinases (related to other MAP3 kinases). In contrast to the classical MAP kinases, these atypical MAPKs require only a single residue in their activation loops to be phosphorylated. The details of NLK and ERK7 (MAPK15) activation remain unknown.
Inactivation of MAPKs is performed by a number of phosphatases. A very conserved family of dedicated phosphatases is the so-called MAP kinase phosphatases (MKPs), a subgroup of dual-specificity phosphatases (DUSPs). As their name implies, these enzymes are capable of hydrolyzing the phosphate from both phosphotyrosine and the phosphothreonine residues. Since removal of either phosphate groups will greatly reduce MAPK activity, essentially abolishing signaling, some tyrosine phosphatases are also involved in inactivating MAP kinases (e.g. the phosphatases HePTP, STEP and PTPRR in mammals).
== Signaling cascades ==
As mentioned above, MAPKs typically form multi-tiered pathways, receiving input several levels above the actual MAP kinase. In contrast to the relatively simple, phosphorylation-dependent activation mechanism of MAPKs and MAP2Ks, MAP3Ks have stunningly complex regulation. Many of the better-known MAP3Ks, such as c-Raf, MEKK4 or MLK3 require multiple steps for their activation. These are typically allosterically-controlled enzymes, tightly locked into an inactive state by multiple mechanisms. The first step en route to their activation consists of relieving their autoinhibition by a smaller ligand (such as Ras for c-Raf, GADD45 for MEKK4 or Cdc42 for MLK3). This commonly (but not always) happens at the cell membrane, where most of their activators are bound (note that small G-proteins are constitutively membrane-associated due to prenylation). That step is followed by side-to-side homo- and heterodimerisation of their now accessible kinase domains. Recently determined complex structures reveal that the dimers are formed in an orientation that leaves both their substrate-binding regions free. Importantly, this dimerisation event also forces the MAP3 kinase domains to adopt a partially active conformation. Full activity is only achieved once these dimers transphosphorylate each other on their activation loops. The latter step can also be achieved or aided by auxiliary protein kinases (MAP4 kinases, members of the Ste20 family). Once a MAP3 kinase is fully active, it may phosphorylate its substrate MAP2 kinases, which in turn will phosphorylate their MAP kinase substrates.
=== In animals ===
The ERK1/2 pathway of mammals is probably the best-characterized MAPK system. The most important upstream activators of this pathway are the Raf proteins (A-Raf, B-Raf or c-Raf), the key mediators of response to growth factors (EGF, FGF, PDGF, etc.); but other MAP3Ks such as c-Mos and Tpl2/Cot can also play the same role. All these enzymes phosphorylate and thus activate the MKK1 and/or MKK2 kinases, that are highly specific activators for ERK1 and ERK2. The latter phosphorylate a number of substrates important for cell proliferation, cell cycle progression, cell division and differentiation (RSK kinases, Elk-1 transcription factor, etc.)
In contrast to the relatively well-insulated ERK1/2 pathway, mammalian p38 and JNK kinases have most of their activators shared at the MAP3K level (MEKK1, MEKK4, ASK1, TAK1, MLK3, TAOK1, etc.). In addition, some MAP2K enzymes may activate both p38 and JNK (MKK4), while others are more specific for either JNK (MKK7) or p38 (MKK3 and MKK6). Due to these interlocks, there are very few if any stimuli that can elicit JNK activation without simultaneously activating p38 or reversed. Both JNK and p38 signaling pathways are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock, and are involved in adaptation to stress, apoptosis or cell differentiation. JNKs have a number of dedicated substrates that only they can phosphorylate (c-Jun, NFAT4, etc.), while p38s also have some unique targets (e.g. the MAPKAP kinases MK2 and MK3), ensuring the need for both in order to respond to stressful stimuli.
ERK5 is part of a fairly well-separated pathway in mammals. Its sole specific upstream activator MKK5 is turned on in response to the MAP3 kinases MEKK2 and MEKK3. The specificity of these interactions are provided by the unique architecture of MKK5 and MEKK2/3, both containing N-terminal PB1 domains, enabling direct heterodimerisation with each other. The PB1 domain of MKK5 also contributes to the ERK5-MKK5 interaction: it provides a special interface (in addition to the D-motif found in MKK5) through which MKK5 can specifically recognize its substrate ERK5. Although the molecular-level details are poorly known, MEKK2 and MEKK3 respond to certain developmental cues to direct endothel formation and cardiac morphogenesis. While also implicated in brain development, the embryonic lethality of ERK5 inactivation due to cardiac abnormalities underlines its central role in mammalian vasculogenesis. It is notable, that conditional knockout of ERK5 in adult animals is also lethal, due to the widespread disruption of endothelial barriers. Mutations in the upstream components of the ERK5 pathway (the CCM complex) are thought to underlie cerebral cavernous malformations in humans.
=== In fungi ===
MAPK pathways of fungi are also well studied. In yeast, the Fus3 MAPK is responsible for cell cycle arrest and mating in response to pheromone stimulation. The pheromone alpha-factor is sensed by a seven transmembrane receptor. The recruitment and activation of Fus3 pathway components are strictly dependent on heterotrimeric G-protein activation. The mating MAPK pathway consist of three tiers (Ste11-Ste7-Fus3), but the MAP2 and MAP3 kinases are shared with another pathway, the Kss1 or filamentous growth pathway. While Fus3 and Kss1 are closely related ERK-type kinases, yeast cells can still activate them separately, with the help of a scaffold protein Ste5 that is selectively recruited by the G-proteins of the mating pathway. The trick is that Ste5 can associate with and "unlock" Fus3 for Ste7 as a substrate in a tertiary complex, while it does not do the same for Kss1, leaving the filamentous growth pathway to be activated only in the absence of Ste5 recruitment.
Fungi also have a pathway reminiscent of mammalian JNK/p38 signaling. This is the Hog1 pathway: activated by high osmolarity (in Saccharomyces cerevisiae) or a number of other abiotic stresses (in Schizosaccharomyces pombe). The MAP2 kinase of this pathway is called Pbs2 (related to mammalian MKK3/4/6/7), the dedicated MAP3 kinases involved in activation are Ssk2 and SSk22. The system in S. cerevisiae is activated by a sophisticated osmosensing module consisting of the Sho1 and Sln1 proteins, but it is yet unclear how other stimuli can elicit activation of Hog1. Yeast also displays a number of other MAPK pathways without close homologs in animals, such as the cell wall integrity pathway (Mpk1/Slt2) or the sporulation pathway (Smk1).
=== In plants ===
Despite the high number of MAPK genes, MAPK pathways of higher plants were studied less than animal or fungal ones. Although their signaling appears very complex, the MPK3, MPK4 and MPK6 kinases of Arabidopsis thaliana are key mediators of responses to osmotic shock, oxidative stress, response to cold and involved in anti-pathogen responses. Asai et al. 2002's model of MAPK mediated immunity passes the effector recognition signal from FLS2 ⇨ MEKK1 ⇨ MKK4 or MKK5 ⇨ MPK3 and MPK6 ⇨ WRKY22 or WRKY29. However the work of Mészáros et al. 2006 and Suarez-Rodriguez et al. 2007 give other orders for this pathway and it is possible that these are parallel pathways operating simultaneously. They are also involved in morphogenesis, since MPK4 mutants display severe dwarfism.
== Evolutionary relationships ==
Members of the MAPK family can be found in every eukaryotic organism examined so far. In particular, both classical and atypical MAP kinases can be traced back to the root of the radiation of major eukaryotic groups. Terrestrial plants contain four groups of classical MAPKs (MAPK-A, MAPK-B, MAPK-C and MAPK-D) that are involved in response to myriads of abiotic stresses. However, none of these groups can be directly equated to the clusters of classical MAPKs found in opisthokonts (fungi and animals). In the latter, the major subgroups of classical MAPKs form the ERK/Fus3-like branch (that is further sub-divided in metazoans into ERK1/2 and ERK5 subgroups), and the p38/Hog1-like kinases (that has also split into the p38 and the JNK subgroups in multicellular animals). In addition, there are several MAPKs in both fungi and animals, whose origins are less clear, either due to high divergence (e.g. NLK), or due to possibly being an early offshoot to the entire MAPK family (ERK3, ERK4, ERK7). In vertebrates, due to the twin whole genome duplications after the cephalochordate/vertebrate split, there are several paralogs in every group. Thus ERK1 and ERK2 both correspond to the Drosophila kinase rolled, JNK1, JNK2 and JNK3 are all orthologous to the gene basket in Drosophila. Although among the p38 group, p38 alpha and beta are clearly paralogous pairs, and so are p38 gamma and delta in vertebrates, the timing of the base split is less clear, given that many metazoans already possess multiple p38 homologs (there are three p38-type kinases in Drosophila, Mpk2(p38a), p38b and p38c). The single ERK5 protein appears to fill a very specialized role (essential for vascular development in vertebrates) wherever it is present. This lineage has been deleted in protostomes, together with its upstream pathway components (MEKK2/3, MKK5), although they are clearly present in cnidarians, sponges and even in certain unicellular organisms (e.g. the choanoflagellate Monosiga brevicollis) closely related to the origins of multicellular animals.
The split between classical and some atypical MAP kinases happened quite early. This is suggested not just by the high divergence between extant genes, but also recent discoveries of atypical MAPKs in primitive, basal eukaryotes. The genome sequencing of Giardia lamblia revealed the presence of two MAPK genes, one of them similar to the already-well-known mammalian MAPKs (ERKs, p38s, etc.), the other one showing similarities to the mammalian ERK7 protein. The situation is similar in the multicellular amoeba Dictyostelium discoideum, where the ddERK1 protein appears to be a classical MAPK, while ddERK2 more closely resembles our ERK7 and ERK3/4 proteins. Atypical MAPKs can also be found in higher plants, although they are poorly known. Similar to the situation in mammals, most aspects of atypical MAPKs are uncharacterized due to the lack of research focus on this area.
== Substrate and partner recognition ==
As typical for the CMGC kinase group, the catalytic site of MAP kinases has a very loose consensus sequence for substrates. Like all their relatives, they only require the target serine / threonine amino acids to be followed by a small amino acid, preferably proline ("proline-directed kinases"). But as SP/TP sites are extremely common in all proteins, additional substrate-recognition mechanisms have evolved to ensure signaling fidelity. Unlike their closest relatives, the cyclin-dependent kinases (CDKs), where substrates are recognized by the cyclin subunit, MAPKs associate with their substrates via auxiliary binding regions on their kinase domains. The most important such region consists of the hydrophobic docking groove and the negatively charged CD-region. Together they recognize the so-called MAPK docking or D-motifs (also called kinase interaction motif / KIM). D-motifs essentially consist of one or two positively charged amino acids, followed by alternating hydrophobic residues (mostly leucines), typically upstream of the phosphorylation site by 10–50 amino acids. Many of the known MAPK substrates contain such D-motifs that can not only bind to, but also provide specific recognition by certain MAPKs. D-motifs are not restricted to substrates: MAP2 kinases also contain such motifs on their N-termini that are absolutely required for MAP2K-MAPK interaction and MAPK activation. Similarly, both dual-specificity MAP kinase phosphatases and MAP-specific tyrosine phosphatases bind to MAP kinases through the same docking site. D-motifs can even be found in certain MAPK pathway regulators and scaffolds (e.g. in the mammalian JIP proteins).
Other, less well characterised substrate-binding sites also exist. One such site (the DEF site) is formed by the activation loop (when in the active conformation) and the MAP kinase-specific insert below it. This site can accommodate peptides with an FxFP consensus sequence, typically downstream of the phosphorylation site. Note that the latter site can only be found in proteins that need to selectively recognize the active MAP kinases, thus they are almost exclusively found in substrates. Different motifs may cooperate with each other, as in the Elk family of transcription factors, that possess both a D-motif and an FxFP motif. The presence of an FxFP motif in the KSR1 scaffold protein also serves to make it an ERK1/2 substrate, providing a negative feedback mechanism to set the correct strength of ERK1/2 activation.
== Scaffold proteins ==
Since the discovery of Ste5 in yeast, scientists were on the hunt to discover similar non-enzymatic scaffolding pathway elements in mammals. There are indeed a number of proteins involved in ERK signaling, that can bind to multiple elements of the pathway: MP1 binds both MKK1/2 and ERK1/2, KSR1 and KSR2 can bind B-Raf or c-Raf, MKK1/2 and ERK1/2. Analogous proteins were also discovered for the JNK pathway: the JIP1/JIP2 and the JIP3/JIP4 families of proteins were all shown to bind MLKs, MKK7 and any JNK kinase. Unfortunately, unlike the yeast Ste5, the mechanisms by which they regulate MAPK activation are considerably less understood. While Ste5 actually forms a ternary complex with Ste7 and Fus3 to promote phosphorylation of the latter, known mammalian scaffold proteins appear to work by very different mechanisms. For example, KSR1 and KSR2 are actually MAP3 kinases and related to the Raf proteins. Although KSRs alone display negligible MAP3 kinase activity, KSR proteins can still participate in the activation of Raf kinases by forming side-to-side heterodimers with them, providing an allosteric pair to turn on each enzymes. JIPs on the other hand, are apparently transport proteins, responsible for enrichment of MAPK signaling components in certain compartments of polarized cells. In this context, JNK-dependent phosphorylation of JIP1 (and possibly JIP2) provides a signal for JIPs to release the JIP-bound and inactive upstream pathway components, thus driving a strong local positive feedback loop. This sophisticated mechanism couples kinesin-dependent transport to local JNK activation, not only in mammals, but also in the fruitfly Drosophila melanogaster.
== As therapeutic targets ==
Since the ERK signaling pathway is involved in both physiological and pathological cell proliferation, it is natural that ERK1/2 inhibitors would represent a desirable class of antineoplastic agents. Indeed, many of the proto-oncogenic "driver" mutations are tied to ERK1/2 signaling, such as constitutively active (mutant) receptor tyrosine kinases, Ras or Raf proteins. Although no MKK1/2 or ERK1/2 inhibitors were developed for clinical use, kinase inhibitors that also inhibit Raf kinases (e.g. Sorafenib) are successful antineoplastic agents against various types of cancer. MEK inhibitor cobimetinib has been investigated in pre-clinical lung cancer models in combination with inhibition of the PI3K pathway, where the two drugs lead to a synergistic response.
JNK kinases are implicated in the development of insulin resistance in obese individuals as well as neurotransmitter excitotoxicity after ischaemic conditions. Inhibition of JNK1 ameliorates insulin resistance in certain animal models. Mice that were genetically engineered to lack a functional JNK3 gene - the major isoform in brain – display enhanced ischemic tolerance and stroke recovery. Although small-molecule JNK inhibitors are under development, none of them proved to be effective in human tests yet. A peptide-based JNK inhibitor (AM-111, a retro-inverse D-motif peptide from JIP1, formerly known as XG-102) is also under clinical development for sensorineural hearing loss.
p38 was once believed to be a perfect target for anti-inflammatory drugs. Yet the failure of more than a dozen chemically different compounds in the clinical phase suggests that p38 kinases might be poor therapeutic targets in autoimmune diseases. Many of these compounds were found to be hepatotoxic to various degree and tolerance to the anti-inflammatory effect developed within weeks. An alternative approach is to evaluate the potential for targeting upstream MAPKs, such as ASK1. Studies in animal models of inflammatory arthritis have yielded promising results, and ASK1 has recently been found to be unique amongst the MAPKs in that it is inducible by inflammatory cytokines such as TNF-α.
== See also ==
== References ==
== External links ==
MAP Kinase Resource .
Table of names for mitogen-activated kinases.
MAPK cascade picture
Mitogen-Activated+Protein+Kinases at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Model of MAPK ultrasensitivity in BioModels Database
Drosophila rolled – The Interactive Fly | Wikipedia/Mitogen-activated_protein_kinase |
G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily related proteins that are cell surface receptors that detect molecules outside the cell and activate cellular responses. They are coupled with G proteins. They pass through the cell membrane seven times in the form of six loops (three extracellular loops interacting with ligand molecules, three intracellular loops interacting with G proteins, an N-terminal extracellular region and a C-terminal intracellular region) of amino acid residues, which is why they are sometimes referred to as seven-transmembrane receptors. Ligands can bind either to the extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices (rhodopsin-like family). They are all activated by agonists, although a spontaneous auto-activation of an empty receptor has also been observed.
G protein-coupled receptors are found only in eukaryotes, including yeast, and choanoflagellates. The ligands that bind and activate these receptors include light-sensitive compounds, odors, pheromones, hormones, and neurotransmitters. They vary in size from small molecules to peptides, to large proteins. G protein-coupled receptors are involved in many diseases.
There are two principal signal transduction pathways involving the G protein-coupled receptors:
the cAMP signal pathway and
the phosphatidylinositol signal pathway.
When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a guanine nucleotide exchange factor (GEF). The GPCR can then activate an associated G protein by exchanging the GDP bound to the G protein for a GTP. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type (Gαs, Gαi/o, Gαq/11, Gα12/13).: 1160
GPCRs are an important drug target, and approximately 34% of all Food and Drug Administration (FDA) approved drugs target 108 members of this family. The global sales volume for these drugs is estimated to be 180 billion US dollars as of 2018. It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of the pharmaceutical research.
== History and significance ==
With the determination of the first structure of the complex between a G-protein coupled receptor (GPCR) and a G-protein trimer (Gαβγ) in 2011 a new chapter of GPCR research was opened for structural investigations of global switches with more than one protein being investigated. The previous breakthroughs involved determination of the crystal structure of the first GPCR, rhodopsin, in 2000 and the crystal structure of the first GPCR with a diffusible ligand (β2AR) in 2007. The way in which the seven transmembrane helices of a GPCR are arranged into a bundle was suspected based on the low-resolution model of frog rhodopsin from cryogenic electron microscopy studies of the two-dimensional crystals. The crystal structure of rhodopsin, that came up three years later, was not a surprise apart from the presence of an additional cytoplasmic helix H8 and a precise location of a loop covering retinal binding site. However, it provided a scaffold which was hoped to be a universal template for homology modeling and drug design for other GPCRs – a notion that proved to be too optimistic.
Results 7 years later were surprising because the crystallization of β2-adrenergic receptor (β2AR) with a diffusible ligand revealed quite a different shape of the receptor extracellular side than that of rhodopsin. This area is important because it is responsible for the ligand binding and is targeted by many drugs. Moreover, the ligand binding site was much more spacious than in the rhodopsin structure and was open to the exterior. In the other receptors crystallized shortly afterwards the binding side was even more easily accessible to the ligand. New structures complemented with biochemical investigations uncovered mechanisms of action of molecular switches which modulate the structure of the receptor leading to activation states for agonists or to complete or partial inactivation states for inverse agonists.
The 2012 Nobel Prize in Chemistry was awarded to Brian Kobilka and Robert Lefkowitz for their work that was "crucial for understanding how G protein-coupled receptors function". There have been at least seven other Nobel Prizes awarded for some aspect of G protein–mediated signaling. As of 2012, two of the top ten global best-selling drugs (Advair Diskus and Abilify) act by targeting G protein-coupled receptors.
== Classification ==
The exact size of the GPCR superfamily is unknown, but at least 831 different human genes (or about 4% of the entire protein-coding genome) have been predicted to code for them from genome sequence analysis. Although numerous classification schemes have been proposed, the superfamily was classically divided into three main classes (A, B, and C) with no detectable shared sequence homology between classes.
The largest class by far is class A, which accounts for nearly 85% of the GPCR genes. Of class A GPCRs, over half of these are predicted to encode olfactory receptors, while the remaining receptors are liganded by known endogenous compounds or are classified as orphan receptors. Despite the lack of sequence homology between classes, all GPCRs have a common structure and mechanism of signal transduction. The very large rhodopsin A group has been further subdivided into 19 subgroups (A1-A19).
According to the classical A-F system, GPCRs can be grouped into six classes based on sequence homology and functional similarity:
Class A (or 1) (Rhodopsin-like)
Class B (or 2) (Secretin receptor family)
Class C (or 3) (Metabotropic glutamate/pheromone)
Class D (or 4) (Fungal mating pheromone receptors)
Class E (or 5) (Cyclic AMP receptors)
Class F (or 6) (Frizzled/Smoothened)
More recently, an alternative classification system called GRAFS (Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, Secretin) has been proposed for vertebrate GPCRs. They correspond to classical classes C, A, B2, F, and B.
An early study based on available DNA sequence suggested that the human genome encodes roughly 750 G protein-coupled receptors, about 350 of which detect hormones, growth factors, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.
Some web-servers and bioinformatics prediction methods have been used for predicting the classification of GPCRs according to their amino acid sequence alone, by means of the pseudo amino acid composition approach.
== Physiological roles ==
GPCRs are involved in a wide variety of physiological processes. Some examples of their physiological roles include:
The visual sense: The opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals. Rhodopsin, for example, uses the conversion of 11-cis-retinal to all-trans-retinal for this purpose.
The gustatory sense (taste): GPCRs in taste cells mediate release of gustducin in response to bitter-, umami- and sweet-tasting substances.
The sense of smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
Behavioral and mood regulation: Receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, histamine, GABA, and glutamate
Regulation of immune system activity and inflammation: chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response. GPCRs are also involved in immune-modulation, e. g. regulating interleukin induction or suppressing TLR-induced immune responses from T cells.
Autonomic nervous system transmission: Both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
Cell density sensing: A novel GPCR role in regulating cell density sensing.
Homeostasis modulation (e.g., water balance).
Involved in growth and metastasis of some types of tumors.
Used in the endocrine system for peptide and amino-acid derivative hormones that bind to GCPRs on the cell membrane of a target cell. This activates cAMP, which in turn activates several kinases, allowing for a cellular response, such as transcription.
== Receptor structure ==
GPCRs are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. The extracellular parts of the receptor can be glycosylated. These extracellular loops also contain two highly conserved cysteine residues that form disulfide bonds to stabilize the receptor structure. Some seven-transmembrane helix proteins (channelrhodopsin) that resemble GPCRs may contain ion channels, within their protein.
In 2000, the first crystal structure of a mammalian GPCR, that of bovine rhodopsin (1F88), was solved. In 2007, the first structure of a human GPCR was solved This human β2-adrenergic receptor GPCR structure proved highly similar to the bovine rhodopsin. The structures of activated or agonist-bound GPCRs have also been determined. These structures indicate how ligand binding at the extracellular side of a receptor leads to conformational changes in the cytoplasmic side of the receptor. The biggest change is an outward movement of the cytoplasmic part of the 5th and 6th transmembrane helix (TM5 and TM6). The structure of activated beta-2 adrenergic receptor in complex with Gs confirmed that the Gα binds to a cavity created by this movement.
GPCRs exhibit a similar structure to some other proteins with seven transmembrane domains, such as microbial rhodopsins and adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2). However, these 7TMH (7-transmembrane helices) receptors and channels do not associate with G proteins. In addition, ADIPOR1 and ADIPOR2 are oriented oppositely to GPCRs in the membrane (i.e. GPCRs usually have an extracellular N-terminus, cytoplasmic C-terminus, whereas ADIPORs are inverted).
== Structure–function relationships ==
In terms of structure, GPCRs are characterized by an extracellular N-terminus, followed by seven transmembrane (7-TM) α-helices (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. The GPCR arranges itself into a tertiary structure resembling a barrel, with the seven transmembrane helices forming a cavity within the plasma membrane that serves a ligand-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is the case for bulkier ligands (e.g., proteins or large peptides), which instead interact with the extracellular loops, or, as illustrated by the class C metabotropic glutamate receptors (mGluRs), the N-terminal tail. The class C GPCRs are distinguished by their large N-terminal tail, which also contains a ligand-binding domain. Upon glutamate-binding to an mGluR, the N-terminal tail undergoes a conformational change that leads to its interaction with the residues of the extracellular loops and TM domains. The eventual effect of all three types of agonist-induced activation is a change in the relative orientations of the TM helices (likened to a twisting motion) leading to a wider intracellular surface and "revelation" of residues of the intracellular helices and TM domains crucial to signal transduction function (i.e., G-protein coupling). Inverse agonists and antagonists may also bind to a number of different sites, but the eventual effect must be prevention of this TM helix reorientation.
The structure of the N- and C-terminal tails of GPCRs may also serve important functions beyond ligand-binding. For example, The C-terminus of M3 muscarinic receptors is sufficient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary for its preassembly with Gq proteins. In particular, the C-terminus often contains serine (Ser) or threonine (Thr) residues that, when phosphorylated, increase the affinity of the intracellular surface for the binding of scaffolding proteins called β-arrestins (β-arr). Once bound, β-arrestins both sterically prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellular-signal regulated kinase (ERK) pathway activation or receptor endocytosis (internalization). As the phosphorylation of these Ser and Thr residues often occurs as a result of GPCR activation, the β-arr-mediated G-protein-decoupling and internalization of GPCRs are important mechanisms of desensitization. In addition, internalized "mega-complexes" consisting of a single GPCR, β-arr(in the tail conformation), and heterotrimeric G protein exist and may account for protein signaling from endosomes.
A final common structural theme among GPCRs is palmitoylation of one or more sites of the C-terminal tail or the intracellular loops. Palmitoylation is the covalent modification of cysteine (Cys) residues via addition of hydrophobic acyl groups, and has the effect of targeting the receptor to cholesterol- and sphingolipid-rich microdomains of the plasma membrane called lipid rafts. As many of the downstream transducer and effector molecules of GPCRs (including those involved in negative feedback pathways) are also targeted to lipid rafts, this has the effect of facilitating rapid receptor signaling.
GPCRs respond to extracellular signals mediated by a huge diversity of agonists, ranging from proteins to biogenic amines to protons, but all transduce this signal via a mechanism of G-protein coupling. This is made possible by a guanine-nucleotide exchange factor (GEF) domain primarily formed by a combination of IL-2 and IL-3 along with adjacent residues of the associated TM helices.
== Mechanism ==
The G protein-coupled receptor is activated by an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a G protein. Further effect depends on the type of G protein. G proteins are subsequently inactivated by GTPase activating proteins, known as RGS proteins.
=== Ligand binding ===
GPCRs include one or more receptors for the following ligands:
sensory signal mediators (e.g., light and olfactory stimulatory molecules);
adenosine, bombesin, bradykinin, endothelin, γ-aminobutyric acid (GABA), hepatocyte growth factor (HGF), melanocortins, neuropeptide Y, opioid peptides, opsins, somatostatin, GH, tachykinins, members of the vasoactive intestinal peptide family, and vasopressin;
biogenic amines (e.g., dopamine, epinephrine, norepinephrine, histamine, serotonin, and melatonin);
glutamate (metabotropic effect);
glucagon;
acetylcholine (muscarinic effect);
chemokines;
lipid mediators of inflammation (e.g., prostaglandins, prostanoids, platelet-activating factor, and leukotrienes);
peptide hormones (e.g., calcitonin, C5a anaphylatoxin, follicle-stimulating hormone [FSH], gonadotropin-releasing hormone [GnRH], neurokinin, thyrotropin-releasing hormone [TRH], and oxytocin);
and endocannabinoids.
GPCRs that act as receptors for stimuli that have not yet been identified are known as orphan receptors.
However, in contrast to other types of receptors that have been studied, wherein ligands bind externally to the membrane, the ligands of GPCRs typically bind within the transmembrane domain. However, protease-activated receptors are activated by cleavage of part of their extracellular domain.
=== Conformational change ===
The transduction of the signal through the membrane by the receptor is not completely understood. It is known that in the inactive state, the GPCR is bound to a heterotrimeric G protein complex. Binding of an agonist to the GPCR results in a conformational change in the receptor that is transmitted to the bound Gα subunit of the heterotrimeric G protein via protein domain dynamics. The activated Gα subunit exchanges GTP in place of GDP which in turn triggers the dissociation of Gα subunit from the Gβγ dimer and from the receptor. The dissociated Gα and Gβγ subunits interact with other intracellular proteins to continue the signal transduction cascade while the freed GPCR is able to rebind to another heterotrimeric G protein to form a new complex that is ready to initiate another round of signal transduction.
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive biophysical states. The binding of ligands to the receptor may shift the equilibrium toward the active receptor states. Three types of ligands exist: Agonists are ligands that shift the equilibrium in favour of active states; inverse agonists are ligands that shift the equilibrium in favour of inactive states; and neutral antagonists are ligands that do not affect the equilibrium. It is not yet known how exactly the active and inactive states differ from each other.
=== G-protein activation/deactivation cycle ===
When the receptor is inactive, the GEF domain may be bound to an also inactive α-subunit of a heterotrimeric G-protein. These "G-proteins" are a trimer of α, β, and γ subunits (known as Gα, Gβ, and Gγ, respectively) that is rendered inactive when reversibly bound to Guanosine diphosphate (GDP) (or, alternatively, no guanine nucleotide) but active when bound to guanosine triphosphate (GTP). Upon receptor activation, the GEF domain, in turn, allosterically activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit. The cell maintains a 10:1 ratio of cytosolic GTP:GDP so exchange for GTP is ensured. At this point, the subunits of the G-protein dissociate from the receptor, as well as each other, to yield a Gα-GTP monomer and a tightly interacting Gβγ dimer, which are now free to modulate the activity of other intracellular proteins. The extent to which they may diffuse, however, is limited due to the palmitoylation of Gα and the presence of an isoprenoid moiety that has been covalently added to the C-termini of Gγ.
Because Gα also has slow GTP→GDP hydrolysis capability, the inactive form of the α-subunit (Gα-GDP) is eventually regenerated, thus allowing reassociation with a Gβγ dimer to form the "resting" G-protein, which can again bind to a GPCR and await activation. The rate of GTP hydrolysis is often accelerated due to the actions of another family of allosteric modulating proteins called regulators of G-protein signaling, or RGS proteins, which are a type of GTPase-activating protein, or GAP. In fact, many of the primary effector proteins (e.g., adenylate cyclases) that become activated/inactivated upon interaction with Gα-GTP also have GAP activity. Thus, even at this early stage in the process, GPCR-initiated signaling has the capacity for self-termination.
=== Crosstalk ===
GPCRs downstream signals have been shown to possibly interact with integrin signals, such as FAK. Integrin signaling will phosphorylate FAK, which can then decrease GPCR Gαs activity.
== Signaling ==
If a receptor in an active state encounters a G protein, it may activate it. Some evidence suggests that receptors and G proteins are actually pre-coupled. For example, binding of G proteins to receptors affects the receptor's affinity for ligands. Activated G proteins are bound to GTP.
Further signal transduction depends on the type of G protein. The enzyme adenylate cyclase is an example of a cellular protein that can be regulated by a G protein, in this case the G protein Gs. Adenylate cyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylate cyclase ends when the G protein returns to the GDP-bound state.
Adenylate cyclases (of which 9 membrane-bound and one cytosolic forms are known in humans) may also be activated or inhibited in other ways (e.g., Ca2+/calmodulin binding), which can modify the activity of these enzymes in an additive or synergistic fashion along with the G proteins.
The signaling pathways activated through a GPCR are limited by the primary sequence and tertiary structure of the GPCR itself but ultimately determined by the particular conformation stabilized by a particular ligand, as well as the availability of transducer molecules. Currently, GPCRs are considered to utilize two primary types of transducers: G-proteins and β-arrestins. Because β-arr's have high affinity only to the phosphorylated form of most GPCRs (see above or below), the majority of signaling is ultimately dependent upon G-protein activation. However, the possibility for interaction does allow for G-protein-independent signaling to occur.
=== G-protein-dependent signaling ===
There are three main G-protein-mediated signaling pathways, mediated by four sub-classes of G-proteins distinguished from each other by sequence homology (Gαs, Gαi/o, Gαq/11, and Gα12/13). Each sub-class of G-protein consists of multiple proteins, each the product of multiple genes or splice variations that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible βγ combinations do not appear to radically differ from one another, these classes are defined according to the isoform of their α-subunit.: 1163
While most GPCRs are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called functional selectivity (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular agonist may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR's GEF domain, even over the course of a single interaction. In addition, a conformation that preferably activates one isoform of Gα may activate another if the preferred is less available. Furthermore, feedback pathways may result in receptor modifications (e.g., phosphorylation) that alter the G-protein preference. Regardless of these various nuances, the GPCR's preferred coupling partner is usually defined according to the G-protein most obviously activated by the endogenous ligand under most physiological or experimental conditions.
==== Gα signaling ====
The effector of both the Gαs and Gαi/o pathways is the cyclic-adenosine monophosphate (cAMP)-generating enzyme adenylate cyclase, or AC. While there are ten different AC gene products in mammals, each with subtle differences in tissue distribution or function, all catalyze the conversion of cytosolic adenosine triphosphate (ATP) to cAMP, and all are directly stimulated by G-proteins of the Gαs class. In contrast, however, interaction with Gα subunits of the Gαi/o type inhibits AC from generating cAMP. Thus, a GPCR coupled to Gαs counteracts the actions of a GPCR coupled to Gαi/o, and vice versa. The level of cytosolic cAMP may then determine the activity of various ion channels as well as members of the ser/thr-specific protein kinase A (PKA) family. Thus cAMP is considered a second messenger and PKA a secondary effector.
The effector of the Gαq/11 pathway is phospholipase C-β (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) to elicit Ca2+ release from the ER, while DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called protein kinase C (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca2+, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca2+ also binds and allosterically activates proteins called calmodulins, which in turn tosolic small GTPase, Rho. Once bound to GTP, Rho can then go on to activate various proteins responsible for cytoskeleton regulation such as Rho-kinase (ROCK). Most GPCRs that couple to Gα12/13 also couple to other sub-classes, often Gαq/11.
==== Gβγ signaling ====
The above descriptions ignore the effects of Gβγ–signalling, which can also be important, in particular in the case of activated Gαi/o-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as G-protein-regulated inwardly rectifying K+ channels (GIRKs), P/Q- and N-type voltage-gated Ca2+ channels, as well as some isoforms of AC and PLC, along with some phosphoinositide-3-kinase (PI3K) isoforms.
=== G-protein-independent signaling ===
Although they are classically thought of working only together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteins may play functional roles independent of GPCRs. GPCRs may signal independently through many proteins already mentioned for their roles in G-protein-dependent signaling such as β-arrs, GRKs, and Srcs. Such signaling has been shown to be physiologically relevant, for example, β-arrestin signaling mediated by the chemokine receptor CXCR3 was necessary for full efficacy chemotaxis of activated T cells. In addition, further scaffolding proteins involved in subcellular localization of GPCRs (e.g., PDZ-domain-containing proteins) may also act as signal transducers. Most often the effector is a member of the MAPK family.
==== Examples ====
In the late 1990s, evidence began accumulating to suggest that some GPCRs are able to signal without G proteins. The ERK2 mitogen-activated protein kinase, a key signal transduction mediator downstream of receptor activation in many pathways, has been shown to be activated in response to cAMP-mediated receptor activation in the slime mold D. discoideum despite the absence of the associated G protein α- and β-subunits.
In mammalian cells, the much-studied β2-adrenoceptor has been demonstrated to activate the ERK2 pathway after arrestin-mediated uncoupling of G-protein-mediated signaling. Therefore, it seems likely that some mechanisms previously believed related purely to receptor desensitisation are actually examples of receptors switching their signaling pathway, rather than simply being switched off.
In kidney cells, the bradykinin receptor B2 has been shown to interact directly with a protein tyrosine phosphatase. The presence of a tyrosine-phosphorylated ITIM (immunoreceptor tyrosine-based inhibitory motif) sequence in the B2 receptor is necessary to mediate this interaction and subsequently the antiproliferative effect of bradykinin.
==== GPCR-independent signaling by heterotrimeric G-proteins ====
Although it is a relatively immature area of research, it appears that heterotrimeric G-proteins may also take part in non-GPCR signaling. There is evidence for roles as signal transducers in nearly all other types of receptor-mediated signaling, including integrins, receptor tyrosine kinases (RTKs), cytokine receptors (JAK/STATs), as well as modulation of various other "accessory" proteins such as GEFs, guanine-nucleotide dissociation inhibitors (GDIs) and protein phosphatases. There may even be specific proteins of these classes whose primary function is as part of GPCR-independent pathways, termed activators of G-protein signalling (AGS). Both the ubiquity of these interactions and the importance of Gα vs. Gβγ subunits to these processes are still unclear.
== Details of cAMP and PIP2 pathways ==
There are two principal signal transduction pathways involving the G protein-linked receptors: the cAMP signal pathway and the phosphatidylinositol signal pathway.
=== cAMP signal pathway ===
The cAMP signal transduction contains five main characters: stimulative hormone receptor (Rs) or inhibitory hormone receptor (Ri); stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi); adenylyl cyclase; protein kinase A (PKA); and cAMP phosphodiesterase.
Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules, while inhibitory hormone receptor (Ri) is a receptor that can bind with inhibitory signal molecules.
Stimulative regulative G-protein is a G-protein linked to stimulative hormone receptor (Rs), and its α subunit upon activation could stimulate the activity of an enzyme or other intracellular metabolism. On the contrary, inhibitory regulative G-protein is linked to an inhibitory hormone receptor, and its α subunit upon activation could inhibit the activity of an enzyme or other intracellular metabolism.
Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes the conversion of ATP to cAMP with the help of cofactor Mg2+ or Mn2+. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator of protein kinase A.
Protein kinase A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylating specific committed enzymes in the metabolic pathway. It can also regulate specific gene expression, cellular secretion, and membrane permeability. The protein enzyme contains two catalytic subunits and two regulatory subunits. When there is no cAMP, the complex is inactive. When cAMP binds to the regulatory subunits, their conformation is altered, causing the dissociation of the regulatory subunits, which activates protein kinase A and allows further biological effects.
These signals then can be terminated by cAMP phosphodiesterase, which is an enzyme that degrades cAMP to 5'-AMP and inactivates protein kinase A.
=== Phosphatidylinositol signal pathway ===
In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G-protein receptor (Gq) on the cell surface and activates phospholipase C, which is located on the plasma membrane. The lipase hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2) into two second messengers: inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds with the IP3 receptor in the membrane of the smooth endoplasmic reticulum and mitochondria to open Ca2+ channels. DAG helps activate protein kinase C (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses.
The effects of Ca2+ are also remarkable: it cooperates with DAG in activating PKC and can activate the CaM kinase pathway, in which calcium-modulated protein calmodulin (CaM) binds Ca2+, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca2+-CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway.
== Receptor regulation ==
GPCRs become desensitized when exposed to their ligand for a long period of time. There are two recognized forms of desensitization: 1) homologous desensitization, in which the activated GPCR is downregulated; and 2) heterologous desensitization, wherein the activated GPCR causes downregulation of a different GPCR. The key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases.
=== Phosphorylation by cAMP-dependent protein kinases ===
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the receptor) via adenylate cyclase and cyclic AMP (cAMP). In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active the more kinases are activated and the more receptors are phosphorylated. In β2-adrenoceptors, this phosphorylation results in the switching of the coupling from the Gs class of G-protein to the Gi class. cAMP-dependent PKA mediated phosphorylation can cause heterologous desensitisation in receptors other than those activated.
=== Phosphorylation by GRKs ===
The G protein-coupled receptor kinases (GRKs) are protein kinases that phosphorylate only active GPCRs. G-protein-coupled receptor kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR) signaling. They constitute a family of seven mammalian serine-threonine protein kinases that phosphorylate agonist-bound receptor. GRKs-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization. Activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins.
Phosphorylation of the receptor can have two consequences:
Translocation: The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysozomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depending on the internalised vesicle's subcellular localisation.
Arrestin linking: The phosphorylated receptor can be linked to arrestin molecules that prevent it from binding (and activating) G proteins, in effect switching it off for a short period of time. This mechanism is used, for example, with rhodopsin in retina cells to compensate for exposure to bright light. In many cases, arrestin's binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β2-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus, the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β2-adrenoreceptors.
=== Mechanisms of GPCR signal termination ===
As mentioned above, G-proteins may terminate their own activation due to their intrinsic GTP→GDP hydrolysis capability. However, this reaction proceeds at a slow rate (≈0.02 times/sec) and, thus, it would take around 50 seconds for any single G-protein to deactivate if other factors did not come into play. Indeed, there are around 30 isoforms of RGS proteins that, when bound to Gα through their GAP domain, accelerate the hydrolysis rate to ≈30 times/sec. This 1500-fold increase in rate allows for the cell to respond to external signals with high speed, as well as spatial resolution due to limited amount of second messenger that can be generated and limited distance a G-protein can diffuse in 0.03 seconds. For the most part, the RGS proteins are promiscuous in their ability to deactivate G-proteins, while which RGS is involved in a given signaling pathway seems more determined by the tissue and GPCR involved than anything else. In addition, RGS proteins have the additional function of increasing the rate of GTP-GDP exchange at GPCRs, (i.e., as a sort of co-GEF) further contributing to the time resolution of GPCR signaling.
In addition, the GPCR may be desensitized itself. This can occur as:
a direct result of ligand occupation, wherein the change in conformation allows recruitment of GPCR-Regulating Kinases (GRKs), which go on to phosphorylate various serine/threonine residues of IL-3 and the C-terminal tail. Upon GRK phosphorylation, the GPCR's affinity for β-arrestin (β-arrestin-1/2 in most tissues) is increased, at which point β-arrestin may bind and act to both sterically hinder G-protein coupling as well as initiate the process of receptor internalization through clathrin-mediated endocytosis. Because only the liganded receptor is desensitized by this mechanism, it is called homologous desensitization
the affinity for β-arrestin may be increased in a ligand occupation and GRK-independent manner through phosphorylation of different ser/thr sites (but also of IL-3 and the C-terminal tail) by PKC and PKA. These phosphorylations are often sufficient to impair G-protein coupling on their own as well.
PKC/PKA may, instead, phosphorylate GRKs, which can also lead to GPCR phosphorylation and β-arrestin binding in an occupation-independent manner. These latter two mechanisms allow for desensitization of one GPCR due to the activities of others, or heterologous desensitization. GRKs may also have GAP domains and so may contribute to inactivation through non-kinase mechanisms as well. A combination of these mechanisms may also occur.
Once β-arrestin is bound to a GPCR, it undergoes a conformational change allowing it to serve as a scaffolding protein for an adaptor complex termed AP-2, which in turn recruits another protein called clathrin. If enough receptors in the local area recruit clathrin in this manner, they aggregate and the membrane buds inwardly as a result of interactions between the molecules of clathrin, in a process called opsonization. Once the pit has been pinched off the plasma membrane due to the actions of two other proteins called amphiphysin and dynamin, it is now an endocytic vesicle. At this point, the adapter molecules and clathrin have dissociated, and the receptor is either trafficked back to the plasma membrane or targeted to lysosomes for degradation.
At any point in this process, the β-arrestins may also recruit other proteins—such as the non-receptor tyrosine kinase (nRTK), c-SRC—which may activate ERK1/2, or other mitogen-activated protein kinase (MAPK) signaling through, for example, phosphorylation of the small GTPase, Ras, or recruit the proteins of the ERK cascade directly (i.e., Raf-1, MEK, ERK-1/2) at which point signaling is initiated due to their close proximity to one another. Another target of c-SRC are the dynamin molecules involved in endocytosis. Dynamins polymerize around the neck of an incoming vesicle, and their phosphorylation by c-SRC provides the energy necessary for the conformational change allowing the final "pinching off" from the membrane.
=== GPCR cellular regulation ===
Receptor desensitization is mediated through a combination phosphorylation, β-arr binding, and endocytosis as described above. Downregulation occurs when endocytosed receptor is embedded in an endosome that is trafficked to merge with an organelle called a lysosome. Because lysosomal membranes are rich in proton pumps, their interiors have low pH (≈4.8 vs. the pH≈7.2 cytosol), which acts to denature the GPCRs. In addition, lysosomes contain many degradative enzymes, including proteases, which can function only at such low pH, and so the peptide bonds joining the residues of the GPCR together may be cleaved. Whether or not a given receptor is trafficked to a lysosome, detained in endosomes, or trafficked back to the plasma membrane depends on a variety of factors, including receptor type and magnitude of the signal.
GPCR regulation is additionally mediated by gene transcription factors. These factors can increase or decrease gene transcription and thus increase or decrease the generation of new receptors (up- or down-regulation) that travel to the cell membrane.
== Receptor oligomerization ==
G-protein-coupled receptor oligomerisation is a widespread phenomenon. One of the best-studied examples is the metabotropic GABAB receptor. This so-called constitutive receptor is formed by heterodimerization of GABABR1 and GABABR2 subunits. Expression of the GABABR1 without the GABABR2 in heterologous systems leads to retention of the subunit in the endoplasmic reticulum. Expression of the GABABR2 subunit alone, meanwhile, leads to surface expression of the subunit, although with no functional activity (i.e., the receptor does not bind agonist and cannot initiate a response following exposure to agonist). Expression of the two subunits together leads to plasma membrane expression of functional receptor. It has been shown that GABABR2 binding to GABABR1 causes masking of a retention signal of functional receptors.
== Origin and diversification of the superfamily ==
Signal transduction mediated by the superfamily of GPCRs dates back to the origin of multicellularity. Mammalian-like GPCRs are found in fungi, and have been classified according to the GRAFS classification system based on GPCR fingerprints. Identification of the superfamily members across the eukaryotic domain, and comparison of the family-specific motifs, have shown that the superfamily of GPCRs have a common origin. Characteristic motifs indicate that three of the five GRAFS families, Rhodopsin, Adhesion, and Frizzled, evolved from the Dictyostelium discoideum cAMP receptors before the split of opisthokonts. Later, the Secretin family evolved from the Adhesion GPCR receptor family before the split of nematodes. Insect GPCRs appear to be in their own group and Taste2 is identified as descending from Rhodopsin. Note that the Secretin/Adhesion split is based on presumed function rather than signature, as the classical Class B (7tm_2, Pfam PF00002) is used to identify both in the studies.
== See also ==
G protein-coupled receptors database
List of MeSH codes (D12.776)
Metabotropic receptor
Orphan receptor
Pepducins, a class of drug candidates targeted at GPCRs
Receptor activated solely by a synthetic ligand, a technique for control of cell signaling through synthetic GPCRs
TOG superfamily
== References ==
== Further reading ==
Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, et al. (April 2003). "The G protein-coupled receptor repertoires of human and mouse". Proceedings of the National Academy of Sciences of the United States of America. 100 (8): 4903–8. Bibcode:2003PNAS..100.4903V. doi:10.1073/pnas.0230374100. PMC 153653. PMID 12679517.
"GPCR Reference Library". Retrieved 11 August 2008. Reference for molecular and mathematical models for the initial receptor response
"The Nobel Prize in Chemistry 2012" (PDF). Archived (PDF) from the original on 18 October 2012. Retrieved 10 October 2012.
== External links ==
G-protein-coupled+receptors at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
GPCR Cell Line Archived 3 April 2015 at the Wayback Machine
"IUPHAR/BPS Guide to PHARMACOLOGY Database (GPCRs)". IUPHAR Database. University of Edinburgh / International Union of Basic and Clinical Pharmacology. Retrieved 6 February 2019.
"GPCRdb". Data, diagrams and web tools for G protein-coupled receptors (GPCRs).; Munk C, Isberg V, Mordalski S, Harpsøe K, Rataj K, Hauser AS, et al. (July 2016). "GPCRdb: the G protein-coupled receptor database - an introduction". British Journal of Pharmacology. 173 (14): 2195–207. doi:10.1111/bph.13509. PMC 4919580. PMID 27155948.
"G Protein-Coupled Receptors on the NET". Archived from the original on 23 July 2011. Retrieved 10 November 2010. a classification of GPCRs
"PSI GPCR Network Center". Archived from the original on 25 July 2013. Retrieved 11 July 2013. a Protein Structure Initiative:Biology Network Center aimed at determining the 3D structures of representative GPCR family proteins
GPCR-HGmod Archived 1 February 2016 at the Wayback Machine, a database of 3D structural models of all human G-protein coupled receptors, built by the GPCR-I-TASSER pipeline Zhang J, Yang J, Jang R, Zhang Y (August 2015). "GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human Genome". Structure. 23 (8): 1538–1549. doi:10.1016/j.str.2015.06.007. PMC 4526412. PMID 26190572. | Wikipedia/G_protein-coupled_receptors |
The G protein-coupled bile acid receptor 1 (GPBAR1) also known as G-protein coupled receptor 19 (GPCR19), membrane-type receptor for bile acids (M-BAR) or Takeda G protein-coupled receptor 5 (TGR5) is a protein that in humans is encoded by the GPBAR1 gene. Activated by bile acids, these receptors play a crucial role in metabolic regulation, including insulin secretion and energy balance, and are found in the gastrointestinal tract as well as other tissues throughout the body.
== History ==
TGR5 receptors were first discovered by Takaharu Maruyama in 2002. It was the first membrane bound G protein coupled receptor that was discovered for faster bile acid signaling. Initially, up until the late 90's, bile acids were known only for its metabolic function of emulsifying fats and keeping cholesterol homeostasis. It wasn't until 1999 when researchers began exploring into its role as a hormone and signaling molecule with the discovery of the nuclear bile acid receptors, Farnesoid X Receptors (FXR).
== Location ==
TGR5 receptors are primarily located in gastrointestinal tracts where bile acid functions are most prevalent. They can also be found throughout the body, including the nervous system, immune system, and various muscle groups, aiding in the tasks that are relevant to their respective locations.
== Function ==
The primary function of the TGR5 receptor is for the binding of bile acid to elicit second messenger systems in the metabolic role of bile acids. It is also a receptor for other agonists, including activating various other pathways responsible for responses like inflammation.
TGR5 receptors are a member of the G protein-coupled receptor (GPCR) superfamily. As mentioned, this protein functions as a cell surface receptor for bile acids. Treatment of cells expressing this GPCR with bile acids induces the production of intracellular cAMP, activation of a MAP kinase signaling pathway, and internalization of the receptor. The receptor is implicated in the suppression of macrophage functions and regulation of energy homeostasis by bile acids.
One effect of this receptor is to activate deiodinases which convert the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3). T3 in turn activates the thyroid hormone receptor which increases metabolic rate.
=== Bile Acid Effects on TGR5 ===
Bile acid binds to the TGR5 receptor which increases the secretion of GLP-1. GLP-1 increases glucose-induced insulin secretion, satiety, and pancreatic beta cell production (responsible for insulin secretion). GLP-1 is also used in medications to treat type 2 diabetes.
GLP-1 undergoes heightened production through 2 pathways. The first pathway is the activation of Adenylyl cyclase and cAMP which begins a secondary messenger cascade to release GLP-1. The second pathway entails the increase in mitochondrial activity in response to nutrients like glucose and fatty acids which causes an increase in the ATP to ADP ratio. This leads to the inactivation of ATP-sensitive potassium channels that causes the cell membrane to depolarize. This depolarization causes an increase in voltage-gated calcium channel activity, sending a flood of calcium ions which triggers a cascade of events leading to increased GLP-1 secretion.
==== Extraintestinal Activation of TGR5 Receptors by Bile Acids ====
Bile acid's ability to act as an antagonist for TGR5 receptors located outside of the gastrointestinal tract means it has the ability to escape the tract and travel to these various regions. Primary bile acids are synthesized by hepatocytes in the liver and get conjugated with Taurine or glycine before they are stored in the gall bladder for stimulated secretion. Upon the presence of fats and proteins in the duodenum from the diet, these primary bile acids get secreted into the intestine where they are converted into secondary bile acids. 95% of these bile acids get reabsorbed into the liver for recirculation, of which 10% escapes this enterohepatic circulation and enters the systemic circulation. It is through their presence in the serum that they are able to get to various other organs where transporters and channels located at their membranes and barriers allow them to access the TGR5 receptors.
== References ==
== Further reading ==
== External links ==
"Bile Acid Receptor". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2016-03-03. Retrieved 2007-11-01.
GPBAR1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
This article incorporates text from the United States National Library of Medicine, which is in the public domain. | Wikipedia/G_protein-coupled_bile_acid_receptor |
A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have unique functions. A set of protein isoforms may be formed from alternative splicings, variable promoter usage, or other post-transcriptional modifications of a single gene; post-translational modifications are generally not considered. (For that, see Proteoforms.) Through RNA splicing mechanisms, mRNA has the ability to select different protein-coding segments (exons) of a gene, or even different parts of exons from RNA to form different mRNA sequences. Each unique sequence produces a specific form of a protein.
The discovery of isoforms could explain the discrepancy between the small number of protein coding regions of genes revealed by the human genome project and the large diversity of proteins seen in an organism: different proteins encoded by the same gene could increase the diversity of the proteome. Isoforms at the RNA level are readily characterized by cDNA transcript studies. Many human genes possess confirmed alternative splicing isoforms. It has been estimated that ~100,000 expressed sequence tags (ESTs) can be identified in humans. Isoforms at the protein level can manifest in the deletion of whole domains or shorter loops, usually located on the surface of the protein.
== Definition ==
One single gene has the ability to produce multiple proteins that differ both in structure and composition; this process is regulated by the alternative splicing of mRNA, though it is not clear to what extent such a process affects the diversity of the human proteome, as the abundance of mRNA transcript isoforms does not necessarily correlate with the abundance of protein isoforms. Three-dimensional protein structure comparisons can be used to help determine which, if any, isoforms represent functional protein products, and the structure of most isoforms in the human proteome has been predicted by AlphaFold and publicly released at isoform.io. The specificity of translated isoforms is derived by the protein's structure/function, as well as the cell type and developmental stage during which they are produced. Determining specificity becomes more complicated when a protein has multiple subunits and each subunit has multiple isoforms.
For example, the 5' AMP-activated protein kinase (AMPK), an enzyme, which performs different roles in human cells, has 3 subunits:
α, catalytic domain, has two isoforms: α1 and α2 which are encoded from PRKAA1 and PRKAA2
β, regulatory domain, has two isoforms: β1 and β2 which are encoded from PRKAB1 and PRKAB2
γ, regulatory domain, has three isoforms: γ1, γ2, and γ3 which are encoded from PRKAG1, PRKAG2, and PRKAG3
In human skeletal muscle, the preferred form is α2β2γ1. But in the human liver, the most abundant form is α1β2γ1.
== Mechanism ==
The primary mechanisms that produce protein isoforms are alternative splicing and variable promoter usage, though modifications due to genetic changes, such as mutations and polymorphisms are sometimes also considered distinct isoforms.
Alternative splicing is the main post-transcriptional modification process that produces mRNA transcript isoforms, and is a major molecular mechanism that may contribute to protein diversity. The spliceosome, a large ribonucleoprotein, is the molecular machine inside the nucleus responsible for RNA cleavage and ligation, removing non-protein coding segments (introns).
Because splicing is a process that occurs between transcription and translation, its primary effects have mainly been studied through genomics techniques—for example, microarray analyses and RNA sequencing have been used to identify alternatively spliced transcripts and measure their abundances. Transcript abundance is often used as a proxy for the abundance of protein isoforms, though proteomics experiments using gel electrophoresis and mass spectrometry have demonstrated that the correlation between transcript and protein counts is often low, and that one protein isoform is usually dominant. One 2015 study states that the cause of this discrepancy likely occurs after translation, though the mechanism is essentially unknown. Consequently, although alternative splicing has been implicated as an important link between variation and disease, there is no conclusive evidence that it acts primarily by producing novel protein isoforms.
Alternative splicing generally describes a tightly regulated process in which alternative transcripts are intentionally generated by the splicing machinery. However, such transcripts are also produced by splicing errors in a process called "noisy splicing," and are also potentially translated into protein isoforms. Although ~95% of multi-exonic genes are thought to be alternatively spliced, one study on noisy splicing observed that most of the different low-abundance transcripts are noise, and predicts that most alternative transcript and protein isoforms present in a cell are not functionally relevant.
Other transcriptional and post-transcriptional regulatory steps can also produce different protein isoforms. Variable promoter usage occurs when the transcriptional machinery of a cell (RNA polymerase, transcription factors, and other enzymes) begin transcription at different promoters—the region of DNA near a gene that serves as an initial binding site—resulting in slightly modified transcripts and protein isoforms.
== Characteristics ==
Generally, one protein isoform is labeled as the canonical sequence based on criteria such as its prevalence and similarity to orthologous—or functionally analogous—sequences in other species. Isoforms are assumed to have similar functional properties, as most have similar sequences, and share some to most exons with the canonical sequence. However, some isoforms show much greater divergence (for example, through trans-splicing), and can share few to no exons with the canonical sequence. In addition, they can have different biological effects—for example, in an extreme case, the function of one isoform can promote cell survival, while another promotes cell death—or can have similar basic functions but differ in their sub-cellular localization. A 2016 study, however, functionally characterized all the isoforms of 1,492 genes and determined that most isoforms behave as "functional alloforms." The authors came to the conclusion that isoforms behave like distinct proteins after observing that the functional of most isoforms did not overlap. Because the study was conducted on cells in vitro, it is not known if the isoforms in the expressed human proteome share these characteristics. Additionally, because the function of each isoform must generally be determined separately, most identified and predicted isoforms still have unknown functions.
== Related concepts ==
=== Glycoform ===
A glycoform is an isoform of a protein that differs only with respect to the number or type of attached glycan. Glycoproteins often consist of a number of different glycoforms, with alterations in the attached saccharide or oligosaccharide. These modifications may result from differences in biosynthesis during the process of glycosylation, or due to the action of glycosidases or glycosyltransferases. Glycoforms may be detected through detailed chemical analysis of separated glycoforms, but more conveniently detected through differential reaction with lectins, as in lectin affinity chromatography and lectin affinity electrophoresis. Typical examples of glycoproteins consisting of glycoforms are the blood proteins as orosomucoid, antitrypsin, and haptoglobin. An unusual glycoform variation is seen in neuronal cell adhesion molecule, NCAM involving polysialic acids, PSA.
== Examples ==
G-actin: despite its conserved nature, it has a varying number of isoforms (at least six in mammals).
Creatine kinase, the presence of which in the blood can be used as an aid in the diagnosis of myocardial infarction, exists in 3 isoforms.
Hyaluronan synthase, the enzyme responsible for the production of hyaluronan, has three isoforms in mammalian cells.
UDP-glucuronosyltransferase, an enzyme superfamily responsible for the detoxification pathway of many drugs, environmental pollutants, and toxic endogenous compounds has 16 known isoforms encoded in the human genome.
G6PDA: normal ratio of active isoforms in cells of any tissue is 1:1 shared with G6PDG. This is precisely the normal isoform ratio in hyperplasia. Only one of these isoforms is found during neoplasia.
Monoamine oxidase, a family of enzymes that catalyze the oxidation of monoamines, exists in two isoforms, MAO-A and MAO-B.
== See also ==
Gene isoform
== References ==
== External links ==
MeSH entry protein isoforms
Definitions Isoform | Wikipedia/Protein_isoforms |
Methods in Molecular Biology is a book series published by Humana Press (an imprint of Springer Science+Business Media) that covers molecular biology research methods and protocols. The book series was introduced by series editor John M. Walker in 1983 and provides step-by-step instructions for carrying out experiments in a research lab. As of January 2020, more than 2000 volumes (2737 as of 15-August-2023) had been published in the series. The protocols are also available online in SpringerLink, and were previously in Springer Protocols.
Each protocol opens with an introductory overview and a list of the materials and reagents needed to complete the experiment. Every protocol is followed by a detailed procedure that is supported with a notes section offering tips and "tricks of the trade" as well as troubleshooting advice.
== See also ==
Biological Procedures Online
== References ==
== External links ==
Official website | Wikipedia/Methods_in_Molecular_Biology |
Soy protein is a protein that is isolated from soybean. It is made from soybean meal that has been dehulled and defatted. Dehulled and defatted soybeans are processed into three kinds of high protein commercial products: soy flour, concentrates, and isolate, which is used in food and industrial manufacturing.
Soy protein is generally regarded as being concentrated in protein bodies, which are estimated to contain at least 60–70% of the total soybean protein. Upon germination of the soybean, the protein will be digested, and the released amino acids will be transported to locations of seedling growth.
Legume proteins, such as soy and pulses, belong to the globulin family of seed storage proteins called legumin and vicilins, or in the case of soybeans, glycinin and beta-conglycinin. Soybeans also contain biologically active or metabolic proteins, such as enzymes, trypsin inhibitors, hemagglutinins, and cysteine proteases similar to papain. The soy cotyledon storage proteins, important for human nutrition, can be extracted most efficiently by water, water plus dilute alkali, or aqueous solutions of sodium chloride from dehulled and defatted soybeans that have undergone only a minimal heat treatment so the protein is close to being native or undenatured.
== History ==
Soy protein has been available since 1936. In that year, organic chemist Percy Lavon Julian designed the world's first plant for the isolation of industrial-grade soy protein called alpha protein. The largest use of industrial-grade protein was, and still is, for paper coatings, in which it serves as a pigment binder. However, Julian's plant must have also been the source of the "soy protein isolate" which Ford's Robert Boyer and Frank Calvert spun into an artificial silk that was then tailored into that now famous "silk is soy" suit that Henry Ford wore on special occasions. The plant's eventual daily output of 40 tons of soy protein isolate made the Soya Products Division into Glidden's most profitable division.
At the start of World War II, Glidden sent a sample of Julian's isolated soy (alpha) protein to National Foam System Inc. (today a unit of Kidde Fire Fighting) which used it to develop Aero-Foam, used by the United States Navy for firefighting and referred to as "bean soup". While not exactly the brainchild of Dr. Julian, it was the meticulous care given to the preparation of the soy protein that made the fire fighting foam possible. When a hydrolysate of isolated soy protein was fed into a water stream, the mixture was converted into a foam by means of an aerating nozzle. The soy protein foam was used to smother oil and gasoline fires aboard ships, and was particularly useful on aircraft carriers. It saved the lives of thousands of sailors.
In 1958, Central Soya of Fort Wayne, Indiana, acquired Julian's Soy Products Division (Chemurgy) of the Glidden Paint Company, Chicago. Central Soya's Bunge Protein Division, in January 2003, joined/merged with DuPont's soy protein business Solae, which in 1997 had acquired Ralston Purina's soy division, Protein Technologies International (PTI) in St. Louis. On May 1, 2012 DuPont announced its complete acquisition of Solae from Bunge.
Food-grade soy protein isolate first became available on October 2, 1959 with the dedication of Central Soya's edible soy isolate, Promine D, production facility on the Glidden Company industrial site in Chicago.: 227–28 An edible soy isolate and edible spun soy fiber have also been available since 1960 from the Ralston Purina Company in St. Louis, who had hired Boyer and Calvert. In 1988, PTI became the world's leading maker of isolated soy protein.
== Food uses ==
Soy protein is used in various foods, such as salad dressings, soups, meat analogues, beverage powders, cheeses, nondairy creamer, frozen desserts, whipped topping, infant formulas, breads, breakfast cereals, pastas, and pet foods.
== Manufacturing uses ==
Soy flour or defatted soy flour (50% protein) glue which originally replaced the more expensive casein glue for Douglas fir plywood is a common choice to replace toxic urea formaldehyde and phenol formaldehyde resin glues with a formaldehyde-free soy glue. Soy protein is used for emulsification and texturizing. Specific applications include adhesives, asphalts, resins, cleaning materials, cosmetics, inks, pleather, paints, paper coatings, pesticides and fungicides, plastics, polyesters, and textile fibres.
== Production methods ==
Edible soy protein isolate is derived from defatted soy flour with a high solubility in water, as measured by the nitrogen solubility index (NSI). The aqueous extraction is carried out at a pH below 9. The extract is clarified to remove the insoluble material and the supernatant liquid is acidified to a pH range of 4-5. The precipitated protein-curd is collected and separated from the whey by centrifuge. The curd is usually neutralized with alkali to form the sodium proteinate salt before drying
Soy protein concentrate is produced by immobilizing the soy globulin proteins while allowing the soluble carbohydrates, soy whey proteins, and salts to be leached from the defatted flakes or flour. The protein is retained by one or more of several treatments: leaching with 20-80% aqueous alcohol/solvent, leaching with aqueous acids in the isoelectric zone of minimum protein solubility, pH 4-5; leaching with chilled water (which may involve calcium or magnesium cations), and leaching with hot water of heat-treated defatted soy meal/flour.
All of these processes result in a product that is 70% protein, 20% carbohydrates (2.7 to 5% crude fiber), 6% ash and about 1% oil, but the solubility may differ. One tonne of defatted soybean flakes will yield about 750 kg of soybean protein concentrate.
== Product types ==
Processed soy protein appears in foods mainly in three forms; soy flour, soy protein isolates, and soy protein concentrates.
=== Isolates ===
Soy protein isolate is a highly refined or purified form of soy protein with a minimum protein content of 90% on a moisture-free basis. It is made from defatted soy flour which has had most of the nonprotein components, fats and carbohydrates removed. Because of this, it has a neutral flavor and will cause less flatulence than soy flours.: 11
Soy isolates are mainly used to improve the texture of meat products, but are also used to increase protein content, to enhance moisture retention, and as an emulsifier.
Pure soy protein isolate is used mainly by the food industry. It is sometimes available in health stores or in the pharmacy section of the supermarket. It is usually found combined with other food ingredients.
=== Concentrates ===
Soy protein concentrate is about 70% soy protein and is basically defatted soy flour without the water-soluble carbohydrates. It is made by removing part of the carbohydrates (soluble sugars) from dehulled and defatted soybeans.
Soy protein concentrate retains most of the fiber of the original soybean. It is widely used as functional or nutritional ingredient in a wide variety of food products, mainly in baked foods, breakfast cereals, and in some meat products. Soy protein concentrate is used in meat and poultry products to increase water and fat retention and to improve nutritional values (more protein, less fat).
Soy protein concentrates are available in different forms: granules, flour and spray-dried. Because they are very digestible, they are well-suited for children, pregnant and lactating women, and the elderly. They are also used in pet foods, milk replacements for babies (human and livestock), and even used for some nonfood applications.
=== Flours ===
Soy flour is made by grinding (usually cooked) soybeans into a fine powder. It comes in three forms: whole or full-fat (contains natural oils); defatted (oils removed, made from press cake) with 50% protein content and with either high water solubility or low water solubility; and lecithinated (lecithin added to defatted flour). A history of soy flour and grits has been published. As soy flour is gluten-free, yeast-raised breads made with soy flour are dense in texture.
Soy grits are similar to soy flour except the soybeans have been toasted and cracked into coarse pieces.
Kinako is a roasted whole soy flour used in Japanese cuisine. The earliest known reference to kinako dates from 1540 CE. A history of kinako has been published.
== Nutrition ==
Soybean protein is a complete protein since it provides all of the essential amino acids for human nutrition. Soybean protein is essentially identical to that of other legume pulses (legume proteins in general consist of 7S and 11S storage proteins), and is one of the least expensive sources of dietary protein. For this reason, soy protein is consumed by vegetarians and vegans.
Soy flour contains 50% protein.
The digestibility of some soyfoods are as follows; steamed soybeans 65.3%, tofu 92.7%, soy milk 92.6%, and soy protein isolate 93–97%. Some studies on rats have indicated the biological value of soy protein isolates is comparable to animal proteins such as casein if enriched with the sulfur-containing amino acid methionine.
When measuring the nutritional value of protein, the original protein efficiency ratio (PER) method, first proposed by Thomas Burr Osborne and Lafayette Mendel in 1917, was the most widely used method until 1990. This method was found to be flawed for the biological evaluation of protein quality because the young rats used in the study had higher relative requirements for sulfur-containing amino acids than did humans. As such, the analytical method universally recognized by the FAO/WHO (1990), as well as the FDA, USDA, United Nations University and the National Academy of Sciences when judging the quality of protein is the protein digestibility-corrected amino acid score, as it is viewed as accurately measuring the correct relative nutritional value of animal and vegetable sources of protein in the diet.
Based on this method, soy protein is considered to have a similar equivalent in protein quality to animal proteins. Egg white has a score of 1.00, soy concentrate 0.99, beef 0.92, and isolated soy protein 0.92. In 1990 at an FAO/WHO meeting, it was decided that proteins having values higher than 1.0 would be rounded or "leveled down" to 1.0, as scores above 1.0 are considered to indicate the protein contains essential amino acids in excess of the human requirements.
=== Biological value ===
Another measure of a protein's use in nutrition is the biological value scale, which dates back to 1911; it relies on nitrogen retention as a measurement of protein quality. Soybean protein isolate has a biological value of 74. Whole soybean has a biological value of 96, and soy milk 91.
== Health effects ==
A meta-analysis concluded soy protein is correlated with significant decreases in serum cholesterol, low density lipoprotein (LDL) cholesterol and triglyceride concentrations. High density lipoprotein (HDL) cholesterol did not change. Although there is only preclinical evidence for a possible mechanism, the meta-analysis report stated that soy phytoestrogens – the isoflavones, genistein and daidzein – may be involved in reducing serum cholesterol levels.
In 1999, the US FDA granted a health claim for labeling of manufactured food products containing soy: "25 grams of soy protein a day, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease." In 2019, the FDA reassessed and supported the 1999 health claim by looking at data from 46 randomized controlled trials.
In 2006, an American Heart Association review of soy protein benefits indicated only weak confirmation for the cholesterol-lowering claim about soy protein. The panel also found soy isoflavones do not reduce postmenopause "hot flashes" in women, nor do isoflavones lower risk of cancers of the breast, uterus, or prostate. Among the conclusions, the authors stated, "In contrast, soy products such as tofu, soy butter, soy nuts, or some soy burgers should be beneficial to cardiovascular and overall health because of their high content of polyunsaturated fats, fiber, vitamins, and minerals and low content of saturated fat. Using these and other soy foods to replace foods high in animal protein that contain saturated fat and cholesterol may confer benefits to cardiovascular health."
In 2012, the European Food Safety Authority (EFSA) published a scientific opinion on isolated soy proteins and reduction of blood LDL-cholesterol concentrations. EFSA concluded that a cause and effect relationship was not established between the consumption of soy protein and a reduction in blood LDL-cholesterol concentrations. In 2010, the EFSA had already rejected health claims that linked the consumption of soy protein to the maintenance or achievement of a normal body weight, the reduction of blood cholesterol concentrations, or the protection of DNA, proteins and lipids from oxidative damage.
== Role in the growth of the soybean plant ==
Soy protein is generally regarded as stored protein held in discrete particles called "protein bodies" estimated to contain at least 60% to 70% of the total protein within the soybean seed. This protein is important to the growth of new soybean plants, and when the soybean seed germinates, the protein will be digested, and the released amino acids will be transported to locations of seedling growth. Legume proteins, such as soy and pulses, belong to the globulin family of seed storage proteins called legumin (11S globulin fraction) and vicilins (7S globulin), or in the case of soybeans, glycinin and beta-conglycinin. Grains contain a third type of storage protein called gluten or "prolamines". Edestin, a legumin class reserve protein from hemp seeds have six identical subunits. There is one hexameric protein in the rhombohedral unit cell.
Soybeans also contain biologically active or metabolic proteins, such as enzymes, trypsin inhibitors, hemagglutinins, and cysteine proteases very similar to papain. The soy cotyledon storage proteins, important for human nutrition, can be extracted most efficiently by water, water plus dilute alkali (pH 7–9), or aqueous solutions of sodium chloride (0.5–2 M) from dehulled and defatted soybeans that have undergone only a minimal heat treatment so the protein is close to being native or undenatured. Soybeans are processed into three kinds of modern protein-rich products; soy flour, soy concentrate, and soy isolate.
For the 11S protein, glycinin, to fold properly into its hexagonal shape (containing six subunits, a hexamer), it must undergo a very limited proteolysis in a manner similar to the cleavage of a peptide from proinsulin to obtain active insulin.
== Uses ==
=== Textured soy protein ===
Textured soy protein (TSP) is made by forming a dough from highly soluble (high NSI) defatted soy flour with water in a screw-type extruder, and heating with or without steam. The dough is extruded through a die into various possible shapes: granules, flakes, chunks, goulash, steakettes (schnitzel), etc., and dried in an oven. TSP made from soy flour contains 50% soy protein and must be rehydrated before use at a weight ratio of 1 TSP:2 water. However, TSP, when made from soy concentrate, contains 70% protein and can be rehydrated at a ratio of 1:3. It can be used as a meat replacement or supplement. The extrusion technology changes the structure of the soy protein, resulting in a fibrous, spongy matrix similar in texture to meat.
While TSP has a shelf life of more than a year when stored dry at room temperature, it should be used at once or stored for no more than three days in the refrigerator after rehydration. It is usually rehydrated with cold or hot water, but a bit of vinegar or lemon juice can be added to quicken the process.
Soy protein products such as TSP are used as low-cost substitutes in meat and poultry products. Food service, retail and institutional (primarily school lunch and correctional) facilities regularly use such "extended" products. Extension may result in diminished flavor, but fat and cholesterol are reduced. Vitamin and mineral fortification can be used to make soy products nutritionally equivalent to animal protein; the protein quality is already roughly equivalent. The soy-based meat substitute textured vegetable protein has been used for more than 50 years as a way of inexpensively and safely extending ground beef up to 30% for hamburgers, without reducing its nutritional value.
== See also ==
Edestin
Hemp protein
List of meat substitutes
Protein quality
Soybeans
Soy allergy
Soy milk
== References ==
=== Works cited ===
Lim TK (2012). "Glycine max". Edible Medicinal and Non-Medicinal Plants. Dordrecht, NL: Springer. pp. 634–714. doi:10.1007/978-94-007-1764-0_79. ISBN 978-94-007-1763-3.
== External links == | Wikipedia/Soy_protein |
Affinity chromatography is a method of separating a biomolecule from a mixture, based on a highly specific macromolecular binding interaction between the biomolecule and another substance. The specific type of binding interaction depends on the biomolecule of interest; antigen and antibody, enzyme and substrate, receptor and ligand, or protein and nucleic acid binding interactions are frequently exploited for isolation of various biomolecules. Affinity chromatography is useful for its high selectivity and resolution of separation, compared to other chromatographic methods.
== Principle ==
Affinity chromatography has the advantage of specific binding interactions between the analyte of interest (normally dissolved in the mobile phase), and a binding partner or ligand (immobilized on the stationary phase). In a typical affinity chromatography experiment, the ligand is attached to a solid, insoluble matrix—usually a polymer such as agarose or polyacrylamide—chemically modified to introduce reactive functional groups with which the ligand can react, forming stable covalent bonds. The stationary phase is first loaded into a column to which the mobile phase is introduced. Molecules that bind to the ligand will remain associated with the stationary phase. A wash buffer is then applied to remove non-target biomolecules by disrupting their weaker interactions with the stationary phase, while the biomolecules of interest will remain bound. Target biomolecules may then be removed by applying a so-called elution buffer, which disrupts interactions between the bound target biomolecules and the ligand. The target molecule is thus recovered in the eluting solution.
Affinity chromatography does not require the molecular weight, charge, hydrophobicity, or other physical properties of the analyte of interest to be known, although knowledge of its binding properties is useful in the design of a separation protocol. Types of binding interactions commonly exploited in affinity chromatography procedures are summarized in the table below.
== Batch and column setups ==
Binding to the solid phase may be achieved by column chromatography whereby the solid medium is packed onto a column, the initial mixture run through the column to allow settling, a wash buffer run through the column and the elution buffer subsequently applied to the column and collected. These steps are usually done at ambient pressure. Alternatively, binding may be achieved using a batch treatment, for example, by adding the initial mixture to the solid phase in a vessel, mixing, separating the solid phase, removing the liquid phase, washing, re-centrifuging, adding the elution buffer, re-centrifuging and removing the elute.
Sometimes a hybrid method is employed such that the binding is done by the batch method, but the solid phase with the target molecule bound is packed onto a column and washing and elution are done on the column.
The ligands used in affinity chromatography are obtained from both organic and inorganic sources. Examples of biological sources are serum proteins, lectins and antibodies. Inorganic sources are moronic acid, metal chelates and triazine dyes.
A third method, expanded bed absorption, which combines the advantages of the two methods mentioned above, has also been developed. The solid phase particles are placed in a column where liquid phase is pumped in from the bottom and exits at the top. The gravity of the particles ensure that the solid phase does not exit the column with the liquid phase.
Affinity columns can be eluted by changing salt concentrations, pH, pI, charge and ionic strength directly or through a gradient to resolve the particles of interest.
More recently, setups employing more than one column in series have been developed. The advantage compared to single column setups is that the resin material can be fully loaded since non-binding product is directly passed on to a consecutive column with fresh column material. These chromatographic processes are known as periodic counter-current chromatography (PCC). The resin costs per amount of produced product can thus be drastically reduced. Since one column can always be eluted and regenerated while the other column is loaded, already two columns are sufficient to make full use of the advantages. Additional columns can give additional flexibility for elution and regeneration times, at the cost of additional equipment and resin costs.
== Specific uses ==
Affinity chromatography can be used in a number of applications, including nucleic acid purification, protein purification from cell free extracts, and purification from blood.
By using affinity chromatography, one can separate proteins that bind to a certain fragment from proteins that do not bind that specific fragment. Because this technique of purification relies on the biological properties of the protein needed, it is a useful technique and proteins can be purified many folds in one step.
=== Various affinity media ===
Many different affinity media exist for a variety of possible uses.
Briefly, they are (generalized) activated/functionalized that work as a functional spacer, support matrix, and eliminates handling of toxic reagents.
Amino acid media is used with a variety of serum proteins, proteins, peptides, and enzymes, as well as rRNA and dsDNA. Avidin biotin media is used in the purification process of biotin/avidin and their derivatives.
Carbohydrate bonding is most often used with glycoproteins or any other carbohydrate-containing substance; carbohydrate is used with lectins, glycoproteins, or any other carbohydrate metabolite protein. Dye ligand media is nonspecific but mimics biological substrates and proteins. Glutathione is useful for separation of GST tagged recombinant proteins. Heparin is a generalized affinity ligand, and it is most useful for separation of plasma coagulation proteins, along with nucleic acid enzymes and lipases
Hydrophobic interaction media are most commonly used to target free carboxyl groups and proteins.
Immunoaffinity media (detailed below) utilizes antigens' and antibodies' high specificity to separate; immobilized metal affinity chromatography is detailed further below and uses interactions between metal ions and proteins (usually specially tagged) to separate; nucleotide/coenzyme that works to separate dehydrogenases, kinases, and transaminases.
Nucleic acids function to trap mRNA, DNA, rRNA, and other nucleic acids/oligonucleotides. Protein A/G method is used to purify immunoglobulins.
Speciality media are designed for a specific class or type of protein/co enzyme; this type of media will only work to separate a specific protein or coenzyme.
=== Immunoaffinity ===
Another use for the procedure is the affinity purification of antibodies from blood serum. If the serum is known to contain antibodies against a specific antigen (for example if the serum comes from an organism immunized against the antigen concerned) then it can be used for the affinity purification of that antigen. This is also known as Immunoaffinity Chromatography. For example, if an organism is immunised against a GST-fusion protein it will produce antibodies against the fusion-protein, and possibly antibodies against the GST tag as well. The protein can then be covalently coupled to a solid support such as agarose and used as an affinity ligand in purifications of antibody from immune serum.
For thoroughness, the GST protein and the GST-fusion protein can each be coupled separately. The serum is initially allowed to bind to the GST affinity matrix. This will remove antibodies against the GST part of the fusion protein. The serum is then separated from the solid support and allowed to bind to the GST-fusion protein matrix. This allows any antibodies that recognize the antigen to be captured on the solid support. Elution of the antibodies of interest is most often achieved using a low pH buffer such as glycine pH 2.8. The eluate is collected into a neutral tris or phosphate buffer, to neutralize the low pH elution buffer and halt any degradation of the antibody's activity. This is a nice example as affinity purification is used to purify the initial GST-fusion protein, to remove the undesirable anti-GST antibodies from the serum and to purify the target antibody.
Monoclonal antibodies can also be selected to bind proteins with great specificity, where protein is released under fairly gentle conditions. This can become of use for further research in the future.
A simplified strategy is often employed to purify antibodies generated against peptide antigens. When the peptide antigens are produced synthetically, a terminal cysteine residue is added at either the N- or C-terminus of the peptide. This cysteine residue contains a sulfhydryl functional group which allows the peptide to be easily conjugated to a carrier protein (e.g. Keyhole limpet hemocyanin (KLH)). The same cysteine-containing peptide is also immobilized onto an agarose resin through the cysteine residue and is then used to purify the antibody.
Most monoclonal antibodies have been purified using affinity chromatography based on immunoglobulin-specific Protein A or Protein G, derived from bacteria.
Immunoaffinity chromatography with monoclonal antibodies immobilized on monolithic column has been successfully used to capture extracellular vesicles (e.g., exosomes and exomeres) from human blood plasma by targeting tetraspanins and integrins found on the surface of the EVs.
Immunoaffinity chromatography is also the basis for immunochromatographic test (ICT) strips, which provide a rapid means of diagnosis in patient care. Using ICT, a technician can make a determination at a patient's bedside, without the need for a laboratory. ICT detection is highly specific to the microbe causing an infection.
=== Immobilized metal ion affinity chromatography ===
Immobilized metal ion affinity chromatography (IMAC) is based on the specific coordinate covalent bond of amino acids, particularly histidine, to metals. This technique works by allowing proteins with an affinity for metal ions to be retained in a column containing immobilized metal ions, such as cobalt, nickel, or copper for the purification of histidine-containing proteins or peptides, iron, zinc or gallium for the purification of phosphorylated proteins or peptides. Many naturally occurring proteins do not have an affinity for metal ions, therefore recombinant DNA technology can be used to introduce such a protein tag into the relevant gene. Methods used to elute the protein of interest include changing the pH, or adding a competitive molecule, such as imidazole.
=== Recombinant proteins ===
Possibly the most common use of affinity chromatography is for the purification of recombinant proteins. Proteins with a known affinity are protein tagged in order to aid their purification. The protein may have been genetically modified so as to allow it to be selected for affinity binding; this is known as a fusion protein. Protein tags include hexahistidine (His), glutathione-S-transferase (GST), maltose binding protein (MBP), and the Colicin E7 variant CL7 tag. Histidine tags have an affinity for nickel, cobalt, zinc, copper and iron ions which have been immobilized by forming coordinate covalent bonds with a chelator incorporated in the stationary phase. For elution, an excess amount of a compound able to act as a metal ion ligand, such as imidazole, is used. GST has an affinity for glutathione which is commercially available immobilized as glutathione agarose. During elution, excess glutathione is used to displace the tagged protein. CL7 has an affinity and specificity for Immunity Protein 7 (Im7) which is commercially available immobilized as Im7 agarose resin. For elution, an active and site-specific protease is applied to the Im7 resin to release the tag-free protein.
=== Lectins ===
Lectin affinity chromatography is a form of affinity chromatography where lectins are used to separate components within the sample. Lectins, such as concanavalin A are proteins which can bind specific alpha-D-mannose and alpha-D-glucose carbohydrate molecules. Some common carbohydrate molecules that is used in lectin affinity chromatography are Con A-Sepharose and WGA-agarose. Another example of a lectin is wheat germ agglutinin which binds D-N-acetyl-glucosamine. The most common application is to separate glycoproteins from non-glycosylated proteins, or one glycoform from another glycoform. Although there are various ways to perform lectin affinity chromatography, the goal is extract a sugar ligand of the desired protein.
=== Specialty ===
Another use for affinity chromatography is the purification of specific proteins using a gel matrix that is unique to a specific protein. For example, the purification of E. coli β-galactosidase is accomplished by affinity chromatography using p-aminobenyl-1-thio-β-D-galactopyranosyl agarose as the affinity matrix. p-aminobenyl-1-thio-β-D-galactopyranosyl agarose is used as the affinity matrix because it contains a galactopyranosyl group, which serves as a good substrate analog for E. coli β-Galactosidase. This property allows the enzyme to bind to the stationary phase of the affinity matrix and β-Galactosidase is eluted by adding increasing concentrations of salt to the column.
==== Alkaline phosphatase ====
Alkaline phosphatase from E. coli can be purified using a DEAE-Cellulose matrix. A. phosphatase has a slight negative charge, allowing it to weakly bind to the positively charged amine groups in the matrix. The enzyme can then be eluted out by adding buffer with higher salt concentrations.
==== Boronate affinity chromatography ====
Boronate affinity chromatography consists of using boronic acid or boronates to elute and quantify amounts of glycoproteins. Clinical adaptations have applied this type of chromatography for use in determining long term assessment of diabetic patients through analysis of their glycated hemoglobin.
=== Serum albumin purification ===
Affinity purification of albumin and macroglobulin contamination is helpful in removing excess albumin and α2-macroglobulin contamination, when performing mass spectrometry. In affinity purification of serum albumin, the stationary used for collecting or attracting serum proteins can be Cibacron Blue-Sepharose. Then the serum proteins can be eluted from the adsorbent with a buffer containing thiocyanate (SCN−).
== Weak affinity chromatography ==
Weak affinity chromatography (WAC) is an affinity chromatography technique for affinity screening in drug development. WAC is an affinity-based liquid chromatographic technique that separates chemical compounds based on their different weak affinities to an immobilized target. The higher affinity a compound has towards the target, the longer it remains in the separation unit, and this will be expressed as a longer retention time. The affinity measure and ranking of affinity can be achieved by processing the obtained retention times of analyzed compounds. Affinity chromatography is part of a larger suite of techniques used in chemoproteomics based drug target identification.
The WAC technology is demonstrated against a number of different protein targets – proteases, kinases, chaperones and protein–protein interaction (PPI) targets. WAC has been shown to be more effective than established methods for fragment based screening.
== History ==
Affinity chromatography was conceived and first developed by Pedro Cuatrecasas and Meir Wilchek.
== References ==
== External links ==
"Affinity Chromatography Principle, Procedure And Advance Detailed Note – 2020".
"What is affinity chromatography" | Wikipedia/Immunoaffinity_chromatography |
Protein production is the biotechnological process of generating a specific protein. It is typically achieved by the manipulation of gene expression in an organism such that it expresses large amounts of a recombinant gene. This includes the transcription of the recombinant DNA to messenger RNA (mRNA), the translation of mRNA into polypeptide chains, which are ultimately folded into functional proteins and may be targeted to specific subcellular or extracellular locations.
Protein production systems (also known as expression systems) are used in the life sciences, biotechnology, and medicine. Molecular biology research uses numerous proteins and enzymes, many of which are from expression systems; particularly DNA polymerase for PCR, reverse transcriptase for RNA analysis, restriction endonucleases for cloning, and to make proteins that are screened in drug discovery as biological targets or as potential drugs themselves. There are also significant applications for expression systems in industrial fermentation, notably the production of biopharmaceuticals such as human insulin to treat diabetes, and to manufacture enzymes.
== Protein production systems ==
Commonly used protein production systems include those derived from bacteria, yeast, baculovirus/insect, mammalian cells, and more recently filamentous fungi such as Myceliophthora thermophila. When biopharmaceuticals are produced with one of these systems, process-related impurities termed host cell proteins also arrive in the final product in trace amounts.
=== Cell-based systems ===
The oldest and most widely used expression systems are cell-based and may be defined as the "combination of an expression vector, its cloned DNA, and the host for the vector that provide a context to allow foreign gene function in a host cell, that is, produce proteins at a high level". Overexpression is an abnormally and excessively high level of gene expression which produces a pronounced gene-related phenotype.
There are many ways to introduce foreign DNA to a cell for expression, and many different host cells may be used for expression — each expression system has distinct advantages and liabilities. Expression systems are normally referred to by the host and the DNA source or the delivery mechanism for the genetic material. For example, common hosts are bacteria (such as E. coli, B. subtilis), yeast (such as S. cerevisiae) or eukaryotic cell lines. Common DNA sources and delivery mechanisms are viruses (such as baculovirus, retrovirus, adenovirus), plasmids, artificial chromosomes and bacteriophage (such as lambda). The best expression system depends on the gene involved, for example the Saccharomyces cerevisiae is often preferred for proteins that require significant posttranslational modification. Insect or mammal cell lines are used when human-like splicing of mRNA is required. Nonetheless, bacterial expression has the advantage of easily producing large amounts of protein, which is required for X-ray crystallography or nuclear magnetic resonance experiments for structure determination.
Because bacteria are prokaryotes, they are not equipped with the full enzymatic machinery to accomplish the required post-translational modifications or molecular folding. Hence, multi-domain eukaryotic proteins expressed in bacteria often are non-functional. Also, many proteins become insoluble as inclusion bodies that are difficult to recover without harsh denaturants and subsequent cumbersome protein-refolding.
To address these concerns, expressions systems using multiple eukaryotic cells were developed for applications requiring the proteins be conformed as in, or closer to eukaryotic organisms: cells of plants (i.e. tobacco), of insects or mammalians (i.e. bovines) are transfected with genes and cultured in suspension and even as tissues or whole organisms, to produce fully folded proteins. Mammalian in vivo expression systems have however low yield and other limitations (time-consuming, toxicity to host cells,..). To combine the high yield/productivity and scalable protein features of bacteria and yeast, and advanced epigenetic features of plants, insects and mammalians systems, other protein production systems are developed using unicellular eukaryotes (i.e. non-pathogenic 'Leishmania' cells).
==== Bacterial systems ====
===== Escherichia coli =====
E. coli is one of the most widely used expression hosts, and DNA is normally introduced in a plasmid expression vector. The techniques for overexpression in E. coli are well developed and work by increasing the number of copies of the gene or increasing the binding strength of the promoter region so assisting transcription.
For example, a DNA sequence for a protein of interest could be cloned or subcloned into a high copy-number plasmid containing the lac (often LacUV5) promoter, which is then transformed into the bacterium E. coli. Addition of IPTG (a lactose analog) activates the lac promoter and causes the bacteria to express the protein of interest.
E. coli strain BL21 and BL21(DE3) are two strains commonly used for protein production. As members of the B lineage, they lack lon and OmpT proteases, protecting the produced proteins from degradation. The DE3 prophage found in BL21(DE3) provides T7 RNA polymerase (driven by the LacUV5 promoter), allowing for vectors with the T7 promoter to be used instead.
===== Corynebacterium =====
Non-pathogenic species of the gram-positive Corynebacterium are used for the commercial production of various amino acids. The C. glutamicum species is widely used for producing glutamate and lysine, components of human food, animal feed and pharmaceutical products.
Expression of functionally active human epidermal growth factor has been done in C. glutamicum, thus demonstrating a potential for industrial-scale production of human proteins. Expressed proteins can be targeted for secretion through either the general, secretory pathway (Sec) or the twin-arginine translocation pathway (Tat).
Unlike gram-negative bacteria, the gram-positive Corynebacterium lack lipopolysaccharides that function as antigenic endotoxins in humans.
===== Pseudomonas fluorescens =====
The non-pathogenic and gram-negative bacteria, Pseudomonas fluorescens, is used for high level production of recombinant proteins; commonly for the development bio-therapeutics and vaccines. P. fluorescens is a metabolically versatile organism, allowing for high throughput screening and rapid development of complex proteins. P. fluorescens is most well known for its ability to rapid and successfully produce high titers of active, soluble protein.
==== Eukaryotic systems ====
===== Yeasts =====
Expression systems using either S. cerevisiae or Pichia pastoris allow stable and lasting production of proteins that are processed similarly to mammalian cells, at high yield, in chemically defined media of proteins.
===== Filamentous fungi =====
Filamentous fungi, especially Aspergillus and Trichoderma, have long been used to produce diverse industrial enzymes from their own genomes ("native", "homologous") and from recombinant DNA ("heterologous").
More recently, Myceliophthora thermophila C1 has been developed into an expression platform for screening and production of native and heterologous proteins.The expression system C1 shows a low viscosity morphology in submerged culture, enabling the use of complex growth and production media. C1 also does not "hyperglycosylate" heterologous proteins, as Aspergillus and Trichoderma tend to do.
===== Baculovirus-infected cells =====
Baculovirus-infected insect cells (Sf9, Sf21, High Five strains) or mammalian cells (HeLa, HEK 293) allow production of glycosylated or membrane proteins that cannot be produced using fungal or bacterial systems. It is useful for production of proteins in high quantity. Genes are not expressed continuously because infected host cells eventually lyse and die during each infection cycle.
===== Non-lytic insect cell expression =====
Non-lytic insect cell expression is an alternative to the lytic baculovirus expression system. In non-lytic expression, vectors are transiently or stably transfected into the chromosomal DNA of insect cells for subsequent gene expression. This is followed by selection and screening of recombinant clones. The non-lytic system has been used to give higher protein yield and quicker expression of recombinant genes compared to baculovirus-infected cell expression. Cell lines used for this system include: Sf9, Sf21 from Spodoptera frugiperda cells, Hi-5 from Trichoplusia ni cells, and Schneider 2 cells and Schneider 3 cells from Drosophila melanogaster cells. With this system, cells do not lyse and several cultivation modes can be used. Additionally, protein production runs are reproducible. This system gives a homogeneous product. A drawback of this system is the requirement of an additional screening step for selecting viable clones.
===== Excavata =====
Leishmania tarentolae (cannot infect mammals) expression systems allow stable and lasting production of proteins at high yield, in chemically defined media. Produced proteins exhibit fully eukaryotic post-translational modifications, including glycosylation and disulfide bond formation.
===== Mammalian systems =====
The most common mammalian expression systems are Chinese Hamster ovary (CHO) and Human embryonic kidney (HEK) cells.
Chinese hamster ovary cell
Mouse myeloma lymphoblstoid (e.g. NS0 cell)
Fully Human
Human embryonic kidney cells (HEK-293)
Human embryonic retinal cells (Crucell's Per.C6)
Human amniocyte cells (Glycotope and CEVEC)
=== Cell-free systems ===
Cell-free production of proteins is performed in vitro using purified RNA polymerase, ribosomes, tRNA and ribonucleotides. These reagents may be produced by extraction from cells or from a cell-based expression system. Due to the low expression levels and high cost of cell-free systems, cell-based systems are more widely used.
== See also ==
Cellosaurus, a database of cell lines
Gene expression
Single-cell protein
Protein purification
Precision fermentation
Host cell protein
List of recombinant proteins
== References ==
== Further reading ==
Higgins SJ, Hames BD (1999). Protein Expression: A Practical Approach. Oxford University Press. ISBN 978-0-19-963623-5.
Baneyx, François (2004). Protein Expression Technologies: Current Status and Future Trends. Garland Science. ISBN 978-0-9545232-5-1.
== External links == | Wikipedia/Protein_production |
Metalloprotein is a generic term for a protein that contains a metal ion cofactor. A large proportion of all proteins are part of this category. For instance, at least 1000 human proteins (out of ~20,000) contain zinc-binding protein domains although there may be up to 3000 human zinc metalloproteins.
== Abundance ==
It is estimated that approximately half of all proteins contain a metal. In another estimate, about one quarter to one third of all proteins are proposed to require metals to carry out their functions. Thus, metalloproteins have many different functions in cells, such as storage and transport of proteins, enzymes and signal transduction proteins, or infectious diseases. The abundance of metal binding proteins may be inherent to the amino acids that proteins use, as even artificial proteins without evolutionary history will readily bind metals.
Most metals in the human body are bound to proteins. For instance, the relatively high concentration of iron in the human body is mostly due to the iron in hemoglobin.
== Coordination chemistry principles ==
In metalloproteins, metal ions are usually coordinated by nitrogen, oxygen or sulfur centers belonging to amino acid residues of the protein. These donor groups are often provided by side-chains on the amino acid residues. Especially important are the imidazole substituent in histidine residues, thiolate substituents in cysteine residues, and carboxylate groups provided by aspartate. Given the diversity of the metalloproteome, virtually all amino acid residues have been shown to bind metal centers. The peptide backbone also provides donor groups; these include deprotonated amides and the amide carbonyl oxygen centers. Lead(II) binding in natural and artificial proteins has been reviewed.
In addition to donor groups that are provided by amino acid residues, many organic cofactors function as ligands. Perhaps most famous are the tetradentate N4 macrocyclic ligands incorporated into the heme protein. Inorganic ligands such as sulfide and oxide are also common.
== Storage and transport metalloproteins ==
These are the second stage product of protein hydrolysis obtained by treatment with slightly stronger acids and alkalies.
=== Oxygen carriers ===
Hemoglobin, which is the principal oxygen-carrier in humans, has four subunits in which the iron(II) ion is coordinated by the planar macrocyclic ligand protoporphyrin IX (PIX) and the imidazole nitrogen atom of a histidine residue. The sixth coordination site contains a water molecule or a dioxygen molecule. By contrast the protein myoglobin, found in muscle cells, has only one such unit. The active site is located in a hydrophobic pocket. This is important as without it the iron(II) would be irreversibly oxidized to iron(III). The equilibrium constant for the formation of HbO2 is such that oxygen is taken up or released depending on the partial pressure of oxygen in the lungs or in muscle. In hemoglobin the four subunits show a cooperativity effect that allows for easy oxygen transfer from hemoglobin to myoglobin.
In both hemoglobin and myoglobin it is sometimes incorrectly stated that the oxygenated species contains iron(III). It is now known that the diamagnetic nature of these species is because the iron(II) atom is in the low-spin state. In oxyhemoglobin the iron atom is located in the plane of the porphyrin ring, but in the paramagnetic deoxyhemoglobin the iron atom lies above the plane of the ring. This change in spin state is a cooperative effect due to the higher crystal field splitting and smaller ionic radius of Fe2+ in the oxyhemoglobin moiety.
Hemerythrin is another iron-containing oxygen carrier. The oxygen binding site is a binuclear iron center. The iron atoms are coordinated to the protein through the carboxylate side chains of a glutamate and aspartate and five histidine residues. The uptake of O2 by hemerythrin is accompanied by two-electron oxidation of the reduced binuclear center to produce bound peroxide (OOH−). The mechanism of oxygen uptake and release have been worked out in detail.
Hemocyanins carry oxygen in the blood of most mollusks, and some arthropods such as the horseshoe crab. They are second only to hemoglobin in biological popularity of use in oxygen transport. On oxygenation the two copper(I) atoms at the active site are oxidized to copper(II) and the dioxygen molecules are reduced to peroxide, O2−2.
Chlorocruorin (as the larger carrier erythrocruorin) is an oxygen-binding hemeprotein present in the blood plasma of many annelids, particularly certain marine polychaetes.
=== Cytochromes ===
Oxidation and reduction reactions are not common in organic chemistry as few organic molecules can act as oxidizing or reducing agents. Iron(II), on the other hand, can easily be oxidized to iron(III). This functionality is used in cytochromes, which function as electron-transfer vectors. The presence of the metal ion allows metalloenzymes to perform functions such as redox reactions that cannot easily be performed by the limited set of functional groups found in amino acids. The iron atom in most cytochromes is contained in a heme group. The differences between those cytochromes lies in the different side-chains. For instance cytochrome a has a heme a prosthetic group and cytochrome b has a heme b prosthetic group. These differences result in different Fe2+/Fe3+ redox potentials such that various cytochromes are involved in the mitochondrial electron transport chain.
Cytochrome P450 enzymes perform the function of inserting an oxygen atom into a C−H bond, an oxidation reaction.
=== Rubredoxin ===
Rubredoxin is an electron-carrier found in sulfur-metabolizing bacteria and archaea. The active site contains an iron ion coordinated by the sulfur atoms of four cysteine residues forming an almost regular tetrahedron. Rubredoxins perform one-electron transfer processes. The oxidation state of the iron atom changes between the +2 and +3 states. In both oxidation states the metal is high spin, which helps to minimize structural changes.
=== Plastocyanin ===
Plastocyanin is one of the family of blue copper proteins that are involved in electron transfer reactions. The copper-binding site is described as distorted trigonal pyramidal. The trigonal plane of the pyramidal base is composed of two nitrogen atoms (N1 and N2) from separate histidines and a sulfur (S1) from a cysteine. Sulfur (S2) from an axial methionine forms the apex. The distortion occurs in the bond lengths between the copper and sulfur ligands. The Cu−S1 contact is shorter (207 pm) than Cu−S2 (282 pm).
The elongated Cu−S2 bonding destabilizes the Cu(II) form and increases the redox potential of the protein. The blue color (597 nm peak absorption) is due to the Cu−S1 bond where S(pπ) to Cu(dx2−y2) charge transfer occurs.
In the reduced form of plastocyanin, His-87 will become protonated with a pKa of 4.4. Protonation prevents it acting as a ligand and the copper site geometry becomes trigonal planar.
=== Metal-ion storage and transfer ===
==== Iron ====
Iron is stored as iron(III) in ferritin. The exact nature of the binding site has not yet been determined. The iron appears to be present as a hydrolysis product such as FeO(OH). Iron is transported by transferrin whose binding site consists of two tyrosines, one aspartic acid and one histidine. The human body has no controlled mechanism for excretion of iron. This can lead to iron overload problems in patients treated with blood transfusions, as, for instance, with β-thalassemia. Iron is actually excreted in urine and is also concentrated in bile which is excreted in feces.
==== Copper ====
Ceruloplasmin is the major copper-carrying protein in the blood. Ceruloplasmin exhibits oxidase activity, which is associated with possible oxidation of Fe(II) into Fe(III), therefore assisting in its transport in the blood plasma in association with transferrin, which can carry iron only in the Fe(III) state.
==== Calcium ====
Osteopontin is involved in mineralization in the extracellular matrices of bones and teeth.
== Metalloenzymes ==
Metalloenzymes all have one feature in common, namely that the metal ion is bound to the protein with one labile coordination site. As with all enzymes, the shape of the active site is crucial. The metal ion is usually located in a pocket whose shape fits the substrate. The metal ion catalyzes reactions that are difficult to achieve in organic chemistry.
=== Carbonic anhydrase ===
In aqueous solution, carbon dioxide forms carbonic acid
CO2 + H2O ⇌ H2CO3
This reaction is very slow in the absence of a catalyst, but quite fast in the presence of the hydroxide ion
CO2 + OH− ⇌ HCO−3
A reaction similar to this is almost instantaneous with carbonic anhydrase. The structure of the active site in carbonic anhydrases is well known from a number of crystal structures. It consists of a zinc ion coordinated by three imidazole nitrogen atoms from three histidine units. The fourth coordination site is occupied by a water molecule. The coordination sphere of the zinc ion is approximately tetrahedral. The positively-charged zinc ion polarizes the coordinated water molecule, and nucleophilic attack by the negatively-charged hydroxide portion on carbon dioxide proceeds rapidly. The catalytic cycle produces the bicarbonate ion and the hydrogen ion as the equilibrium:
H2CO3 ⇌ HCO−3 + H+
favouring dissociation of carbonic acid at biological pH values.
=== Vitamin B12-dependent enzymes ===
The cobalt-containing Vitamin B12 (also known as cobalamin) catalyzes the transfer of methyl (−CH3) groups between two molecules, which involves the breaking of C−C bonds, a process that is energetically expensive in organic reactions. The metal ion lowers the activation energy for the process by forming a transient Co−CH3 bond. The structure of the coenzyme was famously determined by Dorothy Hodgkin and co-workers, for which she received a Nobel Prize in Chemistry. It consists of a cobalt(II) ion coordinated to four nitrogen atoms of a corrin ring and a fifth nitrogen atom from an imidazole group. In the resting state there is a Co−C sigma bond with the 5′ carbon atom of adenosine. This is a naturally occurring organometallic compound, which explains its function in trans-methylation reactions, such as the reaction carried out by methionine synthase.
=== Nitrogenase (nitrogen fixation) ===
The fixation of atmospheric nitrogen is an energy-intensive process, as it involves breaking the very stable triple bond between the nitrogen atoms. The nitrogenases catalyze the process. One such enzyme occurs in Rhizobium bacteria. There are three components to its action: a molybdenum atom at the active site, iron–sulfur clusters that are involved in transporting the electrons needed to reduce the nitrogen, and an abundant energy source in the form of magnesium ATP. This last is provided by a mutualistic symbiosis between the bacteria and a host plant, often a legume. The reaction may be written symbolically as
N2 + 16 MgATP + 8 e− → 2 NH3 + 16 MgADP +16 Pi + H2
where Pi stands for inorganic phosphate. The precise structure of the active site has been difficult to determine. It appears to contain a MoFe7S8 cluster that is able to bind the dinitrogen molecule and, presumably, enable the reduction process to begin. The electrons are transported by the associated "P" cluster, which contains two cubical Fe4S4 clusters joined by sulfur bridges.
=== Superoxide dismutase ===
The superoxide ion, O−2 is generated in biological systems by reduction of molecular oxygen. It has an unpaired electron, so it behaves as a free radical. It is a powerful oxidizing agent. These properties render the superoxide ion very toxic and are deployed to advantage by phagocytes to kill invading microorganisms. Otherwise, the superoxide ion must be destroyed before it does unwanted damage in a cell. The superoxide dismutase enzymes perform this function very efficiently.
The formal oxidation state of the oxygen atoms is −1⁄2. In solutions at neutral pH, the superoxide ion disproportionates to molecular oxygen and hydrogen peroxide.
2 O−2 + 2 H+ → O2 + H2O2
In biology this type of reaction is called a dismutation reaction. It involves both oxidation and reduction of superoxide ions. The superoxide dismutase (SOD) group of enzymes increase the rate of reaction to near the diffusion-limited rate. The key to the action of these enzymes is a metal ion with variable oxidation state that can act either as an oxidizing agent or as a reducing agent.
Oxidation: M(n+1)+ + O−2 → Mn+ + O2
Reduction: Mn+ + O−2 + 2 H+ → M(n+1)+ + H2O2.
In human SOD, the active metal is copper, as Cu(II) or Cu(I), coordinated tetrahedrally by four histidine residues. This enzyme also contains zinc ions for stabilization and is activated by copper chaperone for superoxide dismutase (CCS). Other isozymes may contain iron, manganese or nickel. The activity of Ni-SOD involves nickel(III), an unusual oxidation state for this element. The active site nickel geometry cycles from square planar Ni(II), with thiolate (Cys2 and Cys6) and backbone nitrogen (His1 and Cys2) ligands, to square pyramidal Ni(III) with an added axial His1 side chain ligand.
=== Chlorophyll-containing proteins ===
Chlorophyll plays a crucial role in photosynthesis. It contains a magnesium enclosed in a chlorin ring. However, the magnesium ion is not directly involved in the photosynthetic function and can be replaced by other divalent ions with little loss of activity. Rather, the photon is absorbed by the chlorin ring, whose electronic structure is well-adapted for this purpose.
Initially, the absorption of a photon causes an electron to be excited into a singlet state of the Q band. The excited state undergoes an intersystem crossing from the singlet state to a triplet state in which there are two electrons with parallel spin. This species is, in effect, a free radical, and is very reactive and allows an electron to be transferred to acceptors that are adjacent to the chlorophyll in the chloroplast. In the process chlorophyll is oxidized. Later in the photosynthetic cycle, chlorophyll is reduced back again. This reduction ultimately draws electrons from water, yielding molecular oxygen as a final oxidation product.
=== Hydrogenase ===
Hydrogenases are subclassified into three different types based on the active site metal content: iron–iron hydrogenase, nickel–iron hydrogenase, and iron hydrogenase.
All hydrogenases catalyze reversible H2 uptake, but while the [FeFe] and [NiFe] hydrogenases are true redox catalysts, driving H2 oxidation and H+ reduction
H2 ⇌ 2 H+ + 2 e−
the [Fe] hydrogenases catalyze the reversible heterolytic cleavage of H2.
H2 ⇌ H+ + H−
=== Ribozyme and deoxyribozyme ===
Since discovery of ribozymes by Thomas Cech and Sidney Altman in the early 1980s, ribozymes have been shown to be a distinct class of metalloenzymes. Many ribozymes require metal ions in their active sites for chemical catalysis; hence they are called metalloenzymes. Additionally, metal ions are essential for structural stabilization of ribozymes. Group I intron is the most studied ribozyme which has three metals participating in catalysis. Other known ribozymes include group II intron, RNase P, and several small viral ribozymes (such as hammerhead, hairpin, HDV, and VS) and the large subunit of ribosomes. Several classes of ribozymes have been described.
Deoxyribozymes, also called DNAzymes or catalytic DNA, are artificial DNA-based catalysts that were first produced in 1994. Almost all DNAzymes require metal ions. Although ribozymes mostly catalyze cleavage of RNA substrates, a variety of reactions can be catalyzed by DNAzymes including RNA/DNA cleavage, RNA/DNA ligation, amino acid phosphorylation and dephosphorylation, and carbon–carbon bond formation. Yet, DNAzymes that catalyze RNA cleavage reaction are the most extensively explored ones. 10-23 DNAzyme, discovered in 1997, is one of the most studied catalytic DNAs with clinical applications as a therapeutic agent. 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).
== Signal-transduction metalloproteins ==
=== Calmodulin ===
Calmodulin is an example of a signal-transduction protein. It is a small protein that contains four EF-hand motifs, each of which is able to bind a Ca2+ ion.
In an EF-hand loop protein domain, the calcium ion is coordinated in a pentagonal bipyramidal configuration. Six glutamic acid and aspartic acid residues involved in the binding are in positions 1, 3, 5, 7 and 9 of the polypeptide chain. At position 12, there is a glutamate or aspartate ligand that behaves as a bidentate ligand, providing two oxygen atoms. The ninth residue in the loop is necessarily glycine due to the conformational requirements of the backbone. The coordination sphere of the calcium ion contains only carboxylate oxygen atoms and no nitrogen atoms. This is consistent with the hard nature of the calcium ion.
The protein has two approximately symmetrical domains, separated by a flexible "hinge" region. Binding of calcium causes a conformational change to occur in the protein. Calmodulin participates in an intracellular signaling system by acting as a diffusible second messenger to the initial stimuli.
=== Troponin ===
In both cardiac and skeletal muscles, muscular force production is controlled primarily by changes in the intracellular calcium concentration. In general, when calcium rises, the muscles contract and, when calcium falls, the muscles relax. Troponin, along with actin and tropomyosin, is the protein complex to which calcium binds to trigger the production of muscular force.
=== Transcription factors ===
Many transcription factors contain a structure known as a zinc finger, a structural module in which a region of protein folds around a zinc ion. The zinc does not directly contact the DNA that these proteins bind to. Instead, the cofactor is essential for the stability of the tightly folded protein chain. In these proteins, the zinc ion is usually coordinated by pairs of cysteine and histidine side-chains.
== Other metalloenzymes ==
There are two types of carbon monoxide dehydrogenase: one contains iron and molybdenum, the other contains iron and nickel. Parallels and differences in catalytic strategies have been reviewed.
Pb2+ (lead) can replace Ca2+ (calcium) as, for example, with calmodulin or Zn2+ (zinc) as with metallocarboxypeptidases.
Some other metalloenzymes are given in the following table, according to the metal involved.
== See also ==
== References ==
== External links ==
Metalloprotein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
Catherine Drennan's Seminar: Snapshots of Metalloproteins | Wikipedia/Metalloproteins |
Host cell proteins (HCPs) are process-related protein impurities that are produced by the host organism during biotherapeutic manufacturing and production. During the purification process, a majority of produced HCPs are removed from the final product (>99% of impurities removed). However, residual HCPs still remain in the final distributed pharmaceutical drug. Examples of HCPs that may remain in the desired pharmaceutical product include: monoclonal antibodies (mAbs), antibody-drug-conjugates (ADCs), therapeutic proteins, vaccines, and other protein-based biopharmaceuticals.
HCPs may cause immunogenicity in individuals or reduce the potency, stability or overall effectiveness of a drug. National regulatory organisations, such as the FDA and EMA provide guidelines on acceptable levels of HCPs that may remain in pharmaceutical products before they are made available to the public. The accepted level of HCPs in a final product is evaluated on a case-by-case basis, and depends on multiple factors including: dose, frequency of drug administration, type of drug and severity of disease.
The acceptable range of HCPs in a final pharmaceutical product is large due to limitations with the detection and analytical methods that currently exist. Analysis of HCPs is complex as the HCP mixture consists of a large variety of protein species, all of which are unique to the specific host organisms, and unrelated to the intended and desired recombinant protein. Analysing these large varieties of protein species at very minute concentrations is difficult and requires extremely sensitive equipment which has not been fully developed yet. The reason that HCP levels need to be monitored is due to the uncertain effects they have on the body. At trace amounts, the effects of HCPs on patients are unknown and specific HCPs may affect protein stability and drug effectiveness, or cause immunogenicity in patients. If the stability of the drug is affected, durability of the active substance in the pharmaceutical product could decrease. The effects that the drug is intended to have on patients could also possibly be increased or decreased, leading to health complications that may arise. The degree of immunogenicity on a long-term basis is difficult, and almost impossible, to determine and consequences can include severe threats to the patient’s health.
== Safety risk ==
HCPs in biopharmaceutical products pose a potential safety risk to humans by introducing foreign proteins and biomolecules to the human immune system. Since common host cells used to produce biopharmaceutical drugs are E. coli, yeast, mouse myeloma cell line (NS0) and Chinese hamster ovary (CHO), the resultant HCPs are genetically different to what the human body recognizes. As a consequence of this, the presence of HCPs in humans can activate an immune response, which can lead to possibly severe health concerns.
There is a correlation between the amount of foreign antigens (HPCs) in our body and the level of immune response our body produces. The more HCPs present in a drug, the higher the immune response that will be activated. Several studies have linked a reduction in HCPs to a decline in specific inflammatory cytokines. Other HCPs may be very similar to a human protein and may induce an immune response with cross reactivity against the human protein or the drug substance protein. The exact consequences of HCPs for an individual patient is uncertain and difficult to determine with the current analytical methods used in biopharmaceutical production and analysis.
== Analysis ==
HCPs are identified during the manufacturing of biopharmaceuticals as part of the quality control process.
During the production process several factors, including the genes of the host cell, the way of product expression and the purification steps, influence the final HCP composition and abundance. Several studies report that HCPs are often co-purified along with the product itself by interacting with the recombinant protein.
Enzyme linked immunosorbent assay (ELISA) is the predominant method for HCP analysis in pharmaceutical products due to its high sensitivity to proteins, which allows it to detect the low levels of HCPs in produced drugs. Even though the developmental process requires an extended period of work and several tests with animal models, analysis of HCP content in the final product can be rapidly performed and interpreted. Whilst ELISA possesses the sensitivity to undergo HCP analysis, several limitations are associated with the procedure. The HCP quantification relies mainly on the quantity and affinity of anti-HCP antibodies for detection of the HCP antigens. Anti-HCP antibody pools cannot cover the entire HCP population and weakly immunogenic proteins are impossible to detect, since equivalent antibodies are not generated in the process.
In addition, methods such as the combination of mass spectrometry (MS) and liquid chromatography (LC-MS) have been developed to allow for more efficient and effective HCP analysis and purification. These methods are able to:
Detect varying protein concentrations in a complex sample
Track an ever-changing HCP population and their concentrations during a manufacturing process
Analyse many proteins at once
Measure low abundant HCPs overshadowed by the high abundant target protein product
Characterize HCP-ELISA reagents, including both the antibodies and the associated kit standard
Recently, the MS method has been further improved through the method SWATH LC-MS. SWATH is a data independent acquisition (DIA) form of mass spectrometry, where the mass range is partitioned in small mass windows, which is then analysed with tandem MS (MS/MS). The key advantages are the reproducibility for both individual HCP identification and absolute quantification by applying internal protein standards.
Despite the solid improvements of this method of protein analysis, there are also limitations, the main of which is that it requires a high level of expertise and advanced instrumentation to conduct the analysis.
== See also ==
Biomolecular engineering
Biopharmaceutical
Liquid chromatography–mass spectrometry
Nanomedicine
Mass spectrometry
Protein production
Protein purification
Recombinant DNA
== References == | Wikipedia/Host_cell_protein |
In the mid to late nineteenth century, scientific patterns emerged which contradicted the widely held miasma theory of disease. These findings led medical science to what we now know as the germ theory of disease. The germ theory of disease proposes that invisible microorganisms (bacteria and viruses) are the cause of particular illnesses in both humans and animals. Prior to medicine becoming hard science, there were many philosophical theories about how disease originated and was transmitted. Though there were a few early thinkers that described the possibility of microorganisms, it was not until the mid to late nineteenth century when several noteworthy figures made discoveries which would provide more efficient practices and tools to prevent and treat illness. The mid-19th century figures set the foundation for change, while the late-19th century figures solidified the theory.
== Mid-19th century figures and their discoveries ==
Florence Nightingale
Florence Nightingale, like the majority of people living in the Victorian time period, believed in the miasma theory of disease. Though she was a mathematician and statistician, she was asked by the British secretary of war to join a nursing service during The Crimean War. When Nightingale arrived in Scutari, Turkey, the conditions of the British army hospital were gruesome and putrid. She noticed the leading cause of mortality for soldiers was not battle, but rather infection and illness. Though she still believed at that time "foul air" caused disease (miasma theory), she began a cleaning protocol to improve the air quality. There were men and areas of the hospital covered in feces. The plumbing and sewer system were both broken and their water supply at the hospital was mixed with sewer water. There was an infestation of both vermin and insects. Nightingale reported these concerns to the British Sanitary Commission so they could help with these large items on her agenda to fix. Nightingale also implemented a laundry service for both bedsheets and clothing, she proposed handwashing procedures for nurses, patient bathing practices were introduced, clean bandages were obtained, and healthy meals were provided.
When Florence Nightingale first came to the hospital, the doctors and staff were not interested in hearing her ideas. They were also disinterested in the use of female nurses. However, when the hospital became understaffed and overpopulated, Nightingale and the 38 other women who came to serve, were then allowed to make these changes. Prior to Nightingale and her team, the mortality rate at the hospital was roughly 40%. However, with these new practices in place the number fell to 2% This became public and was printed in the British news. Nightingale, who wandered the hospital at night checking on patients, became known as "The lady with the lamp" and acquired new found prominence within her country.
Nightingale wrote about her experience at the hospital when she returned to England. Notes on Matters Affecting the Health, Efficiency, and Hospital Administration of the British Army was written in 1858 and sent to Queen Victoria. It was a work that outlined the horrific issues witnessed at the British army hospital in Scutari. Nightingale lobbied for hospital reform and worked with epidemiologist William Farr to gather more data about the leading cause of mortality in the British army. It was then she created a visual representation of that data so people could interpret it easily. Her next book was titled Notes on Hospitals and was written in 1859, but like a textbook, it had multiple editions. This book served as a hospital manual, but not just patient care. The work included the optimal way to physically build a hospital, and contained statistics that William Farr helped provide which supported her claims. As a statistician, she was able to compile and describe empirical evidence in her written works which justified the hospital reform changes she deemed necessary. Proposed changes like quarantined wards for certain illnesses and strict hygienic procedures decreased the high rate of infection within the hospitals she reformed. Even with evidence, her proposed reforms were not widely accepted until years after her initial lobbying began.
Though Nightingale first believed bad air was the cause of disease, she used the term "germ" in her contribution to Dr. Richard Quain's medical dictionary which was published in 1883:“Always have chlorinated soda for nurses to wash their hands, especially after dressing or handling a suspicious case. It may destroy germs at the expense of the cuticle, but if it takes off the cuticle, it must be bad for the germs.”
Ignaz Semmelweis
Ignaz Semmelweis was a Hungarian Obstetrician who began assisting Johann Klein at Vienna General Hospital's first two maternity clinics (also called a "lying-in wards") in 1846. Semmelweis became concerned with the number of women dying from a febrile illness called puerperal fever. but it was colloquially referred to as "Childbed fever." Childbed fever often occurred in the first few days after giving birth. This condition caused fever, intense abdominal pains, profound weakness, and ultimately death for many who acquired it. In the 1840s, when Ignaz Semmelweis began his career in obstetrics, an expectant mother entering a maternity ward had a 10-20% chance of dying from this particular illness/complication. For some areas in Europe the figure was greater with an estimated death rate as high as 30%. Childbed fever was an epidemic at the time which made labor and delivery a major cause of distress for families.
One of the clinics he oversaw was run by physicians and medical students, while the other was operated by midwives. Semmelweis noticed the midwife clinic had a significantly lower mortality rate. This compelled Semmelweis to study the techniques and practices of both clinics in great detail to find the distinguishing factors between the two. Detailed autopsies of the women who died on the ward were performed in the mornings at the clinic. Despite his attempts to find a major difference between the clinics, Semmelweis concluded the same procedures and practices were used at both clinics.
The first clue came in the form of tragedy for Semmelweis. A friend at the clinic died after performing an autopsy with a cut on his hand. The cut was sustained from a medical student accidentally slitting his hand with a scalpel during the procedure. This friend had similar symptoms and post-mortem pathology to the mothers who died of childbed fever. Medical students performed autopsies prior to delivering babies, but the midwives only participated in labor and delivery care. Ignaz Semmelweis then made the connection that left over pieces of a dead body could be transmitted via physician's hands into a live body and cause illness. The bacteria which caused childbed fever in Semmelweis's medical clinic was Streptococcus pyogenes. Though he did not have knowledge of specific microorganisms like bacteria, he understood disease could be transferred from one body into another. Like Nightingale, Semmelweis also advocated for the changing of bedsheets for this reason.
Semmelweis then required a strict handwashing regimen at the clinic ran by physicians and medical students using chlorinated water and brushes to remove any cadaver particles from under their fingernails. This decreased the death rate from 11.4% at the clinic to 2.7%. No mothers died in March or August in 1848 after the introduction of the handwashing protocol. In 1860 Semmelweis published a book titled Etiology, the Concept, and the Prevention of Puerperal Fever, but it was met with backlash from physicians. The medical community deemed it to be offensive since doctors considered themselves to be high status and were therefore not dirty or carriers of disease.
Semmelweis did not live to see his findings contribute to the germ theory of disease. He began to become obsessed with speaking only about puerperal fever and developed Alzheimer's-type symptoms which led to him being placed in a mental institution in 1865. That same year Semmelweis died from sepsis after sustaining wounds at the asylum. The wounds were believed to be from an attempted escape or caused by beatings/abuse he endured while detained. After the germ theory was widely accepted, Semmelweis became a celebrated figure with several hospitals and institutions named after him. Roughly 14 years after his death, scientists began to support his ideas. He became known as "The father of hand hygiene" and "The savior of mothers."
John Snow
England had multiple cholera epidemics during the 19th century. The earliest outbreak in Britain occurred in 1831. In that year, 21,800 people died from cholera within the country. These outbreaks were first blamed on the poor because they were said to smell bad and be immoral. This population was believed to cause "bad air." Foul urban air at the time was the prevailing theory of how disease was transmitted (miasma theory). Physician John Snow was an anesthesiologist. He became well respected after anesthetizing Queen Victoria using chloroform during the birth of one of her children in 1847. In 1854 when a deadly cholera outbreak occurred close to his home in London, his priorities changed. Snow became concerned and was determined to discover the origin of the cholera outbreak. Even though the germ theory had not been established yet, he felt the outbreaks were not caused by "bad air" infecting blood, but by something entering a person's gut. Snow determined that inhaling "bad air" would not result in intestinal disease.
The 1854 outbreak was centralized in a suburb of London called Soho. The number of deaths were concerning enough that some families fled their homes to find a new location to live in London. John Snow theorized in the late 1840s that cholera was transmitted through water in an essay titled On the Mode of Communication of Cholera. He specifically believed that it was the contamination of water which spread cholera. At the time, London's sewage system was rudimentary with unmaintained cesspools and the dumping of waste into the River Thames. Snow decided to start his investigation by plotting each public water pump located within the Soho district on a map. He then asked for recent death records and walked the area to find the homes and families of the victims. The victim's families were asked questions about their loved one's routines and he marked each death on the map he had created. The map revealed that Broad Street and the area near it had the most mortalities. On this street was the Broad Street water pump. The houses nearest to that pump were the most affected by the disease. However, Snow noted there were two places nearby that were not affected by the pump so he explored why this was the case. One of these places was a workhouse in walking distance to the pump. This workhouse saw 5 deaths from cholera yet had over 500 workers. He discovered this workhouse had its own private water well which employees drank from instead of the Broad Street pump. Another nearby brewery had no deaths, but the men were given free beer to drink throughout their work day. There were outlier deaths that Snow decided to investigate. These were deaths that occurred outside of the typical pattern on his map. Snow discovered a woman and her niece, though they lived miles away from the pump, died of cholera. After interviewing a surviving family member, he found out that she once lived in the area and she particularly liked the Broad Street water. Because of this, she sent a servant to this particular pump to get water for her. The niece had been over to her house and consumed water from the pump. Another outlier case involved two young school children who died, but lived on a different street which had its own source of water. However, these two girls used Broad Street to travel to their school and back. They were known to drink from the well during their walk.
John Snow had already postulated nearly a decade earlier that water was to blame for cholera epidemics, and this investigation strengthened his claim. Just as his contemporary Nightingale had done, he also made connections between events and used visual empirical evidence to support his claims. He took a sample of water from the Broad Street pump and studied it under a microscope. Unlike other water sources, this pump's water contained an unknown microbe that resembled white wool. Later this bacteria was given the name Vibrio cholerae. It is now recognized as the bacteria which infects a person with cholera. Though the city was not fully convinced of John Snow's theory on cholera, they removed the handle on the pump when Snow asked. This decreased the death rate from cholera rather quickly even though the mortality rates were already in decline.
Later it was discovered that cracks in a nearby cesspool leaked fecal matter into the water at Broad Street. Modern medical science has labeled this transmission of disease as the fecal oral route. But at that time, this route of disease was unknown to both physicians and the public. A baby named Frances Lewis was believed to be the first case which caused the outbreak. Her birth and death certificate match the time of the outbreak. A doctor listed the cause of death as a diarrheal "attack." Her mother cleaned her diapers in buckets then threw the water into the cesspool which leaked into the water supply.
After his diligent investigation into the 1854 cholera outbreak, John Snow became a member of the London Epidemiological Society. Snow published a second edition of his prior book On the Mode of Communication of Cholera in 1855. Snow did not live to see the establishment of the germ theory of disease in the late 1800s. He died of a stroke at the age of 45.
== Late-19th century figures who helped confirm germ theory ==
Joseph Lister
Surgical techniques advanced in the 19th century, but the chances of a patient dying from post-operative infection was 50%. Prior to the discovery of the germ theory of disease, surgeons did not clean their surgical instruments or the operating table between patients. Semmelweis's work on hand hygiene was either ignored or unknown to surgeons. Sawdust covered the floor of an operative theater to soak up bodily fluids. Laudable pus draining from a surgical incision was considered a normal post-operative phenomena. Physicians had special tools to drain this green liquid from the incision site. These tools, which touched infection, were not sanitized between patients. The surgeons believed as long as there wasn't "bad air" in the operating room they had properly cared for the patient.
Joseph Lister was a British surgeon. In 1860 he was chosen to be the Regius Professor over the surgical department at Glasgow University. Lister worked as a wound dresser under surgeon Sir John Eric Erichsen. told Lister the wound created miasmas in the air and wound miasmas could spread to other patients in the surgical ward. This was his explanation for gangrene within a surgical ward. Lister observed that if a wound was kept clean, the patient was less likely to develop infections and the wound could heal. In 1865 Lister read French chemist's Louis Pasteur's work on the fermentation and distilling process at a winery in France. The wine was contaminated and Pasteur used heat to destroy the responsible bacteria. Pasteur also noted if there was an absence of air, the fermentation of wine was impossible. Microbes such as yeast reacted to the air, but they were not spontaneously generated in the air as the miasma theory taught. Lister found inspiration in Pasteur's fermentation work. He wondered if there were microbes within a wound that needed to be destroyed or covered so they wouldn't react to the air. However unlike Pasteur, Lister could not use heat to destroy the microbes in a wound. Instead, he decided to use a chemical called carbolic acid because he heard about the use of creosote to sanitize sewage.
The standard treatment for compression fractures at the time was amputation of the limb. Lister noted that 50% of patients who received an amputation at the hospital died of infection. In August 1865, a boy was brought to the hospital with a compression fracture on his left tibia. Instead of amputating the leg, he advised his team to thoroughly clean the wound with carbolic acid, set the leg with wooden boards, and place a cloth soaked in carbolic acid on top of the injury site. Lister hoped this would allow the child to keep his leg and also prevent fatal sepsis of the wound. After the boy was in the hospital for a few days, there were no signs of infection at the fracture site. The bones then began to fuse and the child made a full recovery. After this successful treatment, Lister continued to treat compression fractures with these same protocols. Lister noticed the key difference between compression fractures and regular fractures: the compression fractures caused an exposed wound. These new treatment protocols reduced the death rate in the "accident ward" to 15% by 1869. Lister decided to not only treat wounds, but also limit the chances of post-operative infection through new surgical practices. He cleaned his patients' bodies with carbolic acid along with his tools and his hands before an operation. However, the Glasgow Infirmary did not believe in his new methods and his wards were not cleaned and well-kept.
In 1869 a professorship position opened at the University of Edinburgh. The medical students there urged administration to appoint Lister to this position. Lister gained a large following of medical students while appointed at Edinburgh.Unlike his time at Glasgow, this facility had a significantly larger population of medical students who respected and followed his work. In spite of his great success in preventing infection, the medical community at large did not accept these new methods. In 1871, Lister would gain notoriety by performing a procedure on Queen Victoria. When her abscess drained pus after his operation, he was quick to develop specialized tubing soaked in carbolic acid to drain the abscess. The queen recovered and praised Lister's efforts. His work became known as "Listerism." Germany was the first country to enact his antiseptic principles within their hospitals. Many hospitals in the United States placed a ban on his antiseptic techniques. After his great success in England, he spoke at an international conference in Philadelphia and this convinced several hospitals to revoke this ban. Germ theory denialism and contagion theory rejection were major hindrances to medical progress in the 19th century.
Since Lister had the queen's blessing, his antiseptic policies became accepted medical practice. Semmelweis did not gain this type of support with his chlorinated lime handwashing protocol. He did not have the public eye on his side nor the medical community. Lister, however, was able to persuade medical students and clinicians. Joseph Lister did see his work contribute to medical science and germ theory; he was celebrated in life instead of after his death. He was granted the title Baron Lister of Lyme Regis and given a place in the Order of Merit. When the news of the queen's survival due to antiseptics became widespread, England became intrigued by bodily cleanliness. Companies profited on this by selling carbolic acid soaps, fumigators, and an oral antiseptic named after Lister (Listerine). Most notably, his acclaim marked the shift away from the miasma theory in medicine. Pasteur's influence on Lister demonstrates the union of scientific research and informed medical practice. Lister's claim that bacteria causes wound infection and that wounds must be kept clean, are still important principles of modern medical care.
Louis Pasteur
Though some nurses and doctors were beginning to become skeptical of the miasma theory in the 19th century, there were no other prevailing explanations for epidemics and infections. Florence Nightingale, Ignaz Semmelweis, and John Snow understood that people could get sick from objects, water, or hands that were contaminated by bodily fluids or substances. However, the answer as to why this was the case remained unknown.
Louis Pasteur was a French chemist who discovered chirality while studying crystals. This discovery became the basis for a new form of chemistry called stereochemistry. While Pasteur was studying paratartrate crystals in 1857, he discovered that his calcium paratartaric acid solutions were growing fungi. The left and right sides of the crystal had split apart from each other. The left side turned into tartaric acid and it fermented. Under his microscope, this tartaric acid was now optically active in polarized light. Only alive substances can be rotated through the polarized light plane. Many of his contemporaries believed fermentation to be a lifeless decomposing process. Pasteur then realized a small, but alive, substance may have caused the fermentation. This led him to examine the process of fermentation more closely. In 1860, his book Researches on the Molecular Asymmetry of Natural Organic Products was published. In this work, he stated that asymmetric molecules distinguished organic substances from non-organic ones. Pasteur was then asked by Napoleon III to study French wineries because a large portion of French wine was contaminated. Pasteur believed that heating the wine could destroy the microorganisms which had contaminated it. This process became known as pasteurization.
Pasteur then became curious as to where these contaminants came from and so he began to study spontaneous generation. At the time, it was believed organisms could self-generate within a rotting piece of food or flesh. As stated previously in Lister's segment, doctors also believed wounds spontaneously generated miasmas within the air in hospital wards. In 1859, Pasteur ran an experiment where he boiled broth in flasks that had long straw-like curved necks. This thin neck allowed a small amount of air into the flask without exposing its contents to particulates in the air or around the flask. One of the flasks was left as it was. There was a flask which did not have the thin neck and this allowed the broth to become exposed to any particles around it. Bacteria quickly grew within this flask. Another flask was left tilted so the broth was nearly pouring out of the straw-like curved top, the liquid became cloudy and bacteria also grew within it. The broth protected from particles took a significantly longer amount of time before any signs of bacterial growth occurred within it. He was then able to disprove spontaneous generation. Only the broth exposed to the particles and microbes around it, grew bacteria at a quick rate. In 1861, Pasteur named his theory of contamination "Germ Theory." He stated the opposite of the miasma theory: microbe carried by the air reacted with live substances causing contamination. These microbes did not generate themselves within the air. By 1862, Pasteur stated microbes were present everywhere. This was considered a major opposition to the predominant miasma theory.
Like wine, the silk industry was also an important part of France's economy. However, large numbers of silkworms began dying from diseases and the French government asked Pasteur to investigate the problem. Pasture connected the disease in silk worms known as pébrine to the parasite Nosema bombycis. The other disease called flacherie caused silkworms to become dark brown. Pébrine was thought to be a form of flacherie since it caused brown dots on the silkworms. But, Pasteur discovered Pébrine and flacherie were separate diseases. Pasteur claimed bacteria within the silkworms' intestinal track caused flacherie. He then used a microscope to sort which eggs were infected and which were not. This was an effective way of discarding the diseased eggs so these worms would not enter the population. Pasteur was able to distinguish the diseases through the specific microorganisms present in the silkworms. This began the path to germ specificity within the theory. Louis Pasteur's contemporary Robert Koch devoted much of his scientific study to discovering certain pathogens and connecting them to specific diseases. These scientists were often in competition with one another and so the Koch-Pasteur rivalry is a well-known part of germ theory's history.
In 1867, Louis Pasteur became a chemistry professor at the Sorbonne, though he continued to study silkworms until 1870, he became curious as to what could cure disease. Pasteur wanted to discover if his work had greater applications than improving alcohol production and diagnosing silkworms. In the 1870s, large numbers of chickens were dying from cholera. When he cultured the bacteria from the chickens, he left these cultures out in the air for long periods of time. By happenchance the bacteria reproduced, yet became weaker and considerably less virulent. He used Edward Jenner's early vaccination concept, but improved upon it by injecting the chickens with this less virulent strain of the disease. These vaccinated chickens survived, however, some still had the bacteria in their feces. Pasteur believed this might explain asymptomatic carriers of disease during epidemics.
In 1878, Louis Pasteur made a presentation to the French Academy of Sciences. The title of the presentation was: The Germ Theory and its Applications to Medicine and Science. Within this presentation he stated that the health of mankind depended upon unseen organisms, "If it is a terrifying thought that life is at the mercy of the multiplication of these minute bodies, it is a consoling hope that Science will not always remain powerless before such enemies." Pasteur also mentioned that Joseph Lister had been successful in using his science in medical practice, "This theory would found a new surgery—already begun by a celebrated English surgeon Dr. Lister who was among the first to understand its fertility." In 1879 at the next French Academy of Sciences conference, he stopped a scientist's presentation on childbed fever. The presenter said that "puerperal miasmas" were to blame for the death of these mothers. Pasteur openly blamed the clinicians' hands and the conditions of the ward as Ignaz Semmelweis discovered. When the scientist said there was no proof of these microbes, Pasture walked up and drew a picture of the streptococcus bacteria responsible for puerperal fever on the blackboard. That same year Pasteur had examined it when blood cultures were taken from the wombs of women who died of child bed fever.
In 1881, Pasteur would develop the vaccine for anthrax after discovering how to lower the bacteria's virality. In his experiment he had 2 groups of livestock: a control group who received no injection and a group he inoculated with anthrax bacteria of low virulence. Twelve days later he injected the fully virulent form of anthrax into both groups. Within 3 days most of the control group had died or were very ill, but the inoculated group survived and had no symptoms of the infection. Two-hundred people showed up to observe the success of Pasteur's vaccination. This gave him fame in many domains because among the crowd were politicians, veterinarians, agriculturists, and journalists. His popularity would lead to the Pasteur Institute system. Brazil's emperor Dom Pedro II was an intellectual who followed Pasteur's work. The first institute to open was not the Paris institute, but instead one located in Rio de Janeiro. The facility was dedicated to the study of rabies.
Louis Pasteur's final contribution was a vaccination for rabies. Unlike bacteria, viruses were less understood at the time and Pasteur could not observe them in his microscope. However, he understood the virus was attacking the nervous system. After a few failed attempts at attenuating the virus, he extracted spinal fluid from rabbits with rabies and left the flasks open to air out and dry. This method finally decreased the virulence of the rabies virus. Dom Pedro III wanted Pasteur to test this successful vaccine on human subjects; specifically convicts sentenced to death. Pasteur wrote a letter back that his "hand trembled" at the thought of injecting a person. Though Pasteur was fearful, he was faced with a choice when a child was brought to Hôpital des Enfants-malades with multiple bites from a rabid dog. The child's doctor Joseph Grancher asked Pasteur to treat the boy even though Pasteur was unsure of the vaccine's effect on a human. Dr. Grancher reminded Pasteur that he would die regardless. Since Louis Pasteur was not a physician, Dr. Grancher injected the boy with his first injection on July 6 of 1885. This child was then given 12 more injections over the span of 10 days. He never contracted rabies and was the first human being to get inoculated.
Louis Pasteur was known as a pioneer of microbiology and "The father of immunology". People from all over the world wanted to get vaccinated for rabies, so in 1880 l’Institut Pasteur was constructed in Paris. Pasteur's health declined and on his last birthday he was widely celebrated by the scientific community. He died in 1895 and is buried within a mausoleum inside of the Pasteur Institute. Scientists continued his research at these institutes and they discovered other pathogens and important prophylactic measures.
Robert Koch
Pasteur proved that microscopic organisms cause disease and other biological processes like fermentation. Robert Koch, a German physician and contemporary of Louis Pasteur, was also interested in such research. However, Koch was instrumental in the discovery and observation of illness-causing bacteria. Koch contributed greatly to science related to the specificity of bacteria . He discovered and confirmed that a specific bacteria causes a specific illness.
In the 1870s, anthrax was a major cause of concern to both farmers and people living in the area of an outbreak. Within a four-year time span, 56,000 animals and nearly 530 people had died of this devastating disease. Koch worked in a home laboratory to unravel the mystery of what caused anthrax. The microscope in this lab was a gift from his wife. Despite these limitations, Koch ran an experiment by injecting mice with anthrax infected blood. He also injected mice with blood from healthy livestock. The mice who received the anthrax infected blood died the next day. After examining the mice that had died, he discovered they had rod shaped organisms within their blood and tissues. He continued to inject the mice by recirculating the diseased blood of the dead mice into the ones that were alive. As Koch continued to do this, the mice still died, and the anthrax rods changed shape upon his evaluation. The elongated rods appeared to be in the process of reproducing. Koch then took the eye of an ox and placed the anthrax bacteria within it. He predicted the bacteria was alive and this was proven to be true when the bacteria multiplied. He kept track of its reproduction and noted the bacteria would create spores by reproducing within itself since it had no living host. When he kept these spores over the years, they could still infect an organism even if they had dried out. He predicted these spores were resilient and remained in fields and pastures even if those fields hadn't been used for animal husbandry in a long time. Koch then suggested farmers cremate an animal who died of anthrax to prevent spore generation from occurring in the ground. This experiment was the first to prove that a specific bacteria caused a specific illness with specific symptoms. In 1876, he published a paper titled "The etiology of anthrax disease based on the evolutionary history of Bacillus anthracis" written in German. It included a drawing of the bacteria, but in 1877 he would become the first scientist to produce a photograph of this bacteria by staining it with dye. It was the first time anyone had seen an actual photograph of a microbe. Even though it would be discovered later that bacillus anthracis is not the only cause of anthrax, this was a monumental experiment that laid the foundation for the field of bacteriology.
Koch felt limited by the technique of using a liquid to create cultures. A liquid base could lead to contamination and uncertainty of proper bacterial growth. His assistant's wife suggested the use of agar because it took a longer time to melt down. Julius Petri, another assistant to Koch, created circular dish with a lit that could hold the agar solution and prevent any impurities from ruining the culture. Starting in 1880, Koch wanted to discover the cause of one of the deadliest illnesses in Europe: tuberculous. At the time, people understood it was transmitted through a contagious substance, but they didn't know what that contagion was. The bacteria was difficult to see and several had tried to view it before him without success. Koch first took tubercules from the lungs of animals, allowed them to dry, then turned them into powders. This method failed to create proper cultures. The staining method that had been successful in revealing bacillus anthracis under the microscope, did not successfully reveal the tuberculosis bacteria to him. The dye, methylene blue, took a full day to stain his animal tissue sample. Koch then used heat to speed the process of staining the tubercle bacilli. This approach lowered the staining period from 24 hours to just 1 hour. After the dye had stained the tissue, he then stained it with a secondary dye called vesuvine which was used to reveal leprosy. When this secondary dye was added, Koch discovered the animal's tissue was stained brown while the tuberculosis bacteria rods were bright blue. Koch's work was not finished though, he still needed to make sure what he was seeing caused tuberculosis. He went on to become the first to person to successfully create a pure M. tuberculosis culture. After doing so, he injected animals with the bacteria and found M. tuberculosis rods in their tissues. But he also discovered that a non-infected animal that was housed with an infected animal would also die of tuberculosis. The bacteria was also found in their tissue. Koch then stated that tuberculosis could be spread from human to human. After discovering M. tuberculosis, culturing it, and proving it caused tuberculosis, Robert Koch was awarded a Nobel Prize in medicine. He gave a lecture on his findings in 1882, at a Berlin Physiological Society gathering. This presentation was considered to be one of the most groundbreaking presentations ever witnessed in the field of medicine.
In 1890, Koch created what he called his four postulates in determining if a microorganism is the causse of a disease. His four original criteria were:
1.The microorganism must be present in every case of the disease.
2. The microorganism must be isolated from the diseased host and grown as a pure culture in the laboratory
3. The microorganism must cause the same disease when introduced into a new host.
4. The microorganism should be recovered from the new host.
These postulates created the foundation for medical bacteriology. Koch did not have an understanding of viruses, so his second postulate is impossible for viral bodies. However, these postulates were causal claims and were reformed over many years. They knowledge that a certain germ is the cause of a particular illness.
Like Louis Pasteur, Robert Koch opened an institute so that he and other scientists could continue this work. It remains in the same location in Germany on a street called Nordufer in Berlin-Wedding. In 1910, Robert Koch died of a heart attack and was placed inside a mausoleum within the Robert Koch Institute. This building houses 1,500 items related to Robert Koch including various writings and scientific materials such as prepared microscope slides. The institute is still an active research and public health facility. In 2020, the facility helped with COVID-19 awareness and response training. Their public health intelligence team aided 70 countries during the pandemic.
== References == | Wikipedia/Germ_theory's_key_19th_century_figures |
The Canadian Journal of Surgery is a bimonthly peer-reviewed open access medical journal covering surgery. It was established in 1957 and is published by the Canadian Medical Association. The current editors-in-chief are Edward J. Harvey and Chad Ball. The journal is sponsored by the Canadian Association of General Surgeons, Canadian Society for Vascular Surgery, Canadian Association of Thoracic Surgeons, and Canadian Society of Surgical Oncology.
== History ==
The journal was established as a result of a collaboration between Canadian departments of surgery, the Royal College of Physicians and Surgeons of Canada, and the Canadian Medical Association. In 1957, leading surgical groups asked the Canadian Medical Association to undertake the publishing of the journal. The founding editorial board consisted of the chairs of surgery at the 12 medical schools in Canada at the time. The president of the Royal College of Physicians and Surgeons of Canada chaired the board. The first issue was published on 1 October 1957. The Royal College of Physicians and Surgeons of Canada subsidized the journal until 1991 when it withdrew in favor of its own journal, Annals of the Royal College of Physicians and Surgeons of Canada. Jean Couture then arranged for the Canadian Association of General Surgeons to become the major sponsor of the journal. Currently the Canadian Journal of Surgery, at 60 years of continuous publication, is the longest surviving journal of record of surgery in 300 years of organised surgery in Canada.
== Citation record ==
Journal Citation Reports shows that as of the end of 2016, the Canadian Journal of Surgery had published 5917 citable articles. The average citation per article was 6.9 so that its Impact Factor increased yearly from 0.5 in 2006 to 2.544 in 2017. The journal's h-index is 55 with a normalized Eigenfactor score of 0.42.
== Editors-in-chief ==
The following persons are or have been editor-in-chief of the journal:
Robert M. Janes, 1957–1964
Frederick G. Kergin, 1964–1972
Lloyd D. MacLean, 1972–1992
C. Barber Mueller, 1972–1992
Roger G. Keith, 1992–1998
Jonathan Larmonth Meakins, 1992–2003
James P. Waddell, 1998–2011
Garth L. Warnock, 2003–2013
Edward Harvey, 2011–present
Vivian C McAlister, 2013–2019
Chad Ball, 2019–present
== References ==
== External links ==
Official website | Wikipedia/Canadian_Journal_of_Surgery |
Zymotic disease was a 19th-century medical term for acute infectious diseases, especially "chief fevers and contagious diseases (e.g. typhus and typhoid fevers, smallpox, scarlet fever, measles, erysipelas, cholera, whooping-cough, diphtheria, etc.)".
Zyme or microzyme was the name of the organism presumed to be the cause of the disease.
As originally employed by William Farr, of the British Registrar-General's department, the term included the diseases which were "epidemic, endemic and contagious," and were regarded as owing their origin to the presence of a morbific principle in the system, acting in a manner analogous to, although not identical with, the process of fermentation.
In the late 19th century, Antoine Béchamp proposed that tiny organisms he termed microzymas, and not cells, are the fundamental building block of life. Béchamp claimed these microzymas are present in all things—animal, vegetable, and mineral—whether living or dead. Microzymas coalesce to form blood clots and bacteria. Depending upon the condition of the host, microzymas assume various forms. In a diseased body, the microzymas become pathological bacteria and viruses. In a healthy body, microzymas form healthy cells. When a plant or animal dies, the microzymas live on. His ideas did not gain acceptance.
The word zymotic comes from the Greek word ζυμοῦν zumoûn which means "to ferment". It was in British official use from 1839. This term was used extensively in the English Bills of Mortality as a cause of death from 1842. In 1877, Thomas Watson wrote in a Scientific American article "Zymotic Disease" describing contagion as the origin of infectious diseases.
Robert Newstead (1859–1947) used this term in a 1908 publication in the Annals of Tropical Medicine and Parasitology, to describe the contribution of house flies (Musca domestica) towards the spread of infectious diseases. However, by the early 1900s, bacteriology "displaced the old fermentation theory", and so the term became obsolete.
In her Diagram of the causes of mortality in the army in the East, Florence Nightingale depicts The blue wedges measured from the centre of the circle represent area for area the deaths from Preventible or Mitigable Zymotic diseases; the red wedges measured from the centre the deaths from wounds, & the black wedges measured from the centre the deaths from all other causes.
== References == | Wikipedia/Zymotic_disease |
The miasma theory (also called the miasmic theory) is an abandoned medical theory that held that diseases—such as cholera, chlamydia, or plague—were caused by a miasma (μίασμα, Ancient Greek for 'pollution'), a noxious form of "bad air", also known as night air. The theory held that epidemics were caused by miasma, emanating from rotting organic matter. Though miasma theory is typically associated with the spread of contagious diseases, some academics in the early nineteenth century suggested that the theory extended to other conditions as well, e.g. one could become obese by inhaling the odor of food.
The miasma theory was advanced by Hippocrates in the fourth century BC and accepted from ancient times in Europe and China. The theory was eventually abandoned by scientists and physicians after 1880, replaced by the germ theory of disease: specific germs, not miasma, caused specific diseases. However, cultural beliefs about getting rid of odor made the clean-up of waste a high priority for cities. It also encouraged the construction of well-ventilated hospital facilities, schools and other buildings.
== Etymology ==
The word miasma comes from ancient Greek and though conceptually, there is no word in English that has the same exact meaning, it can be loosely translated as 'stain' or 'pollution'.
The idea later gave rise to the name malaria (literally 'bad air' in Medieval Italian).
== Views worldwide ==
Miasma was considered to be a poisonous vapor or mist filled with particles from decomposed matter (miasmata) that caused illnesses. The miasmatic position was that diseases were the product of environmental factors such as contaminated water, foul air, and poor hygienic conditions. Such infection was not passed between individuals but would affect individuals within the locale that gave rise to such vapors. It was identifiable by its foul smell. It was also initially believed that miasmas were propagated through worms from ulcers within those affected by a plague.
=== Europe ===
In the fifth or fourth century BC, Hippocrates wrote about the effects of the environs over the human diseases:
Whoever wishes to investigate medicine properly, should proceed thus: in the first place to consider the seasons of the year, and what effects each of them produces for they are not at all alike, but differ much from themselves in regard to their changes. Then the winds, the hot and the cold, especially such as are common to all countries, and then such as are peculiar to each locality. We must also consider the qualities of the waters, for as they differ from one another in taste and weight, so also do they differ much in their qualities. In the same manner, when one comes into a city to which he is a stranger, he ought to consider its situation, how it lies as to the winds and the rising of the sun; for its influence is not the same whether it lies to the north or the south, to the rising or to the setting sun. These things one ought to consider most attentively, and concerning the waters which the inhabitants use, whether they be marshy and soft, or hard, and running from elevated and rocky situations, and then if saltish and unfit for cooking; and the ground, whether it be naked and deficient in water, or wooded and well watered, and whether it lies in a hollow, confined situation, or is elevated and cold; and the mode in which the inhabitants live, and what are their pursuits, whether they are fond of drinking and eating to excess, and given to indolence, or are fond of exercise and labor, and not given to excess in eating and drinking.
In the 1st century BC, the Roman architectural writer Vitruvius described the potential effects of miasma (Latin nebula) from fetid swamplands when visiting a city:
For when the morning breezes blow toward the town at sunrise, if they bring with them mist from marshes and, mingled with the mist, the poisonous breath of creatures of the marshes to be wafted into the bodies of the inhabitants, they will make the site unhealthy.
The miasmatic theory of disease remained popular in the Middle Ages and a sense of effluvia contributed to Robert Boyle's Suspicions about the Hidden Realities of the Air.
In the 1850s, miasma was used to explain the spread of cholera in London and in Paris, partly justifying Haussmann's later renovation of the French capital. The disease was said to be preventable by cleansing and scouring of the body and items. Dr. William Farr, the assistant commissioner for the 1851 London census, was an important supporter of the miasma theory. He believed that cholera was transmitted by air, and that there was a deadly concentration of miasmata near the River Thames' banks. Such a belief was in part accepted because of the general lack of air quality in urbanized areas. The wide acceptance of miasma theory during the cholera outbreaks overshadowed the partially correct theory brought forth by John Snow that cholera was spread through water. This slowed the response to the major outbreaks in the Soho district of London and other areas. The Crimean War nurse Florence Nightingale (1820–1910) was a proponent of the theory and worked to make hospitals sanitary and fresh-smelling. It was stated in 'Notes on Nursing for the Labouring Classes' (1860) that Nightingale would "keep the air [the patient] breathes as pure as the external air."
Fear of miasma registered in many early nineteenth-century warnings concerning what was termed "unhealthy fog". The presence of fog was thought to strongly indicate the presence of miasma. The miasmas were thought to behave like smoke or mist, blown with air currents, wafted by winds. It was thought that miasma did not simply travel on air but changed the air through which it propagated; the atmosphere was infected by miasma, as diseased people were.
=== China ===
In China, miasma (Chinese: 瘴氣; pinyin: Zhàngqì; alternative names 瘴毒, 瘴癘) is an old concept of illness, used extensively by ancient Chinese local chronicles and works of literature. Miasma has different names in Chinese culture. Most of the explanations of miasma refer to it as a kind of sickness, or poison gas.
The ancient Chinese thought that miasma was related to the environment of parts of Southern China. The miasma was thought to be caused by the heat, moisture and the dead air in the Southern Chinese mountains. They thought that insects' waste polluted the air, the fog, and the water, and the untouched forest harbored a great environment for miasma to occur.
In descriptions by ancient travelers, soldiers, or local officials (most of them are men of letters) of the phenomenon of miasma, fog, haze, dust, gas, or poison geological gassing were always mentioned. The miasma was thought to have caused a lot of diseases such as the cold, influenza, heat strokes, malaria, or dysentery. In the medical history of China, malaria had been referred to by different names in different dynasty periods. Poisoning and psittacosis were also called miasma in ancient China because they did not accurately understand the cause of disease.
In the Sui dynasty (581–618 CE), doctor Chao Yuanfang mentioned miasma in his book On Pathogen and Syndromes (諸病源候論). He thought that miasma in Southern China was similar to typhoid fever in Northern China. However, in his opinion, miasma was different from malaria and dysentery. In his book, he discussed dysentery in another chapter, and malaria in a single chapter. He also claimed that miasma caused various diseases, so he suggested that one should find apt and specific ways to resolve problems.
The concept of miasma developed in several stages. First, before the Western Jin dynasty, the concept of miasma was gradually forming; at least, in the Eastern Han dynasty, there was no description of miasma. During the Eastern Jin, large numbers of northern people moved south, and miasma was then recognized by men of letters and nobility. After the Sui and the Tang dynasty, scholars-bureaucrats sent to be the local officials recorded and investigated miasma. As a result, the government became concerned about the severe cases and the causes of miasma by sending doctors to the areas of epidemic to research the disease and heal the patients. In the Ming dynasty and Qing dynasty, versions of local chronicles record different miasma in different places.
However, Southern China was highly developed in the Ming and Qing dynasties. The environment changed rapidly, and after the 19th century, western science and medical knowledge were introduced into China, and people knew how to distinguish and deal with the disease. The concept of miasma therefore faded out due to the progress of medicine in China.
==== Influence in Southern China ====
The terrifying miasma diseases in the southern regions of China made it the primary location for relegating officials and sending criminals to exile since the Qin-Han dynasty. Poet Han Yu (韓愈) of the Tang dynasty, for example, wrote to his nephew who came to see him off after his banishment to the Chao Prefecture in his poem, En Route (左遷至藍關示姪孫湘):
At dawn I sent a single warning to the throne of the Nine Steps;
At evening I was banished to Chao Yang, eight thousand leagues.
Striving on behalf of a noble dynasty to expel an ignoble government,
How should I, withered and worn, deplore my future lot?
The clouds gather on Ch'in Mountains, I cannot see my home;
The snow bars the passes of Lan, my horse cannot go forward.
But I know that you will come from afar, to fulfil your set purpose,
And lovingly gather my bones, on the banks of that plague-stricken river.
The prevalent belief and predominant fear of the southern region with its "poisonous air and gases" is evident in historical documents.
Similar topics and feelings toward the miasma-infected south are often reflected in early Chinese poetry and records. Most scholars of the time agreed that the geological environments in the south had a direct impact on the population composition and growth. Many historical records reflect that females were less prone to miasma infection, and mortality rates were much higher in the south, especially for the men. This directly influenced agriculture cultivation and the southern economy, as men were the engine of agriculture production. Zhou Qufei (周去非), a local magistrate from the Southern Song dynasty, described in his treatise Representative Answers from the South: "... The men are short and tan, while the women were plump and seldom came down with illness," and exclaimed at the populous female population in the Guangxi region.
This inherent environmental threat also prevented immigration from other regions. Hence, development in the damp and sultry south was much slower than in the north, where the dynasties' political power resided for much of early Chinese history.
=== India ===
In India, there was also a miasma theory. Gambir was considered the first antimiasmatic application. This gambir tree is found in Southern India and Sri Lanka.
== Developments from 19th century onwards ==
=== Zymotic theory ===
Based on zymotic theory, people believed vapors called miasmata (singular: miasma) rose from the soil and spread diseases. Miasmata were believed to come from rotting vegetation and foul water—especially in swamps and urban ghettos.
Many people, especially the weak or infirm, avoided breathing night air by going indoors and keeping windows and doors shut. In addition to ideas associated with zymotic theory, there was also a general fear that cold or cool air spread disease. The fear of night air gradually disappeared as understanding about disease increased as well as with improvements in home heating and ventilation. Particularly important was the understanding that the agent spreading malaria was the mosquito (active at night) rather than miasmata.
=== Contagionism versus miasmatism ===
Prior to the late 19th century, night air was considered dangerous in most Western cultures. Throughout the 19th century, the medical community was divided on the explanation for disease proliferation. On one side were the contagionists, believing disease was passed through physical contact, while others believed disease was present in the air in the form of miasma, and thus could proliferate without physical contact. Two members of the latter group were Dr. Thomas S. Smith and Florence Nightingale.
Thomas Southwood Smith spent many years comparing the miasmatic theory to contagionism.
To assume the method of propagation by touch, whether by the person or of infected articles, and to overlook that by the corruption of the air, is at once to increase the real danger, from exposure to noxious effluvia, and to divert attention from the true means of remedy and prevention.
Florence Nightingale:
The idea of "contagion", as explaining the spread of disease, appears to have been adopted at a time when, from the neglect of sanitary arrangements, epidemics attacked whole masses of people, and when men had ceased to consider that nature had any laws for her guidance. Beginning with the poets and historians, the word finally made its way into scientific nomenclature, where it has remained ever since [...] a satisfactory explanation for pestilence and an adequate excuse for non-exertion to prevent its recurrence.
The current germ theory accounts for disease proliferation by both direct and indirect physical contact.
=== Influence on sanitary engineering reforms ===
In the early 19th century, the living conditions in industrialized cities in Britain were increasingly unsanitary. The population was growing at a much faster rate than the infrastructure could support. For example, the population of Manchester doubled within a single decade, leading to overcrowding and a significant increase in waste accumulation. The miasma theory of disease made sense to the sanitary reformers of the mid-19th century. Miasmas explained why cholera and other diseases were epidemic in places where the water was stagnant and foul-smelling. A leading sanitary reformer, London's Edwin Chadwick, asserted that "all smell is disease", and maintained that a fundamental change in the structure of sanitation systems was needed to combat increasing urban mortality rates.
Chadwick saw the problem of cholera and typhoid epidemics as being directly related to urbanization, and he proposed that new, independent sewerage systems should be connected to homes. Chadwick supported his proposal with reports from the London Statistical Society which showed dramatic increases in both morbidity and mortality rates since the beginning of urbanization in the early 19th century. Though Chadwick proposed reform on the basis of the miasma theory, his proposals did contribute to improvements in sanitation, such as preventing the reflux of noxious air from sewers back into houses by using separate drainage systems in the design of sanitation. That led, incidentally, to decreased outbreaks of cholera and thus helped to support the theory.
The miasma theory was consistent with the observation that disease was associated with poor sanitation, and hence foul odours, and that sanitary improvements reduced disease. However, it was inconsistent with the findings arising from microbiology and bacteriology in the later 19th century, which eventually led to the adoption of the germ theory of disease, although consensus was not reached immediately. Concerns over sewer gas, which was a major component of the miasma theory developed by Galen, and brought to prominence by the "Great Stink" in London in the summer of 1858, led proponents of the theory to observe that sewers enclosed the refuse of the human bowel, which medical science had discovered could teem with typhoid, cholera, and other microbes.
The Nuisances Removal and Diseases Prevention Act 1846 was passed to identify whether the transmission of cholera was by air or by water. The act was used to encourage owners to clean their dwellings and connect them to sewers.
Even though eventually disproved by the understanding of bacteria and the discovery of viruses, the miasma theory helped establish the connection between poor sanitation and disease. That encouraged cleanliness and spurred public health reforms which, in Britain, led to the Public Health Act 1848 the Public Health Act 1858, and the Local Government Act 1858. The latter of those enabled the instituting of investigations into the health and sanitary regulations of any town or place, upon the petition of residents or as a result of death rates exceeding the norm. Early medical and sanitary engineering reformers included Henry Austin, Joseph Bazalgette, Edwin Chadwick, Frank Forster, Thomas Hawksley, William Haywood, Henry Letheby, Robert Rawlinson, John Simon, John Snow and Thomas Wicksteed. Their efforts, and associated British regulatory improvements, were reported in the United States as early as 1865.
Particularly notable in 19th century sanitation reform is the work of Joseph Bazalgette, chief engineer to London's Metropolitan Board of Works. Encouraged by the Great Stink, Parliament sanctioned Bazalgette to design and construct a comprehensive system of sewers, which intercepted London's sewage and diverted it away from its water supply. The system helped purify London's water and saved the city from epidemics. In 1866, the last of the three great British cholera
epidemics took hold in a small area of Whitechapel. However, the area was not yet connected to Bazalgette's system, and the confined area of the epidemic acted as testament to the efficiency of the system's design.
Years later, the influence of those sanitary reforms on Britain was described by Richard Rogers:
London was the first city to create a complex civic administration which could coordinate modern urban services, from public transport to housing, clean water to education. London's County Council was acknowledged as the most progressive metropolitan government in the world. Fifty years earlier, London had been the worst slum city of the industrialized world: over-crowded, congested, polluted and ridden with disease...
The miasma theory did contribute to containing disease in urban settlements, but did not allow the adoption of a suitable approach to the reuse of excreta in agriculture. It was a major factor in the practice of collecting human excreta from urban settlements and reusing them in the surrounding farmland. That type of resource recovery scheme was common in major cities in the 19th century before the introduction of sewer-based sanitation systems. Nowadays, the reuse of excreta, when done in a hygienic manner, is known as ecological sanitation, and is promoted as a way of "closing the loop".
Throughout the 19th century, concern about public health and sanitation, along with the influence of the miasma theory, were reasons for the advocacy of the then-controversial practice of cremation. If infectious diseases were spread by noxious gases emitted from decaying organic matter, that included decaying corpses. The public health argument for cremation faded with the eclipsing of the miasma theory of disease.
== Replacement by germ theory ==
Although the connection between germ and disease was proposed quite early, it was not until the late 1800s that the germ theory was generally accepted. The miasmatic theory was challenged by John Snow, suggesting that there was some means by which the disease was spread via a poison or morbid material (orig: materies morbi) in the water. He suggested this before and in response to a cholera epidemic on Broad Street in central London in 1854. Because of the miasmatic theory's predominance among Italian scientists, the discovery in the same year by Filippo Pacini of the bacillus that caused the disease was completely ignored. It was not until 1876 that Robert Koch proved that the bacterium Bacillus anthracis caused anthrax, which brought a definitive end to miasma theory.
=== 1854 Broad Street cholera outbreak ===
The work of John Snow is notable for helping to make the connection between cholera and typhoid epidemics and contaminated water sources, which contributed to the eventual demise of miasma theory. During the cholera epidemic of 1854, Snow traced high mortality rates among the citizens of Soho to a water pump in Broad Street. Snow convinced the local government to remove the pump handle, which resulted in a marked decrease in cases of cholera in the area. In 1857, Snow submitted a paper to the British Medical Journal which attributed high numbers of cholera cases to water sources that were contaminated with human waste. Snow used statistical data to show that citizens who received their water from upstream sources were considerably less likely to develop cholera than those who received their water from downstream sources. Though his research supported his hypothesis that contaminated water, not foul air, was the source of cholera
epidemics, a review committee concluded that Snow's findings were not significant enough to warrant change, and they were summarily dismissed. Additionally, other interests intervened in the process of reform. Many water companies and civic authorities pumped water directly from contaminated sources such as the Thames to public wells, and the idea of changing sources or implementing filtration techniques was an unattractive economic prospect. In the face of such economic interests, reform was slow to be adopted.
In 1855, John Snow made a testimony against the Amendment to the "Nuisances Removal and Diseases Prevention Act" that regularized air pollution of some industries. He claimed that:
That is possible; but I believe that the poison of the cholera is either swallowed in water, or got directly from some other person in the family, or in the room; I believe it is quite an exception for it to be conveyed in the air; though if the matter gets dry it may be wafted a short distance.
The same year, William Farr, who was then the major supporter of the miasma theory, issued a report to criticize the germ theory. Farr and the Committee wrote that:
After careful inquiry, we see no reason to adopt this belief. We do not feel it established that the water was contaminated in the manner alleged; nor is there before us any sufficient evidence to show whether inhabitants of that district, drinking from that well, suffered in proportion more than other inhabitants of the district who drank from other sources.
=== Experiments by Louis Pasteur ===
The more formal experiments on the relationship between germ and disease were conducted by Louis Pasteur between 1860 and 1864. He discovered the pathology of the puerperal fever and the pyogenic vibrio in the blood, and suggested using boric acid to kill these microorganisms before and after confinement.
By 1866, eight years after the death of John Snow, William Farr publicly acknowledged that the miasma theory on the transmission of cholera was wrong, by his statistical justification on the death rate.
=== Anthrax ===
Robert Koch is widely known for his work with anthrax, discovering the causative agent of the fatal disease to be Bacillus anthracis. He published the discovery in a booklet as Die Ätiologie der Milzbrand-Krankheit, Begründet auf die Entwicklungsgeschichte des Bacillus Anthracis (The Etiology of Anthrax Disease, Based on the Developmental History of Bacillus Anthracis) in 1876 while working in Wöllstein. His publication in 1877 on the structure of anthrax bacterium marked the first photography of a bacterium. He discovered the formation of spores in anthrax bacteria, which could remain dormant under specific conditions. However, under optimal conditions, the spores were activated and caused disease. To determine this causative agent, he dry-fixed bacterial cultures onto glass slides, used dyes to stain the cultures, and observed them through a microscope. His work with anthrax is notable in that he was the first to link a specific microorganism with a specific disease, rejecting the idea of spontaneous generation and supporting the germ theory of disease.
== See also ==
Germ theory of disease
Airborne disease
Indoor air quality
== References ==
== Further reading ==
Beasley, Brett (September 30, 2015). "Bad Air: Pollution, Sin, and Science Fiction in William Delisle Hay's The Doom of the Great City (1880)". The Public Domain Review. 5 (18).
Sterner, Carl S. (2007). "A Brief History of Miasmic Theory" (PDF). Bulletin of the History of Medicine. 22 (1948): 747.
Thorsheim, Peter (2006). Inventing Pollution: Coal, Smoke, and Culture in Britain since 1800. Ohio University Press. ISBN 978-0-8214-1681-5.
== External links ==
Prevailing theories before the germ theory
Cholera theories
Term definition | Wikipedia/Miasma_theory |
Germ theory denialism is the pseudoscientific belief that germs do not cause infectious disease, and that the germ theory of disease is wrong. It usually involves arguing that Louis Pasteur's model of infectious disease was wrong, and that Antoine Béchamp's was right. In fact, its origins are rooted in Béchamp's empirically disproven (in the context of disease) theory of pleomorphism. Another obsolete variation is known as terrain theory and postulates that germs morphologically change in response to environmental factors, subsequently causing disease, rather than germs being the sole cause of it.
== History ==
Germ theory denialism is as old as germ theory itself, beginning with the rivalry of Pasteur and Béchamp. Pasteur's work in preventing beverage contamination led him to discover that it was due to microorganisms and led him to become the first scientist to prove the validity of the theory and to popularize it in Europe. Before him, scientists such as Girolamo Fracastoro (who had the idea that fomites could harbor the seeds of contagion), Agostino Bassi (who discovered that the muscardine disease of silkworms was caused by a fungus that was named Beauveria bassiana), Friedrich Henle (who developed the concepts of contagium vivum and contagium animatum), and others had proposed ideas similar to germ theory.
Béchamp strongly contested Pasteur's view, proposing a competing idea known as the pleomorphic theory of disease. This theory says that all life is based on forms that a certain class of organisms take during stages of their life cycles and that germs are attracted to the environment of diseased tissue rather than being the cause of it. Proponents of this idea insist that microbes that live in an organism go through the same stages of their development. According to Günther Enderlein, the stages are as follows:
colloid – microbe (primitive phase)
bacteria (middle phase)
fungus (end phase)
=== Terrain theory ===
The terrain theory is a variation of Béchamp's ideas that is also an obsolete medical theory that held that diseases were caused by the composition of the body. The "terrain", will attract germs to come as scavengers of the weakened or poorly defended tissue. Béchamp believed that the pH of the body is important, and that an acidic pH will attract germs and an alkaline pH will repel them. Pasteur disproved spontaneous generation with a series of experiments in the 1870s. However, understanding the cause of a sickness does not always immediately lead to effective treatment of sickness, and the great decline in mortality during the 19th century stemmed mostly from improvements in hygiene and cleanliness. In fact, one of the first movements to deny the germ theory, the Sanitary Movement, was nevertheless central in developing America's public health infrastructure. Providing clean water and sanitation reduced the environment for pathogens to develop, and mortality rates fell dramatically.
== Status ==
Germ theory denialism is counter to over a century of experiments and practical observations, and the prevailing opinion of almost all doctors and scientists.
A common thread among many alternative medicine proponents is opposition to vaccines, and some use their disbelief in germ theory to justify their claims. Germ theory deniers make many claims about the biological underpinnings of the theory and the historical record that are at odds with what most modern scientists and historians accept. Another claim from the anti-vaccine community involves the theory that all diseases are caused by toxins due to inadequate diet and health practices.
== See also ==
Vaccine hesitancy
HIV/AIDS denialism
COVID-19 misinformation
Category:Germ theory denialists
Hygiene hypothesis
Pleomorphism (microbiology)
== References ==
== External links ==
"RFK Jr. rejects cornerstone of health science: Germ theory". Ars Technica. Retrieved 2025-04-30. | Wikipedia/Germ_theory_denialism |
Climate change adaptation strategies on the German coast include European, national, and regional politics, different economic and civilian sectors as well as coastal protection. In general, climate change refers to statistically identifiable changes in climate properties that persist over a longer period of time. The United Nations Framework Convention on Climate Change (UNFCCC) defines it as a change in climate caused by human activity that can be observed in addition to natural climate variability. This can be described as anthropogenic climate change. Climate change poses local level impacts on the German coast and for the present and future, suitable adaptation strategies are necessary. In 2008, the Federal Cabinet of Germany decided on a German Climate Change Adaptation Strategy with the objective of creating a national action framework for reducing the risks for the population, habitats as well as the economy.
Adaptation is a contested, widely discussed term with no general definition. For the German Adaptation Strategy the definition of the Intergovernmental Panel on Climate Change (IPCC) is utilized, stating that adaptation is the adjustment of natural or human systems to occurring or expected changes in climate in order to reduce harm. This approach views climate change as the major source of vulnerability and does not consider any social causes.
The German Coast comprises 1600 km to the west at the North Sea and 2100 km to the east at the Baltic Sea. In total, five states border the German coast. Lower Saxony, Bremen and Hamburg are part of the North Sea region; Mecklenburg-Vorpommern border the Baltic Sea and Schleswig-Holstein is located at both seas. Coast can be defined as the zone where the land is considerably influenced by the sea and vice versa.
== History of climate change adaptation at the German coast ==
The coastal inhabitants in Germany have always been exposed to the forces of nature, especially to storm floods and had to adapt to changing conditions. It is assumed that in Schleswig-Holstein in the 11th century, people started to build dykes to protect living and usable spaces from sea level rise and storm floods. Adaptation especially to the Anthropogenic Climate Change started in the 21st century, although initially the focus has been on climate protection. The German Government took up climate change adaptation for the first time in 2005 in the frame of its climate protection programme.
== Climate change impacts on the German coast ==
Certain and reliable predictions for impacts of anthropogenic climate change on the German coast regarding temperature, precipitation, sea level and storm flood heights do not exist. Different models show different results and it is assumed that all changes in the range of the results have the same likelihood to occur. For the end of the 21st century, the temperature is expected to rise between +0.6 °C and +6.2 °C in comparison to 1961–1990. For the same period of time, a change of precipitation between -47% and +73% is likely.
Sea level and storm floods are complex phenomena and are influenced by diverse factors, such as astronomical (tides), meteorological (wind), and tectonic (isostatic movements) variables which makes it even more difficult to predict how they will change with climate change. At the Baltic Sea, sea level is expected to rise in line with the expected global average rise in sea level. According to the Intergovernmental Penal on Climate Change (IPCC) 5th Assessment Report, global average sea level is predicted to rise 0.26-0.55 m in the period 2081–2100 in relation to 1986-2005 sea level. Studies show that at the German North Sea coast, sea level from 1843-2008 has risen between 1,6 and 1,8 mm per year. Higher values have been observed at the west coast of Schleswig-Holstein and lower values at the Lower Saxon coast. In future, sea level rise at the North Sea is expected to be higher than the global average as a result of post-glacial land depression. There is now statistical evidence existing on how the storm flood height will change in future at the Baltic Sea. At both seas, a rise in storm flood height is expected due to climate change related sea level rise.
== Politics of climate change adaptation ==
European, national as well as regional politics play a role in climate change adaptation at the German North Sea coast and Baltic Sea coast. In 2009, the European Union presented the White Paper Adapting to Climate Change: Towards a European framework for action which was a first approach to joint climate change adaptation politics. In 2013, the European Union established the EU Strategy on Adaptation to Climate Change. National and local climate change adaptation programs for the German coast are often considered as part of the EU Strategy on Adaptation to Climate Change. In a local setting, urban planning is an important part of adaptation politics.
=== European climate change adaptation politics for the North Sea and Baltic Sea ===
The German North Sea is part of the North Sea Region (NSR) Program 2014 - 2020 of the European Climate Adaptation Platform (Climate-ADAPT). This regional European development fund includes coastal zones of the United Kingdom, Belgium, the Netherlands, Germany, Denmark, Sweden and Norway. NSR developed a cooperation program, which was adopted by the European Commission in August 2015. The cooperation program focuses on adaptation to climate change impacts and on preserving the environment, stimulating a green economy, promoting green transportation and mobility as well as supporting growth in the North Sea Region. Another actor in climate change adaptation in the German North Sea Region is the Wadden Sea Secretariat, a cooperation between Denmark, The Netherlands, and Germany that has been established in 1978 to protect the Wadden Sea as an ecological entity. The Wadden Sea Secretariat addresses and communicates the impacts of climate change on the Wadden Sea. In 1998, the working group Coastal Protection and Sea Level Rise (CPSL) was founded, dealing with the impacts of climate change. Until 2010, the CPSL has published three reports, which provided information for governmental conferences.
The Baltic Sea Region Program was developed by the EU Climate Adaptation Platform (Climate-ADAPT) to strengthen development and cooperation between the abutting nations of the Baltic Sea. In 2013, the predecessor EU Project BALTADAPT (Baltic Sea Region Climate Change Adaptation Strategy) published an action plan for climate change adaptation in the Baltic Sea regions. It focused on strategies for building and sharing knowledge of climate change adaptation, mainstreaming it and on connecting the strategies of the nations in the Baltic Sea Region to adapt to climate change.
=== German climate change adaptation politics for the North Sea and the Baltic Sea ===
The political framework for climate change adaptation in Germany is given by the German Strategy for Adaptation to Climate Change (2008). Regarding climate change at the North Sea and the Baltic Sea, the strategy states that the expected magnitude of damage due to climate change is unclear. In 2011, the German government presented an action plan for climate change adaptation which includes resolutions from the Wadden Sea Secretariat for the North Sea Region. In behalf of the Federal Environmental Agency (UBA), the project KüstenKlima (2014) by the Institut Raum & Energie (...) published a strategy for climate protection and climate change adaptation at the German coast mainly due to coastal management. In the report, it was highlighted that an integrated coastal zone management (IKZM) is an important method for adaptation. IKZM is an informal management approach to strengthen sustainable development by means of integration, communication, good coordination practice, and participation. The Federal Ministry of Education and Research (BMBF) facilitates the project KLIMZUG - Klimawandel in Regionen zukunftsfähig gestalten (2008-2014) which includes adaptation strategies in seven model regions in Germany. The "KLIMZUG" program aimed to integrate climate change adaptation processes into regional development. Three of this model regions are located at the German coast. The program "KLIMZUG-NORD" focuses on the metropolitan region Hamburg, the program "RADOST" on adaptation strategies for the German Baltic Sea coast and "nordwest2050" is a research project for climate change adaptation and innovation processes for the metropolitan region of Bremen and Oldenburg.
At the level of Länder there are also individual climate change adaptation programs.
==== Mecklenburg-Vorpommern ====
The state government of Mecklenburg-Vorpommern presented a first climate protection program in the year 1997 (Aktionsplan Klimaschutz Mecklenburg-Vorpommern).
The Baltic Sea region of Mecklenburg Vorpommern is part of the EU BALTADAPT program.
==== Schleswig-Holstein ====
Based on the German adaptation strategy to climate change, the state government of Schleswig-Holstein for the first time presented a strategy for climate change adaptation (Fahrplan Anpassung an den Klimawandel) in 2011. The program was updated in 2017. The proximity to North Sea and Baltic Sea strongly influenced the program which can be recognized in the highlighted topics water economy and protection of the sea and soil.
==== Bremen ====
Besides actions in coastal protection, there is the project KLAS - Klimaanpassungsstrategie an extreme Regenereignisse in der Stadtgemeinde Bremen promoted by the Federal Ministry for the Environment, Nature Conservation and Nuclear Safety (BMU). The program aims to develop a better risk management for strong rain events.
==== Hamburg ====
Hamburg is a model region for the national project KLIMZUG-NORD. A strategy for climate change adaptation was developed in 2011. In 2013, an action plan for climate change adaptation was published.
==== Lower-Saxony ====
The state government of Lower-Saxony established a government commission for climate protection and adaptation in 2008 to develop a strategy for climate change adaptation and protection. In 2013, the state government enacted the Klimapolitische Umsetzungsstrategie Niedersachen. This program includes coastal protection strategies.
== Adaptation strategies in coastal protection ==
According to DIN 4047–2, coastal protection comprises measures defending the shoreline against destructive interactions with the sea. That includes the protection of the coastal lowlands against flooding to allow the use of these areas as well as the protection of the coastline against shoreline recession and coastal erosion.
When it comes to climate change adaptation, coastal protection in Germany divides into three categories of measures:
Defence of the existing coastline
"hard" solutions (e.g. heightening and fortification of levees)
"soft" solutions (e.g. establishment of shallow water areas for retention of floods)
Adaptation to extreme weather events, e.g. by building on dwelling mounds or other forms of constructional preventions
Moving away from coastal areas to less affected regions, not using or extensively using the coastal regions
=== Coastal protection policy ===
Coastal protection in Germany is organised and structured by legal regulations. Climate change adaptation in Germany has to be integrated in coastal protection plans on all spatial levels in order to achieve effective adaptation of the coastal protection sector. German administration distinguishes between active and passive coastal protection. Active coastal protection refers to measures that support floodplain reclamation and approaches to relocate acting forces (current, breaking wave) seawards (e.g. by beach nourishment) whereas passive coastal protection solidifies the shoreline (so-called hold the line approaches) and supports the absorption of incoming forces to avoid harmful consequences. Passive coastal protection can include seawalls, groynes, detached breakwaters, and revetments. Important actors in coastal risk management are political authorities, inhabitants of the respective region (households) as well as investors.
Traditionally, coastal protection in Germany is focussed on technical protection measures (i.a. levees, artificial flood barriers). This approach has already been followed in the Generalplan Deichverstärkung, Deichverkürzung und Küstenschutz des Landes Schleswig-Holstein of 1963, a specific coastal protection plan for Schleswig-Holstein. Today (2017-2020), technical measures are still most probable to be funded by the state. According to the German Federal agency for the environment (UBA), coastal protection currently focusses on the fortification and heightening of levees and other protective structures, including retaining structures. It is a matter of discussion if and how these types of linear "hard" protection measures can in the face of climate change be extended to planar "soft" protection measures (e.g. (re-)instalment of shallow water areas to simultaneously reach nature conservation and climate protection goals).
Facing future climate risks, coastal protection increasingly integrates landscape-based prevention measures. The German government aims to enhance synergies between "hard" and "soft" coastal protection measures by means of the Integriertes Küstenzonenmanagement approach (Integrated Coastal Zone Management, IKZM). Its former general principle of "defending at all cost" is currently converting towards "living with water" and is putting stronger emphasis on changing climatic conditions. This means for example that in spaces where neither individuals nor material values are at risk, it is an option to partially open up dykes and thereby enable self-acting adaptation. Connected to that is the expressed ambition to coordinate adaptation measures, to fit coastal areas in an overall spatial context and to involve a wide range of relevant actors (e.g. authorities, interest groups, science). Essential weight is put on harmonising economic and social beneficiary claims with protection interests in the coastal zone by elaborating on development trajectories, conflict potentials and solutions at an early stage of planning. Another aspect of coordinated adaptation in coastal protection refers to connections between urban and rural areas. Coastal protection in rural areas in northern Germany should be seen in connection with protection measures in big cities such as Hamburg or Bremen where discussed "soft" measures are less easily to implement. In the cities, linear protection measures like levees and flood walls will probably be further enhanced/fostered but it would be interesting for cities to participate in solutions of laminar coastal protection.
=== Adaptation in practical coastal protection ===
In order to find and establish adequate measures to adapt coastal protection to climate change, responsible actors in coastal protection need to have sound and detailed local and hydromorphological knowledge. Even with that, it is very difficult to predict direct and indirect consequences of climate change on the German coast. Challenging for planning authorities is a lack of clear information on future sea level dynamics. As there are no exact prognoses for sea level rise at the German coasts, planners of coastal protection measures as well as the inhabitants of the region are facing considerable uncertainties. Related to sea level rise, coastal protection has to react to higher base levels in the event of a storm flood. High storm flood levels are expected to be faster reached and longer lasting and storm floods that once only occurred every 350 years are predicted to happen once every 100 years by the middle of the 21st century. Especially in winter, stronger storms and higher levels of storm floods are expected as much as changes in sea conditions that cause major cases of coastal erosion and can pose more strain on levees by increased wave runup. Existing levees have usually been constructed to protect the hinterland against floods that statistically occur once every 350 years. As a result of the expected sea level rise, storm floods become more likely and the levees have to be adapted to that in their construction.
The protection level of these so-called "hard" technical coastal protection measures is currently determined on the basis of records from historic flooding events, and extrapolation (updating) of the previous sea level trends. Experts demand to better include a risk-oriented design of coastal protection measures and land use planning at the German coast and to integrate climate change scenarios (e.g. by respecting long-term climate change scenarios and the suspected rising sea level).
=== Finance ===
Innovative coastal protection measures require consistent economic incentives. In Germany, these can be compensations in the case of income losses resulting from coastal protection measures or buying land for setting back levees. Further, (re-)established water areas can be interesting for tourism or aquaculture.
The German Federal government can fund up to 70% of the investment costs that the Länder spend for coastal protection measures. Within the Sonderrahmenplan: Maßnahmen des Küstenschutzes in Folge des Klimawandels (2009-2025) (special framework for climate change related coastal protection measures), 25 million euros are provided by the state and the Länder. Other funding can be applied from the European development funds EAFRD and ERDF. It is expected that the total costs for coastal protection will considerably rise within the next year to reach 800 to 1000 billion euros.
== Adaptation strategies of the economy ==
Climate change influences the economy in German coastal regions which makes an adaptation in time necessary. This affects different economic sectors like the tourism industry, agriculture, the fishing industry or shipping.
=== Tourism industry ===
==== Impacts of climate change ====
Climate change implies risks and opportunities for the regional tourism of the German coast.
Higher temperatures and less precipitation in summer can enhance the attractiveness of coastal tourist destinations in Germany and extend the bathing season. The bathing season could be up to 60 days longer in 2100 which can entail around 25-30 percent more tourists. Higher numbers of visitors can open opportunities for the tourism industry, but can also lead to an overload for the local infrastructure. It increases the utilization pressure on ecosystems which is problematic as some places at the Baltic Sea have reached their capacity limit already.
Negative consequences are expected due to sea level rise and bigger waves which cause beach erosion and contribute to an inland shifting of the coastline. This can adversely affect the beach tourism. Water sports and other tourism activities can be limited due to heavy swell. Heavy rainfalls and floods can damage tourism institutions.
An increasing growth of algaes, seaweed and bacteria can deteriorate the water quality. This can be dangerous for the health of tourists and therefore reduce the attractiveness of the affected places. More jellyfishes can reduce the attractiveness of seaside resorts.
==== Adaptation strategies ====
The climate change adaptation strategies of the German coast are usually only indirectly linked to tourism as they are mainly coastal protection strategies, but also beneficial for the tourism industry. The adaptation possibilities depend on the individual characteristics of the specific holiday destinations. A difficulty is that climate change is not the only influencing factor on the tourism industry. Other external factors like different travel behavior or demographic changes have to be considered as well. In general, so called "no-regret-measures" are useful, which are strategies that are also beneficial without the effects of climate change as they contribute to a sustainable development of a certain region.
Most important is the preservation of the touristic potential of the regions which means the protection of nature. Second, visitors increasingly demand a climate-conscious behavior of the tourist providers. Every measure should be accompanied with information material for guests and local inhabitants. Some strategies want to strengthen offers that are independent from climate change like indoor halls or wellness.
The current focus of climate change adaptation in the tourism industry is on sharing of information with all decision makers, network building and the development of strategic planning concepts. The adaptation willingness so far is rather low because of the complexity, uncertainty and the potential chances like a longer bathing season.
=== Fishing industry ===
==== Impacts of climate change ====
As a consequence of climate change, the North Sea and Baltic Sea will warm up. The CO2 content of the water will increase which makes it more acid. Together with extreme weather events and sea level rise, it will threaten long exiting habitats. Fish stocks and the population of marine organisms as well as marine food webs and rivalry situations are changing.
In the North Sea, the warmer water leads to a shift of the habitats of cold-loving fish stocks like cod and plaice to lower water temperatures in the North. The population of other marine animals will decline due to warmer winters. Favored by the warming of the sea, new species that have lived in more southern areas before like anchovies or the Pacific oyster will appear in the North Sea. The Baltic Sea as a brackish water is characterized by a highly sensitive ecosystem. Small changes in temperature, salinity and oxygen content lead to a significant shift in the compound of species. Climate change can shift the walking and spawning seasons of fishes and the vulnerability to infections and parasites is increasing.
The shift of habitats of fish populations to the North combines with big financial losses for the local fishing industry which is an important economic sector for some structurally weak coastal areas. It especially affects very small, financially weak fishing companies. If these losses can be compensated by new species is not known yet. Coastal production facilities are in danger of being flooded or damaged by sea level rise and storm floods. Higher swell and extreme weather events can deteriorate the fishing conditions.
It's hard to differentiate between the consequences of climate change and other influencing stress factors like overfishing, shipping or pollutants in the water.
==== Adaptation strategies ====
There are different technical possibilities to make the fishing industry more sustainable. Improved fishing techniques and mesh sizes for nets contribute to reduce by-catches. A real-time monitoring of the catches could support the establishment of sanctuaries by justifying seasonal and territorial restrictions for the fishery. It makes an adaptation of the catch amount and fished species possible. Protection zones would help to recover the full reproductivity of fish stocks. It is important to explain the consumers which fish species can be bought and which not. New sources of income for fishermen, for example in the tourism industry, could be another strategy.
=== Shipping industry ===
The potential climate change impacts at the German coast will pose risks and chances for the shipping industry to which especially harbours will have to adapt to. The economic efficiency of waterways, shipping routes and construction measures depend on water conditions, current as well as sediment transport. The three KLIMZUG projects "RADOST", "nordwest2050" and "KLIMZUG-NORD" include research and adaptation strategies for harbours and the shipping industry in general.
==== Port of Hamburg ====
===== Impacts of climate change =====
It exists high uncertainty concerning the impacts of climate change on the local scale of the Port of Hamburg. A rise in sea level is expected to cause increased tidal range as well as higher flood current speed which will have effects on the water level of the Elbe river. Higher quantities of precipitation and extreme rainfalls related to climate change can lead to increased groundwater potential. Lower precipitation which is also likely can cause higher upstream transportation of sediments.
Floods caused by storm floods, rise in water level due to climate change related sea level rise, higher precipitation and extreme rainfall can lead to disruption of transportation and can have negative effects on industries that depend on harbours. Stronger winds can complicate the storage of empty containers as well as navigation in the Harbour of Hamburg. Inland water transport can be hampered by the rise in sea level as for example the passing underneath bridges might not be possible any more for bigger ships. Increased sediment deposit can lead to lower water level which will limit the size of suitable ships. In contrast, higher air temperature and ice melting can have positive effects for the Hamburg Harbour economy. Less ice and snow would cause less damage on buildings and infrastructure in general which means less costs for reparation. Furthermore, less costs for disruption would result. With the melting of ice, a new shorter waterway to Asia would be accessible. This could be a more time and cost-effective alternative to the current shipping route.
===== Adaptation strategies =====
For the implementation of adaptation strategies, it has to be dealt with a high uncertainty concerning the changes, the assessment of their likelihood as well as the calculation of the necessary resources. For the protection against increased floods and storm floods, on the one hand, technical solutions such as further dykes and the fortification of existing ones, flood barriers and on the other hand, the restoration of natural flood plains are being discussed. It might be necessary to raise existing bridges, roads and railways to ensure the crossability for bigger ships. Drainage systems will have to be adapted in order to deal with longer and higher storm floods as well as with higher middle Elbe water level. For the increased sediment transport, a regular maintenance of the water way in order to maintain a shippable water level will be necessary.
== References ==
== Further reading ==
Klimabündnis Kieler Bucht
KLIMZUG-NORD - Strategische Anpassungsansäze zum Klimawandel in der Metropolregion Hamburg: Klimafolgen und Anpassung | Wikipedia/Climate_change_adaptation_strategies_on_the_German_coast |
Flood management or flood control are methods used to reduce or prevent the detrimental effects of flood waters. Flooding can be caused by a mix of both natural processes, such as extreme weather upstream, and human changes to waterbodies and runoff. Flood management methods can be either of the structural type (i.e. flood control) and of the non-structural type. Structural methods hold back floodwaters physically, while non-structural methods do not. Building hard infrastructure to prevent flooding, such as flood walls, is effective at managing flooding. However, it is best practice within landscape engineering to rely more on soft infrastructure and natural systems, such as marshes and flood plains, for handling the increase in water.
Flood management can include flood risk management, which focuses on measures to reduce risk, vulnerability and exposure to flood disasters and providing risk analysis through, for example, flood risk assessment. Flood mitigation is a related but separate concept describing a broader set of strategies taken to reduce flood risk and potential impact while improving resilience against flood events.
As climate change has led to increased flood risk an intensity, flood management is an important part of climate change adaptation and climate resilience. For example, to prevent or manage coastal flooding, coastal management practices have to handle natural processes like tides but also sea level rise due to climate change. The prevention and mitigation of flooding can be studied on three levels: on individual properties, small communities, and whole towns or cities.
== Terminology ==
Flood management is a broad term that includes measures to control or mitigate flood waters, such as actions to prevent floods from occurring or to minimize their impacts when they do occur.
Flood management methods can be structural or non-structural:
Structural flood management (i.e.: flood control) is the reduction of the effects of a flood using physical solutions, such as reservoirs, levees, dredging and diversions.
Non-structural flood management includes land-use planning, advanced warning systems and flood insurance. Further examples are: "zoning ordinances and codes, flood forecasting, flood proofing, evacuation and channel clearing, flood fight activities, and upstream land treatment or management to control flood damages without physically restraining flood waters".
There are several related terms that are closely connected or encompassed by flood management.
Flood management can include flood risk management, which focuses on measures to reduce risk, vulnerability and exposure to flood disasters and providing risk analysis through, for example, flood risk assessment. In the context of natural hazards and disasters, risk management involves "plans, actions, strategies or policies to reduce the likelihood and/or magnitude of adverse potential consequences, based on assessed or perceived risks".
Flood control, flood protection, flood defence and flood alleviation are all terms that mean "the detention and/or diversion of water during flood events for the purpose of reducing discharge or downstream inundation". Flood control is part of environmental engineering. It involves the management of water movement, such as redirecting flood run-off through the use of floodwalls and flood gates to prevent floodwaters from reaching a particular area.
Flood mitigation is a related but separate concept describing a broader set of strategies taken to reduce flood risk and potential impact while improving resilience against flood events. These methods include prevention, prediction (which enables flood warnings and evacuation), proofing (e.g.: zoning regulations), physical control (nature-based solutions and physical structures like dams and flood walls) and insurance (e.g.: flood insurance policies).
Flood relief methods are used to reduce the effects of flood waters or high water levels during a flooding event. They include evacuation plans and rescue operations. Flood relief is part of the response and recovery phase in a flood management plan.
== Causes of flooding ==
=== Precipitation, absorption, and runoff ===
=== Flood levels: blunting the peak ===
Water levels during a flood tend to rise, then fall, very abruptly. The peak flood level occurs as a very steep, short spike; a quick spurt of water. Anything that slows the surface runoff (marshes, meanders, vegetation, porous materials, turbulent flow, the river spreading over a floodplain) will slow some of the flow more than other parts, spreading the flow over time and blunting the spike. Even slightly blunting the spike significantly decreases the peak flood level. Generally, the higher the peak flood level, the more flood damage is done. Modern flood control seeks to "slow the flow", and deliberately flood some low-lying areas, ideally vegetated, to act as sponges, letting them drain again as the floodwaters go down.
== Purposes ==
Where floods interact with housing, industry and farming that flood management is indicated and in such cases environmentally helpful solutions may provide solutions. Natural flooding has many beneficial environmental effects. This kind of flooding is usually a seasonal occurrence where floods help replenish soil fertility, restore wetlands and promote biodiversity.
=== Reducing the impacts of floods ===
Flooding has many impacts. It damages property and endangers the lives of humans and other species. Rapid water runoff causes soil erosion and concomitant sediment deposition elsewhere (such as further downstream or down a coast). The spawning grounds for fish and other wildlife habitats can become polluted or completely destroyed. Some prolonged high floods can delay traffic in areas which lack elevated roadways. Floods can interfere with drainage and economical use of lands, such as interfering with farming. Structural damage can occur in bridge abutments, bank lines, sewer lines, and other structures within floodways. Waterway navigation and hydroelectric power are often impaired. Financial losses due to floods are typically millions of dollars each year, with the worst floods in recent U.S. history having cost billions of dollars.
=== Protection of individual properties ===
Property owners may fit their homes to stop water entering by blocking doors and air vents, waterproofing important areas and sandbagging the edges of the building. Private precautionary measures are increasingly important in flood risk management.
Flood mitigation at the property level may also involve preventative measures focused on the building site, including scour protection for shoreline developments, improving rainwater in filtration through the use of permeable paving materials and grading away from structures, and inclusion of berms, wetlands or swales in the landscape.
=== Protection of communities ===
When more homes, shops and infrastructure are threatened by the effects of flooding, then the benefits of protection are worth the additional cost. Temporary flood defenses can be constructed in certain locations which are prone to floods and provide protection from rising flood waters. Rivers running through large urban developments are often controlled and channeled. Water rising above a canal's full capacity may cause flooding to spread to other waterways and areas of the community, which causes damage. Defenses (both long-term and short-term) can be constructed to minimize damage, which involves raising the edge of the water with levees, embankments or walls. The high population and value of infrastructure at risk often justifies the high cost of mitigation in larger urban areas.
=== Protection of wider areas such as towns or cities ===
The most effective way of reducing the risk to people and property is through the production of flood risk maps. Most countries have produced maps which show areas prone to flooding based on flood data. In the UK, the Environment Agency has produced maps which show areas at risk. The map to the right shows a flood map for the City of York, including the floodplain for a 1 in 100-year flood (dark blue), the predicted floodplain for a 1 in 1000 year flood (light blue) and low-lying areas in need of flood defence (purple). The most sustainable way of reducing risk is to prevent further development in flood-prone areas and old waterways. It is important for at-risk communities to develop a comprehensive Floodplain Management plan.
In the US, communities that participate in the National Flood Insurance Program must agree to regulate development in flood-prone areas.
=== Strategic retreat ===
One way of reducing the damage caused by flooding is to remove buildings from flood-prone areas, leaving them as parks or returning them to wilderness. Floodplain buyout programs have been operated in places like New Jersey (both before and after Hurricane Sandy), Charlotte, North Carolina, and Missouri.
In the United States, FEMA produces flood insurance rate maps that identify areas of future risk, enabling local governments to apply zoning regulations to prevent or minimize property damage.
=== Resilience ===
Buildings and other urban infrastructure can be designed so that even if a flood does happen, the city can recover quickly and costs are minimized. For example, homes can be put on stilts, electrical and HVAC equipment can be put on the roof instead of in the basement, and subway entrances and tunnels can have built-in movable water barriers. New York City began a substantial effort to plan and build for flood resilience after Hurricane Sandy. Flood resilience technologies support the fast recovery of individuals and communities affected, but their use remains limited.
=== Climate change adaptation ===
== Structural methods ==
Some methods of flood control have been practiced since ancient times. These methods include planting vegetation to retain extra water, terracing hillsides to slow flow downhill, and the construction of floodways (man-made channels to divert floodwater). Other techniques include the construction of levees, lakes, dams, reservoirs, retention ponds to hold extra water during times of flooding.
=== Dams ===
Many dams and their associated reservoirs are designed completely or partially to aid in flood protection and control. Many large dams have flood-control reservations in which the level of a reservoir must be kept below a certain elevation before the onset of the rainy/summer melt season to allow a certain amount of space in which floodwaters can fill. Other beneficial uses of dam created reservoirs include hydroelectric power generation, water conservation, and recreation. Reservoir and dam construction and design is based upon standards, typically set out by the government. In the United States, dam and reservoir design is regulated by the US Army Corps of Engineers (USACE). Design of a dam and reservoir follows guidelines set by the USACE and covers topics such as design flow rates in consideration to meteorological, topographic, streamflow, and soil data for the watershed above the structure.
The term dry dam refers to a dam that serves purely for flood control without any conservation storage (e.g. Mount Morris Dam, Seven Oaks Dam).
=== Diversion canals ===
=== Floodplains and groundwater replenishment ===
Excess water can be used for groundwater replenishment by diversion onto land that can absorb the water. This technique can reduce the impact of later droughts by using the ground as a natural reservoir. It is being used in California, where orchards and vineyards can be flooded without damaging crops, or in other places wilderness areas have been re-engineered to act as floodplains.
=== River defenses ===
In many countries, rivers are prone to floods and are often carefully managed. Defenses such as levees, bunds, reservoirs, and weirs are used to prevent rivers from bursting their banks. A weir, also known as a lowhead dam, is most often used to create millponds, but on the Humber River in Toronto, a weir was built near Raymore Drive to prevent a recurrence of the flood damage caused by Hurricane Hazel in October 1954.
The Leeds flood alleviation scheme uses movable weirs which are lowered during periods of high water to reduce the chances of flooding upstream. Two such weirs, the first in the UK, were installed on the River Aire in October 2017 at Crown Point, Leeds city centre and Knostrop. The Knostrop weir was operated during the 2019 England floods. They are designed to reduce potential flood levels by up to one metre.
=== Coastal defenses ===
Coastal flooding is addressed with coastal defenses, such as sea walls, beach nourishment, and barrier islands.
Tide gates are used in conjunction with dykes and culverts. They can be placed at the mouth of streams or small rivers, where an estuary begins or where tributary streams, or drainage ditches connect to sloughs. Tide gates close during incoming tides to prevent tidal waters from moving upland, and open during outgoing tides to allow waters to drain out via the culvert and into the estuary side of the dike. The opening and closing of the gates is driven by a difference in water level on either side of the gate.
=== Flood barrier ===
==== Self-closing flood barrier ====
The self-closing flood barrier (SCFB) is a flood defense system designed to protect people and property from inland waterway floods caused by heavy rainfall, gales, or rapid melting snow. The SCFB can be built to protect residential properties and whole communities, as well as industrial or other strategic areas. The barrier system is constantly ready to deploy in a flood situation, it can be installed in any length and uses the rising flood water to deploy.
=== Temporary perimeter barriers ===
When permanent defenses fail, emergency measures such as sandbags, inflatable impermeable sacks, or other temporary barriers are used.
In 1988, a method of using water to control flooding was discovered. This was accomplished by containing 2 parallel tubes within a third outer tube. When filled, this structure formed a non-rolling wall of water that can control 80 percent of its height in external water depth, with dry ground behind it. Eight foot tall water filled barriers were used to surround Fort Calhoun Nuclear Generating Station during the 2011 Missouri River Flooding. Instead of trucking in sandbag material for a flood, stacking it, then trucking it out to a hazmat disposal site, flood control can be accomplished by using the on site water. However, these are not fool proof. A 8 feet (2.4 m) high 2,000 feet (610 m) long water filled rubber flood berm that surrounded portions of the plant was punctured by a skid-steer loader and it collapsed flooding a portion of the facility.
AquaFence consists of interlocking panels which are waterproof and puncture-resistant, can be bolted down to resist winds, and use the weight of floodwater to hold them in place. Materials include marine-grade batlic laminate, stainless steel, aluminum and reinforced PVC canvas. The panels are reusable and can be stored flat between uses. The technology was designed as an alternative to building seawalls or placing sandbags in the path of floodwaters.
Other solutions, such as HydroSack, are polypropylene exteriors with wood pulp within, though they are one-time use.
== Non-structural methods ==
=== Flood risk assessment ===
There are several methods of non-structural flood management that form part of flood risk management strategies. These can involve policies that reduces the amount of urban structures built around floodplains or flood prone areas through land zoning regulations. This helps to reduce the amount of mitigation needed to protect humans and buildings from flooding events. Similarly, flood warning systems are important for reducing risks. Following the occurrence of flooding events, other measures such as rebuilding plans and insurance can be integrated into flood risk management plans. Flood risk management strategy diversification is needed to ensure that management strategies cover several different scenarios and ensure best practices.
Flood risk management aims to reduce the human and socio-economic losses caused by flooding and is part of the larger field of risk management. Flood risk management analyzes the relationships between physical systems and socio-economic environments through flood risk assessment and tries to create understanding and action about the risks posed by flooding. The relationships cover a wide range of topics, from drivers and natural processes, to models and socio-economic consequences.
This relationship examines management methods which includes a wide range of flood management methods including but are not limited to flood mapping and physical implication measures. Flood risk management looks at how to reduce flood risk and how to appropriately manage risks that are associated with flooding. Flood risk management includes mitigating and preparing for flooding disasters, analyzing risk, and providing a risk analysis system to mitigate the negative impacts caused by flooding.
Flooding and flood risk are especially important with more extreme weather and sea level rise caused by climate change as more areas will be effected by flood risk.
=== Flood mapping ===
Flood mapping is a tool used by governments and policy makers to delineate the borders of potential flooding events, allowing educated decisions to prevent extreme flooding events. Flood maps are useful to create documentation that allows policy makers to make informed decisions about flood hazards. Flood mapping also provides conceptual models to both the public and private sectors with information about flooding hazards. Flood mapping has been criticized in many areas around the world, due to the absence of public accessibility, technical writing and data, and lack of easy-to-understand information. However, revived attention towards flood mapping has renewed the interest in enhancing current flood mapping for use as a flood risk management method.
=== Flood modelling ===
Flood modelling is a tool used to model flood hazard and the effects on humans and the physical environment. Flood modelling takes into consideration how flood hazards, external and internal processes and factors, and the main drivers of floods interact with each other. Flood modelling combines factors such as terrain, hydrology, and urban topography to reproduce the evolution of a flood in order to identify the different levels of flooding risks associated with each element exposed. The modelling can be carried out using hydraulic models, conceptual models, or geomorphic methods. Nowadays, there is a growing attention also in the production of maps obtained with remote sensing. Flood modelling is helpful for determining building development practices and hazard mitigation methods that reduce the risks associated with flooding.
=== Stakeholder engagement ===
Stakeholder engagement is a useful tool for flood risk management that allows enhanced public engagement for agreements to be reached on policy discussions. Different management considerations can be taken into account including emergency management and disaster risk reduction goals, interactions of land-use planning with the integration of flood risks and required policies. In flood management, stakeholder engagement is seen as an important way to achieve greater cohesion and consensus. Integrating stakeholder engagement into flood management often provides a more complex analysis of the situation; this generally adds more demand in determining collective solutions and increases the time it takes to determine solutions.
=== Wetland Restoration ===
Wetlands are effective for flood management strategies, particularly in coastal regions, because they are able to hold excess water that flows towards inland regions. For example, the communities of multiple bays and river deltas, including the Chesapeake Bay, the Mississippi River delta, and the Yangtze River delta, benefit from local wetlands with respect to flood management, specifically because wetlands are able to protect inland communities from storm surges that these regions often face. Wetlands also support flood mitigation from a financial perspective. For example, during Hurricane Sandy in 2012, coastal wetlands elicited an estimated $625 million in savings related to the prevention of damage to private property, such as homes, and public infrastructure, such as roadways.
== Costs ==
The costs of flood protection rise as more people and property are to be protected. The US FEMA, for example, estimates that for every $1.00 spent on mitigation, $4.00 is saved.
== Examples by country ==
=== North America ===
==== Canada ====
An elaborate system of flood way defenses can be found in the Canadian province of Manitoba. The Red River flows northward from the United States, passing through the city of Winnipeg (where it meets the Assiniboine River) and into Lake Winnipeg. As is the case with all north-flowing rivers in the temperate zone of the Northern Hemisphere, snow melt in southern sections may cause river levels to rise before northern sections have had a chance to completely thaw. This can lead to devastating flooding, as occurred in Winnipeg during the spring of 1950. To protect the city from future floods, the Manitoba government undertook the construction of a massive system of diversions, dikes, and flood ways (including the Red River Floodway and the Portage Diversion). The system kept Winnipeg safe during the 1997 flood which devastated many communities upriver from Winnipeg, including Grand Forks, North Dakota and Ste. Agathe, Manitoba.
==== United States ====
In the United States, the U.S. Army Corps of Engineers is the lead flood control agency. After Hurricane Sandy, New York City's Metropolitan Transportation Authority (MTA) initiated multiple flood barrier projects to protect the transit assets in Manhattan. In one case, the MTA's New York City Transit Authority (NYCT) sealed subway entrances in lower Manhattan using a deployable fabric cover system called Flex-Gate, a system that protects the subway entrances against 14 feet (4.3 m) of water. Extreme storm flood protection levels have been revised based on new Federal Emergency Management Agency guidelines for 100-year and 500-year design flood elevations.
In the New Orleans Metropolitan Area, 35 percent of which sits below sea level, is protected by hundreds of miles of levees and flood gates. This system failed catastrophically, with numerous breaks, during Hurricane Katrina (2005) in the city proper and in eastern sections of the Metro Area, resulting in the inundation of approximately 50 percent of the metropolitan area, ranging from a few inches to twenty feet in coastal communities.
The Morganza Spillway provides a method of diverting water from the Mississippi River when a river flood threatens New Orleans, Baton Rouge and other major cities on the lower Mississippi. It is the largest of a system of spillways and floodways along the Mississippi. Completed in 1954, the spillway has been opened twice, in 1973 and in 2011.
In an act of successful flood prevention, the federal government offered to buy out flood-prone properties in the United States in order to prevent repeated disasters after the 1993 flood across the Midwest. Several communities accepted and the government, in partnership with the state, bought 25,000 properties which they converted into wetlands. These wetlands act as a sponge in storms and in 1995, when the floods returned, the government did not have to expend resources in those areas.
=== Asia ===
In Kyoto, Japan, the Hata clan successfully controlled floods on the Katsura River in around 500 A.D and also constructed a sluice on the Kazuno River.
In China flood diversion areas are rural areas that are deliberately flooded in emergencies in order to protect cities.
The consequences of deforestation and changing land use on the risk and severity of flooding are subjects of discussion. In assessing the impacts of Himalayan deforestation on the Ganges-Brahmaputra Lowlands, it was found that forests would not have prevented or significantly reduced flooding in the case of an extreme weather event. However, more general or overview studies agree on the negative impacts that deforestation has on flood safety - and the positive effects of wise land use and reforestation.
Many have proposed that loss of vegetation (deforestation) will lead to an increased risk of flooding. With natural forest cover the flood duration should decrease. Reducing the rate of deforestation should improve the incidents and severity of floods.
=== Africa ===
In Egypt, both the Aswan Low Dam (1902) and the Aswan High Dam (1976) have controlled various amounts of flooding along the Nile River.
=== Europe ===
==== France ====
Following the misery and destruction caused by the 1910 Great Flood of Paris, the French government built a series of reservoirs called Les Grands Lacs de Seine (or Great Lakes) which helps remove pressure from the Seine during floods, especially the regular winter flooding.
==== United Kingdom ====
London is protected from flooding by Thames Barrier, a huge mechanical barrier across the River Thames, which is raised when the water level reaches a certain point. This project has been operational since 1982 and was designed to protect against a surge of water such as the North Sea flood of 1953.
In 2023 it was found that over 4,000 flood defence schemes in England were ‘almost useless’ with many of them in areas hit by Storm Babet.
==== Russia ====
The Saint Petersburg Dam was completed in 2008 to protect Saint Petersburg from storm surges. It also has a main traffic function, as it completes a ring road around Saint Petersburg. Eleven dams extend for 25.4 kilometres (15.8 mi) and stand 8 metres (26 ft) above water level.
==== The Netherlands ====
The Netherlands has one of the best flood control systems in the world, notably through its construction of dykes. The country faces high flooding risk due to the country's low-lying landscapes. The largest and most elaborate flood defenses are referred to as the Delta Works with the Oosterscheldekering as its crowning achievement. These works in the southwestern part of the country were built in response to the North Sea flood of 1953. The Dutch had already built one of the world's largest dams in the north of the country. The Afsluitdijk closing occurred in 1932.
New ways to deal with water are constantly being developed and tested, such as the underground storage of water, storing water in reservoirs in large parking garages or on playgrounds. Rotterdam started a project to construct a floating housing development of 120 acres (0.49 km2) to deal with rising sea levels. Several approaches, from high-tech sensors detecting imminent levee failure to movable semi-circular structures closing an entire river, are being developed or used around the world. Regular maintenance of hydraulic structures, however, is another crucial part of flood control.
=== Oceania ===
Flooding is the greatest natural hazard in New Zealand (Aotearoa), and its control is primarily managed and funded by local councils. Throughout the country there is a network of more than 5284 km of levees, while gravel extraction to lower river water levels is also a popular flood control technique. The management of flooding in the country is shifting towards nature based solutions, such as the widening of the Hutt River channel in Wellington.
== See also ==
Bioswale – Landscape elements designed to manage surface runoff water
Coastal management – Preventing flooding and erosion of shorelines
Constructed wetland – Artificial wetland to treat wastewater, greywater or stormwater runoff
Disaster risk reduction – Preventing and reducing disaster risk factors
Flood Control Act of 1936 – 1936 United States act of Congress to control floods
Flood risk assessment – Type of risk assessment with respect to floods
Rain garden – Runoff reducing landscaping method
Stormwater detention vault – underground structure designed to manage excess stormwater runoff on a developed sitePages displaying wikidata descriptions as a fallback
Stormwater harvesting
Sustainable drainage system – Designed to reduce the potential impact of development
Tidal barrage – Dam-like structure
Tree box filter – Stormwater treatment system
Water-sensitive urban design – Integrated approach to urban water cycle
Wetland – Type of land area that is flooded or saturated with water
== References ==
== External links ==
Flood articles – BBC News | Wikipedia/Flood_control |
Wastewater treatment is a process which removes and eliminates contaminants from wastewater. It thus converts it into an effluent that can be returned to the water cycle. Once back in the water cycle, the effluent creates an acceptable impact on the environment. It is also possible to reuse it. This process is called water reclamation. The treatment process takes place in a wastewater treatment plant. There are several kinds of wastewater which are treated at the appropriate type of wastewater treatment plant. For domestic wastewater the treatment plant is called a Sewage Treatment. Municipal wastewater or sewage are other names for domestic wastewater. For industrial wastewater, treatment takes place in a separate Industrial wastewater treatment, or in a sewage treatment plant. In the latter case it usually follows pre-treatment. Further types of wastewater treatment plants include Agricultural wastewater treatment and leachate treatment plants.
One common process in wastewater treatment is phase separation, such as sedimentation. Biological and chemical processes such as oxidation are another example. Polishing is also an example. The main by-product from wastewater treatment plants is a type of sludge that is usually treated in the same or another wastewater treatment plant.: Ch.14 Biogas can be another by-product if the process uses anaerobic treatment. Treated wastewater can be reused as reclaimed water. The main purpose of wastewater treatment is for the treated wastewater to be able to be disposed or reused safely. However, before it is treated, the options for disposal or reuse must be considered so the correct treatment process is used on the wastewater.
The term "wastewater treatment" is often used to mean "sewage treatment".
== Types of treatment plants ==
Wastewater treatment plants may be distinguished by the type of wastewater to be treated. There are numerous processes that can be used to treat wastewater depending on the type and extent of contamination. The treatment steps include physical, chemical and biological treatment processes.
Types of wastewater treatment plants include:
Sewage treatment plants
Industrial wastewater treatment plants
Agricultural wastewater treatment plants
Leachate treatment plants
=== Sewage treatment plants ===
=== Industrial wastewater treatment plants ===
=== Agricultural wastewater treatment plants ===
=== Leachate treatment plants ===
Leachate treatment plants are used to treat leachate from landfills. Treatment options include: biological treatment, mechanical treatment by ultrafiltration, treatment with active carbon filters, electrochemical treatment including electrocoagulation by various proprietary technologies and reverse osmosis membrane filtration using disc tube module technology.
== Unit processes ==
The unit processes involved in wastewater treatment include physical processes such as settlement or flotation and biological processes such oxidation or anaerobic treatment. Some wastewaters require specialized treatment methods. At the simplest level, treatment of most wastewaters is carried out through separation of solids from liquids, usually by sedimentation. By progressively converting dissolved material into solids, usually a biological floc or biofilm, which is then settled out or separated, an effluent stream of increasing purity is produced.
=== Phase separation ===
Phase separation transfers impurities into a non-aqueous phase. Phase separation may occur at intermediate points in a treatment sequence to remove solids generated during oxidation or polishing. Grease and oil may be recovered for fuel or saponification. Solids often require dewatering of sludge in a wastewater treatment plant. Disposal options for dried solids vary with the type and concentration of impurities removed from water.
==== Sedimentation ====
Solids such as stones, grit, and sand may be removed from wastewater by gravity when density differences are sufficient to overcome dispersion by turbulence. This is typically achieved using a grit channel designed to produce an optimum flow rate that allows grit to settle and other less-dense solids to be carried forward to the next treatment stage. Gravity separation of solids is the primary treatment of sewage, where the unit process is called "primary settling tanks" or "primary sedimentation tanks". It is also widely used for the treatment of other types of wastewater. Solids that are denser than water will accumulate at the bottom of quiescent settling basins. More complex clarifiers also have skimmers to simultaneously remove floating grease such as soap scum and solids such as feathers, wood chips, or condoms. Containers like the API oil-water separator are specifically designed to separate non-polar liquids.: 111–138
=== Biological and chemical processes ===
==== Oxidation ====
Oxidation reduces the biochemical oxygen demand of wastewater, and may reduce the toxicity of some impurities. Secondary treatment converts organic compounds into carbon dioxide, water, and biosolids through oxidation and reduction reactions. Chemical oxidation is widely used for disinfection.
===== Biochemical oxidation (secondary treatment) =====
===== Chemical oxidation =====
Advanced oxidation processes are used to remove some persistent organic pollutants and concentrations remaining after biochemical oxidation.: 363–408 Disinfection by chemical oxidation kills bacteria and microbial pathogens by adding hydroxyl radicals such as ozone, chlorine or hypochlorite to wastewater.: 1220 These hydroxyl radical then break down complex compounds in the organic pollutants into simple compounds such as water, carbon dioxide, and salts.
==== Anaerobic treatment ====
Anaerobic wastewater treatment processes (for example UASB, EGSB) are also widely applied in the treatment of industrial wastewaters and biological sludge.
=== Polishing ===
Polishing refers to treatments made in further advanced treatment steps after the above methods (also called "fourth stage" treatment). These treatments may also be used independently for some industrial wastewater. Chemical reduction or pH adjustment minimizes chemical reactivity of wastewater following chemical oxidation.: 439 Carbon filtering removes remaining contaminants and impurities by chemical absorption onto activated carbon.: 1138 Filtration through sand (calcium carbonate) or fabric filters is the most common method used in municipal wastewater treatment.
== See also ==
List of largest wastewater treatment plants
List of wastewater treatment technologies
Water treatment
== References ==
== External links ==
Media related to Wastewater treatment at Wikimedia Commons | Wikipedia/Wastewater_treatment |
The Indigenous Environmental Network (IEN) is a coalition of indigenous, grassroots environmental justice activists, primarily based in the United States. Group members have represented Native American concerns at international events such as the United Nations Climate Change conferences in Copenhagen (2009) and Paris (2016). IEN organizes an annual conference to discuss proposed goals and projects for the coming year; each year the conference is held in a different indigenous nation. The network emphasizes environmental protection as a form of spiritual activism. IEN received attention in the news as a major organizer of the fight against the Keystone Pipeline and the Dakota Access Pipeline in the Dakota Access Pipeline protests.
== History ==
The Indigenous Environmental Network was created in 1990, to bring to light environmental and economic injustices faced specifically by the indigenous peoples of North America. Its formation took place at the annual Protecting Mother Earth gatherings that began in 1990 on the Navajo Nation in Dilkon, where the group of activists that would become Diné CARE had recently defeated a hazardous waste incinerator proposal. The IEN also first started from meetings in the home of Lori Goodman in the Navajo Nation, where she would host them in her own kitchen.
=== Ties to environmental justice movement ===
The environmental justice movement seeks to address issues of environmental racism, which arises when people of color and other marginalized populations such as indigenous peoples are disproportionately affected by exposure to hazardous environmental conditions; the unavailability of safe, healthy, and affordable food options; and exclusion from participatory involvement in community decision-making.
Indigenous peoples have historically suffered injustice through environmental racism, having faced repeated despoliation of sacred lands as well as over-exploitation of resources by governments and other actors. This includes dumping, establishment of toxic waste sites, or development of environmentally harmful infrastructure (such as pipelines), specifically on Native American reservations and First Nations reserves. Breaches of indigenous autonomy by the U.S. government are often justified by the claim that the development of indigenous lands would increase economic opportunity for locals—claims that are rarely supported by evidence. Indigenous residents and custodians usually see development projects imposed in this manner as an infringement on their right to self-determination and religious freedom.
=== Past ===
The Indigenous Environmental Network has focused its activism on improving indigenous communities through grassroots efforts; prioritizing projects that protect the land, air, water, sacred sites, and natural resources. To accomplish the preservation of these assets, the network has organized campaigns, public awareness, and community building activities. The IEN meets locally, regionally, and nationally to promote awareness about issues of social justice, but primarily holds focus in North America.
The increase in toxic waste and nuclear waste storage facilities near indigenous lands was a main concern to the IEN during its beginnings in the early 1990s. After the initial focus on environmental hazards presented by these facilities, the network spread awareness across youth and tribal populations that paved the way for it to progress to campaigns and public activism. Every year, a conference is held entitled "Protecting Mother Earth Gatherings", which is aimed at educating the public as well as developing strategies for protecting the lands of indigenous peoples.
In 1995, IEN began hiring staff to represent the ideologies and goals of the organization. IEN workers strive for the preservation of indigenous peoples through tribal grassroots communities and tribal-government environmental staff. IEN has since evolved into a group that works to create change and strengthen tribal communities by protecting and preserving sacred sites.
=== Current activism ===
One of the popular cases of activism that IEN has participated in were the protests against the North Dakota Pipeline project, which is set to run through North Dakota, South Dakota, Iowa and to end in Illinois. The IEN has been a leading participant in coordinating international action such as bank divestments and days of emergency action that protest fascism and the use of fossil fuels that disrupt the livelihood of indigenous peoples.
Indigenous Rising Media is an IEN Project that works to defend the rights of indigenous peoples. It focuses on protecting the sanctity and integrity of Mother Earth and the movement towards a more just and sustainable future. The project has placed information about the North Dakota Pipeline on its website aimed at combating the dangers that directly affect indigenous people.
The group also recently participated in the Peoples Climate March on Washington, D.C., on April 29, 2017. The March was hosted to bring to light the dangers of climate change, and IEN supported the event. The rally was hosted by Dallas Goldtooth, a prominent activist protesting against the North Dakota Pipeline, along with Carrie Fulton, an African-American environmental-justice organizer. The Peoples Climate March took place on the 100th day of Donald Trump's presidency, and served as a protest to policy changes being made regarding environmental protection and conservation.
== Goals and beliefs ==
Educate and empower Indigenous Peoples to address and develop strategies for the protection of our environment, our health, and all life forms – the Circle of Life.
Re-affirm our traditional knowledge and respect of natural laws.
Recognize, support, and promote environmentally sound lifestyles, economic livelihoods and to build healthy sustaining Indigenous communities.
Commitment to influence policies that affect Indigenous Peoples on a local, tribal, state, regional, national and international level.
Include youth and elders in all levels of our work.
Protect our human rights to practice our cultural and spiritual beliefs.
=== Beliefs in practice ===
Certain practices of coal mining, oil drilling, and fishing and hunting in the United States are said to directly infringe upon Native land and values. IEN tries to engage with the American public by raising consciousness about environmental issues that are known to have a particularly strong impact on indigenous peoples. One IEN action for this purpose was dedicating a day, October 13, 1996, to challenging Americans to consume as little energy as possible. The goal of this was to encourage people to think about how much energy they do in fact consume on a daily basis and how this impacts on native communities.
In 1991, at Bear Butte, South Dakota (a sacred site to many of the Plains Indians), the IEN established an Environmental Code of Ethics. Key points include that indigenous people culturally, and Native Americans politically, are tied to their land; Native Americans in the United States and Canada are restricted to reservations if they want to maintain any kind of nationalistic ideals; and that indigenous people often have religious or ancestral ties to specific tracts of land. This unique relationship makes it less likely for them to leave, makes the land more valuable, and makes them even more staunchly opposed to polluting it in any way.
== Spiritual activism ==
The IEN states that part of their mission is to protect and maintain sites sacred to, primarily, indigenous communities in North America. In addressing perceived injustices perpetuated against these peoples, they list protection of sacred, historical and culturally significant areas as one of their main goals. In doing so, they reference their love for Mother Earth as a driving force behind their activism. IEN recognizes humanity's connection to the Earth and believes their activism is restoring and furthering this connection.
The group holds "Protecting Mother Earth Gatherings", in which they discuss techniques and plans for protecting indigenous communities and lands. In their "Rights of Mother Earth" conference held in April 2004, they expressed their commitment in "creating a system of jurisprudence that sees and treats nature and Mother Earth as a fundamental, rights bearing entity." They also argued for a paradigm founded on indigenous thought as well as a philosophy that grants equal rights to nature and honors the interrelationship of all life forms on the planet.
== Environmental justice ==
=== Opposition to pipelines ===
The group began garnering more public attention in 2014, when they began a protest against the Keystone XL oil pipeline. Initial disputes over the pipeline had drawn the attention of the American public in 2011, when groups became concerned that the oil pipeline could contaminate nearby water sources, but this increased as the building of the pipeline was delayed. IEN was one of the larger organizations involved in the debate over the pipeline, allying with other environmentalist groups like the Sierra Club and 350.org.
IEN experienced another surge of media exposure in 2015 as protests against the Dakota Access oil pipeline gained attention. The pipeline is currently complete, with the exception of the section mapped to be located under Lake Oahe, which is a major water source for the native Sioux tribe of Standing Rock in North Dakota. After a federal order requiring protesters to leave the build sites of the pipeline, IEN stated publicly that they would not follow the order in an attempt to further delay the progression of the pipeline. Dallas Goldtooth, an organizer with IEN, told a reporter for The Washington Post that "We are staying here, committed to our prayer. Forced removal and state oppression? This is nothing new to us as native people."
Tom B.K. Goldtooth, founder of IEN, stated after President Donald Trump signed an executive order for the continuation of the building of the pipeline that "Donald Trump will not build his Dakota Access Pipeline without a fight. The granting of an easement, without any environmental review or tribal consultation, is not the end of this fight—it is the new beginning."
=== Conferences ===
IEN hosts annual conferences called the "Protecting Mother Earth Gatherings". The first conference was held in 1990 in Bear Butte, South Dakota. The conferences has changed location almost every year.
At the conference, members of the IEN come together to discuss the group's goals and projects in the upcoming year. Their resolutions are typically published on the internet soon after the end of each conference.
Past conference locations and projects include:
The 1992 conference in Celilo Falls, Oregon, formerly a major salmon fishing site until dams were constructed on the Columbia River, downstream from the Hanford Nuclear Reservation.
The 1993 conference at Sac and Fox Reservation, Oklahoma; IEN helped defeat a proposal for the establishment of a nuclear waste site.
The 1994 conference on Mole Lake Indian Reservation, Wisconsin, where Exxon plans to open a huge zinc-copper mine upstream from the Mole Lake Chippewa's wild rice beds.
The 2001 conference (the 12th Protecting Mother Earth Gathering) in Penticton, British Columbia, Canada, was the first to be held in Canada.
The 2004 conference was again held near sacred Bear Butte, South Dakota.
In 2009, IEN introduced the "Red Road to Copenhagen" initiative; a delegation attended the 15th Session of the Conference of the Parties (COP-15) to the United Nations Framework Convention on Climate Change (UNFCCC) in Copenhagen. The Initiative statement reads: "...this initiative will bring accumulated traditional knowledge of Indigenous peoples from North America coming from climate-energy impact zones and persons experienced in linking an indigenous rights-based framework to climate policy."
IEN prioritizes multigenerational and intertribal organizing, and has specific youth and elders groups. It is governed partly by an Elders Council; their Youth Council solicits the involvement of young indigenous people and tries to make connections between urban youth culture and environmental issues faced by the communities.
Members of IEN were involved in the 2016 Dakota Access Pipeline protests, notably in the media coverage and in establishing the media tent at the Oceti Sakowin camp.
=== Other work ===
The POPs Treaty, now known as the Stockholm Convention after it was signed in May 2001 in Sweden, was designed to ban a number of pesticides and other chemicals from use. During the negotiations, IEN played a key role in expressing to delegates what indigenous peoples wanted from the treaty. Throughout the period, the IEN met with delegates from all over the world in order to sensitise them on how indigenous peoples are impacted by POPs and their expectations from the treaty.
Reducing emissions from deforestation and forest degradation (REDD) is a policy mechanism designed to work for the preservation of global forests and it is backed by many influential environmental organizations like Greenpeace and Conservation International. REDD is centered around the idea of providing forest owners with financial incentive to preserve them. However, in accomplishing this, it also requires the relocation of indigenous peoples who reside in forests that are being targeted and is therefore very controversial among grassroots and indigenous organizations. IEN publicly opposes REDD, claiming that it is a direct violation of the rights of indigenous peoples to have autonomy over their own land.
The IEN opposes carbon taxes.
== References == | Wikipedia/Indigenous_Environmental_Network |
Water resources are natural resources of water that are potentially useful for humans, for example as a source of drinking water supply or irrigation water. These resources can be either freshwater from natural sources, or water produced artificially from other sources, such as from reclaimed water (wastewater) or desalinated water (seawater). 97% of the water on Earth is salt water and only three percent is fresh water; slightly over two-thirds of this is frozen in glaciers and polar ice caps. The remaining unfrozen freshwater is found mainly as groundwater, with only a small fraction present above ground or in the air. Natural sources of fresh water include surface water, under river flow, groundwater and frozen water. People use water resources for agricultural, industrial and household activities.
Water resources are under threat from multiple issues. There is water scarcity, water pollution, water conflict and climate change. Fresh water is in principle a renewable resource. However, the world's supply of groundwater is steadily decreasing. Groundwater depletion (or overdrafting) is occurring for example in Asia, South America and North America.
== Natural sources of fresh water ==
Natural sources of fresh water include surface water, under river flow, groundwater and frozen water.
=== Surface water ===
Surface water is water in a river, lake or fresh water wetland. Surface water is naturally replenished by precipitation and naturally lost through discharge to the oceans, evaporation, evapotranspiration and groundwater recharge. The only natural input to any surface water system is precipitation within its watershed. The total quantity of water in that system at any given time is also dependent on many other factors. These factors include storage capacity in lakes, wetlands and artificial reservoirs, the permeability of the soil beneath these storage bodies, the runoff characteristics of the land in the watershed, the timing of the precipitation and local evaporation rates. All of these factors also affect the proportions of water loss.
Humans often increase storage capacity by constructing reservoirs and decrease it by draining wetlands. Humans often increase runoff quantities and velocities by paving areas and channelizing the stream flow.
Natural surface water can be augmented by importing surface water from another watershed through a canal or pipeline.
Brazil is estimated to have the largest supply of fresh water in the world, followed by Russia and Canada.
==== Water from glaciers ====
Glacier runoff is considered to be surface water. The Himalayas, which are often called "The Roof of the World", contain some of the most extensive and rough high altitude areas on Earth as well as the greatest area of glaciers and permafrost outside of the poles. Ten of Asia's largest rivers flow from there, and more than a billion people's livelihoods depend on them. To complicate matters, temperatures there are rising more rapidly than the global average. In Nepal, the temperature has risen by 0.6 degrees Celsius over the last decade, whereas globally, the Earth has warmed approximately 0.7 degrees Celsius over the last hundred years.
=== Groundwater ===
==== Under river flow ====
Throughout the course of a river, the total volume of water transported downstream will often be a combination of the visible free water flow together with a substantial contribution flowing through rocks and sediments that underlie the river and its floodplain called the hyporheic zone. For many rivers in large valleys, this unseen component of flow may greatly exceed the visible flow. The hyporheic zone often forms a dynamic interface between surface water and groundwater from aquifers, exchanging flow between rivers and aquifers that may be fully charged or depleted. This is especially significant in karst areas where pot-holes and underground rivers are common.
== Artificial sources of usable water ==
There are several artificial sources of fresh water. One is treated wastewater (reclaimed water). Another is atmospheric water generators. Desalinated seawater is another important source. It is important to consider the economic and environmental side effects of these technologies.
=== Wastewater reuse ===
=== Desalinated water ===
=== Research into other options ===
Researchers proposed air capture over oceans which would "significantly increasing freshwater through the capture of humid air over oceans" to address present and, especially, future water scarcity/insecurity.
A 2021 study proposed hypothetical portable solar-powered atmospheric water harvesting devices. However, such off-the-grid generation may sometimes "undermine efforts to develop permanent piped infrastructure" among other problems.
== Water uses ==
The total quantity of water available at any given time is an important consideration. Some human water users have an intermittent need for water. For example, many farms require large quantities of water in the spring, and no water at all in the winter. Other users have a continuous need for water, such as a power plant that requires water for cooling. Over the long term the average rate of precipitation within a watershed is the upper bound for average consumption of natural surface water from that watershed.
=== Agriculture and other irrigation ===
=== Industries ===
It is estimated that 22% of worldwide water is used in industry. Major industrial users include hydroelectric dams, thermoelectric power plants, which use water for cooling, ore and oil refineries, which use water in chemical processes, and manufacturing plants, which use water as a solvent. Water withdrawal can be very high for certain industries, but consumption is generally much lower than that of agriculture.
Water is used in renewable power generation. Hydroelectric power derives energy from the force of water flowing downhill, driving a turbine connected to a generator. This hydroelectricity is a low-cost, non-polluting, renewable energy source. Significantly, hydroelectric power can also be used for load following unlike most renewable energy sources which are intermittent. Ultimately, the energy in a hydroelectric power plant is supplied by the sun. Heat from the sun evaporates water, which condenses as rain in higher altitudes and flows downhill. Pumped-storage hydroelectric plants also exist, which use grid electricity to pump water uphill when demand is low, and use the stored water to produce electricity when demand is high.
Thermoelectric power plants using cooling towers have high consumption, nearly equal to their withdrawal, as most of the withdrawn water is evaporated as part of the cooling process. The withdrawal, however, is lower than in once-through cooling systems.
Water is also used in many large scale industrial processes, such as thermoelectric power production, oil refining, fertilizer production and other chemical plant use, and natural gas extraction from shale rock. Discharge of untreated water from industrial uses is pollution. Pollution includes discharged solutes and increased water temperature (thermal pollution).
=== Drinking water and domestic use (households) ===
It is estimated that 8% of worldwide water use is for domestic purposes. These include drinking water, bathing, cooking, toilet flushing, cleaning, laundry and gardening. Basic domestic water requirements have been estimated by Peter Gleick at around 50 liters per person per day, excluding water for gardens.
Drinking water is water that is of sufficiently high quality so that it can be consumed or used without risk of immediate or long term harm. Such water is commonly called potable water. In most developed countries, the water supplied to domestic, commerce and industry is all of drinking water standard even though only a very small proportion is actually consumed or used in food preparation.
844 million people still lacked even a basic drinking water service in 2017.: 3 Of those, 159 million people worldwide drink water directly from surface water sources, such as lakes and streams.: 3 One in eight people in the world do not have access to safe water. Unsafe drinking water leads to 1.2 million deaths per year according to the World Bank.
== Challenges and threats ==
=== Water scarcity ===
=== Water pollution ===
=== Water conflict ===
=== Climate change ===
=== Groundwater overdrafting ===
The world's supply of groundwater is steadily decreasing. Groundwater depletion (or overdrafting) is occurring for example in Asia, South America and North America. It is still unclear how much natural renewal balances this usage, and whether ecosystems are threatened.
== Water resource management ==
Water resource management is the activity of planning, developing, distributing and managing the optimum use of water resources. It is an aspect of water cycle management. The field of water resources management will have to continue to adapt to the current and future issues facing the allocation of water. With the growing uncertainties of global climate change and the long-term impacts of past management actions, this decision-making will be even more difficult. It is likely that ongoing climate change will lead to situations that have not been encountered. As a result, alternative management strategies, including participatory approaches and adaptive capacity are increasingly being used to strengthen water decision-making.
Ideally, water resource management planning has regard to all the competing demands for water and seeks to allocate water on an equitable basis to satisfy all uses and demands. As with other resource management, this is rarely possible in practice so decision-makers must prioritise issues of sustainability, equity and factor optimisation (in that order!) to achieve acceptable outcomes. One of the biggest concerns for water-based resources in the future is the sustainability of the current and future water resource allocation.
Sustainable Development Goal 6 has a target related to water resources management: "Target 6.5: By 2030, implement integrated water resources management at all levels, including through transboundary cooperation as appropriate."
=== Sustainable water management ===
At present, only about 0.08 percent of all the world's fresh water is accessible. And there is ever-increasing demand for drinking, manufacturing, leisure and agriculture. Due to the small percentage of water available, optimizing the fresh water we have left from natural resources has been a growing challenge around the world.
Much effort in water resource management is directed at optimizing the use of water and in minimizing the environmental impact of water use on the natural environment. The observation of water as an integral part of the ecosystem is based on integrated water resources management, based on the 1992 Dublin Principles (see below).
Sustainable water management requires a holistic approach based on the principles of Integrated Water Resource Management, originally articulated in 1992 at the Dublin (January) and Rio (July) conferences. The four Dublin Principles, promulgated in the Dublin Statement are:
Fresh water is a finite and vulnerable resource, essential to sustain life, development and the environment;
Water development and management should be based on a participatory approach, involving users, planners and policy-makers at all levels;
Women play a central part in the provision, management and safeguarding of water;
Water has an economic value in all its competing uses and should be recognized as an economic good.
Implementation of these principles has guided reform of national water management law around the world since 1992.
Further challenges to sustainable and equitable water resources management include the fact that many water bodies are shared across boundaries which may be international (see water conflict) or intra-national (see Murray-Darling basin).
=== Integrated water resources management ===
Integrated water resources management (IWRM) has been defined by the Global Water Partnership (GWP) as "a process which promotes the coordinated development and management of water, land and related resources, in order to maximize the resultant economic and social welfare in an equitable manner without compromising the sustainability of vital ecosystems".
Some scholars say that IWRM is complementary to water security because water security is a goal or destination, whilst IWRM is the process necessary to achieve that goal.
IWRM is a paradigm that emerged at international conferences in the late 1900s and early 2000s, although participatory water management institutions have existed for centuries. Discussions on a holistic way of managing water resources began already in the 1950s leading up to the 1977 United Nations Water Conference. The development of IWRM was particularly recommended in the final statement of the ministers at the International Conference on Water and the Environment in 1992, known as the Dublin Statement. This concept aims to promote changes in practices which are considered fundamental to improved water resource management. IWRM was a topic of the second World Water Forum, which was attended by a more varied group of stakeholders than the preceding conferences and contributed to the creation of the GWP.
In the International Water Association definition, IWRM rests upon three principles that together act as the overall framework:
Social equity: ensuring equal access for all users (particularly marginalized and poorer user groups) to an adequate quantity and quality of water necessary to sustain human well-being.
Economic efficiency: bringing the greatest benefit to the greatest number of users possible with the available financial and water resources.
Ecological sustainability: requiring that aquatic ecosystems are acknowledged as users and that adequate allocation is made to sustain their natural functioning.
In 2002, the development of IWRM was discussed at the World Summit on Sustainable Development held in Johannesburg, which aimed to encourage the implementation of IWRM at a global level. The third World Water Forum recommended IWRM and discussed information sharing, stakeholder participation, and gender and class dynamics.
Operationally, IWRM approaches involve applying knowledge from various disciplines as well as the insights from diverse stakeholders to devise and implement efficient, equitable and sustainable solutions to water and development problems. As such, IWRM is a comprehensive, participatory planning and implementation tool for managing and developing water resources in a way that balances social and economic needs, and that ensures the protection of ecosystems for future generations. In addition, in light of contributing the achievement of Sustainable Development goals (SDGs), IWRM has been evolving into more sustainable approach as it considers the Nexus approach, which is a cross-sectoral water resource management. The Nexus approach is based on the recognition that "water, energy and food are closely linked through global and local water, carbon and energy cycles or chains."
An IWRM approach aims at avoiding a fragmented approach of water resources management by considering the following aspects: Enabling environment, roles of Institutions, management Instruments. Some of the cross-cutting conditions that are also important to consider when implementing IWRM are: Political will and commitment, capacity development, adequate investment, financial stability and sustainable cost recovery, monitoring and evaluation. There is not one correct administrative model. The art of IWRM lies in selecting, adjusting and applying the right mix of these tools for a given situation. IWRM practices depend on context; at the operational level, the challenge is to translate the agreed principles into concrete action.
=== Managing water in urban settings ===
== By country ==
Water resource management and governance is handled differently by different countries. For example, in the United States, the United States Geological Survey (USGS) and its partners monitor water resources, conduct research and inform the public about groundwater quality. Water resources in specific countries are described below:
== See also ==
List of sovereign states by freshwater withdrawal
List of countries by total renewable water resources
Socio-hydrology – Interdisciplinary field studying the dynamic interactions between water and people
Virtual water – Concept on hidden water in traded commodities
Water resources law – Law and regulations that relate to water resources
Water rights – Right of a user to use water from a water sourcePages displaying short descriptions of redirect targets
Water storage – Storage of water by various means
== References ==
== External links ==
Renewable water resources in the world by country
Portal to international hydrology and water resources
Sustainable Sanitation and Water Management Toolbox | Wikipedia/Integrated_water_resources_management |
Global climate change has increased the occurrence of some infectious diseases. Infectious diseases whose transmission is impacted by climate change include, for example, vector-borne diseases like dengue fever, malaria, tick-borne diseases, leishmaniasis, zika fever, chikungunya and Ebola. One mechanism contributing to increased disease transmission is that climate change is altering the geographic range and seasonality of the insects (or disease vectors) that can carry the diseases. Scientists stated a clear observation in 2022: "The occurrence of climate-related food-borne and waterborne diseases has increased (very high confidence).": 11
Infectious diseases that are sensitive to climate can be grouped into: vector-borne diseases (transmitted via mosquitos, ticks etc.), waterborne diseases (transmitted via viruses or bacteria through water), and food-borne diseases.(spread through pathogens via food): 1107 Climate change affects the distribution of these diseases due to the expanding geographic range and seasonality of these diseases and their vectors.: 9 Like other ways climate change affects human health, climate change exacerbates existing inequalities and challenges in managing infectious disease.
Mosquito-borne diseases that are sensitive to climate include malaria, lymphatic filariasis, Rift Valley fever, yellow fever, dengue fever, Zika virus, and chikungunya. Scientists found in 2022 that rising temperatures are increasing the areas where dengue fever, malaria and other mosquito-carried diseases are able to spread.: 1062 Warmer temperatures are also advancing to higher elevations, allowing mosquitoes to survive in places that were previously in hospitable to them.: 1045 This risks malaria returning to areas where it was previously eradicated.
Ticks are changing their geographic range because of rising temperatures, and this puts new populations at risk. Ticks can spread lyme disease and tick-borne encephalitis. It is expected that climate change will increase the incidence of these diseases in the Northern Hemisphere.: 1094 For example, a review of the literature found that "In the USA, a 2°C warming could increase the number of lyme disease cases by over 20% over the coming decades and lead to an earlier onset and longer length of the annual Lyme disease season".: 1094
Waterborne diseases are transmitted through water. The symptoms of waterborne diseases typically include diarrhea, fever and other flu-like symptoms, neurological disorders, and liver damage. Climate changes have a large effect on the distribution of microbial species. These communities are very complex and can be extremely sensitive to external climate stimuli. There is a range of waterborne diseases and parasites that will pose greater health risks in the future. This will vary by region. For example, in Africa, Cryptosporidium spp. and Giardia duodenalis (protozoan parasites) will increase. This is due to increasing temperatures and drought.: 1095
Scientist also expect that disease outbreaks caused by vibrio (in particular the bacterium that causes cholera, called vibrio cholerae) are increasing in occurrence and intensity.: 1107 One reason is that the area of coastline with suitable conditions for vibrio bacteria has increased due to changes in sea surface temperature and sea surface salinity caused by climate change.: 12 These pathogens can cause gastroenteritis, cholera, wound infections, and sepsis. The increasing occurrence of higher temperature days, heavy rainfall events and flooding due to climate change could lead to an increase in cholera risks.: 1045
== Public health context ==
In 1988, little was known about the effects of climate change on human health. As of 2023, the evidence has grown significantly and is for example summarised in the Sixth Assessment Report of the Intergovernmental Panel on Climate Change. The scientific understanding of potential health risks and observed health impacts caused by climate change is now better understood. One category of health risks is that of infectious diseases. A study concluded in 2022 that "58% (that is, 218 out of 375) of infectious diseases confronted by humanity worldwide have been at some point aggravated by climatic hazards". The World Health Organization considers climate change as one of the greatest threats to human health.
Infectious diseases have played a significant role in human history, impacting the rise and fall of civilizations and facilitating the conquest of new territories. During recent decades, there are significant regional changes in vector and pathogen distribution reported in temperate, peri‐Arctic, Arctic, and tropical highland regions.
Climate change is one of the factors that causes the spread of human diseases. Other key factors, include the mobility of people, animals, and goods; control measures in place; availability of effective drugs; quality of public health services; human behavior; and political stability and conflicts. The March 2022 report from the Intergovernmental Panel on Climate Change (IPCC) warned that without swift climate action we will see an escalation of infectious diseases. They will spread to new regions (may decline in some endemic areas) and surge in areas where they were previously under control. As a result, diseases that have never previously infected humans (Disease X) may 'spill over' from animals
Global warming, increased drought and flooding represent a significant threat to public health, likely leading to the escalation of vector, food and water-borne diseases The effects of climate change on health will impact most populations over the next few decades. However, Africa, and specifically, the African Highlands, are susceptible to being particularly negatively affected. For example, with regard to malaria, in 2010, 91% of the global burden due to malaria deaths occurred in Africa. Several spatiotemporal models have been studied to assess the potential effect of projected climate scenarios on malaria transmission in Africa. It is expected that the most significant climate change effects are confined to specific regions, including the African Highlands.
Climate change may lead to dramatic increases in the prevalence of a variety of infectious diseases. Beginning in the mid-'70s, an "emergence, resurgence and redistribution of infectious diseases" occurred. Reasons for this are likely multi-causal, dependent on a variety of social, environmental and climatic factors, however, many argue that the "volatility of infectious disease may be one of the earliest biological expressions of climate instability".
== Mechanisms and pathways ==
Infectious diseases (also called pathogenic diseases) depend on "a pathogen and a person coming into contact, and the extent to which peoples’ resistance is diminished, or the pathogen is strengthened, by a climatic hazard." Climatic hazards, which can be strengthened by climate change, include warming of land and oceans, heatwaves and marine heatwaves, floods, drought, storms, land cover change, fires and so forth.
Possible pathways that can increase the infectious disease occurrence and which are affected by climate change include:
Climatic hazards bringing pathogens closer to people (e.g. shifts in the geographical range of species)
Climatic hazards bringing people closer to pathogens (e.g. heatwaves bringing more people to recreational water activities)
Pathogens strengthened by climatic hazards (e.g. "improved climate suitability for reproduction, acceleration of the life cycle, increasing seasons/length of likely exposure", for example ocean warming can lead to increased Vibriosis outbreaks)
People impaired by climatic hazards (e.g. from malnutrition due to drought conditions)
Infectious diseases that are sensitive to climate can be grouped into:
water-borne diseases (transmitted via viruses or bacteria, e.g.: E. Coli),
vector-borne diseases (transmitted via mosquitos, ticks etc.), and
food-borne diseases (e.g. Salmonella bacteria, causing Salmonellosis).: 1107
Climate change is affecting the distribution of these diseases due to the expanding geographic range and seasonality of these diseases and their vectors.: 9
Though many infectious diseases are affected by changes in climate, vector-borne diseases, such as malaria, dengue fever and leishmaniasis, present the strongest causal relationship. One reason for that is that temperature and rainfall play a key role in the distribution, magnitude, and viral capacity of mosquitoes, who are primary vectors for many vectors borne diseases. Observation and research detect a shift of pests and pathogens in the distribution away from the equator and towards Earth's poles.
=== Changes to the distribution of vectors ===
Climate change affects vector-borne diseases by affecting the survival, distribution and behavior of vectors such as mosquitoes, ticks and rodents.: 29 The viruses, bacteria and protozoa are carried by these vectors transferring them from one carrier to another. Vectors and pathogens can adapt to the climate fluctuations by shifting and expanding their geographic ranges, which alter the rate of new cases of disease depending on vector-host interaction, host immunity and pathogen evolution. This means that climate change affects infectious diseases by changing the length of the transmission season and their geographical range.
Climate change is leading to latitudinal and altitudinal temperature increases. Global warming projections indicate that surface air warming for a "high scenario" is 4 C, with a likely range of 2.4–6.4 C by 2100. A temperature increase of this size would alter the biology and the ecology of many mosquito vectors and the dynamics of the diseases they transmit such as malaria.
Changes in climate and global warming have significant influences on the biology and distribution of vector-borne diseases, parasites, fungi, and their associated illnesses. Regional changes resulting from changing weather conditions and patterns within temperate climates will stimulate the reproduction of certain insect species that are vectors for disease.
One major disease-spreading insect is the mosquito, which can carry diseases like malaria, West Nile virus, and dengue fever. With regional temperatures changing due to climate change, the range of mosquitos will change as well. The range of mosquitoes will move farther north and south, and places will have a longer period of mosquito habitability than at present, leading to an increase in the mosquito population in these areas. This range shift has already been seen in highland Africa. Since 1970, the incidence of malaria in high-elevation areas in East Africa has increased greatly. This has been proven to be caused by the warming of regional climates.
The vectors of transmission are the major reason for the increased ranges and infection of these diseases. If the vector has a range shift, so do the associated diseases; if the vector increases in activity due to changes in climate, then there is an effect on the transmission of disease. However it will be hard to classify exactly why the range shifts or an increase in infection rates occurs as there are many other factors to consider besides climate change, such as human migration, poverty, infrastructure quality, and land usage; but climate change is still potentially a key factor.
Environmental changes, climate variability, and climate change are such factors that could affect biology and disease ecology of Anopheles vectors and their disease transmission potential.
Anopheles mosquitoes in highland areas are to experience a larger shift in their metabolic rate due to climate change. This climate change is due to the deforestation in the highland areas where these mosquitos' dwell. When the temperature rises, the larvae take a shorter time to mature and, consequently, a greater capacity to produce more offspring. In turn this could potentially lead to an increase in malaria transmission when infected humans are available.
Environmental changes such as deforestation could also increase local temperatures in the highlands thus could enhance the vector capacity of the anopheles. Anopheles mosquitoes are responsible for the transmission of a number of diseases in the world, such as, malaria, lymphatic filariasis and viruses that can cause such ailments, like the O'nyong'nyong virus.
=== Increased water temperature ===
High temperatures can alter the survival, replication, and virulence of a pathogen. Higher temperatures can also increase the pathogen yields in animal reservoirs. During the warmer summer months an increase in yield of bacteria from drinking water delivery systems has been recorded. During times of warmer temperatures water consumption rates are also typically higher. These together increase the probability of pathogen ingestion and infection.
With an increase in not only temperature, but also higher nutrient concentrations due to runoff there will be an increase in cyanobacterial blooms.
=== Changes in precipitation and water cycle ===
Climate change is forecast to have substantial effects on the water cycle, with an increase in both frequency and intensity of droughts and heavy precipitation events.
A literature review in 2016 found that generally there is an increase in diarrheal disease (except for viral diarrheal disease) during or after certain weather conditions: elevated ambient temperature, heavy rainfall, and flooding. These three weather conditions are predicted to increase (or to intensify) with climate change in future. There is already now a high current baseline rate of the diarrheal diseases in developing countries. Climate change therefore poses a real risk of an uptick in these diseases for those regions.
== Selected examples of relevant infectious diseases in humans ==
=== Malaria ===
Increased rainfall could increase the number of mosquitos indirectly by expanding larval habitat and food supply. Malaria, which kills about 300,000 children (under age 5) annually, poses an imminent threat through temperature increase. Models suggest, conservatively, that the risk of malaria will increase 5–15% by 2100 due to climate change. In Africa alone, according to the MARA Project (Mapping Malaria Risk in Africa), there is a projected increase of 16–28% in person-month exposures to malaria by 2100.
Climate is an influential driving force of vector-borne diseases such as malaria. Malaria is especially susceptible to the effects of climate change because mosquitoes lack the mechanisms to regulate their internal temperature. This implies that there is a limited range of climatic conditions within which the pathogen (malaria) and vector (a mosquito) can survive, reproduce, and infect hosts. Vector-borne diseases, such as malaria, have distinctive characteristics that determine pathogenicity. These include the survival and reproduction rate of the vector, the level of vector activity (i.e. the biting or feeding rate), and the development and reproduction rate of the pathogen within the vector or host. Changes in climate factors substantially affect reproduction, development, distribution, and seasonal transmissions of malaria.
Malaria is a mosquito-borne parasitic disease that infects humans and other animals caused by microorganisms in the Plasmodium family. It begins with a bite from an infected female mosquito, which introduces the parasite through its saliva and into the infected host's circulatory system. It then travels through the bloodstream into the liver, where it can mature and reproduce.
=== Dengue fever ===
Dengue fever is an infectious disease caused by dengue viruses known to be in the tropical regions. It is transmitted by the mosquito Aedes, or A. aegypti. Dengue incidence has increased in the last few decades and is projected to continue to do so with changing climate conditions. Dengue can be fatal. Dengue fever is spread by the bite of the female mosquito known as Aedes aegypti. The female mosquito is a highly effective vector of this disease.
The evidence for the spread of dengue fever is that climate change is altering the geographic range and seasonality of the mosquito that can carry dengue. Because there are multiple drivers of transmission, it is easier to model and project changes in the geographic range and seasonality. The drivers for the recent spread of this disease are globalization, trade, urbanization, population growth, increased international travel, and climate change. The same trends also led to the spread of different serotypes of the disease to new areas, and to the emergence of dengue hemorrhagic fever.
The World Health Organization (WHO) has reported an increase from a thousand to one million confirmed cases between 1955 and 2007. The presence and number of Aedes aegypti mosquitoes is strongly influenced by the amount of water-bearing containers or pockets of stagnant water in an area, daily temperature and variation in temperature, moisture, and solar radiation. While dengue fever is primarily considered a tropical and subtropical disease, the geographic ranges of the Aedes aegypti are expanding. The cases of dengue fever have increased dramatically since the 1970s and it continues to become more prevalent.
Dengue is ranked as the most important vector-borne viral disease in the world. An estimated 50–100 million dengue fever infections occur annually. In just the past 50 years, transmission has increased drastically with new cases of the disease (incidence) increasing 30-fold. The number of reported cases has continually increased along with dengue spreading to new areas.
=== Tick borne disease ===
Tick-borne disease, which affect humans and other animals, are caused by infectious agents transmitted by tick bites. A high humidity of greater than 85% is ideal for a tick to start and finish its life cycle. Studies have indicated that temperature and vapor play a significant role in determining the range for tick population. More specifically, maximum temperature has been found to play the most influential variable in sustaining tick populations. Higher temperatures augment both hatching and developmental rates while hindering overall survival. Temperature is so important to overall survival that an average monthly minimum temperature of below -7 °C in the winter can prevent an area from maintaining established populations.
The effect of climate on the tick life cycle is one of the more difficult projections to make in relation to climate and vector-borne disease. Unlike other vectors, tick life cycles span multiple seasons as they mature from larva to nymph to adult. Further, infection and spread of diseases such as Lyme disease happen across the multiple stages and different classes of vertebrate hosts, adding additional variables to consider. Although it is a European species from the Lyme borreliosis spirochetes, Borrelia garinii was documented from infected ticks on seabirds in North America. Further research is needed to improve evolutionary models predicting distributional changes in this tick-borne system in the face of climate change. Infection of ticks happen in the larval/nymph stage (after the first blood meal) when they are exposed to Borrelia burgdorferi (the spirochete responsible for Lyme disease), but transmission to humans doesn't occur until the adult stages.
The expansion of tick populations is concurrent with global climatic change. Species distribution models of recent years indicate that the deer tick, known as I. scapularis, is pushing its distribution to higher latitudes of the Northeastern United States and Canada, as well as pushing and maintaining populations in the South Central and Northern Midwest regions of the United States. Climate models project further expansion of tick habit north into Canada as progressing Northwest from the Northeastern United States. Additionally, however, tick populations are expected to retreat from the Southeastern coast of the U.S., but this has not yet been observed. It's estimated that coinciding with this expansion, increased average temperatures may double tick populations by 2020 as well as bring an earlier start to the tick exposure season.
In the face of these expanding threats, strong collaboration between government officials and environmental scientists is necessary for advancing preventive and reactive response measures. Without acknowledging the climate changes that make environments more habitable for disease carriers, policy and infrastructure will lag behind vector borne disease spread.
In the United States, the Centers for Disease Control and Prevention (CDC) is conducting a grant program called Building Resilience Against Climate Effects (BRACE) which details a 5 step process for combating climate effects like tick borne disease spread.
=== Leishmaniasis ===
As in other vector-borne diseases, one of the reasons climate changes can affect the incidence of leishmaniasis is the susceptibility of the sandfly vectors to changes in temperature, rainfall and humidity; these conditions will alter their range of distribution and seasonality. For example, modelling studies have predicted that climate change will increase suitable conditions for Phlebotomus vector species in Central Europe. Another model that looked at the distribution of Lutzomyia longipalpis, an important visceral leishmaniasis vector, suggested an increased range of this species in the Amazon Basin. A different study model that factored data on climate, policy and socio-economic changes of land use, found that the effects were different for cutaneous and visceral leishmaniasis, emphasizing the importance of considering each disease and region separately.
Parasite development inside the sand can also be affected by temperature changes. For instance, Leishmania peruviana infections were lost during sand defecation when the infected vector was kept at higher temperatures, whereas in the same experiment Leishmania infantum and Leishmania braziliensis temperature seemed to make no difference.
Leishmaniasis is a neglected tropical disease, caused by parasites of the genus Leishmania and transmitted by sandflies; it is distributed mostly in tropical and subtropical regions around the world, wherever the sand fly vector and reservoir hosts are present. The WHO estimates 12 million people around the world are living with leishmaniasis. Risk factors for the spread of this disease include poverty, urbanization, deforestation, and climate change.
=== Ebola ===
The Ebola virus has been infecting people from time to time, leading to outbreaks in several African countries. The average case fatality rate of the Ebola virus is approximately 40% and there have been more than 28,600 cases with 11,310 deaths. Many researchers are linking deforestation to the disease, observing that change in the landscape increases wildlife contact with humans.
Recent studies are holding climate change indirectly liable for the uptick in Ebola: Seasonal droughts alongside strong winds, thunderstorms, heat waves, floods, landslides, and a change in rainfall patterns also impact wildlife migration. These conditions pull them away from their natural environment and closer to human proximity. One example of an Ebola outbreak caused by climate change or a shift in nature was seen during the drought of Central Africa. This ultimately amplified food insecurity leading West African communities to eat animals such as bats who were infected with the virus.
=== Zika fever ===
Zika virus, a vector-borne virus was historically presented in cluster outbreaks in the tropical regions of Africa and Asia. Zika fever epidemics have affected larger populations including Micronesia and South Pacific Islands in 2007, and the Americas in 2013. Brazil has experienced one of the largest outbreaks of Zika virus with approximately 1.5 million cases reported in 2015. Pregnant women infected with Zika virus are at a higher risk of giving birth to children with congenital malformations, including microcephaly.
In the context of climate change and temperature rise, it is predicted that Zika virus will affect more than 1.3 billion people by 2050. This is largely due to the expansion of environments conducive to vector growth and life cycles, such as those with temperatures ranging from 23.9 °C to 34 °C. Mosquito behaviors are also affected by the change in temperature including increased breeding and biting rates. Furthermore, extreme climate patterns, including drought, floods and heatwaves are known to exacerbate the proliferation of mosquito breeding ground and as a result, escalate the rate of virus-borne diseases.
=== COVID-19 ===
There is no direct evidence that the spread of COVID-19 is worsened or is caused by climate change, although investigations continue. As of 2020, the World Health Organization summarized the current knowledge about the issue as follows: "There is no evidence of a direct connection between climate change and the emergence or transmission of COVID-19 disease. [...] However, climate change may indirectly affect the COVID-19 response, as it undermines environmental determinants of health, and places additional stress on health systems."
A 2021 study found possible links between climate change and transmission of COVID-19 by bats. The authors found that climate-driven changes in the distribution and richness of bat species increased the likelihood of bat-borne coronaviruses in the Yunnan province, Myanmar, and Laos. This region was also the habitat of Sunda pangolins and masked palm civits which were suspected as intermediate hosts of COVID-19 between bats and humans. The authors suggest, therefore, that climate change possibly contributed to some extent to the emergence of the pandemic.
Climate changed might induce changes to bat habitats which may have driven them closer to populated areas. Increased aridity and drought periods are predicted to push bats out of their endemic areas and into populated areas. This creates a knock-on effect of increasing their interactions with humans and hence the likelihood of zoonotic disease transfer.
=== Vibrio infections ===
Scientist expect that disease outbreaks caused by vibrio (in particular the bacterium that causes cholera, called vibrio cholerae) are increasing in occurrence and intensity.: 1107 One reason is that the area of coastline with suitable conditions for vibrio bacteria has increased due to changes in sea surface temperature and sea surface salinity caused by climate change.: 12 These pathogens can cause gastroenteritis, cholera, wound infections, and sepsis. It has been observed that in the period of 2011–21, the "area of coastline suitable for Vibrio bacterial transmission has increased by 35% in the Baltics, 25% in the Atlantic Northeast, and 4% in the Pacific Northwest.: 12 Furthermore, the increasing occurrence of higher temperature days, heavy rainfall events and flooding due to climate change could lead to an increase in cholera risks.: 1045
Vibrio illnesses are waterborne disease and are increasing worldwide. Vibrio infections are recently being reported where historically it did not occur. The warming climate seems to be playing a substantial role in the increase in cases and area of occurrence.
Vibrio infections are caused by consuming raw or undercooked seafood, or by exposing an open wound to contaminated sea water. Vibrio infections are most likely to occur during the warm season, May through October.
=== Skin Rashes ===
Climate change affects human health adversely and its impact on the skin is no exception. It is one of the greatest threats to our capacity to benefit in the context of “Skin Care for All.” In a study conducted in South Africa, the reduced work capacities and outputs were attributed to heat waves, which caused severe sunburns, sleeplessness, irritability, and exhaustion in workers. Risk assessments were conducted for extreme health impacts across African countries, especially Kenya, both at the regional and city scale. Rising temperature and humidity increase skin bacteria growth overall geographical distribution of other organisms that infect humans. The different organisms that form the skin microflora have variable optimal temperature for survival and growth. Staphylococcus aureus and Corynebacterium sp. amongst others are more tolerant to rising temperatures and higher salt conditions compared to other, non-commensal bacteria.
=== Diarrhea diseases ===
One of the most commonly transmitted waterborne disease categories are the diarrhea diseases. These diseases are transmitted through unsafe drinking water or recreational water contact. Diarrheal diseases account for 10–12% of deaths in children under five, as the second leading cause of death in children this age. They are also the second leading cause of death in low and middle income countries. Diarrhea diseases account for an estimated 1.4–1.9 million deaths worldwide.
=== Fungal infections ===
Fungal infections will also see an increase due to the warming of certain climates. For example, the fungus Cryptococcus gattii has been found in Canada but is normally found in warmer climates such as in Australia. There are now two strains of this fungus in the northwestern part of North America, affecting many terrestrial animals. The spread of this fungus is hypothesized to be linked to climate change.
=== Emergence of new infectious diseases ===
There is concern about the emergence of new diseases from the fungal kingdom. Mammals have endothermy and homeothermy, which allows them to maintain elevated body temperature through life; but it can be defeated if the fungi were to adapt to higher temperatures and survive in the body. Fungi that are pathogenic for insects can be experimentally adapted to replicate at mammalian temperatures through cycles of progressive warming. This demonstrates that fungi are able to adapt rapidly to higher temperatures. The emergence of Candida auris on three continents is proposed to be as a result of global warming and has raised the danger that increased warmth by itself will trigger adaptations on certain microbes to make them pathogenic for humans.
It is projected that interspecies viral sharing, that can lead to novel viral spillovers, will increase due to ongoing climate change-caused geographic range-shifts of mammals (most importantly bats). Risk hotspots would mainly be located at "high elevations, in biodiversity hotspots, and in areas of high human population density in Asia and Africa".
Climate change may also lead to new infectious diseases due to changes in microbial and vector geographic range. Microbes that are harmful to humans can adapt to higher temperatures, which will allow them to build better tolerance against human endothermy defences.
== Infectious diseases in wild animals ==
Climate change and increasing temperatures will also impact the health of wildlife animals as well. Specifically, climate change will impact wildlife disease, specifically affecting "geographic range and distribution of wildlife diseases, plant and animal phenology, wildlife host-pathogen interactions, and disease patterns in wildlife".
The health of wild animals, particularly birds, is assumed to be a better indicator of early climate change effects because very little or no control measures are undertaken to protect them.
=== Geographic range and distribution of wildlife diseases ===
Northern geographic shifts of disease vectors and parasitic disease in the Northern Hemisphere have likely been due to global warming. The geographic range of a lung parasite that impacts ungulates like caribou and mountain goats, Parelaphostrongylus odocoilei, has been shifting northward since 1995, and a tick vector for Lyme disease and other tick-borne zoonotic diseases known as Ixodes scapularis has been expanding its presence northward as well. It is also predicted that climate warming will also lead to changes in disease distribution at certain altitudes. At high elevation in the Hawaiian Islands, for example, it is expected that climate warming will allow for year-round transmission of avian malaria. This increased opportunity for transmission will likely be devastating to endangered native Hawaiian birds at those altitudes that have little or no resistance to the disease.
=== Phenology and wildlife diseases ===
Phenology is the study of seasonal cycles, and with climate change the seasonal biologic cycles of many animals have already been affected. For example, the transmission of tick-borne encephalitis (TBE) is higher to humans when early spring temperatures are warmer. The warmer temperatures result in an overlap in feeding activity of ticks who are infected with the virus (nymphal) with ticks who aren't (larval). This overlapped feeding leads to more of the uninfected larval ticks acquiring the infection and therefore increases the risk of humans being infected with TBE. On the other hand, cooler spring temperatures would result in less overlapped feeding activity, and would therefore decrease the risk of zoonotic transmission of TBE.
=== Wildlife host-to-pathogen interaction ===
The transmission of pathogens can be achieved through either direct contact from a diseased animal to another, or indirectly through a host like infected prey or a vector. Higher temperatures as a result of climate change results in an increased presence of disease producing agents in hosts and vectors, and also increases the "survival of animals that harbor disease". Survival of Parelaphostrongylus tenuis, a brain worm of white-tailed deer that affects moose, could be increased due to the higher temperatures and milder winters that are caused by climate change. In moose, this brain causes neurological disease and eventually ends up being fatal. Moose are already facing heat stress due to climate change, and may have increased susceptibility to parasitic and infectious diseases like the brain worm.
=== Wildlife disease patterns ===
Predicting the impact climate change might have on disease patterns in different geographic regions can be difficult, because its effects likely have high variability. This has been more evident in marine ecosystems than terrestrial environments, where massive decline in coral reefs has been observed due to disease spread.
== Infectious diseases in domestic animals and livestock ==
Vector-borne diseases seriously affect the health of domestic animals and livestock (e.g., trypanosomiasis, Rift Valley Fever, and bluetongue). Therefore, climate change will also indirectly affect the health of humans through its multifaceted impacts on food security, including livestock and plant crops.
Mosquitoes also carry diseases like Dirofilaria immitis which affect dogs (dog heartworm). Therefore, tropical diseases will probably migrate and become endemic in many other ecosystems due to an increase in mosquito range.
== Responses ==
The policy implications of climate change and infectious diseases fall into two categories:
Enacting policy that will reduce greenhouse gas emissions, thus slowing down climate change, and
Mitigating problems that have already arisen, and will inevitably continue to develop, due to climate change.
Addressing both of these areas is of importance, as those in the poorest countries face the greatest burden. Additionally, when countries are forced to contend with a disease like malaria (for example), their prospects for economic growth are slowed. This contributes to continued and worsening global inequality.
Policies are required that will significantly increase investments in public health in developing countries. This achieves two goals, the first being better outcomes related to diseases like malaria in the affected area, and the second being an overall better health environment for populations. It is also important to focus on "one-health approaches." This means collaborating on an interdisciplinary level, across various geographic areas, to come up with workable solutions. As is the case when responding to the effects of climate change, vulnerable populations including children and the elderly will need to be prioritized by any intervention.
The United Nations Environment Programme states that: "The most fundamental way to protect ourselves from zoonotic diseases is to prevent destruction of nature. Where ecosystems are healthy and bio-diverse, they are resilient, adaptable and help to regulate diseases."
=== Monitoring and research ===
Significant progress has been achieved in terms of surveillance systems, disease and vector control measures, vaccine development, diagnostic tests, and mathematical risk modeling/mapping in recent decades.
A tool that has been used to predict this distribution trend is the Dynamic Mosquito Simulation Process (DyMSiM). DyMSiM uses epidemiological and entomological data and practices to model future mosquito distributions based upon climate conditions and mosquitos living in the area. This modeling technique helps identify the distribution of specific species of mosquito, some of which are more susceptible to viral infection than others.
Scientists are carrying out attribution studies, to find the degree to which climate change affects the spread of infectious diseases. There is also a need for scenario modeling which can help further our understanding of future climate change consequences on infectious disease rates. Surveillance and monitoring of infectious diseases and their vectors is important to better understand these diseases. Governments should accurately model changes in vector populations as well as the burden of disease, educate the public on ways to mitigate infection and prepare health systems for the increasing disease load.
== See also ==
Disease ecology
Effects of climate change on human health
Environmental health
== References == | Wikipedia/Climate_change_and_infectious_diseases |
In climatology, the Coupled Model Intercomparison Project (CMIP) is a collaborative framework designed to improve knowledge of climate change. It was organized in 1995 by the Working Group on Coupled Modelling (WGCM) of the World Climate Research Programme (WCRP). It is developed in phases to foster the climate model improvements but also to support national and international assessments of climate change. A related project is the Atmospheric Model Intercomparison Project (AMIP) for global coupled ocean-atmosphere general circulation models (GCMs).
Coupled models are computer-based models of the Earth's climate, in which different parts (such as atmosphere, oceans, land, ice) are "coupled" together, and interact in simulations.
== CMIP phases ==
The Program for Climate Model Diagnosis and Intercomparison (PCMDI) at Lawrence Livermore National Laboratory has been supporting the several CMIP phases by helping WGCM to determine the scope of the project, by maintaining the project's data base and by participating in data analysis. CMIP has received model output from the pre-industrial climate simulations ("control runs") and 1% per year increasing-CO2 simulations of about 30 coupled GCMs. More recent phases of the project, including 20th Century Climate in Coupled Models (20C3M), include more realistic scenarios of climate forcing for both historical, paleoclimate and future scenarios.
=== CMIP Phases 1 and 2 ===
The response to the CMIP1 announcement was very successful and up to 18 global coupled models participated in the data collection representing most of the international groups with global coupled GCMs. In consequence, at the September 1996 meeting of the CLIVAR NEG2 numerical experimentation group in Victoria, Canada, it was decided that CMIP2 will be an inter-comparison of 1% per year compound CO2 increase integrations (80 years in length) where CO2 doubles at around year 70.
=== CMIP Phase 3 ===
During 2005 and 2006, a collection of climate model outputs was coordinated and stored by PCMDI. The climate model outputs included simulations of past, present and future climate scenarios. This activity enabled those climate models, outside the major modeling centers to perform research of relevance to climate scientists preparing the IPCC Fourth Assessment Report (IPCC-AR4). For the CMIP3 a list of 20 different experiments were proposed, and the PCMDI kept the documentation of all the global climate model involved. Additional information and data-sets are in.
=== CMIP Phase 5 ===
The next phase of the project (2010–2014) was CMIP5. CMIP5 included more metadata describing model simulations than previous phases. The METAFOR project created an exhaustive schema describing the scientific, technical, and numerical aspects of CMIP runs which was archived along with the output data.
A main objective of the CMIP5 experiments was to address outstanding scientific questions that arose as part of the IPCC AR4 process, improve understanding of climate, and to provide estimates of future climate change that will be useful to those considering its possible consequences. The IPCC Fifth Assessment Report summarizes information of CMIP5 experiments, while the CMIP5 experimental protocol was endorsed by the 12th Session of the WCRP Working on this Group on Coupled Modelling (WGCM). Additional information and data-sets are in.
=== CMIP Phase 6 ===
Planning meetings for Phase 6 began in 2013, and an overview of the design and organization was published in 2016. By 2018 CMIP6 had endorsed 23 Model Intercomparison Projects (MIPs) involving 33 modeling groups in 16 countries. A small number of common experiments were also planned. The deadline for submission of papers to contribute to the IPCC 6th Assessment Report Working Group I is early 2020.
The structure of the CMIP6 has been extended with respect to CMIP5 by providing an equivalent framework named CMIP Diagnostic, Evaluation and Characterization of Klima (DECK) (klima is Greek for "climate"), together with a set of Endorsed MIPs to improve the description of aspects of climate models beyond the core set of common experiments included in DECK. However, CMIP-Endorsed Model Intercomparison Projects (MIPs) are still built on the DECK and CMIP historical simulations, therefore their main goal is just to address a wider range of specific questions. This structure will be kept in future CMIP experiments.
CMIP6 also aims to be consistent regarding common standards and documentation. To achieve that it includes methods to facilitate a wider distribution and characterization of model outputs, and common standard tools for their analyses. A number of guides has been created for data managers, modelers and users.
A set of official/common forcings datasets are available for the studies under DECK, as well as several MIPS. That allows for more sensible comparisons on the model ensemble created under the CMIP6 umbrella.
These common dataset forcings are stored and coordinated by input4MIPS (input datasets for Model Intercomparison Projects).
Historical Short-Lived Climate Forcers (SLCF) and greenhouse gas (CO2 and CH4) Emissions
Biomass Burning Emissions
Global Gridded Land-use Forcing Datasets
Historical greenhouse gases concentrations: a full description is published via the CMIP6 Special Issue publication
Ozone Concentrations and Nitrogen (N)-Deposition; description of ozone radiative forcing based on this dataset is published.
Aerosol Optical Properties and Relative Change in Cloud Droplet Number Concentration
Solar Forcing:
Stratospheric Aerosol Data Set
AMIP Sea Surface Temperature and Sea Ice Datasets
Beyond these historical forcings, CMIP6 also has a common set of future scenarios comprising land use and emissions as required for the future Shared Socioeconomic Pathways (SSPs) which have replaced the Representative Concentration Pathways (RCPs) from prior models.
=== CMIP Phase 7 ===
First data is expected end-2025. For CMIP7 a more continuous release approach than in previous phases was announced: In addition to DECK releases and a growing number of community MIPS, so-called fast track experiments supporting specific requirements will be released.
== See also ==
Climate model
Intergovernmental Panel on Climate Change
Representative Concentration Pathway
Shared Socioeconomic Pathways
== References ==
== External links ==
Coupled Model Intercomparison Project (CMIP)
An Overview of Results from the Coupled Model Intercomparison Project (CMIP)
MIPS Overview, included CMIP1 to CMIP5 phases
CMIP5 Summary
CMIP5 Design Documents
CMIP6 homepage (WCRP)
CMIP Related Publications | Wikipedia/Coupled_Model_Intercomparison_Project |
Integrated Coastal Zone Management (ICZM), also known as Integrated Coastal Management (ICM), or Integrated Coastal Planning is a coastal management process that uses an integrated approach to manage all aspects of the coastal zone, including geographical and political boundaries, in an attempt to achieve sustainability. This notion was conceptualized in 1992 during the Earth Summit in Rio de Janeiro. The specifics regarding ICZM are outlined in the proceedings of the summit within Agenda 21, Chapter 17.
== Overview ==
Framework
Integrated Coastal Zone Management (ICZM) provides a globally recognized decision-making framework that is flexible enough to develop solutions tailored to the unique environmental needs of national, regional, and local coastlines. ICZM management must adopt a holistic approach, recognizing the complex and dynamic interactions within the coastal environment. The management framework should be applied to a clearly defined geographical area, which may be complex, and must operate with a high level of integration.
=== Importance ===
==== Significance and management of coastal zones ====
The Integrated Coastal Zone Management (ICZM) is a key element for the sustainable development of coastal zones. However, this recent notion may not be adapted to all cases. The Sumatra earthquake and the Indian Ocean tsunami had a significant impact on the coastal environment and stakeholders' perceptions of mitigation and management of coastal hazards.
The dynamic processes that occur within the coastal zones produce diverse and productive ecosystems that have been of great importance historically for human populations. Coastal margins equate to only 8% of the world's surface area but provide 25% of global productivity. Stress on this environment is caused by the fact that approximately 70% of the world's population lives within a day's walk of the coast. Moreover, two-thirds of the world's cities are located on the coast.
Valuable resources such as fish and minerals are considered common property and are in high demand among coastal dwellers for subsistence, recreation, and economic development. Through the perception of common property, these resources have been subjected to intensive and specific exploitation. For example, 90% of the world's fish harvest comes from within national exclusive economic zones, most of which are within the sight of the shore. This type of practice has led to a problem that has cumulative effects. The addition of other activities adds to the strain placed on this environment. Human activity in coastal zones often contributes to the degradation of these ecosystems through the extraction of unsustainable quantities of resources. This impact is compounded by the introduction of pollutant waste, further stressing the environment. These challenges underscore the importance of effective management strategies. Given the complexity of human interactions within coastal areas, a holistic approach is considered essential for achieving sustainable outcomes.
==== Goals ====
For ICZM to be successful it must adhere to the principles that define sustainability and act upon them in ways that are integrated. An optimal balance between environmental protection and the development of economic and social sectors is paramount. As part of the holistic approach ICZM applies, many aspects within a coastal zone are expected to be considered and accounted for. These include but are not limited to: the spatial, functional, legal, policy, knowledge, and participation dimensions. Below are four identified goals of ICZM:
Maintaining the functional integrity of coastal resource systems.
Reducing resource-use conflicts.
Maintaining environmental health.
Facilitating multisectoral development.
Failure to include these aspects and goals would lead to a form of unsustainable management, undermining the paradigms explicit to ICZM.
=== Five-step process ===
Problem and needs assessment: Issues and problems need to be identified and assessments of these need to be quantified. This first step will include integration between government, sectoral entities and local residents. The assessments also have to be broad in their application.
Plan: After the issues and problems have been identified and weighted, an effective management plan can be made. The plan will be specific to the area in question.
Institutionalization of plan: The adoption of the plan is carried out, which could be in the form of legally binding statutory plans, strategies or objectives which are generally quite powerful or they can be non-statutory processes and can act as a guide for future development. This duality is largely beneficial as the future can be taken into account, but still provide for a firm stance based in the present.
Implementation: Operationalization of the plan through law enforcement, education, development, etc. The implementation activities are unique to their environments and can take many forms.
Evaluation: The last phase is evaluation of the whole process. The principles of sustainability mean that there is no ‘end state.’ ICZM is an ongoing process which should constantly readjust the equilibrium between economic development and the protection of the environment. Feedback is a crucial part of the process and allows for continued effectiveness even when a situation may change.
Public participation and stakeholder involvement are essential in ICZM processes, not only from a democratic perspective but also from a technical and instrumental standpoint, to reduce decision-making conflicts (Ioppolo et al., 2013).[1]"
=== Dimensions of coastal zone management ===
==== Defining coastal zones ====
Defining the coastal zone is of particular importance to the idea of ICZM. But the fuzziness of borders due to the dynamic nature of the coast makes it difficult to clearly define. Most simply the coast can be thought of as an area of interaction between the land and the ocean. Ketchum (1972) defined the area as:
The band of dry land and adjacent ocean space (water and submerged land) in which terrestrial processes and land uses directly affect oceanic processes and uses, and vice versa.
The diverse features of coastal regions and the varying spatial scales of interacting systems present significant challenges for management. Coasts, being dynamic and influenced by a variety of factors globally, are shaped by processes such as river systems, which can extend far inland and increase the complexity of the coastal zone. These complexities make it difficult to clearly define hinterlands and establish effective management strategies.
In addition to physical characteristics, coastal zones encompass ecosystems, resources, and human activities, the latter being a primary driver of disruption to natural coastal systems. Management is further complicated by the use of administrative boundaries, which often rely on arbitrary lines that fragment the zone. This fragmented approach can result in management strategies that focus on individual sectors, such as land use or fisheries, potentially causing negative impacts in other sectors.
==== Finding sustainable solutions ====
The concept behind the idea of ICZM is sustainability. For ICZM to succeed, it must be sustainable. Sustainability entails a continuous process of decision making, so there is never an end-state just a readjustment of the equilibrium between development and the protection of the environment. The concept of Sustainability or sustainable development came to fruition in the 1987 report of the World Commission on Environment and Development, Our Common Future. It stated sustainable development is “to meet the needs of the present without compromising the ability of future generations to meet their own needs”.
Three main points:
Economic development to improve the quality of life of people
Environmentally appropriate development
Equitable development
To simplify these points, sustainability should acknowledge the right of humans to live a life that is healthy and productive. It should allow for equal distribution of benefits to all people and in doing so protect the environment through appropriate use.
Sustainability is by no means a set of prescriptive actions, more accurately it is a way of thinking. Adapting this way of thinking paves the way for a longer-term view with a more holistic approach, something successful ICZM can achieve.
Finding integration and synergies
The term ‘integration’ can be adopted for many different purposes, it is therefore quite important to define the term in the context of the management of the coastal zone to appreciate the intentions of ICZM. Integration within ICZM occurs in and between many different levels, 5 types of integration occur within ICZM;
Integration among sectors: Within the coastal environment there are many sectors that operate. These human activities are largely economic activities such as tourism, fisheries, and port companies. A sense of co-operation between sectors is the main requirement for sector integration within ICZM. This comes from the realisation of a common goal focused around sustainability and the appreciation of one another within the area.
Integration between land and water elements of the coastal zone: This is the realisation of the physical environment being a whole. The coastal environment is a dynamic relationship between many processes all of which are interdependent. The link must be made between imposing a change on one system or feature and its inevitable ‘flow on’ effects.
Integration among levels of government: Between levels of governance, consistency and co-operation is needed throughout planning and policy making. ICZM is most effective where initiatives have common purpose at local, regional, and national levels. Common goals and actions increase efficiency and mitigate confusion.
Integration between nations: This sees ICZM as an important tool on a global scale. If goals and beliefs are common on a supranational scale, large scale problems could be mitigated or avoided.
Integration among disciplines: Throughout ICZM, knowledge should be accepted from all disciplines. All means of scientific, cultural, traditional, political and local expertise need to be accounted for. By including all these elements, a truly holistic approach towards management can be achieved.
The term integration in a coastal management context has many horizontal and vertical aspects, which reflects the complexity of the task and proves a challenge to implement.
=== Constraints ===
Successful implementation is still a major challenge to the idea of ICZM.
==== Top-down and bottom-up approach ====
Major constraints of ICZM are mostly institutional, rather than technological. The ‘top-down’ approach of administrative decision making sees problematisation as a tool promoting ICZM through the idea of sustainability. Community-based ‘bottom-up’ approaches can perceive problems and issues that are specific to a local area. The benefit of this is that the problems are real and acknowledged rather than searched for to fit an imposed strategy or policy. Public consultation and involvement is very important for current ‘top-down’ approaches, as it can incorporate this ‘bottom-up’ idea into the policies made. Prescriptive ‘top-down’ methods have not able to effectively address problems of resource utilization in poor coastal communities as perceptions of the coastal zone differ with regard to developed and developing countries. This leads on to another constraint to ICZM, the idea of common property.
==== Human factors ====
The coastal environment has huge historical and cultural connections with human activity. Its wealth of resources have provided for millennia, with regard to ICZM how does management become legally binding if the dominant perception of the coast is of a common area available to all? And should it? Enforcing restrictions or change to activities within the coastal zone can be difficult as these resources are often very important to people's livelihoods. The idea of the coast being common property fouls ‘top-down’ approaches. The idea of common property itself is not all that clean, and this perception can lead to cumulative exploitation of resources – the very problem this management seeks to extinguish.
== Adoption ==
=== European Union ===
The European Parliament and the European Council "adopted in 2002 a recommendation on Integrated Coastal Zone Management which defines the principles sound coastal planning and management. These include the need to base planning on sound and shared knowledge, the need to take a long-term and cross-sector perspective, to pro-actively involve stakeholders and the need to take into account both the terrestrial and the marine components of the coastal zone".
=== Iran ===
Preparation of comprehensive management plans for optimum utilization of existent sources and potentials in all developed and developing countries is one of the appropriate approaches for constant and permanent utilization of natural, human and financial sources. The versatility of natural sources in coastal areas has made private and governmental users and investors to participate in this section to gain the utmost profits. Therefore, the necessity of preparation and implementation of management plans for perpetual utilization of existent sources in coastal areas has become inevitable.
Iran, possessing some 6000 km of coastline in north and south, owns abundant economic capacities in coastal zones and regarding the versatility of nature and coast operators and management of coastal activities and operations, necessity of attention to Integrated Coastal Zone Management becomes more significant. Such necessity has gained its legal support through ratification of arrangements no. 40 from transportation chapter of third and article no. 63 of fourth economic, social and cultural economic schedule and its executive regulations.
The General Director of coasts and ports engineering of Ports and Maritime Organization was detailed to take the studies of ICZM into consideration. The first phase of these studies began in spring 2003 and was fulfilled in autumn 2006. The outcome of this phase was compilation of following reports accomplished by several national and international skilled consultants:
1- Project Methodology
2- Scrutinized scope of services related to studies
3- Investigation of studies' needs and project preparation and performance
4- Study, definition and determination of Iranian coastal zone boundaries
6- Investigation of International concepts, methods and experiences about Integrated Coastal Zone Management
7- Study and investigation of different features of Integrated Coastal Zone Management in Iran
8- Preparation and designation of geographic database
9- Purchasing and preparing basic data
The second phase of studies started in autumn of 2005 and since then this phase has been fully accomplished and presented, In which six competent Iranian consultants with some cooperation of international consultants are responsible for preparing the eleven results of the second part of the studies.
=== Mediterranean ===
At the Conference of the Plenipotentiaries on the ICZM Protocol that took place on 20–21 January 2008 in Madrid, the ICZM Protocol was signed. Under the presidency of the Minister of Environment of Spain, H.E. Ms. Cristina Narbona Ruiz, fourteen Contracting Parties of the Barcelona Convention signed the Protocol. These are the following: Algeria, Croatia, France, Greece, Israel, Italy, Malta, Monaco, Montenegro, Morocco, Slovenia, Spain, Syria and Tunisia. All other Parties announced to do so in the very near future. This is the 7th Protocol in the framework of the Barcelona Convention, and the decision to approve the draft text and recommendation to the Conference of the Plenipotentiaries to sign it was taken at the 15th Ordinary Meeting of the Contracting Parties during their meeting in Almeria, on 15–18 January 2008. All the parties are convinced that this Protocol is a crucial milestone in the history of the Mediterranean Action Plan of the United Nations Environment Programme (UNEP/MAP), the first-ever Regional Seas Programme under UNEP's umbrella. It will allow the countries to better manage their coastal zones, as well as to deal with the emerging coastal environmental challenges, such as climate change.
The ICZM Protocol is a unique legal instrument in the entire international community and the Mediterranean countries are proud of this fact. They are willing to share these experiences with other coastal countries of the world. The signing of the Protocol came after six years of dedicated work of all the Parties. Syria entered history for being the sixth, and "enter-into-force", country for the ICZM Protocol! Namely, the President of the Syrian Arab Republic issued a Legislative Decree No. 85 dated 31 September 2010 for the ratification of the ICZM Protocol. With this 6th ratification, the ICZM Protocol entered into force one month later provided that Syria deposits the instrument of ratification to the depositary country, i.e. Spain.
In September 2012, Croatia and Morocco ratified the Protocol, which brought the number of ratifications to 9 (Slovenia, Montenegro, Albania, Spain, France, European Union, Syria, Croatia, Morocco).
The Action Plan for the implementation of the ICZM Protocol 2012-2019 was adopted on the occasion of the CoP 17, held in Paris from 8 to 10 February 2012. The core purposes and objectives of this Action Plan are to implement the Protocol based on country-based planning and regional co-ordination, namely:
1. Support the effective implementation of the ICZM Protocol at regional, national and local levels including through a Common Regional Framework for ICZM;
2. Strengthen the capacities of Contracting Parties to implement the Protocol and use in an effective manner ICZM policies, instruments, tools and processes; and
3. Promote the ICZM Protocol and its implementation within the region and globally by developing synergies with relevant Conventions and Agreements.
A roadmap for the implementation of the ICZM Process, prepared by Priority Actions Programme Regional Activity Centre (PAP/RAC), is available on the Coastal Wiki platform of the PEGASO and ENCORA projects: ICZM Process.
On May 8, 2014, the Israeli Government ratified the ICZM Protocol. This Resolution (#1588) was made in accordance with Article 19(b) of the Government Rules of Procedure. The ICZM Protocol ratification by Israel brings the number of ratifications to 10.
=== New Zealand ===
New Zealand is unique as it uses sustainable management within legislation, with a high level of importance placed on to the coastal environment. The Resource Management Act (RMA) (1991) promoted sustainable development and mandated the preparation of a New Zealand Coastal Policy Statement (NZCPS), a national framework for coastal planning. It is the only national policy statement that was mandatory. All subsequent planning must not be inconsistent with the NZCPS, making it a very important document. Regional authorities are required to produce Regional coastal policy plans under the RMA (1991) but strangely enough, they only need to include the marine environment seaward of the mean high water mark. But many regional councils have chosen to integrate the ‘dry’ landward area within their plans, breaking down the artificial barriers. This attempt at ICZM is still in its early days running into many legislative hurdles and is yet to achieve a fully ecosystems-based approach. But as part of ICZM, evaluation and adoption of changes is important and ongoing changes to the NZCPS in the form of reviews is currently happening. This will provide an excellent stepping stone for future initiatives and the development of a fully integrated form of coastal management.
== See also ==
== References ==
== External links ==
European Commission Coastal Zone Policy
ENCORA Coastal WIKI -EU Coordination Action on ICZM
Overview ICZM courses in Europe
Examining Best Practices in Coastal Zone Planning Lessons and Applications for British Columbia's Central Coast
Coastal Zone Management Policy and Politics Class Archived 2009-03-24 at the Wayback Machine
Safecoast Knowledge exchange on coastal flooding and climate change in the North Sea region
ICZM principles Archived 2007-07-17 at the Wayback Machine
ZonaCostera | KüstenZone | CoastalZone Archived 2007-09-27 at the Wayback Machine | FrangeCôtière | KustStrook: Wiki in development with relevant and on-time information, useful for the integrated management of the coastal zones of our world. Integrated development is everybody's business!
EUCC Marine Team: ICZM in Europe
Coastal Zone Management Unit in Barbados
Integrated Coastal Zone Management in Iran
Integrated coastal zone management (ICZM) is a dynamic
Videos
Free Educational Videos about Coastal Policy and Zone Management
The Future of Coastal Policy textbook overview | Wikipedia/Integrated_coastal_zone_management |
BioScience is a monthly peer-reviewed scientific journal that is published by Oxford University Press on behalf of the American Institute of Biological Sciences. It was established in 1964 and was preceded by the AIBS Bulletin (1951–1963).
The journal publishes literature reviews of current research in biology, as well as essays and discussion sections on education, public policy, history of biology, and theoretical issues.
== Abstracting and indexing ==
The journal is abstracted and indexed in MEDLINE/PubMed (1973–1979), the Science Citation Index, Current Contents/Agriculture, Biology & Environmental Sciences, The Zoological Record, and BIOSIS Previews. According to the Journal Citation Reports, the journal has a 2020 impact factor of 8.589.
== References ==
== External links ==
Official website
Journal page at the American Institute of Biological Sciences | Wikipedia/BioScience |
Numerical climate models (or climate system models) are mathematical models that can simulate the interactions of important drivers of climate. These drivers are the atmosphere, oceans, land surface and ice. Scientists use climate models to study the dynamics of the climate system and to make projections of future climate and of climate change. Climate models can also be qualitative (i.e. not numerical) models and contain narratives, largely descriptive, of possible futures.
Climate models take account of incoming energy from the Sun as well as outgoing energy from Earth. An imbalance results in a change in temperature. The incoming energy from the Sun is in the form of short wave electromagnetic radiation, chiefly visible and short-wave (near) infrared. The outgoing energy is in the form of long wave (far) infrared electromagnetic energy. These processes are part of the greenhouse effect.
Climate models vary in complexity. For example, a simple radiant heat transfer model treats the Earth as a single point and averages outgoing energy. This can be expanded vertically (radiative-convective models) and horizontally. More complex models are the coupled atmosphere–ocean–sea ice global climate models. These types of models solve the full equations for mass transfer, energy transfer and radiant exchange. In addition, other types of models can be interlinked. For example Earth System Models include also land use as well as land use changes. This allows researchers to predict the interactions between climate and ecosystems.
Climate models are systems of differential equations based on the basic laws of physics, fluid motion, and chemistry. Scientists divide the planet into a 3-dimensional grid and apply the basic equations to those grids. Atmospheric models calculate winds, heat transfer, radiation, relative humidity, and surface hydrology within each grid and evaluate interactions with neighboring points. These are coupled with oceanic models to simulate climate variability and change that occurs on different timescales due to shifting ocean currents and the much larger heat storage capacity of the global ocean. External drivers of change may also be applied. Including an ice-sheet model better accounts for long term effects such as sea level rise.
== Uses ==
There are three major types of institution where climate models are developed, implemented and used:
National meteorological services: Most national weather services have a climatology section.
Universities: Relevant departments include atmospheric sciences, meteorology, climatology, and geography.
National and international research laboratories: Examples include the National Center for Atmospheric Research (NCAR, in Boulder, Colorado, US), the Geophysical Fluid Dynamics Laboratory (GFDL, in Princeton, New Jersey, US), Los Alamos National Laboratory, the Hadley Centre for Climate Prediction and Research (in Exeter, UK), the Max Planck Institute for Meteorology in Hamburg, Germany, or the Laboratoire des Sciences du Climat et de l'Environnement (LSCE), France.
Big climate models are essential but they are not perfect. Attention still needs to be given to the real world (what is happening and why). The global models are essential to assimilate all the observations, especially from space (satellites) and produce comprehensive analyses of what is happening, and then they can be used to make predictions/projections. Simple models have a role to play that is widely abused and fails to recognize the simplifications such as not including a water cycle.
== General circulation models (GCMs) ==
== Energy balance models (EBMs) ==
Simulation of the climate system in full 3-D space and time was impractical prior to the establishment of large computational facilities starting in the 1960s. In order to begin to understand which factors may have changed Earth's paleoclimate states, the constituent and dimensional complexities of the system needed to be reduced. A simple quantitative model that balanced incoming/outgoing energy was first developed for the atmosphere in the late 19th century. Other EBMs similarly seek an economical description of surface temperatures by applying the conservation of energy constraint to individual columns of the Earth-atmosphere system.
Essential features of EBMs include their relative conceptual simplicity and their ability to sometimes produce analytical solutions.: 19 Some models account for effects of ocean, land, or ice features on the surface budget. Others include interactions with parts of the water cycle or carbon cycle. A variety of these and other reduced system models can be useful for specialized tasks that supplement GCMs, particularly to bridge gaps between simulation and understanding.
=== Zero-dimensional models ===
Zero-dimensional models consider Earth as a point in space, analogous to the pale blue dot viewed by Voyager 1 or an astronomer's view of very distant objects. This dimensionless view while highly limited is still useful in that the laws of physics are applicable in a bulk fashion to unknown objects, or in an appropriate lumped manner if some major properties of the object are known. For example, astronomers know that most planets in our own solar system feature some kind of solid/liquid surface surrounded by a gaseous atmosphere.
==== Model with combined surface and atmosphere ====
A very simple model of the radiative equilibrium of the Earth is
(
1
−
a
)
S
π
r
2
=
4
π
r
2
ϵ
σ
T
4
{\displaystyle (1-a)S\pi r^{2}=4\pi r^{2}\epsilon \sigma T^{4}}
where
the left hand side represents the total incoming shortwave power (in Watts) from the Sun
the right hand side represents the total outgoing longwave power (in Watts) from Earth, calculated from the Stefan–Boltzmann law.
The constant parameters include
S is the solar constant – the incoming solar radiation per unit area—about 1367 W·m−2
r is Earth's radius—approximately 6.371×106 m
π is the mathematical constant (3.141...)
σ
{\displaystyle \sigma }
is the Stefan–Boltzmann constant—approximately 5.67×10−8 J·K−4·m−2·s−1
The constant
π
r
2
{\displaystyle \pi \,r^{2}}
can be factored out, giving a nildimensional equation for the equilibrium
(
1
−
a
)
S
=
4
ϵ
σ
T
4
{\displaystyle (1-a)S=4\epsilon \sigma T^{4}}
where
the left hand side represents the incoming shortwave energy flux from the Sun in W·m−2
the right hand side represents the outgoing longwave energy flux from Earth in W·m−2.
The remaining variable parameters which are specific to the planet include
a
{\displaystyle a}
is Earth's average albedo, measured to be 0.3.
T
{\displaystyle T}
is Earth's average surface temperature, measured as about 288 K as of year 2020
ϵ
{\displaystyle \epsilon }
is the effective emissivity of Earth's combined surface and atmosphere (including clouds). It is a quantity between 0 and 1 that is calculated from the equilibrium to be about 0.61. For the zero-dimensional treatment it is equivalent to an average value over all viewing angles.
This very simple model is quite instructive. For example, it shows the temperature sensitivity to changes in the solar constant, Earth albedo, or effective Earth emissivity. The effective emissivity also gauges the strength of the atmospheric greenhouse effect, since it is the ratio of the thermal emissions escaping to space versus those emanating from the surface.
The calculated emissivity can be compared to available data. Terrestrial surface emissivities are all in the range of 0.96 to 0.99 (except for some small desert areas which may be as low as 0.7). Clouds, however, which cover about half of the planet's surface, have an average emissivity of about 0.5 (which must be reduced by the fourth power of the ratio of cloud absolute temperature to average surface absolute temperature) and an average cloud temperature of about 258 K (−15 °C; 5 °F). Taking all this properly into account results in an effective earth emissivity of about 0.64 (earth average temperature 285 K (12 °C; 53 °F)).
==== Models with separated surface and atmospheric layers ====
Dimensionless models have also been constructed with functionally separated atmospheric layers from the surface. The simplest of these is the zero-dimensional, one-layer model, which may be readily extended to an arbitrary number of atmospheric layers. The surface and atmospheric layer(s) are each characterized by a corresponding temperature and emissivity value, but no thickness. Applying radiative equilibrium (i.e conservation of energy) at the interfaces between layers produces a set of coupled equations which are solvable.
Layered models produce temperatures that better estimate those observed for Earth's surface and atmospheric levels. They likewise further illustrate the radiative heat transfer processes which underlie the greenhouse effect. Quantification of this phenomenon using a version of the one-layer model was first published by Svante Arrhenius in year 1896.
=== Radiative-convective models ===
Water vapor is a main determinant of the emissivity of Earth's atmosphere. It both influences the flows of radiation and is influenced by convective flows of heat in a manner that is consistent with its equilibrium concentration and temperature as a function of elevation (i.e. relative humidity distribution). This has been shown by refining the zero dimension model in the vertical to a one-dimensional radiative-convective model which considers two processes of energy transport:
upwelling and downwelling radiative transfer through atmospheric layers that both absorb and emit infrared radiation
upward transport of heat by air and vapor convection, which is especially important in the lower troposphere.
Radiative-convective models have advantages over simpler models and also lay a foundation for more complex models. They can estimate both surface temperature and the temperature variation with elevation in a more realistic manner. They also simulate the observed decline in upper atmospheric temperature and rise in surface temperature when trace amounts of other non-condensible greenhouse gases such as carbon dioxide are included.
Other parameters are sometimes included to simulate localized effects in other dimensions and to address the factors that move energy about Earth. For example, the effect of ice-albedo feedback on global climate sensitivity has been investigated using a one-dimensional radiative-convective climate model.
=== Higher-dimension models ===
The zero-dimensional model may be expanded to consider the energy transported horizontally in the atmosphere. This kind of model may well be zonally averaged. This model has the advantage of allowing a rational dependence of local albedo and emissivity on temperature – the poles can be allowed to be icy and the equator warm – but the lack of true dynamics means that horizontal transports have to be specified.
Early examples include research of Mikhail Budyko and William D. Sellers who worked on the Budyko-Sellers model. This work also showed the role of positive feedback in the climate system and has been considered foundational for the energy balance models since its publication in 1969.
== Earth systems models of intermediate complexity (EMICs) ==
Depending on the nature of questions asked and the pertinent time scales, there are, on the one extreme, conceptual, more inductive models, and, on the other extreme, general circulation models operating at the highest spatial and temporal resolution currently feasible. Models of intermediate complexity bridge the gap. One example is the Climber-3 model. Its atmosphere is a 2.5-dimensional statistical-dynamical model with 7.5° × 22.5° resolution and time step of half a day; the ocean is MOM-3 (Modular Ocean Model) with a 3.75° × 3.75° grid and 24 vertical levels.
== Box models ==
Box models are simplified versions of complex systems, reducing them to boxes (or reservoirs) linked by fluxes. The boxes are assumed to be mixed homogeneously. Within a given box, the concentration of any chemical species is therefore uniform. However, the abundance of a species within a given box may vary as a function of time due to the input to (or loss from) the box or due to the production, consumption or decay of this species within the box.
Simple box models, i.e. box model with a small number of boxes whose properties (e.g. their volume) do not change with time, are often useful to derive analytical formulas describing the dynamics and steady-state abundance of a species. More complex box models are usually solved using numerical techniques.
Box models are used extensively to model environmental systems or ecosystems and in studies of ocean circulation and the carbon cycle.
They are instances of a multi-compartment model.
In 1961 Henry Stommel was the first to use a simple 2-box model to study factors that influence ocean circulation.
== History ==
=== Increase of forecasts confidence over time ===
The Coupled Model Intercomparison Project (CMIP) has been a leading effort to foster improvements in GCMs and climate change understanding since 1995.
The IPCC stated in 2010 it has increased confidence in forecasts coming from climate models:"There is considerable confidence that climate models provide credible quantitative estimates of future climate change, particularly at continental scales and above. This confidence comes from the foundation of the models in accepted physical principles and from their ability to reproduce observed features of current climate and past climate changes. Confidence in model estimates is higher for some climate variables (e.g., temperature) than for others (e.g., precipitation). Over several decades of development, models have consistently provided a robust and unambiguous picture of significant climate warming in response to increasing greenhouse gases."
== Coordination of research ==
The World Climate Research Programme (WCRP), hosted by the World Meteorological Organization (WMO), coordinates research activities on climate modelling worldwide.
A 2012 U.S. National Research Council report discussed how the large and diverse U.S. climate modeling enterprise could evolve to become more unified. Efficiencies could be gained by developing a common software infrastructure shared by all U.S. climate researchers, and holding an annual climate modeling forum, the report found.
== Issues ==
=== Electricity consumption ===
Cloud-resolving climate models are nowadays run on high intensity super-computers which have a high power consumption and thus cause CO2 emissions. They require exascale computing (billion billion – i.e., a quintillion – calculations per second). For example, the Frontier exascale supercomputer consumes 29 MW. It can simulate a year’s worth of climate at cloud resolving scales in a day.
Techniques that could lead to energy savings, include for example: "reducing floating point precision computation; developing machine learning algorithms to avoid unnecessary computations; and creating a new generation of scalable numerical algorithms that would enable higher throughput in terms of simulated years per wall clock day."
=== Parametrization ===
== See also ==
Atmospheric reanalysis
Chemical transport model
Atmospheric Radiation Measurement (ARM) (in the US)
Climate Data Exchange
Climateprediction.net
Numerical Weather Prediction
Static atmospheric model
Tropical cyclone prediction model
Verification and validation of computer simulation models
CICE sea ice model
== References ==
== External links ==
Timeline: The History of Climate Modelling CarbonBrief, 16 January 2018
Why results from the next generation of climate models matter CarbonBrief, Guest post by Belcher, Boucher, Sutton, 21 March 2019
Climate models on the web:
NCAR/UCAR Community Climate System Model (CCSM)
Do it yourself climate prediction
Primary research GCM developed by NASA/GISS (Goddard Institute for Space Studies)
Original NASA/GISS global climate model (GCM) with a user-friendly interface for PCs and Macs
CCCma model info and interface to retrieve model data | Wikipedia/Climate_model |
There is a strong scientific consensus that greenhouse effect due to carbon dioxide is a main driver of climate change. Following is an illustrative model meant for a pedagogical purpose, showing the main physical determinants of the effect.
Under this understanding, global warming is determined by a simple energy budget: In the long run, Earth emits radiation in the same amount as it receives from the sun. However, the amount emitted depends both on Earth's temperature and on its albedo: The more reflective the Earth in a certain wavelength, the less radiation it would both receive and emit in this wavelength; the warmer the Earth, the more radiation it emits. Thus changes in the albedo may have an effect on Earth's temperature, and the effect can be calculated by assuming a new steady state would be arrived at.
In most of the electromagnetic spectrum, atmospheric carbon dioxide either blocks the radiation emitted from the ground almost completely, or is almost transparent, so that increasing the amount of carbon dioxide in the atmosphere, e.g. doubling the amount, will have negligible effects. However, in some narrow parts of the spectrum this is not so; doubling the amount of atmospheric carbon dioxide will make Earth's atmosphere relatively opaque to in these wavelengths, which would result in Earth emitting light in these wavelengths from the upper layers of the atmosphere, rather from lower layers or from the ground. Since the upper layers are colder, the amount emitted would be lower, leading to warming of Earth until the reduction in emission is compensated by the rise in temperature.
Furthermore, such warming may cause a feedback mechanism due to other changes in Earth's albedo, e.g. due to ice melting.
== Structure of the atmosphere ==
Most of the air—including ~88% of the CO2—is located in the lower part of the atmosphere known as troposphere. The troposphere is thicker in the equator and thinner at the poles, but the global mean of its thickness is around 11 km.
Inside the troposphere, the temperature drops approximately linearly at a rate of 6.5 Celsius degrees per km, from a global mean of 288 Kelvin (15 Celsius) on the ground to 220 K (-53 Celsius). At higher altitudes, up to 20 km, the temperature is approximately constant; this layer is called the tropopause.
The troposphere and tropopause together consist of ~99% of the atmospheric CO2. Inside the troposphere, the CO2 drops with altitude approximately exponentially, with a typical length of 6.3 km; this means that the density at height y is approximately proportional to exp(-y/6.3 km), and it goes down to 37% at 6.3 km, and to 17% at 11 km. Higher through the tropopause, density continues dropping exponentially, albeit faster, with a typical length of 4.2 km.
== Effect of carbon dioxide on the Earth's energy budget ==
Earth constantly absorbs energy from sunlight and emits thermal radiation as infrared light.
In the long run, Earth radiates the same amount of energy per second as it absorbs, because the amount of thermal radiation emitted depends upon temperature: If Earth absorbs more energy per second than it radiates, Earth heats up and the thermal radiation will increase, until balance is restored; if Earth absorbs less energy than it radiates, it cools down and the thermal radiation will decrease, again until balance is restored.
Atmospheric CO2 absorbs some of the energy radiated by the ground, but it emits itself thermal radiation: For example, in some wavelengths the atmosphere is totally opaque due to absorption by CO2; at these wavelengths, looking at Earth from outer space one would not see the ground, but the atmospheric CO2, and hence its thermal radiation—rather than the ground's thermal radiation. Had the atmosphere been at the same temperature as the ground, this would not change Earth's energy budget; but since the radiation is emitted from atmosphere layers that are cooler than the ground, less radiation is emitted.
As CO2 content of the atmosphere increases due to human activity, this process intensifies, and the total radiation emitted by Earth diminishes; therefore, Earth heats up until the balance is restored.
== Radiation absorption by carbon dioxide ==
CO2 absorbs the ground's thermal radiation mainly at wavelengths between 13 and 17 micron. At this wavelength range, it is almost solely responsible for the attenuation of radiation from the ground. The amount of ground radiation that is transmitted through the atmosphere in each wavelength is related to the optical depth of the atmosphere at this wavelength, OD, by:
T
=
e
−
O
D
{\displaystyle T=e^{-OD}}
The optical depth itself is given by Beer–Lambert law:
O
D
(
y
)
=
σ
∫
y
∞
n
(
y
′
)
d
y
′
{\displaystyle OD(y)=\sigma \int _{y}^{\infty }n(y^{\prime })dy^{\prime }}
where σ is the absorption cross section of a single CO2 molecule, and n(y) is the
number density of these molecules at altitude y. Due to the high dependence of the cross section in wavelength, the OD changes from around 0.1 at 13 microns to ~10 at 14 microns and even higher beyond 100 at 15 microns, then dropping off to ~10 at 16 microns, ~1 at 17 microns and below 0.1 at 18 microns. Note that the OD depends on the total number of molecules per unit area in the atmosphere, and therefore rises linearly with its CO2 content.
Looked upon from outer space into the atmosphere at a specific wavelength, one would see to different degrees different layers of the atmosphere, but on average one would see down to an altitude such that the part of the atmosphere from this altitude and up has an optical depth of ~1. Earth will therefore radiate at this wavelength approximately according to the temperature of that altitude. The effect of increasing CO2 atmospheric content means that the optical depth increases, so that the altitude seen from outer space increases; as long as it increases within the troposphere, the radiation temperature drops and the radiation decreases. When it reaches the tropopause, any further increase in CO2 levels will have no noticeable effect, since the temperature no longer depends there on the altitude.
At wavelengths of 14 to 16 microns, even the tropopause, having ~0.12 of the amount of CO2 of the whole atmosphere, has OD>1. Therefore, at these wavelengths Earth radiates mainly in the tropopause temperature, and addition of CO2 does not change this. At wavelengths smaller than 13 microns or larger than 18 microns, the atmospheric absorption is negligible, and addition of CO2 hardly changes this. Therefore, the effect of CO2 increase on radiation is relevant in wavelengths 13–14 and 16–18 microns, and addition on CO2 mainly contributes to the opacity of the troposphere, changing the altitude that is effectively seen from outer space within the troposphere.
== Calculating the effect on radiation ==
=== One layer model ===
We now turn to calculating the effect of CO2 on radiation, using a one-layer model, i.e. we treat the whole troposphere as a single layer:
Looking at a particular wavelength λ up to λ+dλ, the whole atmosphere has an optical depth OD, while the tropopause has an optical depth 0.12*OD; the troposphere has an optical depth of 0.88*OD.
Thus,
e
−
0.12
⋅
O
D
{\displaystyle e^{-0.12\cdot OD}}
of the radiation from below the tropopause is transmitted out, but this includes
e
−
0.88
⋅
O
D
{\displaystyle e^{-0.88\cdot OD}}
of the radiation that originates from the ground.
Thus, the weight of the troposphere in determining the radiation that is emitted to outer space is:
e
−
0.12
⋅
O
D
⋅
(
1
−
e
−
0.88
⋅
O
D
)
=
e
−
0.12
⋅
O
D
−
e
−
O
D
{\displaystyle e^{-0.12\cdot OD}\cdot (1-e^{-0.88\cdot OD})=e^{-0.12\cdot OD}-e^{-OD}}
A relative increase in the CO2 concentration means an equal relative increase in the total CO2 content of the atmosphere, dN/N where N is the number of CO2 molecules.
Adding a minute number of such molecules dN will increase the troposphere's weight in determining the radiation for the relevant wavelengths, approximately by the relative amount dN/N, and thus by:
d
N
N
⋅
(
e
−
0.12
⋅
O
D
−
e
−
O
D
)
{\displaystyle {\frac {dN}{N}}\cdot (e^{-0.12\cdot OD}-e^{-OD})}
Since CO2 hardly influences sunlight absorption by Earth, the radiative forcing due to an increase in CO2 content is equal to the difference in the flux radiated by Earth due to such an increase. To calculate this, one must multiply the above by the difference in radiation due to the difference in temperature. According to Planck's law, this is:
2
π
h
c
2
λ
5
d
λ
e
h
c
/
λ
k
T
−
1
≈
2
π
h
c
2
d
λ
λ
5
e
−
h
c
/
λ
k
T
{\displaystyle {\frac {2\pi hc^{2}}{\lambda ^{5}}}{\frac {d\lambda }{e^{hc/\lambda kT}-1}}\approx {\frac {2\pi hc^{2}d\lambda }{\lambda ^{5}}}e^{-hc/\lambda kT}}
The ground is at temperature T0 = 288 K, and for the troposphere we will take a typical temperature, the one at the average height of molecules, 6.3 km, where the temperature is T1247 K.
Therefore, dI, the change in Earth's emitted radiation is, in a rough approximation, is:
d
I
=
d
N
N
2
π
h
c
2
d
λ
λ
5
(
e
−
h
c
/
λ
k
T
1
−
e
−
h
c
/
λ
k
T
0
)
(
e
−
0.12
⋅
O
D
−
e
−
O
D
)
{\displaystyle dI={\frac {dN}{N}}{\frac {2\pi hc^{2}d\lambda }{\lambda ^{5}}}(e^{-hc/\lambda kT_{1}}-e^{-hc/\lambda kT_{0}})(e^{-0.12\cdot OD}-e^{-OD})}
Since dN/N = d(ln N), this can be written as:
d
I
d
l
n
N
=
2
π
h
c
2
d
λ
λ
5
(
e
−
h
c
/
λ
k
T
1
−
e
−
h
c
/
λ
k
T
0
)
(
e
−
0.12
⋅
O
D
−
e
−
O
D
)
{\displaystyle {\frac {dI}{dlnN}}={\frac {2\pi hc^{2}d\lambda }{\lambda ^{5}}}(e^{-hc/\lambda kT_{1}}-e^{-hc/\lambda kT_{0}})(e^{-0.12\cdot OD}-e^{-OD})}
=
3.7
⋅
10
8
(
W
/
m
2
)
⋅
d
λ
λ
5
∗
μ
m
4
[
e
x
p
(
−
58.3
μ
m
/
λ
)
−
e
x
p
(
−
50
μ
m
/
λ
)
]
(
e
−
0.12
⋅
O
D
−
e
−
O
D
)
{\displaystyle =3.7\cdot 10^{8}(W/m^{2})\cdot {\frac {d\lambda }{\lambda ^{5}}}*{\mu }m^{4}[exp(-58.3{\mu }m/\lambda )-exp(-50{\mu }m/\lambda )](e^{-0.12\cdot OD}-e^{-OD})}
The function
e
−
0.12
⋅
x
−
e
−
x
{\displaystyle e^{-0.12\cdot x}-e^{-x}}
is maximal for x = 2.41, with a maximal value of 0.66, and it drops to half this value at x=0.5 and x = 9.2. Thus we look at wavelengths for which the OD is between 0.5 and 9.2: This gives a wavelength band at the width of approximately 1 micron around 17 microns, and less than 1 micron around 13.5 microns. We therefore take:
λ = 13.5 microns and again 17 microns (summing contributions from both)
dλ = 0.5 micron for the 13.5 microns band, and 1 micron for the 17 microns band.
e
−
0.12
⋅
O
D
−
e
−
O
D
≈
0.5
{\displaystyle e^{-0.12\cdot OD}-e^{-OD}\approx 0.5}
Which gives -2.3 W/m2 for the 13.5 microns band, and -2.7 W/m2 for the 17 microns band, for a total of 5 W/m2.
A 2-fold increase in CO2 content changes the wavelengths ranges only slightly, and so this derivative is approximately constant along such an increase. Thus, a 2-fold increase in CO2 content will reduce the radiation emitted by Earth by approximately:
ln(2)*5 W/m2 = 3.4 W/m2.
More generally, an increase by a factor c/c0 gives:
ln(c/c0)*5 W/m2
These results are close to the approximation of a more elaborate yet simplified model giving
ln(c/c0)*5.35 W/m2, and the radiative forcing due to CO2 doubling with much more complicated models giving 3.1 W/m2.
=== Emission Layer Displacement Model ===
We may make a more elaborate calculation by treating the atmosphere as compounded of many thin layers. For each such layer, at height y and thickness dy, the weight of this layer in determining the radiation temperature seen from outer space is a generalization of the expression arrived at earlier for the troposphere. It is:
e
O
D
(
y
+
d
y
)
−
e
−
O
D
(
y
)
=
−
d
d
y
d
O
D
(
y
)
y
e
−
O
D
(
y
)
{\displaystyle e^{OD(y+dy)}-e^{-OD(y)}=-{\frac {d}{dy}}{\frac {dOD(y)}{y}}e^{-OD(y)}}
where OD(y) is the optical depth of the part of the atmosphere from y upwards.
The total effect of CO2 on the radiation at wavelengths λ to λ+dλ is therefore:
−
∫
0
∞
d
d
y
d
O
D
(
y
)
y
e
−
O
D
(
y
)
[
B
(
λ
,
d
λ
,
T
(
y
)
)
−
B
(
λ
,
d
λ
,
T
0
)
]
d
y
{\displaystyle -\int _{0}^{\infty }{\frac {d}{dy}}{\frac {dOD(y)}{y}}e^{-OD(y)}[B(\lambda ,d\lambda ,T(y))-B(\lambda ,d\lambda ,T_{0})]dy}
=
∫
0
∞
d
d
y
d
e
−
O
D
(
y
)
y
[
B
(
λ
,
d
λ
,
T
(
y
)
)
−
B
(
λ
,
d
λ
,
T
0
)
]
d
y
{\displaystyle =\int _{0}^{\infty }{\frac {d}{dy}}{\frac {de^{-OD(y)}}{y}}[B(\lambda ,d\lambda ,T(y))-B(\lambda ,d\lambda ,T_{0})]dy}
where B is the expression for radiation according to Planck's law presented above:
B
(
λ
,
d
λ
,
T
)
=
2
π
h
c
2
λ
5
d
λ
e
h
c
/
λ
k
T
−
1
≈
2
π
h
c
2
d
λ
λ
5
e
−
h
c
/
λ
k
T
{\displaystyle B(\lambda ,d\lambda ,T)={\frac {2\pi hc^{2}}{\lambda ^{5}}}{\frac {d\lambda }{e^{hc/\lambda kT}-1}}\approx {\frac {2\pi hc^{2}d\lambda }{\lambda ^{5}}}e^{-hc/\lambda kT}}
and the infinity here can be taken actually as the top of the tropopause.
Thus the effect of a relative change in CO2 concentration, dN/N = dn0/n0 (where n0 is the density number near ground), would be (noting that dN/N = d(ln N) = d(ln n0):
d
I
d
l
n
N
=
d
d
l
n
N
{
∫
0
∞
d
d
y
d
e
−
O
D
(
y
)
y
[
B
(
λ
,
d
λ
,
T
(
y
)
)
−
B
(
λ
,
d
λ
,
T
(
0
)
)
]
d
y
}
{\displaystyle {\frac {dI}{dlnN}}={\frac {d}{dlnN}}\{\int _{0}^{\infty }{\frac {d}{dy}}{\frac {de^{-OD(y)}}{y}}[B(\lambda ,d\lambda ,T(y))-B(\lambda ,d\lambda ,T(_{0}))]dy\}}
=
d
d
l
n
N
{
e
−
O
D
(
∞
)
[
B
(
λ
,
d
λ
,
T
(
∞
)
)
−
B
(
λ
,
d
λ
,
T
(
0
)
)
]
−
∫
0
∞
e
−
O
D
(
y
)
d
d
y
B
(
λ
,
d
λ
,
T
(
y
)
)
d
y
}
{\displaystyle ={\frac {d}{dlnN}}\{e^{-OD(\infty )}[B(\lambda ,d\lambda ,T(\infty ))-B(\lambda ,d\lambda ,T(_{0}))]-\int _{0}^{\infty }e^{-OD(y)}{\frac {d}{dy}}B(\lambda ,d\lambda ,T(y))dy\}}
where we have used integration by part.
Because B does not depend on N, and because
e
−
O
D
(
∞
)
=
1
{\displaystyle e^{-OD(\infty )}=1}
, we have:
d
I
d
l
n
N
=
−
∫
0
∞
d
d
l
n
N
e
−
O
D
(
y
)
d
d
y
B
(
λ
,
d
λ
,
T
(
y
)
)
d
y
=
−
∫
0
∞
d
d
l
n
N
e
−
O
D
(
y
)
d
d
T
B
(
λ
,
d
λ
,
T
(
y
)
)
d
T
d
y
d
y
{\displaystyle {\frac {dI}{dlnN}}=-\int _{0}^{\infty }{\frac {d}{dlnN}}e^{-OD(y)}{\frac {d}{dy}}B(\lambda ,d\lambda ,T(y))dy=-\int _{0}^{\infty }{\frac {d}{dlnN}}e^{-OD(y)}{\frac {d}{dT}}B(\lambda ,d\lambda ,T(y)){\frac {dT}{dy}}dy}
Now,
d
T
d
y
{\displaystyle {\frac {dT}{dy}}}
is constant in the troposphere and zero in the tropopause. We denote the height of the border between them as U. So:
d
I
d
l
n
N
=
−
d
T
d
y
∫
0
U
d
d
l
n
N
e
−
O
D
(
y
)
d
d
T
B
(
λ
,
d
λ
,
T
(
y
)
)
d
y
{\displaystyle {\frac {dI}{dlnN}}=-{\frac {dT}{dy}}\int _{0}^{U}{\frac {d}{dlnN}}e^{-OD(y)}{\frac {d}{dT}}B(\lambda ,d\lambda ,T(y))dy}
The optical depth is proportional to the integral of the number density over y, as does the pressure. Therefore, OD(y) is proportional to the pressure p(y), which within the troposphere (height 0 to U) falls exponentially with decay constant 1/Hp (Hp~5.6 km for CO2), thus:
O
D
(
y
)
=
σ
∫
y
∞
n
(
y
′
)
d
y
′
=
σ
n
0
e
−
y
/
H
p
=
σ
e
−
[
y
−
H
p
l
n
(
n
0
)
]
/
H
p
{\displaystyle OD(y)=\sigma \int _{y}^{\infty }n(y^{\prime })dy^{\prime }=\sigma n_{0}e^{-y/H_{p}}=\sigma e^{-[y-H_{p}ln(n_{0})]/H_{p}}}
Since
l
n
(
n
0
)
=
l
n
(
N
)
{\displaystyle ln(n_{0})=ln(N)}
+ constant, viewed as a function of both y and N, we have:
O
D
(
y
)
=
O
D
(
y
−
H
p
⋅
l
n
N
)
{\displaystyle OD(y)=OD(y-H_{p}\cdot lnN)}
And therefore differentiating with respect to ln N is the same as differentiating with respect to y, times a factor of
−
H
p
{\displaystyle -H_{p}}
.
We arrive at:
d
I
d
l
n
N
=
H
p
⋅
d
T
d
y
∫
0
U
d
d
y
e
−
O
D
(
y
)
d
d
T
B
(
λ
,
d
λ
,
T
(
y
)
)
d
y
{\displaystyle {\frac {dI}{dlnN}}=H_{p}\cdot {\frac {dT}{dy}}\int _{0}^{U}{\frac {d}{dy}}e^{-OD(y)}{\frac {d}{dT}}B(\lambda ,d\lambda ,T(y))dy}
.
Since the temperature only changes by ~25% within the troposphere, one may take a (rough) linear approximation of B with T at the relevant wavelengths, and get:
d
I
d
l
n
N
≈
H
p
⋅
d
d
T
B
(
λ
,
d
λ
,
T
)
d
T
d
y
∫
0
U
d
d
y
e
−
O
D
(
y
)
d
y
=
H
p
⋅
d
d
T
B
(
λ
,
d
λ
,
T
)
d
T
d
y
(
e
−
O
D
(
U
)
−
e
−
O
D
(
0
)
)
{\displaystyle {\frac {dI}{dlnN}}\approx H_{p}\cdot {\frac {d}{dT}}B(\lambda ,d\lambda ,T){\frac {dT}{dy}}\int _{0}^{U}{\frac {d}{dy}}e^{-OD(y)}dy=H_{p}\cdot {\frac {d}{dT}}B(\lambda ,d\lambda ,T){\frac {dT}{dy}}(e^{-OD(U)}-e^{-OD(0)})}
Due to the linear approximation of B we have:
H
p
⋅
d
d
T
B
(
λ
,
d
λ
,
T
)
d
T
d
y
=
[
T
(
H
p
)
−
T
0
]
⋅
d
d
T
B
(
λ
,
d
λ
,
T
)
=
B
(
λ
,
d
λ
,
T
1
)
−
B
(
λ
,
d
λ
,
T
0
)
{\displaystyle H_{p}\cdot {\frac {d}{dT}}B(\lambda ,d\lambda ,T){\frac {dT}{dy}}=[T(H_{p})-T_{0}]\cdot {\frac {d}{dT}}B(\lambda ,d\lambda ,T)=B(\lambda ,d\lambda ,T_{1})-B(\lambda ,d\lambda ,T_{0})}
with T1 taken at Hp, so that totally:
d
I
d
l
n
N
≈
[
B
(
λ
,
d
λ
,
T
1
)
−
B
(
λ
,
d
λ
,
T
0
)
]
(
e
−
O
D
(
U
)
−
e
−
O
D
(
0
)
)
{\displaystyle {\frac {dI}{dlnN}}\approx [B(\lambda ,d\lambda ,T_{1})-B(\lambda ,d\lambda ,T_{0})](e^{-OD(U)}-e^{-OD(0)})}
giving the same result as in the one-layer model presented above, as well as the logarithmic dependence on N, except that now we see T1 is taken at 5.6 km (the pressure drop height scale), rather than 6.3 km (the density drop height scale).
== Comparison to the total radiation emitted by Earth ==
The total average energy per unit time radiated by Earth is equal to the average energy flux j times the surface area 4πR2, where R is Earth's radius. On the other hand, the average energy flux absorbed from sunlight is the solar constant S0 times Earth's cross section of πR2, times the fraction absorbed by Earth, which is one minus Earth's albedo a.
The average energy per unit time radiated out is equal to the average energy per unit time absorbed from sunlight, so:
4
π
R
2
⋅
j
=
π
R
2
⋅
(
1
−
a
)
⋅
S
0
{\displaystyle 4\pi R^{2}\cdot j=\pi R^{2}\cdot (1-a)\cdot S_{0}}
giving:
j
=
1
4
⋅
(
1
−
a
)
⋅
S
0
=
1
4
⋅
(
1
−
0.3
)
⋅
1360
W
/
m
2
=
240
W
/
m
2
{\displaystyle j={\frac {1}{4}}\cdot (1-a)\cdot S_{0}={\frac {1}{4}}\cdot (1-0.3)\cdot 1360W/m^{2}=240W/m^{2}}
Based on the value of 3.1 W/m^2 obtained above in the section on the one layer model, the radiative forcing due to CO2 relative to the average radiated flux is therefore:
3.1
(
W
/
m
2
)
/
240
(
W
/
m
2
)
=
1.3
%
{\displaystyle 3.1(W/m^{2})/240(W/m^{2})=1.3\%}
An exact calculation using the MODTRAN model, over all wavelengths and including methane and ozone greenhouse gasses, as shown in the plot above, gives, for tropical latitudes, an outgoing flux
j
=
{\displaystyle j=}
298.645 W/m2 for current CO2 levels and
j
=
{\displaystyle j=}
295.286 W/m2 after CO2 doubling, i.e. a radiative forcing of 1.1%, under clear sky conditions, as well as a ground temperature of 299.7o K (26.6o Celsius). The radiative forcing is largely similar in different latitudes and under different weather conditions.
== Effect on global warming ==
On average, the total power of the thermal radiation emitted by Earth is equal to the power absorbed from sunlight. As CO2 levels rise, the emitted radiation can maintain this equilibrium only if the temperature increases, so that the total emitted radiation is unchanged (averaged over enough time, in the order of few years so that diurnal and annual periods are averaged upon).
According to Stefan–Boltzmann law, the total emitted power by Earth per unit area is:
j
=
ϵ
σ
B
⋅
T
4
{\displaystyle j=\epsilon \sigma _{B}\cdot T^{4}}
where σB is Stefan–Boltzmann constant and ε is the emissivity in the relevant wavelengths. T is some average temperature representing the effective radiation temperature.
CO2 content changes the effective T, but instead one may treat T to be a typical ground or lower-atmosphere temperature (same as T0 or close to it) and consider CO2 content as changing the emissivity ε. We thus re-interpret ε in the above equation as an effective emissivity that includes the CO2 effect;, and take T=T0. A change in CO2 content thus causes a change dε in this effective emissivity, so that
d
ϵ
ϵ
{\displaystyle {\frac {d\epsilon }{\epsilon }}}
is the radiative forcing, divided by the total energy flux radiated by Earth.
The relative change in the total radiated energy flux due to changes in emissivity and temperature is:
d
j
j
=
d
ϵ
ϵ
+
4
d
T
T
{\displaystyle {\frac {dj}{j}}={\frac {d\epsilon }{\epsilon }}+4{\frac {dT}{T}}}
Thus, if the total emitted power is to remain unchanged, a radiative forcing relative to the total energy flux radiated by Earth, causes a 1/4-fold relative change in temperature.
Thus:
Δ
T
=
1
4
T
⋅
Δ
j
j
=
1
4
⋅
288
K
⋅
1.3
%
=
0.94
K
{\displaystyle \Delta T={\frac {1}{4}}T\cdot {\frac {\Delta j}{j}}={\frac {1}{4}}\cdot 288K\cdot 1.3\%=0.94K}
=== Ice–albedo feedback ===
Since warming of Earth means less ice on the ground on average, it would cause lower albedo and more sunlight absorbed, hence further increasing Earth's temperature.
As a rough estimate, we note that the average temperature on most of Earth are between -20 and +30 Celsius degree, a good guess will be that 2% of its surface are between -1 and 0 °C, and thus an equivalent area of its surface will be changed from ice-covered (or snow-covered) to either ocean or forest.
For comparison, in the northern hemisphere, the arctic sea ice has shrunk between 1979 and 2015 by 1.43x1012 m2 at maxima and 2.52x1012 m2 at minima, for an average of almost 2x1012 m2, which is 0.4% of Earth's total surface of 510x1012 m2. At this time the global temperature rose by ~0.6 °C. The areas of inland glaciers combined (not including the antarctice ice sheet), the antarctic sea ice, and the arctic sea ice are all comparable, so one may expect the change in ice of the arctic sea ice is roughly a third of the total change, giving 1.2% of the Earth surface turned from ice to ocean or bare ground per 0.6 °C, or equivalently 2% per 1 °C. The antarctic ice cap size oscillates, and it is hard to predict its future course, with factors such as relative thermal insulated and constraints due to the Antarctic Circumpolar Current probably playing a part.
As the difference in albedo between ice and e.g. ocean is around 2/3, this means that due to a 1 °C rise, the albedo will drop by 2%*2/3 = 4/3%. However this will mainly happen in northern and southern latitudes, around 60 degrees off the equator, and so the effective area is actually 2% * cos(60o) = 1%, and the global albedo drop would be 2/3%.
Since a change in radiation of 1.3% causes a direct change of 1 degree Celsius (without feedback), as calculated above, and this causes another change of 2/3% in radiation due to positive feedback, whice is half the original change, this means the total factor caused by this feedback mechanism would be:
1
+
1
/
2
+
(
1
/
2
)
2
+
(
1
/
2
)
3
.
.
.
=
2
{\displaystyle 1+1/2+(1/2)^{2}+(1/2)^{3}...=2}
Thus, this feedback would double the effect of the change in radiation, causing a change of ~ 2 K in the global temperature, which is indeed the commonly accepted short-term value. For long-term value, including further feedback mechanisms, ~3K is considered more probable.
== References == | Wikipedia/Illustrative_model_of_greenhouse_effect_on_climate_change |
Chemiosmosis is the movement of ions across a semipermeable membrane bound structure, down their electrochemical gradient. An important example is the formation of adenosine triphosphate (ATP) by the movement of hydrogen ions (H+) across a membrane during cellular respiration or photosynthesis.
Hydrogen ions, or protons, will diffuse from a region of high proton concentration to a region of lower proton concentration, and an electrochemical concentration gradient of protons across a membrane can be harnessed to make ATP. This process is related to osmosis, the movement of water across a selective membrane, which is why it is called "chemiosmosis".
ATP synthase is the enzyme that makes ATP by chemiosmosis. It allows protons to pass through the membrane and uses the free energy difference to convert phosphorylate adenosine diphosphate (ADP) into ATP. The ATP synthase contains two parts: CF0 (present in thylakoid membrane) and CF1 (protrudes on the outer surface of thylakoid membrane). The breakdown of the proton gradient leads to conformational change in CF1—providing enough energy in the process to convert ADP to ATP. The generation of ATP by chemiosmosis occurs in mitochondria and chloroplasts, as well as in most bacteria and archaea. For instance, in chloroplasts during photosynthesis, an electron transport chain pumps H+ ions (protons) in the stroma (fluid) through the thylakoid membrane to the thylakoid spaces. The stored energy is used to photophosphorylate ADP, making ATP, as protons move through ATP synthase.
== The chemiosmotic hypothesis ==
Peter D. Mitchell proposed the chemiosmotic hypothesis in 1961. In brief, the hypothesis was that most adenosine triphosphate (ATP) synthesis in respiring cells comes from the electrochemical gradient across the inner membranes of mitochondria by using the energy of NADH and FADH2 formed during the oxidative breakdown of energy-rich molecules such as glucose.
Molecules such as glucose are metabolized to produce acetyl CoA as a fairly energy-rich intermediate. The oxidation of acetyl coenzyme A (acetyl-CoA) in the mitochondrial matrix is coupled to the reduction of a carrier molecule such as nicotinamide adenine dinucleotide (NAD) and flavin adenine dinucleotide (FAD).
The carriers pass electrons to the electron transport chain (ETC) in the inner mitochondrial membrane, which in turn pass them to other proteins in the ETC. The energy at every redox transfer step is used to pump protons from the matrix into the intermembrane space, storing energy in the form of a transmembrane electrochemical gradient. The protons move back across the inner membrane through the enzyme ATP synthase. The flow of protons back into the matrix of the mitochondrion via ATP synthase provides enough energy for ADP to combine with inorganic phosphate to form ATP.
This was a radical proposal at the time, and was not well accepted. The prevailing view was that the energy of electron transfer was stored as a stable high potential intermediate, a chemically more conservative concept. The problem with the older paradigm is that no high energy intermediate was ever found, and the evidence for proton pumping by the complexes of the electron transfer chain grew too great to be ignored. Eventually the weight of evidence began to favor the chemiosmotic hypothesis, and in 1978 Peter D. Mitchell was awarded the Nobel Prize in Chemistry.
Chemiosmotic coupling is important for ATP production in mitochondria, chloroplasts
and many bacteria and archaea.
== Proton-motive force ==
The movement of ions across the membrane depends on a combination of two factors:
Diffusion force caused by a concentration gradient - all particles tend to diffuse from higher concentration to lower.
Electrostatic force caused by electrical potential gradient - cations like protons H+ tend to diffuse down the electrical potential, from the positive (P) side of the membrane to the negative (N) side. Anions diffuse spontaneously in the opposite direction.
These two gradients taken together can be expressed as an electrochemical gradient.
Lipid bilayers of biological membranes, however, are barriers for ions. This is why energy can be stored as a combination of these two gradients across the membrane. Only special membrane proteins like ion channels can sometimes allow ions to move across the membrane (see also: Membrane transport). In the chemiosmotic hypothesis a transmembrane ATP synthase is central to convert energy of spontaneous flow of protons through them into chemical energy of ATP bonds.
Hence researchers created the term proton-motive force (PMF), derived from the electrochemical gradient mentioned earlier. It can be described as the measure of the potential energy stored (chemiosmotic potential) as a combination of proton and voltage (electrical potential) gradients across a membrane. The electrical gradient is a consequence of the charge separation across the membrane (when the protons H+ move without a counterion, such as chloride Cl−).
In most cases the proton-motive force is generated by an electron transport chain which acts as a proton pump, using the Gibbs free energy of redox reactions to pump protons (hydrogen ions) out across the membrane, separating the charge across the membrane. In mitochondria, energy released by the electron transport chain is used to move protons from the mitochondrial matrix (N side) to the intermembrane space (P side). Moving the protons out of the mitochondrion creates a lower concentration of positively charged protons inside it, resulting in excess negative charge on the inside of the membrane. The electrical potential gradient is about -170 mV , negative inside (N). These gradients - charge difference and the proton concentration difference both create a combined electrochemical gradient across the membrane, often expressed as the proton-motive force (PMF). In mitochondria, the PMF is almost entirely made up of the electrical component but in chloroplasts the PMF is made up mostly of the pH gradient because the charge of protons H+ is neutralized by the movement of Cl− and other anions. In either case, the PMF needs to be greater than about 460 mV (45 kJ/mol) for the ATP synthase to be able to make ATP.
=== Equations ===
The proton-motive force is derived from the Gibbs free energy. Let N denote the inside of a cell, and P denote the outside. Then
Δ
G
=
z
F
Δ
ψ
+
R
T
ln
[
X
z
+
]
N
[
X
z
+
]
P
{\displaystyle \Delta \!G=zF\Delta \!\psi +RT\ln {\frac {[\mathrm {X} ^{z+}]_{\text{N}}}{[\mathrm {X} ^{z+}]_{\text{P}}}}}
where
Δ
G
{\displaystyle \Delta \!G}
is the Gibbs free energy change per unit amount of cations transferred from P to N;
z
{\displaystyle z}
is the charge number of the cation
X
z
+
{\displaystyle \mathrm {X} ^{z+}}
;
Δ
ψ
{\displaystyle \Delta \psi }
is the electric potential of N relative to P;
[
X
z
+
]
P
{\displaystyle [\mathrm {X} ^{z+}]_{\text{P}}}
and
[
X
z
+
]
N
{\displaystyle [\mathrm {X} ^{z+}]_{\text{N}}}
are the cation concentrations at P and N, respectively;
F
{\displaystyle F}
is the Faraday constant;
R
{\displaystyle R}
is the gas constant; and
T
{\displaystyle T}
is the temperature.
The molar Gibbs free energy change
Δ
G
{\displaystyle \Delta \!G}
is frequently interpreted as a molar electrochemical ion potential
Δ
μ
X
z
+
=
Δ
G
{\displaystyle \Delta \!\mu _{\mathrm {X} ^{z+}}=\Delta \!G}
.
For an electrochemical proton gradient
z
=
1
{\displaystyle z=1}
and as a consequence:
Δ
μ
H
+
=
F
Δ
ψ
+
R
T
ln
[
H
+
]
N
[
H
+
]
P
=
F
Δ
ψ
−
(
ln
10
)
R
T
Δ
p
H
{\displaystyle \Delta \!\mu _{\mathrm {H} ^{+}}=F\Delta \!\psi +RT\ln {\frac {[\mathrm {H} ^{+}]_{\text{N}}}{[\mathrm {H} ^{+}]_{\text{P}}}}=F\Delta \!\psi -(\ln 10)RT\Delta \mathrm {pH} }
where
Δ
p
H
=
p
H
N
−
p
H
P
{\displaystyle \Delta \!\mathrm {pH} =\mathrm {pH} _{\mathrm {N} }-\mathrm {pH} _{\mathrm {P} }}
.
Mitchell defined the proton-motive force (PMF) as
Δ
p
=
−
Δ
μ
H
+
F
{\displaystyle \Delta \!p=-{\frac {\Delta \!\mu _{\mathrm {H^{+}} }}{F}}}
.
For example,
Δ
μ
H
+
=
1
k
J
m
o
l
−
1
{\displaystyle \Delta \!\mu _{\mathrm {H} ^{+}}=1\,\mathrm {kJ} \,\mathrm {mol} ^{-1}}
implies
Δ
p
=
10.4
m
V
{\displaystyle \Delta \!p=10.4\,\mathrm {mV} }
. At
298
K
{\displaystyle 298\,\mathrm {K} }
this equation takes the form:
Δ
p
=
−
Δ
ψ
+
(
59.1
m
V
)
Δ
p
H
{\displaystyle \Delta \!p=-\Delta \!\psi +\left(59.1\,\mathrm {mV} \right)\Delta \!\mathrm {pH} }
.
Note that for spontaneous proton import from the P side (relatively more positive and acidic) to the N side (relatively more negative and alkaline),
Δ
μ
H
+
{\displaystyle \Delta \!\mu _{\mathrm {H} ^{+}}}
is negative (similar to
Δ
G
{\displaystyle \Delta \!G}
) whereas PMF is positive (similar to redox cell potential
Δ
E
{\displaystyle \Delta E}
).
It is worth noting that, as with any transmembrane transport process, the PMF is directional. The sign of the transmembrane electric potential difference
Δ
ψ
{\displaystyle \Delta \!\psi }
is chosen to represent the change in potential energy per unit charge flowing into the cell as above. Furthermore, due to redox-driven proton pumping by coupling sites, the proton gradient is always inside-alkaline. For both of these reasons, protons flow in spontaneously, from the P side to the N side; the available free energy is used to synthesize ATP (see below). For this reason, PMF is defined for proton import, which is spontaneous. PMF for proton export, i.e., proton pumping as catalyzed by the coupling sites, is simply the negative of PMF(import).
The spontaneity of proton import (from the P to the N side) is universal in all bioenergetic membranes. This fact was not recognized before the 1990s, because the chloroplast thylakoid lumen was interpreted as an interior phase, but in fact it is topologically equivalent to the exterior of the chloroplast. Azzone et al. stressed that the inside phase (N side of the membrane) is the bacterial cytoplasm, mitochondrial matrix, or chloroplast stroma; the outside (P) side is the bacterial periplasmic space, mitochondrial intermembrane space, or chloroplast lumen. Furthermore, 3D tomography of the mitochondrial inner membrane shows its extensive invaginations to be stacked, similar to thylakoid disks; hence the mitochondrial intermembrane space is topologically quite similar to the chloroplast lumen.:
The energy expressed here as Gibbs free energy, electrochemical proton gradient, or proton-motive force (PMF), is a combination of two gradients across the membrane:
the concentration gradient (via
Δ
p
H
{\displaystyle \Delta \!\mathrm {pH} }
) and
electric potential gradient
Δ
ψ
{\displaystyle \Delta \!\psi }
.
When a system reaches equilibrium,
Δ
ρ
=
0
{\displaystyle \Delta \!\rho =0}
; nevertheless, the concentrations on either side of the membrane need not be equal. Spontaneous movement across the potential membrane is determined by both concentration and electric potential gradients.
The molar Gibbs free energy
Δ
G
p
{\displaystyle \Delta \!G_{\mathrm {p} }}
of ATP synthesis
A
D
P
4
−
+
H
+
+
H
O
P
O
3
2
−
→
A
T
P
4
−
+
H
2
O
{\displaystyle \mathrm {ADP} ^{4-}+\mathrm {H} ^{+}+\mathrm {HOPO} _{3}^{2-}\rightarrow \mathrm {ATP} ^{4-}+\mathrm {H_{2}O} }
is also called phosphorylation potential. The equilibrium concentration ratio
[
H
+
]
/
[
A
T
P
]
{\displaystyle [\mathrm {H} ^{+}]/[\mathrm {ATP} ]}
can be calculated by comparing
Δ
p
{\displaystyle \Delta \!p}
and
Δ
G
p
{\displaystyle \Delta \!G_{\mathrm {p} }}
, for example in case of the mammalian mitochondrion:
H+ / ATP = ΔGp / (Δp / 10.4 kJ·mol−1/mV) = 40.2 kJ·mol−1 / (173.5 mV / 10.4 kJ·mol−1/mV) = 40.2 / 16.7 = 2.4. The actual ratio of the proton-binding c-subunit to the ATP-synthesizing beta-subunit copy numbers is 8/3 = 2.67, showing that under these conditions, the mitochondrion functions at 90% (2.4/2.67) efficiency.
In fact, the thermodynamic efficiency is mostly lower in eukaryotic cells because ATP must be exported from the matrix to the cytoplasm, and ADP and phosphate must be imported from the cytoplasm. This "costs" one "extra" proton import per ATP, hence the actual efficiency is only 65% (= 2.4/3.67).
== In mitochondria ==
The complete breakdown of glucose releasing its energy is called cellular respiration. The last steps of this process occur in mitochondria. The reduced molecules NADH and FADH2 are generated by the Krebs cycle, glycolysis, and pyruvate processing. These molecules pass electrons to an electron transport chain, which releases the energy of oxygen to create a proton gradient across the inner mitochondrial membrane. ATP synthase then uses the energy stored in this gradient to make ATP. This process is called oxidative phosphorylation because it uses energy released by the oxidation of NADH and FADH2 to phosphorylate ADP into ATP.
== In plants ==
The light reactions of photosynthesis generate ATP by the action of chemiosmosis. The photons in sunlight are received by the antenna complex of Photosystem II, which excites electrons to a higher energy level. These electrons travel down an electron transport chain, causing protons to be actively pumped across the thylakoid membrane into the thylakoid lumen. These protons then flow down their electrochemical potential gradient through an enzyme called ATP-synthase, creating ATP by the phosphorylation of ADP to ATP. The electrons from the initial light reaction reach Photosystem I, then are raised to a higher energy level by light energy and then received by an electron acceptor and reduce NADP+ to NADPH. The electrons lost from Photosystem II get replaced by the oxidation of water, which is "split" into protons and oxygen by the oxygen-evolving complex (OEC, also known as WOC, or the water-oxidizing complex). To generate one molecule of diatomic oxygen, 10 photons must be absorbed by Photosystems I and II, four electrons must move through the two photosystems, and 2 NADPH are generated (later used for carbon dioxide fixation in the Calvin Cycle).
== In prokaryotes ==
Bacteria and archaea also can use chemiosmosis to generate ATP. Cyanobacteria, green sulfur bacteria, and purple bacteria synthesize ATP by a process called photophosphorylation. These bacteria use the energy of light to create a proton gradient using a photosynthetic electron transport chain. Non-photosynthetic bacteria such as E. coli also contain ATP synthase. In fact, mitochondria and chloroplasts are the product of endosymbiosis and trace back to incorporated prokaryotes. This process is described in the endosymbiotic theory. The origin of the mitochondrion triggered the origin of eukaryotes, and the origin of the plastid the origin of the Archaeplastida, one of the major eukaryotic supergroups.
Chemiosmotic phosphorylation is the third pathway that produces ATP from inorganic phosphate and an ADP molecule. This process is part of oxidative phosphorylation.
== Emergence of chemiosmosis ==
=== Thermal cycling model ===
A stepwise model for the emergence of chemiosmosis, a key element in the origin of life on earth, proposes that primordial organisms used thermal cycling as an energy source (thermosynthesis), functioning essentially as a heat engine:
self-organized convection in natural waters causing thermal cycling →
added β-subunit of F1 ATP Synthase
(generated ATP by thermal cycling of subunit during suspension in convection cell: thermosynthesis) →
added membrane and Fo ATP Synthase moiety
(generated ATP by change in electrical polarization of membrane during thermal cycling: thermosynthesis) →
added metastable, light-induced electric dipoles in membrane
(primitive photosynthesis) →
added quinones and membrane-spanning light-induced electric dipoles
(today's bacterial photosynthesis, which makes use of chemiosmosis).
=== External proton gradient model ===
Biochemist Nick Lane has proposed the following hypothesis. Deep-sea hydrothermal vents, emitting hot acidic or alkaline water, would have created external proton gradients. These provided energy that primordial organisms could have exploited. To keep the flows separate, such an organism could have wedged itself in the rock of the hydrothermal vent, exposed to the hydrothermal flow on one side and the more alkaline water on the other. As long as the organism's membrane (or passive ion channels within it) is permeable to protons, the mechanism can function without ion pumps. Such a proto-organism could then have evolved further mechanisms such as ion pumps and ATP synthase.
=== Meteoritic quinones ===
A proposed alternative source to chemiosmotic energy developing across membranous structures is if an electron acceptor, ferricyanide, is within a vesicle and the electron donor is outside, quinones transported by carbonaceous meteorites pick up electrons and protons from the donor. They would release electrons across the lipid membrane by diffusion to ferricyanide within the vesicles and release protons which produces gradients above pH 2, the process is conducive to the development of proton gradients.
== See also ==
Cellular respiration
Citric acid cycle
Electrochemical gradient
Glycolysis
Oxidative phosphorylation
== References ==
== Further reading ==
Biochemistry textbook reference, from the NCBI bookshelf – Jeremy M. Berg; John L. Tymoczko; Lubert Stryer (eds.). "18.4. A Proton Gradient Powers the Synthesis of ATP". Biochemistry (5th ed.). W. H. Freeman.
A set of experiments aiming to test some tenets of the chemiosmotic theory – Ogawa S, Lee TM (August 1984). "The relation between the internal phosphorylation potential and the proton motive force in mitochondria during ATP synthesis and hydrolysis". The Journal of Biological Chemistry. 259 (16): 10004–10011. doi:10.1016/S0021-9258(18)90918-X. PMID 6469951.
== External links ==
Chemiosmosis (University of Wisconsin) | Wikipedia/Proton_motive_force |
Issues in Science and Religion is a book by Ian Barbour. A biography provided by the John Templeton Foundation and published by PBS online states this book "has been credited with literally creating the contemporary field of science and religion."
== Contents ==
The book is divided into three parts. The first part is concerned with the history of science and religion, the second with the methods of science and religion, and the third with the issues themselves.
Barbour provides introductions to several schools of philosophy in order to give the reader knowledge enough to understand how relations between science and religion look from these distinct viewpoints. The book also includes several specific, non-philosophical areas of science are employed in its discussion. Several specific concepts and objects are brought up in the discussion generally along with summaries of significant criticisms.
== Part 1: Religion and the History of Science ==
In this part Barbour provides an overview of how scientific discovery has influenced theology throughout the 17th, 18th, 19th and 20th centuries. The major scientific discoveries made in the 17th century included those made by Galileo and Newton. The scientific discoveries made by Galileo and Newton began to describe and explain the natural and physical laws by which the earth operates. These discoveries drastically changed the way that man viewed the world and nature. This in turn caused shifts in theological thought. Natural theology emerged, where God was able to fill the scientific gaps and was responsible for the orderliness of nature. The idea of God as the "Divine Clockmaker" and the beginning of Deism can also be traced back to the 17th century.
During the 18th century the Age of Reason and Romanticism greatly shaped views on science and theology. Deism became very popular during this time among many Enlightenment scholars. Romanticism, on the other hand, led to an appreciation of the underlying spirituality in nature and in man, and God's personal relationship with man and nature. This in turn led to the concepts of moral and religious experience, which focused on man's intuition and imagination in relation to their religious experience.
The theory of evolution was developed by Darwin in the 19th century. This essentially eliminated the "God of the gaps" that had come about in the 17th century. Liberal theologians accepted the theory of evolution, and held the opinion that God works continuously through the evolutionary process. On the other hand, conservatives still insisted on Biblical literalism, and they rejected Darwin's theory. For the most part theologians began to focus more on the human experience for their basis of theology.
In the next two parts of the book, Barbour goes into details of the 20th century.
== Part 2: Religion and the Methods of Science ==
In this section a whole chapter is devoted to the methods of scientific discovery. Barbour asserts that scientific discovery is based on a critical realism, where it is recognized that scientific theory is not infallible in itself but is based on universal truths. Due to this line of thinking, as scientific knowledge changes an overall advance is made. The next chapter compares the study of science to the study of history. This chapter focuses on the objectivity of science versus the subjectivity of history. History is seen as subjective because one is dealing with the humanities and there is a level of personal involvement. Although throughout history certain patterns of human behavior emerge, these patterns are never entirely predictable or repeatable. Where in science, all events that are observed must be repeatable and produce the same results in order to uphold natural laws. The following chapter examines the methods of religion. In this chapter some comparisons are made between the methods of science and the methods of religion, in particular regarding experience, community and the use of models to explain an event or concept. Although there are parallels between the methods of science and religion, there are also difference. One major difference is the same as the difference between science and history. Like history, religion is subjective due to the personal involvement required of religion. The final chapter of this section discusses the language used in religion and science. This chapter asserts that although there are many similarities in the methods and language of science and religion, the two subjects remain distinctly different in their purposes.
== Part 3: Religion and the Theory of Science ==
The first chapter in this section examines contemporary physics, in particular indeterminacy as shown in the Heisenberg Uncertainty Principle. This indeterminacy in the behavior of atoms can be generalized to apply to humanity as a whole. This argument rests on the unpredictability of a single person and their action. Barbour concludes this chapter by stating that although physics can be used to explain human freedom to some extent, it will never produce an entirely satisfactory argument for it. The next chapter addresses how the idea that man is simply a machine that can be broken up into respective systems and thus is completely predictable, is not satisfactory in the scientific world. It can be seen through science and the study of DNA, that each human has a unique identity and sense of selfhood. This is supported biblically, in that God's love for each human being is unique to that person. The next chapter expresses varying viewpoints on creation and evolution, from conservative to liberal theology. In more conservative lines of thought biblical literalism points to the creation of man as a divine point in creation, and therefore rejects the idea of man evolving from other life forms. The liberal side of theology embraces the theory of evolution, and incorporates it with scripture into a doctrine of continuing creation. The final chapter in this book examines God's relation to nature. There are many different views on how God is related to nature. Those who hold more conservative views believe in God's sovereignty over nature. Others look at God's role in nature through a historical context, where God has evoked certain responses in nature throughout the course of time.
== See also ==
Relationship between religion and science
List of science and religion scholars
== References ==
== Further reading ==
Holmes Rolston III, Science and Religion: A Critical Survey (Random House 1987, McGraw Hill, Harcourt Brace; new edition, Templeton Foundation Press, 2006), p. 78 n.10
John Hedley Brooke, Bibliographic Essay (pages 348–403) in Science and Religion: Some Historical Perspectives, 1991, Cambridge University Press, ISBN 0-521-23961-3:
=== Reviews ===
David Ray Griffin, Zygon, volume 23, issue 1, March 1988, pages 57–81, abstract
Ian Barbour, "A Response to David Griffin" Zygon, volume 23, issue 1, March 1988, p. 83-88
G. D. Yarnold, The Journal of Religion, Volume 48, Issue 2, April 1968, pages 181-189
E.L. Mascall, Journal of Theological Studies, Volume 18, 1967, pages 542-543
Times Literary Supplement, March 23, 1967, page 249
John M. Bailey, American Journal of Physics, Volume 36, Issue 6, 1968, pages 562–563. | Wikipedia/Issues_in_Science_and_Religion |
The relationship between religion and science involves discussions that interconnect the study of the natural world, history, philosophy, and theology. Even though the ancient and medieval worlds did not have conceptions resembling the modern understandings of "science" or of "religion", certain elements of modern ideas on the subject recur throughout history. The pair-structured phrases "religion and science" and "science and religion" first emerged in the literature during the 19th century. This coincided with the refining of "science" (from the studies of "natural philosophy") and of "religion" as distinct concepts in the preceding few centuries—partly due to professionalization of the sciences, the Protestant Reformation, colonization, and globalization. Since then the relationship between science and religion has been characterized in terms of "conflict", "harmony", "complexity", and "mutual independence", among others.
Both science and religion are complex social and cultural endeavors that may vary across cultures and change over time. Most scientific and technical innovations until the scientific revolution were achieved by societies organized by religious traditions. Ancient pagan, Islamic, and Christian scholars pioneered individual elements of the scientific method. Roger Bacon, often credited with formalizing the scientific method, was a Franciscan friar and medieval Christians who studied nature emphasized natural explanations. Confucian thought, whether religious or non-religious in nature, has held different views of science over time. Many 21st-century Buddhists view science as complementary to their beliefs, although the philosophical integrity of such Buddhist modernism has been challenged. While the classification of the material world by the ancient Indians and Greeks into air, earth, fire, and water was more metaphysical, and figures like Anaxagoras questioned certain popular views of Greek divinities, medieval Middle Eastern scholars empirically classified materials.
Events in Europe such as the Galileo affair of the early 17th century, associated with the scientific revolution and the Age of Enlightenment, led scholars such as John William Draper to postulate (c. 1874) a conflict thesis, suggesting that religion and science have been in conflict methodologically, factually and politically throughout history. Some contemporary philosophers and scientists, such as Richard Dawkins, Lawrence Krauss, Peter Atkins, and Donald Prothero subscribe to this thesis; however, historians such as Stephen Shapin state "it is a very long time since these attitudes have been held by historians of science."
Many scientists, philosophers, and theologians throughout history, from Augustine of Hippo to Thomas Aquinas to Francisco Ayala, Kenneth R. Miller, and Francis Collins, have seen compatibility or interdependence between religion and science. Biologist Stephen Jay Gould regarded religion and science as "non-overlapping magisteria", addressing fundamentally separate forms of knowledge and aspects of life. Some historians of science and mathematicians, including John Lennox, Thomas Berry, and Brian Swimme, propose an interconnection between science and religion, while others such as Ian Barbour believe there are even parallels. Public acceptance of scientific facts may sometimes be influenced by religious beliefs such as in the United States, where some reject the concept of evolution by natural selection, especially regarding Human beings. Nevertheless, the American National Academy of Sciences has written that "the evidence for evolution can be fully compatible with religious faith",
a view endorsed by many religious denominations.
== History ==
=== Concepts of science and religion ===
The concepts of "science" and "religion" are a recent invention: "religion" emerged in the 17th century in the midst of colonization, globalization and as a consequence of the Protestant reformation. "Science" emerged in the 19th century in the midst of attempts to narrowly define those who studied nature. Originally what is now known as "science" was pioneered as "natural philosophy".
It was in the 19th century that the terms "Buddhism", "Hinduism", "Taoism", "Confucianism" and "World Religions" first emerged. In the ancient and medieval world, the etymological Latin roots of both science (scientia) and religion (religio) were understood as inner qualities of the individual or virtues, never as doctrines, practices, or actual sources of knowledge.
The 19th century also experienced the concept of "science" receiving its modern shape with new titles emerging such as "biology" and "biologist", "physics", and "physicist", among other technical fields and titles; institutions and communities were founded, and unprecedented applications to and interactions with other aspects of society and culture occurred. The term scientist was coined by the naturalist-theologian William Whewell in 1834 and it was applied to those who sought knowledge and understanding of nature. From the ancient world, starting with Aristotle, to the 19th century, the practice of studying nature was commonly referred to as "natural philosophy". Isaac Newton's book Philosophiae Naturalis Principia Mathematica (1687), whose title translates to "Mathematical Principles of Natural Philosophy", reflects the then-current use of the words "natural philosophy", akin to "systematic study of nature". Even in the 19th century, a treatise by Lord Kelvin and Peter Guthrie Tait's, which helped define much of modern physics, was titled Treatise on Natural Philosophy (1867).
It was in the 17th century that the concept of "religion" received its modern shape despite the fact that ancient texts like the Bible, the Quran, and other texts did not have a concept of religion in the original languages and neither did the people or the cultures in which these texts were written. In the 19th century, Max Müller noted that what is called ancient religion today, would have been called "law" in antiquity. For example, there is no precise equivalent of "religion" in Hebrew, and Judaism does not distinguish clearly between religious, national, racial, or ethnic identities. The Sanskrit word "dharma", sometimes translated as "religion", also means law or duty. Throughout classical India, the study of law consisted of concepts such as penance through piety and ceremonial as well as practical traditions. Medieval Japan at first had a similar union between "imperial law" and universal or "Buddha law", but these later became independent sources of power. Throughout its long history, Japan had no concept of "religion" since there was no corresponding Japanese word, nor anything close to its meaning, but when American warships appeared off the coast of Japan in 1853 and forced the Japanese government to sign treaties demanding, among other things, freedom of religion, the country had to contend with this Western idea.
=== Middle Ages and Renaissance ===
The development of sciences (especially natural philosophy) in Western Europe during the Middle Ages, has a considerable foundation in the works of the Arabs who translated Greek and Latin compositions. The works of Aristotle played a major role in the institutionalization, systematization, and expansion of reason. Christianity accepted reason within the ambit of faith. In Christendom, ideas articulated via divine revelation were assumed to be true, and thus via the law of non-contradiction, it was maintained that the natural world must accord with this revealed truth. Any apparent contradiction would indicate either a misunderstanding of the natural world or a misunderstanding of revelation. The prominent scholastic Thomas Aquinas writes in the Summa Theologica concerning apparent contradictions:
"In discussing questions of this kind two rules are to observed, as Augustine teaches (Gen. ad lit. i, 18). The first is, to hold the truth of Scripture without wavering. The second is that since Holy Scripture can be explained in a multiplicity of senses, one should adhere to a particular explanation, only in such measure as to be ready to abandon it, if it be proved with certainty to be false; lest Holy Scripture be exposed to the ridicule of unbelievers, and obstacles be placed to their believing." (Summa 1a, 68, 1)
where the referenced text from Augustine of Hippo reads:
"In matters that are obscure and far beyond our vision, even in such as we may find treated in Holy Scripture, different interpretations are sometimes possible without prejudice to the faith we have received. In such a case, we should not rush in headlong and so firmly take our stand on one side that, if further progress in the search of truth justly undermines this position, we too fall with it. That would be to battle not for the teaching of Holy Scripture but for our own, wishing its teaching to conform to ours, whereas we ought to wish ours to conform to that of Sacred Scripture." (Gen. ad lit. i, 18)
In medieval universities, the faculty for natural philosophy and theology were separate, and discussions pertaining to theological issues were often not allowed to be undertaken by the faculty of philosophy. Natural philosophy, as taught in the arts faculties of the universities, was seen as an essential area of study in its own right and was considered necessary for almost every area of study. It was an independent field, separated from theology, and enjoyed a good deal of intellectual freedom as long as it was restricted to the natural world. In general, there was religious support for natural science by the late Middle Ages and a recognition that it was an important element of learning.
The extent to which medieval science led directly to the new philosophy of the scientific revolution remains a subject for debate, but it certainly had a significant influence.
The Middle Ages laid ground for the developments that took place in science, during the Renaissance which immediately succeeded it. By 1630, ancient authority from classical literature and philosophy, as well as their necessity, started eroding, although scientists were still expected to be fluent in Latin, the international language of Europe's intellectuals. With the sheer success of science and the steady advance of rationalism, the individual scientist gained prestige. Along with the inventions of this period, especially the printing press by Johannes Gutenberg, allowing for the dissemination of the Bible in vernacular languages. This allowed more people to read and learn from the scripture, leading to the Evangelical movement. The people who spread this message concentrated more on individual agency rather than the structures of the Church.
==== Medieval Contributors ====
Some medieval contributors to science included: Boethius (c. 477–524), John Philoponus (c. 490–570), Bede the Venerable (c. 672–735), Alcuin of York (c. 735–804), Leo the Mathematician (c. 790–869), Gerbert of Aurillac (c. 946–1003), Constantine the African (c. 1020–1087), Adelard of Bath (c. 1080–1152), Robert Grosseteste (c. 1168–1253), St. Albert the Great (c. 1200–1280), Roger Bacon (c. 1214–1294), William of Ockham (c. 1287–1347), Jean Burdian (c. 1301–1358), Thomas Bradwardine (1300–1349), Nicole Oresme (c. 1320–1382), Nicholas of Cusa (c. 1401–1464).
=== Modern period ===
In the 17th century, founders of the Royal Society largely held conventional and orthodox religious views, and a number of them were prominent Churchmen. While theological issues that had the potential to be divisive were typically excluded from formal discussions of the early Society, many of its fellows nonetheless believed that their scientific activities provided support for traditional religious belief. Clerical involvement in the Royal Society remained high until the mid-nineteenth century when science became more professionalized.
Albert Einstein supported the compatibility of some interpretations of religion with science. In "Science, Philosophy and Religion, A Symposium" published by the Conference on Science, Philosophy and Religion in Their Relation to the Democratic Way of Life, Inc., New York in 1941, Einstein stated:
Accordingly, a religious person is devout in the sense that he has no doubt of the significance and loftiness of those superpersonal objects and goals which neither require nor are capable of rational foundation. They exist with the same necessity and matter-of-factness as he himself. In this sense religion is the age-old endeavor of mankind to become clearly and completely conscious of these values and goals and constantly to strengthen and extend their effect. If one conceives of religion and science according to these definitions then a conflict between them appears impossible. For science can only ascertain what is, but not what should be, and outside of its domain value judgments of all kinds remain necessary. Religion, on the other hand, deals only with evaluations of human thought and action: it cannot justifiably speak of facts and relationships between facts. According to this interpretation the well-known conflicts between religion and science in the past must all be ascribed to a misapprehension of the situation which has been described.
Einstein thus expresses views of ethical non-naturalism (contrasted to ethical naturalism).
Prominent modern scientists who are atheists include evolutionary biologist Richard Dawkins and Nobel Prize–winning physicist Steven Weinberg. Prominent scientists advocating religious belief include Nobel Prize–winning physicist and United Church of Christ member Charles Townes, evangelical Christian and past head of the Human Genome Project Francis Collins, and climatologist John T. Houghton.
== Perspectives ==
The kinds of interactions that might arise between science and religion have been categorized by theologian, Anglican priest, and physicist John Polkinghorne: (1) conflict between the disciplines, (2) independence of the disciplines, (3) dialogue between the disciplines where they overlap and (4) integration of both into one field.
This typology is similar to ones used by theologians Ian Barbour and John Haught. More typologies that categorize this relationship can be found among the works of other science and religion scholars such as theologian and biochemist Arthur Peacocke.
=== Incompatibility ===
According to Guillermo Paz-y-Miño-C and Avelina Espinosa, the historical conflict between evolution and religion is intrinsic to the incompatibility between scientific rationalism/empiricism and the belief in supernatural causation/faith. According to evolutionary biologist Jerry Coyne, views on evolution and levels of religiosity in some countries, along with the existence of books explaining reconciliation between evolution and religion, indicate that people have trouble in believing both at the same time, thus implying incompatibility. According to physical chemist Peter Atkins, "whereas religion scorns the power of human comprehension, science respects it." Planetary scientist Carolyn Porco describes a hope that "the confrontation between science and formal religion will come to an end when the role played by science in the lives of all people is the same played by religion today."
Geologist and paleontologist Donald Prothero has stated that religion is the reason "questions about evolution, the age of the earth, cosmology, and human evolution nearly always cause Americans to flunk science literacy tests compared to other nations." However, Jon Miller, who studies science literacy across nations, states that Americans in general are slightly more scientifically literate than Europeans and the Japanese.
According to cosmologist and astrophysicist Lawrence Krauss, compatibility or incompatibility is a theological concern, not a scientific concern. In Lisa Randall's view, questions of incompatibility or otherwise are not answerable, since by accepting revelations one is abandoning rules of logic which are needed to identify if there are indeed contradictions between holding certain beliefs. Daniel Dennett holds that incompatibility exists because religion is not problematic to a certain point before it collapses into a number of excuses for keeping certain beliefs, in light of evolutionary implications.
According to theoretical physicist Steven Weinberg, teaching cosmology and evolution to students should decrease their self-importance in the universe, as well as their religiosity. Evolutionary developmental biologist PZ Myers' view is that all scientists should be atheists, and that science should never accommodate any religious beliefs. Physicist Sean M. Carroll claims that since religion makes claims that are supernatural, both science and religion are incompatible.
Evolutionary biologist Richard Dawkins is openly hostile to religion because he believes it actively debauches the scientific enterprise and education involving science. According to Dawkins, religion "subverts science and saps the intellect". He believes that when science teachers attempt to expound on evolution, there is hostility aimed towards them by parents who are skeptical because they believe it conflicts with their own religious beliefs, and that even in some textbooks have had the word 'evolution' systematically removed. He has worked to argue the negative effects that he believes religion has on education of science.
According to Renny Thomas' study on Indian scientists, atheistic scientists in India called themselves atheists even while accepting that their lifestyle is very much a part of tradition and religion. Thus, they differ from Western atheists in that for them following the lifestyle of a religion is not antithetical to atheism.
==== Criticism ====
Others such as Francis Collins, George F. R. Ellis, Kenneth R. Miller, Katharine Hayhoe, George Coyne and Simon Conway Morris argue for compatibility since they do not agree that science is incompatible with religion and vice versa. They argue that science provides many opportunities to look for and find God in nature and to reflect on their beliefs. According to Kenneth Miller, he disagrees with Jerry Coyne's assessment and argues that since significant portions of scientists are religious and the proportion of Americans believing in evolution is much higher, it implies that both are indeed compatible. Elsewhere, Miller has argued that when scientists make claims on science and theism or atheism, they are not arguing scientifically at all and are stepping beyond the scope of science into discourses of meaning and purpose. What he finds particularly odd and unjustified is in how atheists often come to invoke scientific authority on their non-scientific philosophical conclusions like there being no point or no meaning to the universe as the only viable option when the scientific method and science never have had any way of addressing questions of meaning or God in the first place. Furthermore, he notes that since evolution made the brain and since the brain can handle both religion and science, there is no natural incompatibility between the concepts at the biological level.
Karl Giberson argues that when discussing compatibility, some scientific intellectuals often ignore the viewpoints of intellectual leaders in theology and instead argue against less informed masses, thereby, defining religion by non-intellectuals and slanting the debate unjustly. He argues that leaders in science sometimes trump older scientific baggage and that leaders in theology do the same, so once theological intellectuals are taken into account, people who represent extreme positions like Ken Ham and Eugenie Scott will become irrelevant. Cynthia Tolman notes that religion does not have a method per se partly because religions emerge through time from diverse cultures, but when it comes to Christian theology and ultimate truths, she notes that people often rely on scripture, tradition, reason, and experience to test and gauge what they experience and what they should believe.
==== Conflict thesis ====
The conflict thesis, which holds that religion and science have been in conflict continuously throughout history, was popularized in the 19th century by John William Draper's and Andrew Dickson White's accounts. It was in the 19th century that relationship between science and religion became an actual formal topic of discourse, while before this no one had pitted science against religion or vice versa, though occasional complex interactions had been expressed before the 19th century. Most contemporary historians of science now reject the conflict thesis in its original form and no longer support it. Instead, it has been superseded by subsequent historical research which has resulted in a more nuanced understanding. Historian of science, Gary Ferngren, has stated: "Although popular images of controversy continue to exemplify the supposed hostility of Christianity to new scientific theories, studies have shown that Christianity has often nurtured and encouraged scientific endeavour, while at other times the two have co-existed without either tension or attempts at harmonization. If Galileo and the Scopes trial come to mind as examples of conflict, they were the exceptions rather than the rule."
Most historians today have moved away from a conflict model, which is based mainly on two historical episodes (Galileo and Darwin), toward compatibility theses (either the integration thesis or non-overlapping magisteria) or toward a "complexity" model, because religious figures were on both sides of each dispute and there was no overall aim by any party involved to discredit religion.
An often cited example of conflict, that has been clarified by historical research in the 20th century, was the Galileo affair, whereby interpretations of the Bible were used to attack ideas by Copernicus on heliocentrism. By 1616 Galileo went to Rome to try to persuade Catholic Church authorities not to ban Copernicus' ideas. In the end, a decree of the Congregation of the Index was issued, declaring that the ideas that the Sun stood still and that the Earth moved were "false" and "altogether contrary to Holy Scripture", and suspending Copernicus's De Revolutionibus until it could be corrected. Galileo was found "vehemently suspect of heresy", namely of having held the opinions that the Sun lies motionless at the center of the universe, that the Earth is not at its centre and moves. He was required to "abjure, curse and detest" those opinions. However, before all this, Pope Urban VIII had personally asked Galileo to give arguments for and against heliocentrism in a book, and to be careful not to advocate heliocentrism as physically proven since the scientific consensus at the time was that the evidence for heliocentrism was very weak. The Church had merely sided with the scientific consensus of the time. Pope Urban VIII asked that his own views on the matter be included in Galileo's book. Only the latter was fulfilled by Galileo. Whether unknowingly or deliberately, Simplicio, the defender of the Aristotelian/Ptolemaic geocentric view in Dialogue Concerning the Two Chief World Systems, was often portrayed as an unlearned fool who lacked mathematical training. Although the preface of his book claims that the character is named after a famous Aristotelian philosopher (Simplicius in Latin, Simplicio in Italian), the name "Simplicio" in Italian also has the connotation of "simpleton". Unfortunately for his relationship with the Pope, Galileo put the words of Urban VIII into the mouth of Simplicio. Most historians agree Galileo did not act out of malice and felt blindsided by the reaction to his book. However, the Pope did not take the suspected public ridicule lightly, nor the physical Copernican advocacy. Galileo had alienated one of his biggest and most powerful supporters, the Pope, and was called to Rome to defend his writings.
The actual evidences that finally proved heliocentrism came centuries after Galileo: the stellar aberration of light by James Bradley in the 18th century, the orbital motions of binary stars by William Herschel in the 19th century, the accurate measurement of the stellar parallax in the 19th century, and Newtonian mechanics in the 17th century. According to physicist Christopher Graney, Galileo's own observations did not actually support the Copernican view, but were more consistent with Tycho Brahe's hybrid model where that Earth did not move and everything else circled around it and the Sun.
British philosopher A. C. Grayling, still believes there is competition between science and religions in areas related to the origin of the universe, the nature of human beings and the possibility of miracles.
=== Independence ===
A modern view, described by Stephen Jay Gould as "non-overlapping magisteria" (NOMA), is that science and religion deal with fundamentally separate aspects of human experience and so, when each stays within its own domain, they co-exist peacefully. While Gould spoke of independence from the perspective of science, W. T. Stace viewed independence from the perspective of the philosophy of religion. Stace felt that science and religion, when each is viewed in its own domain, are both consistent and complete. They originate from different perceptions of reality, as Arnold O. Benz points out, but meet each other, for example, in the feeling of amazement and in ethics.
The USA's National Academy of Sciences supports the view that science and religion are independent.
Science and religion are based on different aspects of human experience. In science, explanations must be based on evidence drawn from examining the natural world. Scientifically based observations or experiments that conflict with an explanation eventually must lead to modification or even abandonment of that explanation. Religious faith, in contrast, does not depend on empirical evidence, is not necessarily modified in the face of conflicting evidence, and typically involves supernatural forces or entities. Because they are not a part of nature, supernatural entities cannot be investigated by science. In this sense, science and religion are separate and address aspects of human understanding in different ways. Attempts to put science and religion against each other create controversy where none needs to exist.
According to Archbishop John Habgood, both science and religion represent distinct ways of approaching experience and these differences are sources of debate. He views science as descriptive and religion as prescriptive. He stated that if science and mathematics concentrate on what the world ought to be, in the way that religion does, it may lead to improperly ascribing properties to the natural world as happened among the followers of Pythagoras in the sixth century B.C. In contrast, proponents of a normative moral science take issue with the idea that science has no way of guiding "oughts". Habgood also stated that he believed that the reverse situation, where religion attempts to be descriptive, can also lead to inappropriately assigning properties to the natural world. A notable example is the now defunct belief in the Ptolemaic (geocentric) planetary model that held sway until changes in scientific and religious thinking were brought about by Galileo and proponents of his views.
In the view of the Lubavitcher rabbi Menachem Mendel Schneerson, non-Euclidean geometry such as Lobachevsky's hyperbolic geometry and Riemann's elliptic geometry proved that Euclid's axioms, such as, "there is only one straight line between two points", are in fact arbitrary. Therefore, science, which relies on arbitrary axioms, can never refute Torah, which is absolute truth.
==== Parallels in method ====
According to Ian Barbour, Thomas S. Kuhn asserted that science is made up of paradigms that arise from cultural traditions, which is similar to the secular perspective on religion.
Michael Polanyi asserted that it is merely a commitment to universality that protects against subjectivity and has nothing at all to do with personal detachment as found in many conceptions of the scientific method. Polanyi further asserted that all knowledge is personal and therefore the scientist must be performing a very personal if not necessarily subjective role when doing science. Polanyi added that the scientist often merely follows intuitions of "intellectual beauty, symmetry, and 'empirical agreement'". Polanyi held that science requires moral commitments similar to those found in religion.
Two physicists, Charles A. Coulson and Harold K. Schilling, both claimed that "the methods of science and religion have much in common." Schilling asserted that both fields—science and religion—have "a threefold structure—of experience, theoretical interpretation, and practical application." Coulson asserted that science, like religion, "advances by creative imagination" and not by "mere collecting of facts," while stating that religion should and does "involve critical reflection on experience not unlike that which goes on in science." Religious language and scientific language also show parallels (cf. rhetoric of science).
=== Dialogue ===
The religion and science community consists of those scholars who involve themselves with what has been called the "religion-and-science dialogue" or the "religion-and-science field." The community belongs to neither the scientific nor the religious community, but is said to be a third overlapping community of interested and involved scientists, priests, clergymen, theologians and engaged non-professionals. Institutions interested in the intersection between science and religion include the Center for Theology and the Natural Sciences, the Institute on Religion in an Age of Science, the Ian Ramsey Centre, and the Faraday Institute. Journals addressing the relationship between science and religion include Theology and Science and Zygon. Eugenie Scott has written that the "science and religion" movement is, overall, composed mainly of theists who have a healthy respect for science and may be beneficial to the public understanding of science. She contends that the "Christian scholarship" movement is not a problem for science, but that the "Theistic science" movement, which proposes abandoning methodological materialism, does cause problems in understanding of the nature of science. The Gifford Lectures were established in 1885 to further the discussion between "natural theology" and the scientific community. This annual series continues and has included William James, John Dewey, Carl Sagan, and many other professors from various fields.
The modern dialogue between religion and science is rooted in Ian Barbour's 1966 book Issues in Science and Religion. Since that time it has grown into a serious academic field, with academic chairs in the subject area, and two dedicated academic journals, Zygon and Theology and Science. Articles are also sometimes found in mainstream science journals such as American Journal of Physics
and Science.
Philosopher Alvin Plantinga has argued that there is superficial conflict but deep concord between science and religion, and that there is deep conflict between science and naturalism. Plantinga, in his book Where the Conflict Really Lies: Science, Religion, and Naturalism, heavily contests the linkage of naturalism with science, as conceived by Richard Dawkins, Daniel Dennett and like-minded thinkers; while Daniel Dennett thinks that Plantinga stretches science to an unacceptable extent. Philosopher Maarten Boudry, in reviewing the book, has commented that he resorts to creationism and fails to "stave off the conflict between theism and evolution." Cognitive scientist Justin L. Barrett, by contrast, reviews the same book and writes that "those most needing to hear Plantinga's message may fail to give it a fair hearing for rhetorical rather than analytical reasons."
=== Integration ===
As a general view, this holds that while interactions are complex between influences of science, theology, politics, social, and economic concerns, the productive engagements between science and religion throughout history should be duly stressed as the norm.
Scientific and theological perspectives often coexist peacefully. Christians and some non-Christian religions have historically integrated well with scientific ideas, as in the ancient Egyptian technological mastery applied to monotheistic ends, the scientific advances made by Muslim scholars during the Ottoman Empire and mathematics under Hinduism and Buddhism. Even many 19th-century Christian communities welcomed scientists who claimed that science was not at all concerned with discovering the ultimate nature of reality. According to Lawrence M. Principe, the Johns Hopkins University Drew Professor of the Humanities, from a historical perspective this points out that much of the current-day clashes occur between limited extremists—both religious and scientistic fundamentalists—over a very few topics, and that the movement of ideas back and forth between scientific and theological thought has been more usual. To Principe, this perspective would point to the fundamentally common respect for written learning in religious traditions of rabbinical literature, Christian theology, and the Islamic Golden Age, including a Transmission of the Classics from Greek to Islamic to Christian traditions which helped spark the Renaissance. Religions have also given key participation in development of modern universities and libraries; centers of learning & scholarship were coincident with religious institutions—whether pagan, Muslim, or Christian.
== Individual religions ==
=== Baháʼí Faith ===
A fundamental principle of the Baháʼí Faith is the harmony of religion and science. Baháʼí scripture asserts that true science and true religion can never be in conflict. `Abdu'l-Bahá, the son of the founder of the religion, stated that religion without science is superstition and that science without religion is materialism. He also admonished that true religion must conform to the conclusions of science.
=== Buddhism ===
Buddhism and science have been regarded as compatible by numerous authors. Some philosophic and psychological teachings found in Buddhism share points in common with modern Western scientific and philosophic thought. For example, Buddhism encourages the impartial investigation of nature (an activity referred to as Dhamma-Vicaya in the Pali Canon)—the principal object of study being oneself. Buddhism and science both show a strong emphasis on causality. However, Buddhism does not focus on materialism.
Tenzin Gyatso, the 14th Dalai Lama, mentions that empirical scientific evidence supersedes the traditional teachings of Buddhism when the two are in conflict. In his book The Universe in a Single Atom he wrote, "My confidence in venturing into science lies in my basic belief that as in science, so in Buddhism, understanding the nature of reality is pursued by means of critical investigation." He also stated, "If scientific analysis were conclusively to demonstrate certain claims in Buddhism to be false," he says, "then we must accept the findings of science and abandon those claims."
=== Christianity ===
Among early Christian teachers, Tertullian (c. 160–220) held a generally negative opinion of Greek philosophy, while Origen (c. 185–254) regarded it much more favorably and required his students to read nearly every work available to them.
Earlier attempts at reconciliation of Christianity with Newtonian mechanics appear quite different from later attempts at reconciliation with the newer scientific ideas of evolution or relativity. Many early interpretations of evolution polarized themselves around a struggle for existence. These ideas were significantly countered by later findings of universal patterns of biological cooperation. According to John Habgood, the universe seems to be a mix of good and evil, beauty and pain, and that suffering may somehow be part of the process of creation. Habgood holds that Christians should not be surprised that suffering may be used creatively by God, given their faith in the symbol of the Cross.
Robert John Russell has examined consonance and dissonance between modern physics, evolutionary biology, and Christian theology.
Christian philosophers Augustine of Hippo (354–430) and Thomas Aquinas (1225–1274) held that scriptures can have multiple interpretations on certain areas where the matters were far beyond their reach, therefore one should leave room for future findings to shed light on the meanings. The "Handmaiden" tradition, which saw secular studies of the universe as a very important and helpful part of arriving at a better understanding of scripture, was adopted throughout Christian history from early on. Also the sense that God created the world as a self operating system is what motivated many Christians throughout the Middle Ages to investigate nature.
Modern historians of science such as J.L. Heilbron, Alistair Cameron Crombie, David Lindberg, Edward Grant, Thomas Goldstein, and Ted Davis have reviewed the popular notion that medieval Christianity was a negative influence in the development of civilization and science. In their views, not only did the monks save and cultivate the remnants of ancient civilization during the barbarian invasions, but the medieval church promoted learning and science through its sponsorship of many universities which, under its leadership, grew rapidly in Europe in the 11th and 12th centuries. Saint Thomas Aquinas, the Church's "model theologian", not only argued that reason is in harmony with faith, he even recognized that reason can contribute to understanding revelation, and so encouraged intellectual development. He was not unlike other medieval theologians who sought out reason in the effort to defend his faith. Some modern scholars, such as Stanley Jaki, have claimed that Christianity with its particular worldview, was a crucial factor for the emergence of modern science.
David C. Lindberg states that the widespread popular belief that the Middle Ages was a time of ignorance and superstition due to the Christian church is a "caricature". According to Lindberg, while there are some portions of the classical tradition which suggest this view, these were exceptional cases. It was common to tolerate and encourage critical thinking about the nature of the world. The relation between Christianity and science is complex and cannot be simplified to either harmony or conflict, according to Lindberg. Lindberg reports that "the late medieval scholar rarely experienced the coercive power of the church and would have regarded himself as free (particularly in the natural sciences) to follow reason and observation wherever they led. There was no warfare between science and the church." Ted Peters in Encyclopedia of Religion writes that although there is some truth in the "Galileo's condemnation" story but through exaggerations, it has now become "a modern myth perpetuated by those wishing to see warfare between science and religion who were allegedly persecuted by an atavistic and dogma-bound ecclesiastical authority". In 1992, the Catholic Church's seeming vindication of Galileo attracted much comment in the media.
A degree of concord between science and religion can be seen in religious belief and empirical science. The belief that God created the world and therefore humans, can lead to the view that he arranged for humans to know the world. This is underwritten by the doctrine of imago dei. In the words of Thomas Aquinas, "Since human beings are said to be in the image of God in virtue of their having a nature that includes an intellect, such a nature is most in the image of God in virtue of being most able to imitate God".
During the Enlightenment, a period "characterized by dramatic revolutions in science" and the rise of Protestant challenges to the authority of the Catholic Church via individual liberty, the authority of Christian scriptures became strongly challenged. As science advanced, acceptance of a literal version of the Bible became "increasingly untenable" and some in that period presented ways of interpreting scripture according to its spirit on its authority and truth.
After the Black Death in Europe, there occurred a generalized decrease in faith in the Catholic Church. The "Natural Sciences" during the Medieval Era focused largely on scientific arguments. The Copernicans, who were generally a small group of privately sponsored individuals, who were deemed Heretics by the Church in some instances. Copernicus and his work challenged the view held by the Catholic Church and the common scientific view at the time, yet according to scholar J. L. Heilbron, the Roman Catholic Church sometimes provided financial support to the Copernicans. In doing so, the Church did support and promote scientific research when the goals in question were in alignment with those of the faith, so long as the findings were in line with the rhetoric of the Church. A case example is the Catholic need for an accurate calendar. Calendar reform was a touchy subject: civilians doubted the accuracy of the mathematics and were upset that the process unfairly selected curators of the reform. The Roman Catholic Church needed a precise date for the Easter Sabbath, and thus the Church was highly supportive of calendar reform. The need for the correct date of Easter was also the impetus of cathedral construction. Cathedrals essentially functioned as massive scale sun dials and, in some cases, camera obscuras. They were efficient scientific devices because they rose high enough for their naves to determine the summer and winter solstices. Heilbron contends that as far back as the twelfth century, the Roman Catholic Church was funding scientific discovery and the recovery of ancient Greek scientific texts. However, the Copernican revolution challenged the view held the Catholic Church and placed the Sun at the center of the Solar System.
==== Perspectives on evolution ====
In recent history, the theory of evolution has been at the center of some controversy between Christianity and science. Christians who accept a literal interpretation of the biblical account of creation find incompatibility between Darwinian evolution and their interpretation of the Christian faith. Creation science or scientific creationism is a branch of creationism that attempts to provide scientific support for a literal reading of the Genesis creation narrative in the Book of Genesis and attempts to disprove generally accepted scientific facts, theories and scientific paradigms about the geological history of the Earth, cosmology of the early universe,
the chemical origins of life and biological evolution. It began in the 1960s as a fundamentalist Christian effort in the United States to prove Biblical inerrancy and falsify the scientific evidence for evolution. It has since developed a sizable religious following in the United States, with creation science ministries branching worldwide. In 1925, The State of Tennessee passed the Butler Act, which prohibited the teaching of the theory of evolution in all schools in the state. Later that year, a similar law was passed in Mississippi, and likewise, Arkansas in 1927. In 1968, these "anti-monkey" laws were struck down by the Supreme Court of the United States as unconstitutional, "because they established a religious doctrine violating both the First and Fourth Amendments to the Constitution."
Most scientists have rejected creation science for several reasons, including that its claims do not refer to natural causes and cannot be tested. In 1987, the United States Supreme Court ruled that creationism is religion, not science, and cannot be advocated in public school classrooms. In 2018, the Orlando Sentinel reported that "Some private schools in Florida that rely on public funding teach students" Creationism.
Theistic evolution attempts to reconcile Christian beliefs and science by accepting the scientific understanding of the age of the Earth and the process of evolution. It includes a range of beliefs, including views described as evolutionary creationism, which accepts some findings of modern science but also upholds classical religious teachings about God and creation in Christian context.
==== Roman Catholicism ====
While refined and clarified over the centuries, the Roman Catholic position on the relationship between science and religion is one of harmony, and has maintained the teaching of natural law as set forth by Thomas Aquinas. For example, regarding scientific study such as that of evolution, the church's unofficial position is an example of theistic evolution, stating that faith and scientific findings regarding human evolution are not in conflict, though humans are regarded as a special creation, and that the existence of God is required to explain both monogenism and the spiritual component of human origins. Catholic schools have included all manners of scientific study in their curriculum for many centuries.
Galileo once stated that "The intention of the Holy Spirit is to teach us how to go to heaven, not how the heavens go." In 1981, Pope John Paul II, then leader of the Roman Catholic Church, spoke of the relationship this way: "The Bible itself speaks to us of the origin of the universe and its make-up, not in order to provide us with a scientific treatise, but in order to state the correct relationships of man with God and with the universe. Sacred Scripture wishes simply to declare that the world was created by God, and in order to teach this truth it expresses itself in the terms of the cosmology in use at the time of the writer".
Pope Francis, in his encyclical letter Laudato si', affirms his opinion that "science and religion, with their distinctive approaches to understanding reality, can
enter into an intense dialogue fruitful for both".
==== Influence of a biblical worldview on early modern science ====
According to Andrew Dickson White's A History of the Warfare of Science with Theology in Christendom from the 19th century, a biblical world view affected negatively the progress of science through time. Dickinson also argues that immediately following the Reformation matters were even worse. The interpretations of Scripture by Luther and Calvin became as sacred to their followers as the Scripture itself. For instance, when Georg Calixtus ventured, in interpreting the Psalms, to question the accepted belief that "the waters above the heavens" were contained in a vast receptacle upheld by a solid vault, he was bitterly denounced as heretical. Today, much of the scholarship in which the conflict thesis was originally based is considered to be inaccurate. For instance, the claim that early Christians rejected scientific findings by the Greco-Romans is false, since the "handmaiden" view of secular studies was seen to shed light on theology. This view was widely adapted throughout the early medieval period and afterwards by theologians (such as Augustine) and ultimately resulted in fostering interest in knowledge about nature through time. Also, the claim that people of the Middle Ages widely believed that the Earth was flat was first propagated in the same period that originated the conflict thesis and is still very common in popular culture. Modern scholars regard this claim as mistaken, as the contemporary historians of science David C. Lindberg and Ronald L. Numbers write: "there was scarcely a Christian scholar of the Middle Ages who did not acknowledge [earth's] sphericity and even know its approximate circumference." From the fall of Rome to the time of Columbus, all major scholars and many vernacular writers interested in the physical shape of the earth held a spherical view with the exception of Lactantius and Cosmas.
H. Floris Cohen argued for a biblical Protestant, but not excluding Catholicism, influence on the early development of modern science. He presented Dutch historian R. Hooykaas' argument that a biblical world-view holds all the necessary antidotes for the hubris of Greek rationalism: a respect for manual labour, leading to more experimentation and empiricism, and a supreme God that left nature open to emulation and manipulation. It supports the idea early modern science rose due to a combination of Greek and biblical thought.
Oxford historian Peter Harrison is another who has argued that a biblical worldview was significant for the development of modern science. Harrison contends that Protestant approaches to the book of scripture had significant, if largely unintended, consequences for the interpretation of the book of nature. Harrison has also suggested that literal readings of the Genesis narratives of the Creation and Fall motivated and legitimated scientific activity in seventeenth-century England. For many of its seventeenth-century practitioners, science was imagined to be a means of restoring a human dominion over nature that had been lost as a consequence of the Fall.
Historian and professor of religion Eugene M. Klaaren holds that "a belief in divine creation" was central to an emergence of science in seventeenth-century England. The philosopher Michael Foster has published analytical philosophy connecting Christian doctrines of creation with empiricism. Historian William B. Ashworth has argued against the historical notion of distinctive mind-sets and the idea of Catholic and Protestant sciences. Historians James R. Jacob and Margaret C. Jacob have argued for a linkage between seventeenth-century Anglican intellectual transformations and influential English scientists (e.g., Robert Boyle and Isaac Newton). John Dillenberger and Christopher B. Kaiser have written theological surveys, which also cover additional interactions occurring in the 18th, 19th, and 20th centuries. Philosopher of Religion, Richard Jones, has written a philosophical critique of the "dependency thesis" which assumes that modern science emerged from Christian sources and doctrines. Though he acknowledges that modern science emerged in a religious framework, that Christianity greatly elevated the importance of science by sanctioning and religiously legitimizing it in the medieval period, and that Christianity created a favorable social context for it to grow; he argues that direct Christian beliefs or doctrines were not primary sources of scientific pursuits by natural philosophers, nor was Christianity, in and of itself, exclusively or directly necessary in developing or practicing modern science.
Oxford University historian and theologian John Hedley Brooke wrote that "when natural philosophers referred to laws of nature, they were not glibly choosing that metaphor. Laws were the result of legislation by an intelligent deity. Thus the philosopher René Descartes (1596–1650) insisted that he was discovering the "laws that God has put into nature." Later Newton would declare that the regulation of the solar system presupposed the "counsel and dominion of an intelligent and powerful Being." Historian Ronald L. Numbers stated that this thesis "received a boost" from mathematician and philosopher Alfred North Whitehead's Science and the Modern World (1925). Numbers has also argued, "Despite the manifest shortcomings of the claim that Christianity gave birth to science—most glaringly, it ignores or minimizes the contributions of ancient Greeks and medieval Muslims—it too, refuses to succumb to the death it deserves." The sociologist Rodney Stark of Baylor University, argued in contrast that "Christian theology was essential for the rise of science."
Protestantism had an important influence on science. According to the Merton Thesis there was a positive correlation between the rise of Puritanism and Protestant Pietism on the one hand and early experimental science on the other. The Merton Thesis has two separate parts: Firstly, it presents a theory that science changes due to an accumulation of observations and improvement in experimental techniques and methodology; secondly, it puts forward the argument that the popularity of science in 17th-century England and the religious demography of the Royal Society (English scientists of that time were predominantly Puritans or other Protestants) can be explained by a correlation between Protestantism and the scientific values. In his theory, Robert K. Merton focused on English Puritanism and German Pietism as having been responsible for the development of the scientific revolution of the 17th and 18th centuries. Merton explained that the connection between religious affiliation and interest in science was the result of a significant synergy between the ascetic Protestant values and those of modern science. Protestant values encouraged scientific research by allowing science to study God's influence on the world and thus providing a religious justification for scientific research.
Some scholars have noted a direct tie between "particular aspects of traditional Christianity" and the rise of science. Other scholars and historians attribute Christianity to having contributed to the rise of the Scientific Revolution.
==== Reconciliation in Britain in the early 20th century ====
In Reconciling Science and Religion: The Debate in Early-twentieth-century Britain, historian of biology Peter J. Bowler argues that in contrast to the conflicts between science and religion in the U.S. in the 1920s (most famously the Scopes Trial), during this period Great Britain experienced a concerted effort at reconciliation, championed by intellectually conservative scientists, supported by liberal theologians but opposed by younger scientists and secularists and conservative Christians. These attempts at reconciliation fell apart in the 1930s due to increased social tensions, moves towards neo-orthodox theology and the acceptance of the modern evolutionary synthesis.
In the 20th century, several ecumenical organizations promoting a harmony between science and Christianity were founded, most notably the American Scientific Affiliation, The Biologos Foundation, Christians in Science, The Society of Ordained Scientists, and The Veritas Forum.
=== Confucianism and traditional Chinese religion ===
The historical process of Confucianism has largely been antipathic towards scientific discovery. However the religio-philosophical system itself is more neutral on the subject than such an analysis might suggest. In his writings On Heaven, Xunzi espoused a proto-scientific world view. However, during the Han Synthesis the more anti-empirical Mencius was favored and combined with Daoist skepticism regarding the nature of reality. Likewise, during the medieval period, Zhu Xi argued against technical investigation and specialization proposed by Chen Liang. After contact with the West, scholars such as Wang Fuzhi would rely on Buddhist/Daoist skepticism to denounce all science as a subjective pursuit limited by humanity's fundamental ignorance of the true nature of the world.
The Jesuits from Europe taught Western math and science to the Chinese bureaucrats in hopes of religious conversion. This process saw several challenges of both European and Chinese spiritual and scientific beliefs. The keynote text of Chinese scientific philosophy, The Book of Changes (or Yi Jing) was initially mocked and disregarded by the Westerners. In return, Confucian scholars Dai Zhen and Ji Yun found the concept of phantoms laughable and ridiculous. The Book of Changes outlined orthodoxy cosmology in the Qing, including yin and yang and the five cosmic phases. Sometimes the missionary exploits proved dangerous for the Westerners. Jesuit missionaries and scholars Ferdinand Vervbiest and Adam Schall were punished after using scientific methods to determine the exact time of the 1664 eclipse. However, the European mission eastward did not only cause conflict. Joachim Bouvet, a theologian who held equal respect for both the Bible and the Book of Changes, was productive in his mission of spreading the Christian faith.
After the May Fourth Movement, attempts to modernize Confucianism and reconcile it with scientific understanding were attempted by many scholars including Feng Youlan and Xiong Shili. Given the close relationship that Confucianism shares with Buddhism, many of the same arguments used to reconcile Buddhism with science also readily translate to Confucianism. However, modern scholars have also attempted to define the relationship between science and Confucianism on Confucianism's own terms and the results have usually led to the conclusion that Confucianism and science are fundamentally compatible.
=== Hinduism ===
In Hinduism, the dividing line between objective sciences and spiritual knowledge (adhyatma vidya) is a linguistic paradox. Hindu scholastic activities and ancient Indian scientific advancements were so interconnected that many Hindu scriptures are also ancient scientific manuals and vice versa. In 1835, English was made the primary language for teaching in higher education in India, exposing Hindu scholars to Western secular ideas; this started a renaissance regarding religious and philosophical thought. Hindu sages maintained that logical argument and rational proof using Nyaya is the way to obtain correct knowledge. The scientific level of understanding focuses on how things work and from where they originate, while Hinduism strives to understand the ultimate purposes for the existence of living things. To obtain and broaden the knowledge of the world for spiritual perfection, many refer to the Bhāgavata for guidance because it draws upon a scientific and theological dialogue. Hinduism offers methods to correct and transform itself in course of time. For instance, Hindu views on the development of life include a range of viewpoints in regards to evolution, creationism, and the origin of life within the traditions of Hinduism. For instance, it has been suggested that Wallace-Darwininan evolutionary thought was a part of Hindu thought centuries before modern times. The Shankara and the Sāmkhya did not have a problem with the theory of evolution, but instead, argued about the existence of God and what happened after death. These two distinct groups argued among each other's philosophies because of their texts, not the idea of evolution. With the publication of Darwin's On the Origin of Species, many Hindus were eager to connect their scriptures to Darwinism, finding similarities between Brahma's creation, Vishnu's incarnations, and evolution theories.
Samkhya, the oldest school of Hindu philosophy prescribes a particular method to analyze knowledge. According to Samkhya, all knowledge is possible through three means of valid knowledge –
Pratyakṣa or Dṛṣṭam – direct sense perception,
Anumāna – logical inference and
Śabda or Āptavacana – verbal testimony.
Nyaya, the Hindu school of logic, accepts all these 3 means and in addition accepts one more – Upamāna (comparison).
The accounts of the emergence of life within the universe vary in description, but classically the deity called Brahma, from a Trimurti of three deities also including Vishnu and Shiva, is described as performing the act of 'creation', or more specifically of 'propagating life within the universe' with the other two deities being responsible for 'preservation' and 'destruction' (of the universe) respectively. In this respect some Hindu schools do not treat the scriptural creation myth literally and often the creation stories themselves do not go into specific detail, thus leaving open the possibility of incorporating at least some theories in support of evolution. Some Hindus find support for, or foreshadowing of evolutionary ideas in scriptures, namely the Vedas.
The incarnations of Vishnu (Dashavatara) is almost identical to the scientific explanation of the sequence of biological evolution of man and animals. The sequence of avatars starts from an aquatic organism (Matsya), to an amphibian (Kurma), to a land-animal (Varaha), to a humanoid (Narasimha), to a dwarf human (Vamana), to 5 forms of well developed human beings (Parashurama, Rama, Balarama/Buddha, Krishna, Kalki) who showcase an increasing form of complexity (Axe-man, King, Plougher/Sage, wise Statesman, mighty Warrior). In fact, many Hindu gods are represented with features of animals as well as those of humans, leading many Hindus to easily accept evolutionary links between animals and humans. In India, the home country of Hindus, educated Hindus widely accept the theory of biological evolution. In a survey of 909 people, 77% of respondents in India agreed with Charles Darwin's Theory of Evolution, and 85 per cent of God-believing people said they believe in evolution as well.
As per Vedas, another explanation for the creation is based on the five elements: earth, water, fire, air and aether.
The Hindu religion traces its beginnings to the Vedas. Everything that is established in the Hindu faith such as the gods and goddesses, doctrines, chants, spiritual insights, etc. flow from the poetry of Vedic hymns. The Vedas offer an honor to the sun and moon, water and wind, and to the order in Nature that is universal. This naturalism is the beginning of what further becomes the connection between Hinduism and science.
=== Islam ===
From an Islamic standpoint, science, the study of nature, is considered to be linked to the concept of Tawhid (the Oneness of God), as are all other branches of knowledge. In Islam, nature is not seen as a separate entity, but rather as an integral part of Islam's holistic outlook on God, humanity, and the world. The Islamic view of science and nature is continuous with that of religion and God. This link implies a sacred aspect to the pursuit of scientific knowledge by Muslims, as nature itself is viewed in the Qur'an as a compilation of signs pointing to the Divine. It was with this understanding that science was studied and understood in Islamic civilizations, specifically during the eighth to sixteenth centuries, prior to the colonization of the Muslim world. Robert Briffault, in The Making of Humanity, asserts that the very existence of science, as it is understood in the modern sense, is rooted in the scientific thought and knowledge that emerged in Islamic civilizations during this time. Ibn al-Haytham, an Arab Muslim, was an early proponent of the concept that a hypothesis must be proved by experiments based on confirmable procedures or mathematical evidence—hence understanding the scientific method 200 years before Renaissance scientists. Ibn al-Haytham described his theology:
I constantly sought knowledge and truth, and it became my belief that for gaining access to the effulgence and closeness to God, there is no better way than that of searching for truth and knowledge.
With the decline of Islamic Civilizations in the late Middle Ages and the rise of Europe, the Islamic scientific tradition shifted into a new period. Institutions that had existed for centuries in the Muslim world looked to the new scientific institutions of European powers. This changed the practice of science in the Muslim world, as Islamic scientists had to confront the western approach to scientific learning, which was based on a different philosophy of nature. From the time of this initial upheaval of the Islamic scientific tradition to the present day, Muslim scientists and scholars have developed a spectrum of viewpoints on the place of scientific learning within the context of Islam, none of which are universally accepted or practiced. However, most maintain the view that the acquisition of knowledge and scientific pursuit in general is not in disaccord with Islamic thought and religious belief.
During the thirteenth century, the Caliphate system in the Islamic Empire fell, and scientific discovery thrived. The Islamic Civilization has a long history of scientific advancement; and their theological practices catalyzed a great deal of scientific discovery. In fact, it was due to necessities of Muslim worship and their vast empire that much science and philosophy was created. People needed to know in which direction they needed to pray toward to face Mecca. Many historians through time have asserted that all modern science originates from ancient Greek scholarship; but scholars like Martin Bernal have claimed that most ancient Greek scholarship relied heavily on the work of scholars from ancient Egypt and the Levant. Ancient Egypt was the foundational site of the Hermetic School, which believed that the sun represented an invisible God. Amongst other things, Islamic civilization was key because it documented and recorded Greek scholarship.
==== Ahmadiyya ====
The Ahmadiyya movement emphasize that "there is no contradiction between Islam and science". For example, Ahmadi Muslims universally accept in principle the process of evolution, albeit divinely guided, and actively promote it. Over the course of several decades the movement has issued various publications in support of the scientific concepts behind the process of evolution, and frequently engages in promoting how religious scriptures, such as the Qur'an, supports the concept. For general purposes, the second Khalifa of the community, Mirza Basheer-ud-Din Mahmood Ahmad says:
The Holy Quran directs attention towards science, time and again, rather than evoking prejudice against it. The Quran has never advised against studying science, lest the reader should become a non-believer; because it has no such fear or concern. The Holy Quran is not worried that if people will learn the laws of nature its spell will break. The Quran has not prevented people from science, rather it states, "Say, 'Reflect on what is happening in the heavens and the earth.'" (Al Younus)
=== Jainism ===
==== Biology ====
Jainism classifies life into two main divisions those who are static by nature (sthavar) and those who are mobile (trasa).
Jain texts describes life in plant long before Jagdish Chandra Bose proved that plants have life. In the Jain philosophy the plant lives are termed as 'Vanaspatikaya'.
==== Jainism and non-creationism ====
Jain theory of causality holds that a cause and its effect are always identical in nature and an immaterial entity like a creator God cannot be the cause of a material entity like the universe. According to Jain belief, it is not possible to create matter out of nothing.[a] The universe and its constituents– soul, matter, space, time, and natural laws have always existed (a static universe, similar to that proposed by the steady state cosmological model).
== Surveys on scientists and the general public ==
=== Scientists ===
Between 1901 and 2000, 654 Nobel prize laureates belonged to 28 different religions. Most (65%) have identified Christianity in its various forms as their religious preference. Specifically on the science-related prizes, Christians have won a total of 73% of all the Chemistry, 65% in Physics, 62% in Medicine, and 54% in all Economics awards. Jews have won 17% of the prizes in Chemistry, 26% in Medicine, and 23% in Physics. Atheists, Agnostics, and Freethinkers have won 7% of the prizes in Chemistry, 9% in Medicine, and 5% in Physics. Muslims have won 13 prizes (three were in scientific categories).
According to scholar Benjamin Beit-Hallahmi, between 1901–2001, about 57% of laureates in scientific fields were Christians, and 26% were of Jewish descent (including Jewish atheists).
==== Global ====
According to a global study on scientists, a significant portion of scientists around the world have religious identities, beliefs, and practices overall. Furthermore, the majority of scientists do not believe there is inherent conflict in being religious and a scientist and stated that "the conflict perspective on science and religion is an invention of the West" since such a view is not prevalent among most of scientists around the world. Instead of seeing religion and science as 'always in conflict' they rather view it through the lenses of various cultural dimensions to the relations between religion and science.
==== Europe ====
According to a study from 2023 "30–39% of Western-European researchers identify with “some religious affiliation”. "30–37% of scientists identify as non-believers or atheists, and an additional 10–28% as agnostic (with wide geographical differences)".
==== United States ====
In 1916, 1,000 leading American scientists were randomly chosen from American Men of Science and 42% believed God existed, 42% disbelieved, and 17% had doubts/did not know; however, when the study was replicated 80 years later using American Men and Women of Science in 1996, the results were very much the same with 39% believing God exists, 45% disbelieved, and 15% had doubts/did not know. In the same 1996 survey, for scientists in the fields of biology, mathematics, and physics/astronomy, belief in a god that is "in intellectual and affective communication with humankind" was most popular among mathematicians (about 45%) and least popular among physicists (about 22%).
In terms of belief in God among elite scientists, such as "great scientists" in the "American Men of Science" or members of the National Academies of Science; 53% disbelieved, 21% were agnostic, and 28% believed in 1914; 68% disbelieved, 17% were agnostic, and 15% believed in 1933; and 72% disbelieved, 21% were agnostic, and 7% believed in 1998. However Eugenie Scott argued that there are methodological issues in the study, including ambiguity in the questions such using a personal definition of God instead of broader definitions of God. A study with simplified wording to include impersonal or non-interventionist ideas of God concluded that 40% of "prominent scientists" in the US believe in a god.
Others have also observed some methodological issues which impacted the results.
A survey conducted between 2005 and 2007 by Elaine Howard Ecklund of University at Buffalo, The State University of New York of 1,646 natural and social science professors at 21 US research universities found that, in terms of belief in God or a higher power, more than 60% expressed either disbelief or agnosticism and more than 30% expressed belief. More specifically, nearly 34% answered "I do not believe in God" and about 30% answered "I do not know if there is a God and there is no way to find out." In the same study, 28% said they believed in God and 8% believed in a higher power that was not God. Ecklund stated that scientists were often able to consider themselves spiritual without religion or belief in god. Ecklund and Scheitle concluded, from their study, that the individuals from non-religious backgrounds disproportionately had self-selected into scientific professions and that the assumption that becoming a scientist necessarily leads to loss of religion is untenable since the study did not strongly support the idea that scientists had dropped religious identities due to their scientific training. Instead, factors such as upbringing, age, and family size were significant influences on religious identification since those who had religious upbringing were more likely to be religious and those who had a non-religious upbringing were more likely to not be religious. The authors also found little difference in religiosity between social and natural scientists.
In terms of perceptions, most social and natural scientists from 21 American universities did not perceive conflict between science and religion, while 37% did. However, in the study, scientists who had experienced limited exposure to religion tended to perceive conflict. In the same study they found that nearly one in five atheist scientists who are parents (17%) are part of religious congregations and have attended a religious service more than once in the past year. Some of the reasons for doing so are their scientific identity (wishing to expose their children to all sources of knowledge so they can make up their own minds), spousal influence, and desire for community.
A 2009 report by the Pew Research Center found that members of the American Association for the Advancement of Science (AAAS) were "much less religious than the general public," with 51% believing in some form of deity or higher power. Specifically, 33% of those polled believe in God, 18% believe in a universal spirit or higher power, and 41% did not believe in either God or a higher power. 48% say they have a religious affiliation, equal to the number who say they are not affiliated with any religious tradition. 17% were atheists, 11% were agnostics, 20% were nothing in particular, 8% were Jewish, 10% were Catholic, 16% were Protestant, 4% were Evangelical, 10% were other religion. The survey also found younger scientists to be "substantially more likely than their older counterparts to say they believe in God". Among the surveyed fields, chemists were the most likely to say they believe in God.
Elaine Ecklund conducted a study from 2011 to 2014 involving the general US population, including rank and file scientists, in collaboration with the AAAS. The study noted that 76% of the scientists identified with a religious tradition. 85% of evangelical scientists had no doubts about the existence of God, compared to 35% of the whole scientific population. In terms of religion and science, 85% of evangelical scientists saw no conflict (73% collaboration, 12% independence), while 75% of the whole scientific population saw no conflict (40% collaboration, 35% independence).
Religious beliefs of US professors were examined using a nationally representative sample of more than 1,400 professors. They found that in the social sciences: 23% did not believe in God, 16% did not know if God existed, 43% believed God existed, and 16% believed in a higher power. Out of the natural sciences: 20% did not believe in God, 33% did not know if God existed, 44% believed God existed, and 4% believed in a higher power. Overall, out of the whole study: 10% were atheists, 13% were agnostic, 19% believe in a higher power, 4% believe in God some of the time, 17% had doubts but believed in God, 35% believed in God and had no doubts.
In 2005, Farr Curlin, a University of Chicago Instructor in Medicine and a member of the MacLean Center for Clinical Medical Ethics, noted in a study that doctors tend to be science-minded religious people. He helped author a study that "found that 76 percent of doctors believe in God and 59 percent believe in some sort of afterlife." Furthermore, "90 percent of doctors in the United States attend religious services at least occasionally, compared to 81 percent of all adults." He reasoned, "The responsibility to care for those who are suffering and the rewards of helping those in need resonate throughout most religious traditions.". A study from 2017 showed 65% of physicians believe in God.
==== Other or multiple countries ====
According to the Study of Secularism in Society and Culture's report on 1,100 scientists in India: 66% are Hindu, 14% did not report a religion, 10% are atheist/no religion, 3% are Muslim, 3% are Christian, 4% are Buddhist, Sikh or other. 39% have a belief in a god, 6% have belief in a god sometimes, 30% do not believe in a god but believe in a higher power, 13% do not know if there is a god, and 12% do not believe in a god. 49% believe in the efficacy of prayer, 90% strongly agree or somewhat agree with approving degrees in Ayurvedic medicine. Furthermore, the term "secularism" is understood to have diverse and simultaneous meanings among Indian scientists: 93% believe it to be tolerance of religions and philosophies, 83% see it as involving separation of church and state, 53% see it as not identifying with religious traditions, 40% see it as absence of religious beliefs, and 20% see it as atheism. Accordingly, 75% of Indian scientists had a "secular" outlook in terms of being tolerant of other religions.
According to the Religion Among Scientists in International Context (RASIC) study on 1,581 scientists from the United Kingdom and 1,763 scientists from India, along with 200 interviews: 65% of U.K. scientists identified as nonreligious and only 6% of Indian scientists identify as nonreligious, 12% of scientists in the U.K. attend religious services on a regular basis and 32% of scientists in India do. In terms of the Indian scientists, 73% of scientists responded that there are basic truths in many religions, 27% said they believe in God and 38% expressed belief in a higher power of some kind. In terms of perceptions of conflict between science and religion, less than half of both U.K. scientists (38%) and Indian scientists (18%) perceived conflict between religion and science.
According to Elaine Ecklund's research on 1,293 atheist scientists from the US and UK, a majority of atheist scientists came from a nonreligious upbringing and never had a religious affiliation. Also, fewer than half of the atheist scientists who were exposed to religion in their youth said science played a role in them becoming an atheist.
=== General public ===
Global studies which have pooled data on religion and science from 1981 to 2001, have noted that countries with greater faith in science also often have stronger religious beliefs, while less religious countries have more skepticism of the impact of science and technology.
Other research cites the National Science Foundation's finding that America has more favorable public attitudes towards science than Europe, Russia, and Japan despite differences in levels of religiosity in these cultures.
Other cross-national studies have found no correlations supporting the contention that religiosity undermines interest in science topics or activities among the general populations globally.
Cross-cultural studies indicate that people tend to use both natural and supernatural explanations for explaining numerous things about the world such as illness, death, and origins. In other words, they do not think of natural and supernatural explanations as antagonistic or dichotomous, but instead see them as coexisting and complementary. The reconciliation of natural and supernatural explanations is normal and pervasive from a psychological standpoint across cultures.
==== Europe ====
A study conducted on adolescents from Christian schools in Northern Ireland, noted a positive relationship between attitudes towards Christianity and science once attitudes towards scientism and creationism were accounted for.
A study on people from Sweden concludes that though the Swedes are among the most non-religious, paranormal beliefs are prevalent among both the young and adult populations. This is likely due to a loss of confidence in institutions such as the Church and Science.
Concerning specific topics like creationism, it is not an exclusively American phenomenon. A poll on adult Europeans revealed that 40% believed in naturalistic evolution, 21% in theistic evolution, 20% in special creation, and 19% are undecided; with the highest concentrations of young earth creationists in Switzerland (21%), Austria (20%), Germany (18%). Other countries such as Netherlands, Britain, and Australia have experienced growth in such views as well.
==== United States ====
According to a 2015 Pew Research Center Study on the public perceptions on science, people's perceptions on conflict with science have more to do with their perceptions of other people's beliefs than their own personal beliefs. For instance, the majority of people with a religious affiliation (68%) saw no conflict between their own personal religious beliefs and science while the majority of those without a religious affiliation (76%) perceived science and religion to be in conflict. The study noted that people who are not affiliated with any religion, also known as "religiously unaffiliated", often have supernatural beliefs and spiritual practices despite them not being affiliated with any religion and also that "just one-in-six religiously unaffiliated adults (16%) say their own religious beliefs conflict with science." Furthermore, the study observed, "The share of all adults who perceive a conflict between science and their own religious beliefs has declined somewhat in recent years, from 36% in 2009 to 30% in 2014. Among those who are affiliated with a religion, the share of people who say there is a conflict between science and their personal religious beliefs dropped from 41% to 34% during this period."
In a 2024 Pew research center report, only 35% of "nones" (atheist, agnostics, and nothing in particular on religious affiliation); believe that the natural world is all there is, while the majority of nones (63%) believe there are spiritual things beyond the world; and the majority of nones (56%) also believe there are some things that science cannot explain.
The 2013 MIT Survey on Science, Religion and Origins examined the views of religious people in America on origins science topics like evolution, the Big Bang, and perceptions of conflicts between science and religion. It found that a large majority of religious people see no conflict between science and religion and only 11% of religious people belong to religions openly rejecting evolution. The fact that the gap between personal and official beliefs of their religions is so large suggests that part of the problem, might be defused by people learning more about their own religious doctrine and the science it endorses, thereby bridging this belief gap. The study concluded that "mainstream religion and mainstream science are neither attacking one another nor perceiving a conflict." Furthermore, they note that this conciliatory view is shared by most leading science organizations such as the American Association for the Advancement of Science (AAAS).
A study was made in collaboration with the AAAS collecting data on the general public from 2011 to 2014, with the focus on evangelicals and evangelical scientists. Even though evangelicals make up only 26% of the US population, the study found that nearly 70 percent of all evangelical Christians do not view science and religion as being in conflict with each other (48% saw them as complementary and 21% saw them as independent) while 73% of the general US population saw no conflict either.
According to Elaine Ecklund's 2018 study, the majority of religious groups see religion and science in collaboration or independent of each other, while the majority of groups without religion see science and religion in conflict.
Other lines of research on perceptions of science among the American public conclude that most religious groups see no general epistemological conflict with science and they have no differences with nonreligious groups in the propensity of seeking out scientific knowledge, although there may be subtle epistemic or moral conflicts when scientists make counterclaims to religious tenets. Findings from the Pew Center note similar findings and also note that the majority of Americans (80–90%) show strong support for scientific research, agree that science makes society and individual's lives better, and 8 in 10 Americans would be happy if their children were to become scientists. Even strict creationists tend to have very favorable views on science.
According to a 2007 poll by the Pew Forum, "while large majorities of Americans respect science and scientists, they are not always willing to accept scientific findings that squarely contradict their religious beliefs." The Pew Forum states that specific factual disagreements are "not common today", though 40% to 50% of Americans do not accept the evolution of humans and other living things, with the "strongest opposition" coming from evangelical Christians at 65% saying life did not evolve. 51% of the population believes humans and other living things evolved: 26% through natural selection only, 21% somehow guided, 4% do not know. In the U.S., biological evolution is the only concrete example of conflict where a significant portion of the American public denies scientific consensus for religious reasons. In terms of advanced industrialized nations, the United States is the most religious.
A 2009 study from the Pew Research Center on Americans perceptions of science, showed a broad consensus that most Americans, including most religious Americans, hold scientific research and scientists themselves in high regard. The study showed that 84% of Americans say they view science as having a mostly positive impact on society. Among those who attend religious services at least once a week, the number is roughly the same at 80%. Furthermore, 70% of U.S. adults think scientists contribute "a lot" to society.
A 2011 study on a national sample of US college students examined whether these students viewed the science / religion relationship as reflecting primarily conflict, collaboration, or independence. The study concluded that the majority of undergraduates in both the natural and social sciences do not see conflict between science and religion. Another finding in the study was that it is more likely for students to move away from a conflict perspective to an independence or collaboration perspective than towards a conflict view.
In the US, people who had no religious affiliation were no more likely than the religious population to have New Age beliefs and practices.
== See also ==
== References ==
== Sources ==
== Further reading ==
== External links == | Wikipedia/Science_and_theology |
Cognitive science of religion is the study of religious thought, theory, and behavior from the perspective of the cognitive sciences. Scholars in this field seek to explain how human minds acquire, generate, and transmit religious thoughts, practices, and schemas by means of ordinary cognitive capacities.
== History ==
Although religion has been the subject of serious scientific study since at least the late nineteenth century, the study of religion as a cognitive phenomenon is relatively recent. While it often relies upon earlier research within anthropology of religion and sociology of religion, cognitive science of religion considers the results of that work within the context of evolutionary and cognitive theories. As such, cognitive science of religion was only made possible by the cognitive revolution of the 1950s and the development, starting in the 1970s, of sociobiology and other approaches explaining human behaviour in evolutionary terms, especially evolutionary psychology.
While Dan Sperber foreshadowed cognitive science of religion in his 1975 book Rethinking Symbolism, the earliest research to fall within the scope of the discipline was published during the 1980s. Stewart E. Guthrie's "A cognitive theory of religion" was significant for examining anthropomorphism in religion. This work ultimately led to the development of the concept of the hyperactive agency detection device, which is a key concept within cognitive science of religion. The work of Scott Atran on Cognitive Foundations of Natural History: Towards an Anthropology of Science contrasted the cognitive processing of attention-arresting, and therefore memorable and culturally transmissible, aspects of counter-intuitive "mythico-religious beliefs" (e.g., bodiless beings) with counter-intuitive aspects of scientific thinking that also initially violate common-sense ontological assumptions about the structure of the world (e.g., invisible creatures).
The field was formally established in the 1990s. During that decade, a large number of highly influential and foundational books and articles were published. These included Rethinking Religion: Connecting Cognition and Culture and Bringing Ritual to Mind: Psychological Foundations of Cultural Forms by E. Thomas Lawson and Robert McCauley, Naturalness of Religious Ideas by Pascal Boyer, Inside the Cult and Arguments and Icons by Harvey Whitehouse, and Guthrie's book-length development of his earlier theories in Faces in the Clouds. In the 1990s, these and other researchers, who had been working independently in a variety of different disciplines, discovered each other's work and found valuable parallels between their approaches, with the result that something of a self-aware research tradition began to coalesce. By 2000, the field was well-enough defined for Justin L. Barrett to coin the term 'cognitive science of religion' in his article "Exploring the natural foundations of religion".
The field remains somewhat loosely defined, bringing together researchers from various subfields. Much of the cohesion in the field comes not from shared detailed theoretical commitments but from a shared methodological perspective: the willingness to view religion in cognitive and evolutionary terms.
== Theoretical basis ==
Despite a lack of agreement concerning the theoretical basis for work in cognitive science of religion, it is possible to outline some tendencies. Most significant of these is reliance upon the theories developed within evolutionary psychology. That particular approach to evolutionary explanations of human behaviour is particularly suitable to the cognitive byproduct explanation of religion that is most popular among cognitive scientists of religion. This is because of the focus on byproduct and ancestral trait explanations within evolutionary psychology. A particularly significant concept associated with this approach is modularity of mind, used as it is to underpin accounts of the mental mechanisms seen to be responsible for religious beliefs. Important examples of work that falls under this rubric are provided by research carried out by Pascal Boyer and Justin L. Barrett.
These theoretical commitments are not shared by all cognitive scientists of religion, however. Ongoing debates regarding the comparative advantages of different evolutionary explanations for human behaviour find a reflection within cognitive science of religion with dual inheritance theory recently gaining adherents among researchers in the field, including Armin Geertz and Ara Norenzayan. The perceived advantage of this theoretical framework is its ability to deal with more complex interactions between cognitive and cultural phenomena, but it comes at the cost of experimental design having to take into consideration a richer range of possibilities.
== Main concepts ==
=== Cognitive byproduct ===
The view that religious beliefs and practices should be understood as nonfunctional but as produced by human cognitive mechanisms that are functional outside of the context of religion. Examples of this are the hyperactive agent detection device and the minimally counterintuitive concepts or the process of initiation explaining Buddhism and Taoism. The cognitive byproduct explanation of religion is an application of the concept of spandrel and of the concept of exaptation explored by Stephen Jay Gould among others. The view that religious beliefs and practices are evolutionary spandrels has a number of critics.
=== Minimally counterintuitive concepts ===
Concepts that mostly fit human preconceptions but break with them in one or two striking ways. These concepts are both easy to remember (thanks to the counterintuitive elements) and easy to use (thanks to largely agreeing with what people expect). Examples include talking trees and noncorporeal agents. Pascal Boyer argues that many religious entities fit into this category. Upal labelled the fact that minimally counterintuitive ideas are better remembered than intuitive and maximally counterintuitive ideas as the minimal counterintuitiveness effect or the MCI-effect.
=== Hyperactive agency detection device ===
Cognitive scientist Justin L. Barrett postulates that this mental mechanism, whose function is to identify the activity of agents, may contribute to belief in the presence of the supernatural. Given the relative costs of failing to spot an agent, the mechanism is said to be hyperactive, producing a large number of false positive errors. Stewart E. Guthrie and others have claimed these errors can explain the appearance of supernatural concepts.
=== Pro-social adaptation ===
According to the prosocial adaptation account of religion, religious beliefs and practices should be understood as having the function of eliciting adaptive prosocial behaviour and avoiding the free rider problem. Within the cognitive science of religion this approach is primarily pursued by Richard Sosis. David Sloan Wilson is another major proponent of this approach and interprets religion as a group-level adaptation, but his work is generally seen as falling outside the cognitive science of religion.
=== Costly signaling ===
Practices that, due to their inherent cost, can be relied upon to provide an honest signal regarding the intentions of the agent. Richard Sosis has suggested that religious practices can be explained as costly signals of the willingness to cooperate. A similar line of argument has been pursued by Lyle Steadman and Craig Palmer. Alternatively, D. Jason Slone has argued that religiosity may be a costly signal used as a mating strategy insofar as religiosity serves as a proxy for "family values".
=== Dual inheritance ===
In the context of cognitive science of religion, dual inheritance theory can be understood as attempting to combine the cognitive byproduct and prosocial adaptation accounts using the theoretical approach developed by Robert Boyd and Peter Richerson, among others. The basic view is that while belief in supernatural entities is a cognitive byproduct, cultural traditions have recruited such beliefs to motivate prosocial behaviour. A sophisticated statement of this approach can be found in Scott Atran and Joseph Henrich (2010).
== See also ==
== References ==
== Further reading ==
== External links ==
Religion as Anthropomorphism with Stewart Guthrie.
Religion is Natural and Science is Not with Robert McCauley.
God's Mind, Your Mind, and Theory of Mind with Will Gervais.
Method and Theory in the Cognitive Sciences of Religion with Robert McCauley.
"Practice What You Preach" : CREDs and CRUDs with Jonathan Lanman. | Wikipedia/Cognitive_science_of_religion |
Most scientific and technical innovations prior to the Scientific Revolution were achieved by societies organized by religious traditions. Ancient Christian scholars pioneered individual elements of the scientific method. Historically, Christianity has been and still is a patron of sciences. It has been prolific in the foundation of schools, universities and hospitals, and many Christian clergy have been active in the sciences and have made significant contributions to the development of science.
Historians of science such as Pierre Duhem credit medieval Catholic mathematicians and philosophers such as John Buridan, Nicole Oresme and Roger Bacon as the founders of modern science. Duhem concluded that "the mechanics and physics of which modern times are justifiably proud to proceed, by an uninterrupted series of scarcely perceptible improvements, from doctrines professed in the heart of the medieval schools". Many of the most distinguished classical scholars in the Byzantine Empire held high office in the Eastern Orthodox Church. Protestantism has had an important influence on science, according to the Merton Thesis, there was a positive correlation between the rise of English Puritanism and German Pietism on the one hand, and early experimental science on the other.
Christian scholars and scientists have made noted contributions to science and technology fields, as well as medicine, both historically and in modern times. Some scholars state that Christianity contributed to the rise of the Scientific Revolution. Between 1901 and 2001, about 56.5% of Nobel prize laureates in scientific fields were Christians, and 26% were of Jewish descent (including Jewish atheists).
Events in Christian Europe, such as the Galileo affair, that were associated with the Scientific Revolution and the Age of Enlightenment led some scholars such as John William Draper to postulate a conflict thesis, holding that religion and science have been in conflict throughout history. While the conflict thesis remains popular in atheistic and antireligious circles, it has lost favor among most contemporary historians of science. Most contemporary historians of science believe the Galileo affair is an exception in the overall relationship between science and Christianity and have also corrected numerous false interpretations of this event.
== Overview ==
Most sources of knowledge available to the early Christians were connected to pagan worldviews as the early Christians largely lived among pagans. There were various opinions on how Christianity should regard pagan learning, which included its ideas about nature. For instance, among early Christian teachers, from Tertullian (c. 160–220) held a generally negative opinion of Greek philosophy, while Origen (c. 185–254) regarded it much more favourably and required his students to read nearly every work available to them.
Earlier attempts at reconciliation of Christianity with Newtonian mechanics appear quite different from later attempts at reconciliation with the newer scientific ideas of evolution or relativity. Many early interpretations of evolution polarized themselves around a struggle for existence. These ideas were significantly countered by later findings of universal patterns of biological cooperation. According to John Habgood, all man really knows here is that the universe seems to be a mix of good and evil, beauty and pain, and that suffering may somehow be part of the process of creation. Habgood holds that Christians should not be surprised that suffering may be used creatively by God, given their faith in the symbol of the Cross. Robert John Russell has examined consonance and dissonance between modern physics, evolutionary biology, and Christian theology.
Christian philosophers Augustine of Hippo (354–430) and Thomas Aquinas held that scriptures can have multiple interpretations on certain areas where the matters were far beyond their reach, therefore one should leave room for future findings to shed light on the meanings. Augustine argued:Usually, even a non-Christian knows something about the earth, the heavens, and the other elements of this world, about the motion and orbit of the stars ... Now, it is a disgraceful and dangerous thing for an infidel to hear a Christian, presumably giving the meaning of Holy Scripture, talking non-sense on these topics; and we should take all means to prevent such an embarrassing situation, in which people show up vast ignorance in a Christian and laugh it to scorn. The shame is not so much that an ignorant individual is derided, but that people outside the household of the faith think our sacred writers held such opinions, and, to the great loss of those for whose salvation we toil, the writers of our Scripture are criticized and rejected as unlearned men.The "Handmaiden" tradition, which saw secular studies of the universe as a very important and helpful part of arriving at a better understanding of scripture, was adopted throughout Christian history from early on. Also, the sense that God created the world as a self-operating system is what motivated many Christians throughout the Middle Ages to investigate nature.
The Byzantine Empire was one of the peaks in Christian history and Christian civilization, and Constantinople remained the leading city of the Christian world in size, wealth, and culture. There was a renewed interest in classical Greek philosophy, as well as an increase in literary output in vernacular Greek. The Byzantine science played an important role in the transmission of classical knowledge to the Islamic world and to Renaissance Italy, and also in the transmission of Islamic science to Renaissance Italy. Many of the most distinguished classical scholars held high office in the Eastern Orthodox Church.
Modern historians of science such as J.L. Heilbron, Alistair Cameron Crombie, David Lindberg, Edward Grant, Thomas Goldstein, and Ted Davis have reviewed the popular notion that medieval Christianity was a negative influence in the development of civilization and science. In their views, not only did the monks save and cultivate the remnants of ancient civilization during the barbarian invasions, but the medieval church promoted learnings and science through its sponsorship of many universities which, under its leadership, grew rapidly in Europe in the eleventh and twelfth centuries. St. Thomas Aquinas, the Church's "model theologian", not only argued that reason is in harmony with faith, he even recognized that reason can contribute to understanding revelation, and so encouraged intellectual development. He was not unlike other medieval theologians who sought out reason in the effort to defend his faith. Some of today's scholars, such as Stanley Jaki, have claimed that Christianity with its particular worldview, was a crucial factor for the emergence of modern science. According to professor Noah J. Efron, virtually all modern scholars and historians agree that Christianity moved many early-modern intellectuals to study nature systematically.
Physics teacher David Hutchings and intellectual historian James C. Ungureanu credit the central tenets of traditional Christianity for having been the greatest benefit to scientific thinking, while at the same time noting the irony of the conflict thesis:And yet, as impossible as it might seem, both Conflict and Warfare are plagued by an even greater irony than that. It turns out that when they went after Christian doctrine for being the ultimate enemy of science, they were engaging in friendly fire. For, in actual fact, no other body of thought has ever been of greater benefit to scientific thinking than the central tenets of traditional Christianity have—in the whole of human history.David C. Lindberg states that the widespread popular belief that the Middle Ages was a time of ignorance and superstition due to the Christian church is a "caricature". According to Lindberg, while there are some portions of the classical tradition which suggest this view, these were exceptional cases. It was common to tolerate and encourage critical thinking about the nature of the world. The relation between Christianity and science is complex and cannot be simplified to either harmony or conflict, according to Lindberg. Lindberg reports that "the late medieval scholar rarely experienced the coercive power of the church and would have regarded himself as free (particularly in the natural sciences) to follow reason and observation wherever they led. There was no warfare between science and the church." Ted Peters in Encyclopedia of Religion writes that although there is some truth in the "Galileo's condemnation" story but through exaggerations, it has now become "a modern myth perpetuated by those wishing to see warfare between science and religion who were allegedly persecuted by an atavistic and dogma-bound ecclesiastical authority". In 1992, the Catholic Church's seeming vindication of Galileo attracted much comment in the media:
Generations of historians and sociologists have discovered many ways in which Christians, Christian beliefs, and Christian institutions played crucial roles in fashioning the tenets, methods, and institutions of what in time became modern science. They found that some forms of Christianity provided the motivation to study nature systematically.
A degree of concord between science and religion can be seen in religious belief and empirical science. The belief that God created the world and therefore humans, can lead to the view that he arranged for humans to know the world. This is underwritten by the doctrine of imago dei. In the words of Thomas Aquinas, "Since human beings are said to be in the image of God in virtue of their having a nature that includes an intellect, such a nature is most in the image of God in virtue of being most able to imitate God".
During the Enlightenment, a period "characterized by dramatic revolutions in science" and the rise of Protestant challenges to the authority of the Catholic Church via individual liberty, the authority of Christian scriptures became strongly challenged. As science advanced, acceptance of a literal version of the Bible became "increasingly untenable" and some in that period presented ways of interpreting scripture according to its spirit on its authority and truth.
Regarding the subject on the distribution of Nobel Prizes by religion between 1901 and 2000, the data taken from Baruch A. Shalev, shows that between the years 1901 and 2000 reveals that 654 Laureates belong to 28 different religion. 65.4% have identified Christianity in its various forms as their religious preference. Overall, Christians have won a total of 78.3% of all the Nobel Prizes in Peace, 72.5% in Chemistry, 65.3% in Physics, 62% in Medicine, 54% in Economics and 49.5% of all Literature awards.
== History ==
=== Roots of the Scientific Revolution ===
Between 1150 and 1200, Christian scholars had traveled to Sicily and Spain to retrieve the writings of Aristotle, which had been lost to the West after the Fall of the Roman Empire. This produced a period of cultural ferment that one "modern historian has called the twelfth century renaissance". Thomas Aquinas responded by writing his monumental summas in support of human reason as compatible with faith. Christian theology adapted to Aristotle's secular and humanistic natural philosophy. By the Late Middle Ages, Aquinas's rationalism was being heatedly debated in the new universities. William Ockham resolved the conflict by arguing that faith and reason should be pursued separately so that each could achieve its own end. Historians of science David C. Lindberg, Ronald Numbers and Edward Grant have described what followed as a "medieval scientific revival". Science historian Noah Efron has written that Christianity provided the early "tenets, methods, and institutions of what in time became modern science".
Modern western universities have their origins directly in the Medieval Church. They began as cathedral schools, and all students were considered clerics. This was a benefit as it placed the students under ecclesiastical jurisdiction and thus imparted certain legal immunities and protections. The cathedral schools eventually became partially detached from the cathedrals and formed their own institutions, the earliest being the University of Bologna (1088), the University of Oxford (1096), and the University of Paris (c. 1150).
Some scholars have noted a direct tie between "particular aspects of traditional Christianity" and the rise of science. Other scholars and historians have credited Christianity with laying the foundation for the Scientific Revolution. According to Robert K. Merton, the values of English Puritanism and German Pietism led to the Scientific Revolution of the 17th and 18th centuries. (The Merton Thesis is both widely accepted and disputed.) Merton explained that the connection between religious affiliation and interest in science was the result of a significant synergy between the ascetic Protestant values and those of modern science.
=== Influence of biblical worldviews on early modern science ===
At first, according to Andrew Dickson White's 1896 book A History of the Warfare of Science with Theology in Christendom, a biblical worldview affected negatively the progress of science through time. Dickinson also argues that immediately following the Reformation matters were even worse. The interpretations of Scripture by Luther and Calvin became as sacred to their followers as the Scripture itself. For instance, when Georg Calixtus ventured, in interpreting the Psalms, to question the accepted belief that "the waters above the heavens" were contained in a vast receptacle upheld by a solid vault, he was bitterly denounced as heretical. Today, much of the scholarship in which the conflict thesis was originally based is considered to be inaccurate. For instance, the claim that early Christians rejected scientific findings by the Greco-Romans is false, since the "handmaiden" view of secular studies was seen to shed light on theology. This view was widely adapted throughout the early medieval period and afterwards by theologians (such as Augustine) and ultimately resulted in fostering interest in knowledge about nature through time. Also, the claim that people of the Middle Ages widely believed that the Earth was flat was first propagated in the same period that originated the conflict thesis and is still very common in popular culture. Modern scholars regard this claim as mistaken, as the contemporary historians of science David C. Lindberg and Ronald L. Numbers write: "there was scarcely a Christian scholar of the Middle Ages who did not acknowledge [earth's] sphericity and even know its approximate circumference." From the fall of Rome to the time of Columbus, all major scholars and many vernacular writers interested in the physical shape of the Earth held a spherical view with the exception of Lactantius and Cosmas.
H. Floris Cohen argued for a biblical Protestant, but not excluding Catholicism, influence on the early development of modern science. He presented Dutch historian R. Hooykaas' argument that a biblical world-view holds all the necessary antidotes for the hubris of Greek rationalism: a respect for manual labour, leading to more experimentation and empiricism, and a supreme God that left nature and open to emulation and manipulation. It supports the idea early modern science rose due to a combination of Greek and biblical thought.
Oxford historian Peter Harrison is another who has argued that a Biblical worldview was significant for the development of modern science. Harrison contends that Protestant approaches to the book of scripture had significant, if largely unintended, consequences for the interpretation of the book of nature. Harrison has also suggested that literal readings of the Genesis narratives of the Creation and Fall motivated and legitimated scientific activity in seventeenth-century England. For many of its seventeenth-century practitioners, science was imagined to be a means of restoring a human dominion over nature that had been lost as a consequence of the Fall.
Historian and professor of religion Eugene M. Klaaren holds that "a belief in divine creation" was central to an emergence of science in seventeenth-century England. The philosopher Michael Foster has published analytical philosophy connecting Christian doctrines of creation with empiricism. Historian William B. Ashworth has argued against the historical notion of distinctive mind-sets and the idea of Catholic and Protestant sciences. Historians James R. Jacob and Margaret C. Jacob have argued for a linkage between seventeenth-century Anglican intellectual transformations and influential English scientists (e.g., Robert Boyle and Isaac Newton). John Dillenberger and Christopher B. Kaiser have written theological surveys, which also cover additional interactions occurring in the eighteenth, nineteenth, and twentieth centuries. Philosopher of Religion, Richard Jones, has written a philosophical critique of the "dependency thesis" which assumes that modern science emerged from Christian sources and doctrines. Though he acknowledges that modern science emerged in a religious framework, that Christianity greatly elevated the importance of science by sanctioning and religiously legitimizing it in medieval period, and that Christianity created a favorable social context for it to grow; he argues that direct Christian beliefs or doctrines were not primary source of scientific pursuits by natural philosophers, nor was Christianity, in and of itself, exclusively or directly necessary in developing or practicing modern science.
Oxford University historian and theologian John Hedley Brooke wrote that "when natural philosophers referred to laws of nature, they were not glibly choosing that metaphor. Laws were the result of legislation by an intelligent deity. Thus, the philosopher René Descartes (1596–1650) insisted that he was discovering the "laws that God has put into nature." Later Newton would declare that the regulation of the Solar System presupposed the "counsel and dominion of an intelligent and powerful Being." Historian Ronald L. Numbers stated that this thesis "received a boost" from mathematician and philosopher Alfred North Whitehead's Science and the Modern World (1925). Numbers has also argued, "Despite the manifest shortcomings of the claim that Christianity gave birth to science—most glaringly, it ignores or minimizes the contributions of ancient Greeks and medieval Muslims—it too, refuses to succumb to the death it deserves." The sociologist Rodney Stark of Baylor University, argued in contrast that "Christian theology was essential for the rise of science."
=== Reconciliation in Britain in the early 20th century ===
In Reconciling Science and Religion: The Debate in Early-twentieth-century Britain, historian of biology Peter J. Bowler argues that in contrast to the conflicts between science and religion in the U.S. in the 1920s (most famously the Scopes Trial), during this period Great Britain experienced a concerted effort at reconciliation, championed by intellectually conservative scientists, supported by liberal theologians but opposed by younger scientists and secularists and conservative Christians. These attempts at reconciliation fell apart in the 1930s due to increased social tensions, moves towards neo-orthodox theology and the acceptance of the modern evolutionary synthesis.
In the twentieth century, several ecumenical organizations promoting a harmony between science and Christianity were founded, most notably the American Scientific Affiliation, The Biologos Foundation, Christians in Science, The Society of Ordained Scientists, and The Veritas Forum.
== Branches of Christianity ==
=== Catholicism ===
While refined and clarified over the centuries, the Catholic position on the relationship between science and religion is one of harmony and has maintained the teaching of natural law as set forth by Thomas Aquinas. For example, regarding scientific study such as that of evolution, the church's unofficial position is an example of theistic evolution, stating that faith and scientific findings regarding human evolution are not in conflict, though humans are regarded as a special creation, and that the existence of God is required to explain both monogenism and the spiritual component of human origins. Catholic schools have included all manners of scientific study in their curriculum for many centuries. Historian John Heilbron says that "The Roman Catholic Church gave more financial and social support to the study of astronomy for over six centuries, from the recovery of ancient learning during the late Middle Ages into the Enlightenment, then any other, and probably all, other Institutions."
The first universities in Europe were established by Catholic Church monks. The first Western European institutions generally considered to be universities were established in present-day Italy (including the Kingdom of Sicily, the Kingdom of Naples, and the Kingdom of Italy), the Kingdom of England, the Kingdom of France, Holy Roman Empire, the Kingdom of Spain, the Kingdom of Portugal and the Kingdom of Scotland between the 11th and 15th centuries for the study of the arts and the higher disciplines of theology, law, and medicine. These universities evolved from much older Christian cathedral schools and monastic schools, and it is difficult to define the exact date when they became true universities, though the lists of studia generalia for higher education in Europe held by the Vatican are a useful guide:
Today almost all historians agree that Christianity (Catholicism as well Protestantism) moved many early-modem intellectuals to study nature systematically. Historians have also found that notions borrowed from Christian belief found their ways into scientific discourse, with glorious results.
Galileo once stated "The intention of the Holy Spirit is to teach us how to go to heaven, not how the heavens go." In 1981, John Paul II, then pope of the Catholic Church, spoke of the relationship this way: "The Bible itself speaks to us of the origin of the universe and its make-up, not in order to provide us with a scientific treatise, but in order to state the correct relationships of Man with God and with the universe. Sacred Scripture wishes simply to declare that the world was created by God, and in order to teach this truth it expresses itself in the terms of the cosmology in use at the time of the writer". The influence of the Church on Western letters and learning has been formidable. The ancient texts of the Bible have deeply influenced Western art, literature and culture. For centuries following the collapse of the Western Roman Empire, small monastic communities were practically the only outposts of literacy in Western Europe. In time, the cathedral schools developed into Europe's earliest universities and the church has established thousands of primary, secondary and tertiary institutions throughout the world in the centuries since. The Church and clergymen have also sought at different times to censor texts and scholars. Thus, different schools of opinion exist as to the role and influence of the Church in relation to western letters and learning.
One view, first propounded by Enlightenment philosophers, asserts that the Church's doctrines are entirely superstitious and have hindered the progress of civilization. Communist states have made similar arguments in their education in order to inculcate a negative view of Catholicism (and religion in general) in their citizens. The most famous incidents cited by such critics are narratives of the Church in relation to Copernicus, Galileo Galilei and Johannes Kepler.
In opposition to this view, some historians of science, including non-Catholics such as J.L. Heilbron, A.C. Crombie, David Lindberg, Edward Grant, Thomas Goldstein, and Ted Davis, have argued that the Church had a significant, positive influence on the development of Western civilization. They hold that, not only did monks save and cultivate the remnants of ancient civilization during the barbarian invasions, but that the Church promoted learning and science through its sponsorship of many universities which, under its leadership, grew rapidly in Europe in the eleventh and twelfth centuries. St.Thomas Aquinas, the Church's "model theologian," argued that reason is in harmony with faith, and that reason can contribute to a deeper understanding of revelation, and so encouraged intellectual development. The Church's priest-scientists, many of whom were Jesuits, have been among the leading lights in astronomy, genetics, geomagnetism, meteorology, seismology, and solar physics, becoming some of the "fathers" of these sciences. Examples include important churchmen such as the Augustinian abbot Gregor Mendel (pioneer in the study of genetics), Roger Bacon (a Franciscan friar who was one of the early advocates of the scientific method), and Belgian priest Georges Lemaître (the first to propose the Big Bang theory; see Religious interpretations of the Big Bang theory). Other notable priest scientists have included Albertus Magnus, Robert Grosseteste, Nicholas Steno, Francesco Grimaldi, Giambattista Riccioli, Roger Boscovich, and Athanasius Kircher. Even more numerous are Catholic laity involved in science: Henri Becquerel who discovered radioactivity; Galvani, Volta, Ampere, Marconi, pioneers in electricity and telecommunications; Lavoisier, "father of modern chemistry"; Vesalius, founder of modern human anatomy; and Cauchy, one of the mathematicians who laid the rigorous foundations of calculus.
Throughout history many Catholic clerics have made significant contributions to science. These cleric-scientists include Nicolaus Copernicus, Gregor Mendel, Georges Lemaître, Albertus Magnus, Roger Bacon, Pierre Gassendi, Roger Joseph Boscovich, Marin Mersenne, Bernard Bolzano, Francesco Maria Grimaldi, Nicole Oresme, Jean Buridan, Robert Grosseteste, Christopher Clavius, Nicolas Steno, Athanasius Kircher, Giovanni Battista Riccioli, William of Ockham, and others. The Catholic Church has also produced many lay scientists and mathematicians.
==== Cistercian in science ====
The Catholic Cistercian order used its own numbering system, which could express numbers from 0 to 9999 in a single sign. According to one modern Cistercian, "enterprise and entrepreneurial spirit" have always been a part of the order's identity, and the Cistercians "were catalysts for development of a market economy" in twelfth-century Europe. Until the Industrial Revolution, most of the technological advances in Europe were made in the monasteries. According to the medievalist Jean Gimpel, their high level of industrial technology facilitated the diffusion of new techniques: "Every monastery had a model factory, often as large as the church and only several feet away, and waterpower drove the machinery of the various industries located on its floor." Waterpower was used for crushing wheat, sieving flour, fulling cloth and tanning – a "level of technological achievement [that] could have been observed in practically all" of the Cistercian monasteries.
The English science historian James Burke examines the impact of Cistercian waterpower, derived from Roman watermill technology such as that of Barbegal aqueduct and mill near Arles in the fourth of his ten-part Connections TV series, called "Faith in Numbers". The Cistercians made major contributions to culture and technology in medieval Europe: Cistercian architecture is considered one of the most beautiful styles of medieval architecture; and the Cistercians were the main force of technological diffusion in fields such as agriculture and hydraulic engineering.
==== Jesuits in science ====
Between the sixteenth and eighteenth centuries, the teaching of science in Jesuit schools, as laid down in the Ratio atque Institutio Studiorum Societatis Iesu ("The Official Plan of studies for the Society of Jesus") of 1599, was almost entirely based on the works of Aristotle.
The Jesuits, nevertheless, have made numerous significant contributions to the development of science. For example, the Jesuits have dedicated significant study to earthquakes, and seismology has been described as "the Jesuit science". The Jesuits have been described as "the single most important contributor to experimental physics in the seventeenth century". According to Jonathan Wright in his book God's Soldiers, by the eighteenth century the Jesuits had "contributed to the development of pendulum clocks, pantographs, barometers, reflecting telescopes and microscopes, to scientific fields as various as magnetism, optics and electricity. They observed, in some cases before anyone else, the colored bands on Jupiter's surface, the Andromeda nebula and Saturn's rings. They theorized about the circulation of the blood (independently of Harvey), the theoretical possibility of flight, the way the moon affected the tides, and the wave-like nature of light."
The Jesuit China missions of the sixteenth and seventeenth centuries introduced Western science and astronomy, then undergoing its own revolution, to China. One modern historian writes that in late Ming courts, the Jesuits were "regarded as impressive especially for their knowledge of astronomy, calendar-making, mathematics, hydraulics, and geography". The Society of Jesus introduced, according to Thomas Woods, "a substantial body of scientific knowledge and a vast array of mental tools for understanding the physical universe, including the Euclidean geometry that made planetary motion comprehensible". Another expert quoted by Woods said the scientific revolution brought by the Jesuits coincided with a time when science was at a very low level in China.
The missionary efforts and other work of the Society of Jesus, or Jesuits, between the 16th and 17th century played a significant role in continuing the transmission of knowledge, science, and culture between China and the West, and influenced Christian culture in Chinese society today.
=== Protestant influence ===
Protestantism has promoted economic growth and entrepreneurship, especially in the period after the Scientific and the Industrial Revolution. Scholars have identified a positive correlation between the rise of Protestantism and human capital formation, work ethic, economic development, and the development of the state system.
Protestantism had an important influence on science, according to the Merton thesis there was a positive correlation between the rise of Puritanism and Protestant Pietism on the one hand and early experimental science on the other. The Merton thesis has two separate parts: Firstly, it presents a theory that science changes due to an accumulation of observations and improvement in experimental techniques and methodology; secondly, it puts forward the argument that the popularity of science in seventeenth-century England and the religious demography of the Royal Society (English scientists of that time were predominantly Puritans or other Protestants) can be explained by a correlation between Protestantism and the scientific values. In his theory, Robert K. Merton focused on English Puritanism and German Pietism as having been responsible for the development of the Scientific Revolution of the seventeenth and eighteenth centuries. Merton explained that the connection between religious affiliation and interest in science was the result of a significant synergy between the ascetic Protestant values and those of modern science. Protestant values encouraged scientific research by allowing science to study God's influence on the world and thus providing a religious justification for scientific research.
According of Scientific Elite: Nobel Laureates in the United States by Harriet Zuckerman, a review of American Nobel Prize winners awarded between 1901 and 1972, 72% of American Nobel Prize laureates, have identified from Protestant background. Overall, Americans of Protestant background have won a total of 84.2% of all awarded Nobel Prizes in Chemistry, 60% in Medicine, 58.6% in Physics, between 1901 and 1972.
Some of the first colleges and universities in America, including Harvard, Yale, Princeton, Columbia, Dartmouth, Pennsylvania, Duke, Boston, Williams, Bowdoin, Middlebury, and Amherst, all were founded by mainline Protestant denominations.
==== Quakers in science ====
The Religious Society of Friends, commonly known as Quakers, encouraged some values which may have been conducive to encouraging scientific talents. A theory suggested by David Hackett Fischer in his book Albion's Seed indicated early Quakers in the US preferred "practical study" to the more traditional studies of Greek or Latin popular with the elite. Another theory suggests their avoidance of dogma or clergy gave them a greater flexibility in response to science.
Despite those arguments a major factor is agreed to be that the Quakers were initially discouraged or forbidden to go to the major law or humanities schools in Britain due to the Test Act. They also at times faced similar discriminations in the United States, as many of the colonial universities had a Puritan or Anglican orientation. This led them to attend "Godless" institutions or forced them to rely on hands-on scientific experimentation rather than academia.
Because of these issues it has been stated Quakers are better represented in science than most religions. There are sources, Pendlehill (Thomas 2000) and Encyclopædia Britannica, that indicate that for over two centuries they were overrepresented in the Royal Society. Mention is made of this possibility in studies referenced in religiosity and intellince and in a book by Arthur Raistrick. Whether this is still accurate, there have been several noteworthy members of this denomination in science. The following names a few.
=== Eastern Christian influence ===
Christian scientists and scholars (particularly Nestorian and Jacobite Christians) contributed to the Arab Islamic Civilization during the Ummayad and the Abbasid periods by translating works of Greek philosophers to Syriac and afterwards to Arabic. Over a century and a half, primarily Middle Eastern Oriental Syriac Christian scholars in House of Wisdom translated all scientific and philosophic Greek texts into Arabic language in the House of Wisdom. They also excelled in philosophy, science (Masawaiyh, Eutychius of Alexandria, and Jabril ibn Bukhtishu) and theology (such as Tatian, Bardaisan, Babai the Great, Nestorius, and Thomas of Marga) and the personal physicians of the Abbasid Caliphs were often Christians, such as the long-serving Bukhtishu dynasty. Many scholars of the House of Wisdom were of Assyrian Christian background.
Among the Copts in Egypt, every monastery and probably every church once had its own library of manuscripts.
In the fifth century AD, nine Christian Syrian Monks translated Greek, Hebrew, and Syriac works into the Ethiopian language of Ge'ez and organized Christian monastic orders and schools, some of which are still in existence today. By the sixth century AD, Assyrian Christians had begun exporting back to the Byzantine Empire their own works on science, philosophy and medicine. the literary output of the Assyrians was vast. The third largest corpus of Christian writing, after Latin and Greek, is by the Assyrians in the Assyrian language. In the field of medicine, the Assyrian Bukhtishu family produced nine generations of physicians, and founded the great medical school at Gundeshapur in Iran. When Abbasid Caliph al-Mansur became ill and no physician in Baghdad could cure him, he sent for the dean of the medical school in Gundeshapur, which was renowned as the best of its time The Assyrian philosopher Job of Edessa developed a physical theory of the universe, in the Assyrian language, that rivaled Aristotle's theory, and that sought to replace matter with forces (a theory that anticipated some ideas in quantum mechanics, such as the spontaneous creation and destruction of matter that occurs in the quantum vacuum). One of the greatest Assyrian achievements of the fourth century was the founding of one of the oldest universities in the world, the School of Nisibis, which had three departments, theology, philosophy and medicine, and which became a magnet and center of intellectual development in the Middle East. The statutes of the School of Nisibis, which have been preserved, later became the model upon which the first Italian university was based. The first Mongolian writing system (which was first set down by assyiran monks) used the Assyrian Aramaic and Syriac alphabets, with the name "Tora Bora" being an Assyrian phrase meaning "arid mountain." The hierarchical structure of Buddhism is modeled after the Church of the East. The Assyrian Christian Stephanos translated the work of Greek physician Pedanius Dioscorides into the Arabic language, and for over a century, this translated medical text was used by the Muslim states.
In the field of Optics, Nestorian Christian Hunayn ibn-Ishaq's textbook on ophthalmology called the Ten Treatises on the Eye, which was written in 950 A.D., remained the authoritative source on the subject in the western world until the 1800s.
It was a Christian scholar and Bishop from Nisibis named Severus Sebokht who was the first to describe and incorporate Indian mathematical symbols in the mid 7th century, which were then adopted into Islamic culture and are now known as the Arabic numerals.
During the fourth through the seventh centuries, scholarly work in the Syriac and Greek languages was either newly initiated, or carried on from the Hellenistic period. Centers of learning and of transmission of classical wisdom included colleges such as the School of Nisibis, and later the School of Edessa, and the renowned hospital and medical academy of Jundishapur; libraries included the Library of Alexandria and the Imperial Library of Constantinople; other centers of translation and learning functioned at Merv, Salonika, Nishapur and Ctesiphon, situated just south of what later became Baghdad. The House of Wisdom was a library, translation institute, and academy established in Abbasid-era Baghdad, Iraq. Nestorians played a prominent role in the formation of Arab culture, with the Jundishapur school being prominent in the late Sassanid, Umayyad and early Abbasid periods. The distinguished historian of science George Sarton called Jundishapur "the greatest intellectual center of the time." Notably, eight generations of the Nestorian Bukhtishu family served as private doctors to caliphs and sultans between the eighth and eleventh centuries.
The common and persistent myth claiming that Islamic scholars "saved" the classical work of Aristotle and other Greek philosophers from destruction and then graciously passed it on to Europe is baseless. According to the myth, these works would otherwise have perished in the long European Dark Age between the fifth and tenth centuries. Ancient Greek texts and Greek culture were never "lost" to be somehow "recovered" and "transmitted" by Islamic scholars, as many keep claiming: the texts were always there, preserved and studied by the scholars and monks of the Byzantines and passed on to the rest of Europe and to the Islamic world at various times. Aristotle had been translated in France at the abbey of Mont Saint-Michel before translations of Aristotle into Arabic (via the Syriac of the Christian scholars from the conquered lands of the Byzantine Empire). Michael Harris points out:
The great writings of the classical era, particularly those of Greece ... were always available to the Byzantines and to those Western peoples in cultural and diplomatic contact with the Eastern Empire.... Of the Greek classics known today, at least seventy-five percent are known through Byzantine copies.
Historian John Julius Norwich adds that “much of what we know about antiquity—especially Hellenic and Roman literature and Roman law—would have been lost forever if it weren't for the scholars and scribes of Constantinople.”
The Byzantine science played an important role in the transmission of classical knowledge to the Islamic world and to Renaissance Italy, and also in the transmission of Islamic science to Renaissance Italy. Many of the most distinguished classical scholars held high office in the Eastern Orthodox Church. The migration waves of Byzantine scholars and émigrés in the period following the Crusader sacking of Constantinople in 1204 and the end of the Byzantine Empire in 1453, is considered by many scholars key to the revival of Greek and Roman studies that led to the development of the Renaissance humanism and science. These émigrés brought to Western Europe the relatively well-preserved remnants and accumulated knowledge of their own (Greek) civilization, which had mostly not survived the Early Middle Ages in the West. According to the Encyclopædia Britannica: "Many modern scholars also agree that the exodus of Greeks to Italy as a result of this event marked the end of the Middle Ages and the beginning of the Renaissance". The Byzantines pioneered the concept of the hospital as an institution offering medical care and the possibility of a cure for the patients, as a reflection of the ideals of Christian charity, rather than merely a place to die.
Paper, which the Muslims received from China in the eighth century, was being used in the Byzantine Empire by the ninth century. There were very large private libraries, and monasteries possessed huge libraries with hundreds of books that were lent to people in each monastery's region. Thus were preserved the works of classical antiquity.
When Saint Cyril was sent by the Byzantine emperor in an embassy to the Arabs in the ninth century, he astonished his Muslim hosts with his knowledge of philosophy and science as well as theology. Historian Maria Mavroudi recounts:
When asked how it was possible for him to know all that he did, he [Cyril] drew an analogy between the Muslim reaction to his erudition and the pride of someone who kept sea water in a wine skin and boasted of possessing a rare liquid. He finally encountered someone from a region by the sea, who explained that only a madman would brag about the contents of the wine skin, since people from his own homeland possessed an endless abundance of sea water. The Muslims are like the man with the wine skin and the [Greeks] like the man from the sea because, according to the saint's concluding remark in his response, all learning emanated from the [Greeks].
== Perspectives on evolution ==
In recent history, the theory of evolution has been at the centre of controversy between Christianity and science, largely in America. Christians who accept a literal interpretation of the biblical account of creation find incompatibility between Darwinian evolution and their interpretation of the Christian faith. Creation science or scientific creationism is a branch of creationism that attempts to provide scientific support for the Genesis creation narrative in the Book of Genesis and attempts to disprove generally accepted scientific facts, theories and scientific paradigms about the geological history of Earth, formation of the Solar System, Big Bang cosmology, the chemical origins of life and evolution. It began in the 1960s as a fundamentalist Christian effort in the United States to prove Biblical inerrancy and falsify the scientific evidence for evolution. It has since developed a sizable religious following in the United States, with creation science ministries branching worldwide. In 1925, The State of Tennessee passed the Butler Act, which prohibited the teaching of the theory of evolution in all schools in the state. Later that year, a similar law was passed in Mississippi, and likewise, Arkansas in 1927. In 1968, these "anti-monkey" laws were struck down by the Supreme Court of the United States as unconstitutional, "because they established a religious doctrine violating both the First and Fourth Amendments to the Constitution."
Most scientists have rejected creation science for several reasons, including that its claims do not refer to natural causes and cannot be tested. In 1987, the United States Supreme Court ruled that creationism is religion, not science, and cannot be advocated in public school classrooms.
Theistic evolution is a discipline that accepts the current scientific understanding of the age of the Earth and the theory of evolution. It includes a range of beliefs, including views described as evolutionary creationism, which accepts contemporary science, but also upholds classical religious understandings of God and creation in Christian context. This position has been endorsed by the Catholic Church. Proponents of theistic evolution include prominent Christian philosopher and theologian, William Lane Craig, Founder of BioLogos, Francis Collins, Prominent conservative Christian Theologian, Tim Keller, and prominent Christian philosopher Alvin Plantinga.
== Modern reception ==
=== Individual scientists' views ===
Christian Scholars and Scientists have made noted contributions to science and technology fields, as well as medicine, both historically and in modern times. Many well-known historical figures who influenced Western science considered themselves Christian such as Nicolaus Copernicus, Galileo Galilei, Johannes Kepler, Isaac Newton Robert Boyle, Francis Bacon, Gottfried Wilhelm Leibniz, Emanuel Swedenborg, Alessandro Volta, Carl Friedrich Gauss, Antoine Lavoisier, André-Marie Ampère, John Dalton, James Clerk Maxwell, William Thomson, 1st Baron Kelvin, Louis Pasteur, Michael Faraday, and J. J. Thomson.
Isaac Newton, for example, believed that gravity caused the planets to revolve about the Sun, and credited God with the design. In the concluding General Scholium to the Philosophiae Naturalis Principia Mathematica, he wrote: "This most beautiful System of the Sun, Planets and Comets, could only proceed from the counsel and dominion of an intelligent and powerful being." Other famous founders of science who adhered to Christian beliefs include Galileo, Johannes Kepler, René Descartes, Blaise Pascal, and others.
Throughout history many Catholic clerics have made significant contributions to science. These cleric-scientists include Nicolaus Copernicus, Gregor Mendel, Georges Lemaître, Albertus Magnus, Roger Bacon, Pierre Gassendi, Roger Joseph Boscovich, Marin Mersenne, Bernard Bolzano, Francesco Maria Grimaldi, Nicole Oresme, Jean Buridan, Robert Grosseteste, Christopher Clavius, Nicolas Steno, Athanasius Kircher, Giovanni Battista Riccioli, William of Ockham, and others. The Catholic Church has also produced many lay scientists and mathematicians.
Prominent modern scientists advocating Christian belief include Nobel Prize–winning physicists Charles Townes (United Church of Christ member) and William Daniel Phillips (United Methodist Church member), evangelical Christian and past head of the Human Genome Project Francis Collins, and climatologist John T. Houghton.
=== Scientific Revolution ===
Some scholars have noted a direct tie between "particular aspects of traditional Christianity" and the rise of science.
Protestantism has had an important influence on science, according to the Merton thesis, there was a positive correlation between the rise of English Puritanism and German Pietism on the one hand and early experimental science on the other. Robert K. Merton focused on English Puritanism and German Pietism as having been responsible for the development of the scientific revolution of the seventeenth and eighteenth centuries. He explained that the connection between religious affiliation and interest in science was the result of a significant synergy between the ascetic Protestant values and those of modern science.
The history professor Peter Harrison attributes Christianity to having contributed to the rise of the Scientific Revolution:
historians of science have long known that religious factors played a significantly positive role in the emergence and persistence of modern science in the West. Not only were many of the key figures in the rise of science individuals with sincere religious commitments, but the new approaches to nature that they pioneered were underpinned in various ways by religious assumptions. ... Yet, many of the leading figures in the scientific revolution imagined themselves to be champions of a science that was more compatible with Christianity than the medieval ideas about the natural world that they replaced.
=== Nobel Prize ===
According to 100 Years of Nobel Prizes a review of Nobel prizes award between 1901 and 2000 reveals that (65.4%) of Nobel Prizes Laureates, have identified Christianity in its various forms as their religious preference (427 prizes). Overall, Christians are considered a total of 72.5% in Chemistry between 1901 and 2000, 65.3% in Physics, 62% in Medicine, 54% in Economics. Between 1901 and 2000 it was revealed that among 654 Laureates 31.9% have identified as Protestant in its various forms (208 prize), 20.3% were Christians (no information about their denominations; 133 prize), 11.6% have identified as Catholic and 1.6% have identified as Eastern Orthodox. Although Christians make up over 33.2% of the world's population, they have won a total of 65.4% of all Nobel prizes between 1901 and 2000.
In an estimate by scholar Benjamin Beit-Hallahmi, between 1901 and 2001, about 57.1% of Nobel prize winners were either Christians or with a Christian background. Between 1901 and 2001, about 56.5% of laureates in scientific fields were Christians. According to scholar Benjamin Beit-Hallahmi, Protestants were overrepresented in scientific categories and Catholics were well-represented in the Literature and Peace categories.
In an estimate made by Weijia Zhang from Arizona State University and Robert G. Fuller from University of Nebraska–Lincoln, between 1901 and 1990, 60% of Physics Nobel prize winners had Christian backgrounds.
According of Scientific Elite: Nobel Laureates in the United States by Harriet Zuckerman, a review of American Nobel prizes winners awarded between 1901 and 1972, 72% of American Nobel Prize Laureates, have identified from Protestant background. Overall, Americans of Protestant background have won a total of 84.2% of all awarded Nobel Prizes in Chemistry, 60% in Medicine, 58.6% in Physics, between 1901 and 1972.
=== Criticism ===
Events in Christian Europe, such as the Galileo affair, that were associated with the Scientific Revolution and the Age of Enlightenment led scholars such as John William Draper to postulate a conflict thesis, holding that religion and science have been in conflict methodologically, factually and politically throughout history. This thesis is held by several scientists like Richard Dawkins and Lawrence Krauss. While the conflict thesis remains popular in atheistic and antireligious circles, it has lost favor among most contemporary historians of science, and the majority of scientists in elite universities in the U.S. do not hold a conflict view.
More recently, Thomas E. Woods, Jr., asserts that, despite the widely held conception of the Catholic Church as being anti-science, this conventional wisdom has been the subject of "drastic revision" by historians of science over the last 50 years. Woods asserts that the mainstream view now is that the "Church [has] played a positive role in the development of science ... even if this new consensus has not yet managed to trickle down to the general public." Science historian Ronald L. Numbers corroborates this view, writing that "Historians of science have known for years that White's and Draper's accounts are more propaganda than history. ...Yet the message has rarely escaped the ivory tower."
While figures like John William Draper and Andrew Dickson White are frequently cited in historical literature as the primary architects of the conflict thesis, historian James C. Ungureanu demonstrates this attribution is fundamentally misleading. In his work, Science, Religion, and the Protestant Tradition: Retracing the Origins of Conflict (2019), Ungureanu reveals that Draper and White were not, in fact, original theorists but rather popularizers who synthesized and amplified pre-existing 19th-century Protestant, anti-Catholic polemic. Ungureanu argues that both authors extensively borrowed rhetorical frameworks and historical examples crafted by progressive liberal theologians engaged in intra-Protestant debates seeking to reform Christianity against perceived Catholic-like dogmatism. Their influential narratives, therefore, were less objective historical accounts and more theologically motivated constructs, shaped by specific religious controversies (particularly anti-Catholicism and liberal Protestant agendas), thus undercutting the thesis's claim to universal historical truth. Ungureanu's scholarship reframes the origins of the conflict narrative as a product of partisan religious discourse rather than a neutral reading of the past.
==== Trial of Galileo ====
In 1610, Galileo published his Sidereus Nuncius (Starry Messenger), describing observations made with his new telescope. These and other discoveries exposed difficulties with the understanding of the heavens that was common at the time. Scientists, along with the Catholic Church, had adopted Aristotle's view of the Earth as fixed in place, since Aristotle's rediscovery 300 years prior. Jeffrey Foss writes that, by Galileo's time, the Aristotelian-Ptolemaic view of the universe had become "fully integrated with Catholic theology".: 285
Scientists of the day largely rejected Galileo's assertions, since most had no telescope, and Galileo had no physical theory to explain how planets could orbit the Sun which, according to Aristotelian physics, was impossible. (That would not be resolved for another hundred years.) Galileo's peers alerted religious authorities to his "errors" and asked them to intervene.: 285–286 In response, the church forbade Galileo from teaching it, though it did not forbid discussing it, so long as it was clear it was merely a hypothesis. Galileo published books and asserted scientific superiority.: 285 He was summoned before the Roman Inquisition twice. First warned, he was next sentenced to house arrest on a charge of "grave suspicion of heresy".: 286
The Galileo affair has been considered by many to be a defining moment in the history of the relationship between religion and science. Since the creation of the Conflict thesis by Andrew Dickson White and John William Draper in the late nineteenth century, religion has been depicted as oppressive and oppositional to science. Edward Daub explains that, while "twentieth century historians of science dismantled White and Draper's claims, it is still popular in public perception". Casting Galileo's story as a contest between science and religion is an oversimplification, writes Jeffrey Foss.: 286 Galileo was heir to a long scientific tradition with deep medieval Christian roots.
== See also ==
== Notes ==
=== Works cited ===
Numbers, Ronald L. (2006). The Creationists: From Scientific Creationism to Intelligent Design. Harvard University Press. ISBN 978-0-674-02339-0.
Shalev, Baruch A. (2003). 100 Years of Nobel Prizes. Atlantic Publishers & Dist. ISBN 978-81-269-0278-1.
Thomas, Anne (24 April 2000), This I Know Experimentally, Spring 2000 Monday Night Lecture Series: Science and Religion, Pendle Hill (published 6 October 2003), archived from the original on 1 May 2006, retrieved 29 June 2009
== Further reading ==
Buxhoeveden, Daniel; Woloschak, Gayle, eds. (2011). Science and the Eastern Orthodox Church (1. ed.). Farnham: Ashgate. ISBN 9781409481614.
Spierer, Eugen. God-of-the-Gaps Arguments in Light of Luther's Theology of the Cross. Archived 19 August 2019 at the Wayback Machine
Matthews, Roy T.; Platt, F. DeWitt (1991). The Western Humanities. Mayfield Publishing Co. ISBN 0874847850.
== External links ==
Christianity And The Scientist by Ian G. Barbour Archived 4 March 2016 at the Wayback Machine
Cambridge Christians in Science (CiS) group Archived 3 July 2019 at the Wayback Machine
Christians in Science website
Ian Ramsey Centre, Oxford
The Society of Ordained Scientists-Mostly Church of England
"Science in Christian Perspective" The (ASA)
Canadian Scientific and Christian Affiliation (CSCA)
The International Society for Science & Religion's founding members.(Of various faiths including Christianity)
Association of Christians in the Mathematical Sciences
Secular Humanism.org article on Science and Religion Archived 19 June 2010 at the Wayback Machine | Wikipedia/Christianity_and_science |
Divine command theory (also known as theological voluntarism) is a meta-ethical theory which proposes that an action's status as morally good is equivalent to whether it is commanded by God. The theory asserts that what is moral is determined by God's commands and that for a person to be moral he is to follow God's commands. Followers of both monotheistic and polytheistic religions in ancient and modern times have often accepted the importance of God's commands in establishing morality.
Numerous variants of the theory have been presented: historically, figures including Saint Augustine, Duns Scotus, William of Ockham and Søren Kierkegaard have presented various versions of divine command theory; more recently, Robert Merrihew Adams has proposed a "modified divine command theory" based on the omnibenevolence of God in which morality is linked to human conceptions of right and wrong. Paul Copan has argued in favour of the theory from a Christian viewpoint, and Linda Trinkaus Zagzebski's divine motivation theory proposes that God's motivations, rather than commands, are the source of morality.
Semantic challenges to divine command theory have been proposed; the philosopher William Wainwright argued that to be commanded by God and to be morally obligatory do not have an identical meaning, which he believed would make defining obligation difficult. He also contended that, as knowledge of God is required for morality by divine command theory, atheists and agnostics could not be moral; he saw this as a weakness of the theory. Others have challenged the theory on modal grounds by arguing that, even if God's command and morality correlate in this world, they may not do so in other possible worlds. In addition, the Euthyphro dilemma, first proposed by Plato (in the context of polytheistic Greek religion), presented a dilemma which threatened either to result in the moral arbitrariness of morality itself, or to result in the irrelevance of God to morality. Divine command theory has also been criticised for its apparent incompatibility with the omnibenevolence of God, moral autonomy and religious pluralism, although some scholars have defended the theory from these challenges.
== General form ==
Although "divine command" is the standard term in the literature, God addresses people in all sorts of ways. The scholastics distinguished between five different forms of God's revealed will, and they can be summarized in a Latin dactylic hexameter, "Praecipit et prohibet, permittit, consultit, implet". Praecipit means "gives precepts to". Precepts tell people to do something. They can include warning, admonishment or exhortation. Prohibet means "prohibits". A prohibition is a command not to do something. Permittit means "permits". A permission is not a command because a person is permitted both to do the thing and not to do it. Consultit means "counsels". They can include advice, instruction or invitation. They are different from commands as the latter generally generate obligation, and there is normally some expectation of condemnation if the command is not carried out. Finally, implet means "fulfils", which are directly effective commands. They do not need language-using human recipients. An example is "Let there be light", and there is light. Sometimes "command" is taken to mean the whole family of speech acts, but sometimes it only includes those prescriptions which generate obligation.
Philosophers including William of Ockham (c. 1287–1347), St Augustine (354–430), Duns Scotus (c. 1265–1308), and John Calvin (1509–1564) have presented various forms of divine command theory. The theory generally teaches that moral truth does not exist independently of God and that divine commands determine morality. Stronger versions of the theory assert that God's command is the only reason that a good action is moral, while weaker variations cast divine command as a vital component within a greater reason. The theory asserts that good actions are morally good as a result of divine command, and many religious believers subscribe to some form of divine command theory. Because of these premises, adherents believe that moral obligation is obedience to God's commands; what is morally right is what God desires.
Divine command theory features in the ethics of many contemporary religions – including Judaism, Islam, the Bahá'í Faith, and Christianity – as well as featuring in numerous polytheistic religions. In ancient Athens, citizens commonly held that moral truth was tied directly to divine commands, and religious piety was almost equivalent to morality. Although Christianity does not entail divine command theory, people commonly associate the two. DCT can be a plausible theory to Christians because the traditional conception of God as the creator of the universe parallels the idea that he created moral truths. The theory is supported by the Christian view that God is all-powerful because this implies that God creates moral truths, rather than moral truths existing independently of him, which seems inconsistent with his omnipotence.
=== Augustine ===
Saint Augustine offered a version of divine command theory that began by casting ethics as the pursuit of the supreme good, which delivers human happiness. He argued that to achieve this happiness, humans must love objects that are worthy of human love in the correct manner; this requires humans to love God, which then allows them to correctly love that which is worthy of being loved. Augustine's ethics proposed that the act of loving God enables humans to properly orient their loves, leading to human happiness and fulfilment. Augustine supported Plato's view that a well-ordered soul is a desirable consequence of morality. However, unlike Plato, he believed that achieving a well-ordered soul had a higher purpose: living in accordance with God's commands. His view of morality was thus heteronomous, as he believed in deference to a higher authority (God), rather than acting autonomously.
=== John Duns Scotus ===
Scholastic philosopher John Duns Scotus argued that the only moral obligations that God could not take away from humans involve loving God, as God is, definitionally, the most loveable thing. Scotus argued that the natural law, in the strictest sense, contains only what is self-evidently analytically true and that God could not make these statements false. This means that the commands of natural law do not depend on God's will, and thus form the first three commandments of the Ten Commandments. The last seven of the Ten Commandments do not belong to the natural law in the strictest sense. Whilst humanity's duties to God are self-evident, true by definition, and unchangeable even by God, mankind's duties to others (found on the second tablet) were arbitrarily willed by God and are within his power to revoke and replace (although, the third commandment, to honour the Sabbath and keep it holy, has a little of both, as humanity is absolutely obliged to render worship to God, but there is no obligation in natural law to do it on this day or that). Scotus does note, however that the last seven commandments:
...are highly consonant with [the natural law], though they do not follow necessarily from first practical principles that are known in virtue of their terms and are necessarily known by any intellect that understands their terms. And it is certain that all the precepts of the second table belong to the natural law in this second way, since their rectitude is highly consonant with first practical principles that are known necessarily.
Scotus justifies this position with the example of a peaceful society, noting that the possession of private property is not necessary to have a peaceful society, but that "those of weak character" would be more easily made peaceful with private property than without. Hence, the last seven commandments do belong to the natural law, but not in the strictest sense, as they belong to the natural law by rectitude rather than by definition.
=== Thomas Aquinas ===
Whilst Thomas Aquinas, as a natural law theorist, is generally seen as holding that morality is not willed by God, Kelly James Clark and Anne Poortenga have presented a defence of divine command theory based on Aquinas' moral theory. Aquinas proposed a theory of natural law which asserted that something is moral if it works towards the purpose of human existence, and so human nature can determine what is moral. Clark and Poortenga argued that God created human nature and thus commanded a certain morality; hence he cannot arbitrarily change what is right or wrong for humans.
=== Immanuel Kant ===
The deontological ethics of Immanuel Kant has been cast as rejecting divine command theory by several figures, among whom is ethicist R. M. Hare. Kant's view that morality should be determined by the categorical imperative – duty to the moral law, rather than acting for a specific end – has been viewed as incompatible with divine command theory. Philosopher and theologian John E. Hare has noted that some philosophers see divine command theory as an example of Kant's heteronomous will – motives besides the moral law, which Kant regarded as non-moral. American philosopher Lewis White Beck takes Kant's argument to be a refutation of the theory that morality depends on divine authority. John E. Hare challenges this view, arguing that Kantian ethics should be seen as compatible with divine command theory.
=== Robert Adams ===
American philosopher Robert Merrihew Adams proposes what he calls a "modified divine command theory". Adams presents the basic form of his theory by asserting that two statements are equivalent:
It is wrong to do X.
It is contrary to God's commands to do X.
He proposes that God's commands precede moral truths and must be explained in terms of moral truths, not the other way around. Adams writes that his theory is an attempt to define what being ethically 'wrong' consists of and accepts that it is only useful to those within a Judeo-Christian context. In dealing with the criticism that a seemingly immoral act would be obligatory if God commanded it, he proposes that God does not command cruelty for its own sake. Adams does not propose that it would be logically impossible for God to command cruelty, rather that it would be unthinkable for him to do so because of his nature. Adams emphasises the importance of faith in God, specifically faith in God's goodness, as well as his existence.
Adams proposes that an action is morally wrong if and only if it defies the commands of a loving God. If cruelty was commanded, he would not be loving; Adams argued that, in this instance, God's commands would not have to be obeyed and also that his theory of ethical wrongness would break down. He proposed that divine command morality assumes that human concepts of right and wrong are met by God's commands and that the theory can only be applied if this is the case. Adams' theory attempts to counter the challenge that morality might be arbitrary, as moral commands are not based solely on the commands of God, but are founded on his omnibenevolence. It attempts to challenge the claim that an external standard of morality prevents God from being sovereign by making him the source of morality and his character the moral law.
Adams proposes that in many Judeo-Christian contexts, the term 'wrong' is used to mean being contrary to God's commands. In ethical contexts, he believes that 'wrong' entails an emotional attitude against an action and that these two uses of wrongness usually correlate. Adams suggests that a believer's concept of morality is founded in their religious belief and that right and wrong are tied to their belief in God; this works because God always commands what believers accept to be right. If God commanded what a believer perceived as wrong, the believer would not say it is right or wrong to disobey him; rather their concept of morality would break down.
Michael Austin writes that an implication of this modified divine command theory is that God cannot command cruelty for its own sake; this could be argued to be inconsistent with God's omnipotence. Aquinas argued that God's omnipotence should be understood as the ability to do all things that are possible: he attempted to refute the idea that God's inability to perform illogical actions challenges his omnipotence. Austin contends that commanding cruelty for its own sake is not illogical, so is not covered by Aquinas' defence, although Aquinas had argued that sin is the falling short of a perfect action and thus not compatible with omnipotence.
=== Alternative theories ===
Paul Copan argues from a Christian viewpoint that man, made in God's image, conforms to God's sense of morality. The description of actions as right or wrong are therefore relevant to God; a person's sense of what is right or wrong corresponds to God's.
We would not know goodness without God's endowing us with a moral constitution. We have rights, dignity, freedom, and responsibility because God has designed us this way. In this, we reflect God's moral goodness as His image-bearers.
As an alternative to divine command theory, Linda Zagzebski has proposed divine motivation theory, which still fits into a monotheistic framework. According to this theory, goodness is determined by God's motives, rather than by what he commands. Divine motivation theory is similar to virtue ethics because it considers the character of an agent, and whether they are in accordance with God's, as the standard for moral value. Zagzebski argues that things in the world have objective moral properties, such as being lovable, which are given to them through God's perception of them. God's attitude towards something is cast as a morally good attitude. The theory casts God as a good example for morality, and humans should imitate his virtues as much as is possible for finite, imperfect beings.
== Objections ==
=== Semantic objections ===
Philosopher William Wainwright considered a challenge to the theory on semantic grounds, arguing that "being commanded by God" and "being obligatory" do not mean the same thing, contrary to what the theory suggests. He used the example of water not having an identical meaning to H2O to propose that "being commanded by God" does not have an identical meaning to "being obligatory". This was not an objection to the truth of divine command theory, but Wainwright believed it demonstrated that the theory should not be used to formulate assertions about the meaning of obligation. Wainwright also noted that divine command theory might imply that one can only have moral knowledge if one has knowledge of God; Edward Wierenga argued that, if this is the case, the theory seems to deny atheists and agnostics moral knowledge. Hugh Storer Chandler has challenged the theory based on modal ideas of what might exist in different worlds. He suggested that, even if one accepts that being commanded by God and being morally right are the same, they may not be synonyms because they might be different in other possible worlds.
=== Moral motivation ===
Michael Austin has noted that divine command theory could be criticised for prompting people to be moral with impure motivations. He writes of the objection that a moral life should be sought because morality is valued, rather than to avoid punishment or receive a reward. This punishment and reward system of motivation could be seen as inadequate.
=== Euthyphro dilemma ===
The Euthyphro dilemma was proposed in Plato's dialogue between Socrates and Euthyphro. In the scene, Socrates and Euthyphro are discussing the nature of piety when Socrates presents the dilemma, which can be presented as the question "Is X good because God commands it, or does God command X because it is good?".
Is the pious loved by the gods because it is pious, or is it pious because it is loved by the gods?
The Euthyphro dilemma can elicit the response that an action is good because God commands the action, or that God commands an action because it is good. If the first is chosen, it would imply that whatever God commands must be good: even if he commanded someone to inflict suffering, then inflicting suffering must be moral. If the latter is chosen, then morality is no longer dependent on God, defeating the divine command theory. Additionally, if God is subject to an external law, he is not sovereign or omnipotent, which would challenge the orthodox conception of God. Proponents of the Euthyphro dilemma might claim that divine command theory is obviously wrong because either answer challenges the ability of God to give moral laws.
William of Ockham responded to the Euthyphro Dilemma by 'biting the bullet'. He argued that, if God did command people to be cruel, then that would be morally obligatory, proposing that the only limitation to what God can make obligatory is the principle of non-contradiction. Robert Adams defended Ockham's view, noting that it is only a logical possibility that God would command what mankind considers to be immoral, not an actuality. Even if God could logically command these actions, he would not because that is not his character. Eleonore Stump and Norman Kretzmann have responded to the Euthyphro dilemma by appealing to the doctrine of divine simplicity, a concept associated with Aquinas and Aristotle which suggests that the substance and attributes of God are identical. They propose that God and goodness are identical and that this is what makes his commands good.
American philosopher William Alston responded to the Euthyphro dilemma by considering what it means for God to be morally good. If divine command theory is accepted, it implies that God is good because he obeys his own commands; Alston argued that this is not the case and that God's goodness is distinct from abiding by moral obligations. He suggested that a moral obligation implies that there is some possibility that the agent may not honour their obligation; Alston argued that this possibility does not exist for God, so his morality must be distinct from simply obeying his own commands. Alston contended that God is the supreme standard of morality and acts according to his character, which is necessarily good. There is no more arbitrariness in this view than accepting another moral standard.
=== Omnibenevolence ===
Gottfried Wilhelm Leibniz, and some more recent philosophers, challenged the theory of divine command because it seems to entail that God's goodness consists of his following his own commands. It is argued that, if divine command theory is accepted, God's obligations would be what he commanded himself to do; the concept of God commanding himself is seen as incoherent. Neither could God hold any virtues, as a virtue would be the disposition to follow his own commands – if he cannot logically command himself, then he cannot logically have any virtues. Edward Wierenga counters this by claiming that whatever God chooses to do is good, but that his nature means that his actions would always be praiseworthy. William Wainwright argues that, although God does not act because of his commands, it is still logical to say that God has reasons for his actions. He proposes that God is motivated by what is morally good and, when he commands what is morally good, it becomes morally obligatory.
=== Autonomy ===
Michael Austin draws attention to an objection from autonomy, which argues that morality requires an agent to freely choose which principles they live by. This challenges the view of divine command theory that God's will determines what is good because humans are no longer autonomous, but followers of an imposed moral law, making autonomy incompatible with divine command theory. Robert Adams challenges this criticism, arguing that humans must still choose to accept or reject God's commands and rely on their independent judgement about whether or not to follow them.
=== Pluralism ===
Austin considers the view that, in a world of religious pluralism, it is impossible to know which god's or religion's commands should be followed, especially because some religions contradict others, leaving it impossible to accept all of them. Within religions there are also various interpretations of what is commanded. Austin notes that some of the responses to the autonomy objection may be relevant, as an agent must choose whichever religion and morality they judge to be correct. He argues that divine command theory is also consistent with the view that moral truths can be found in all religions and that moral revelation can be found apart from religion. Heimir Geirsson and Margaret Holmgren argue against the view that different religions can lead to the same God because some religions are incompatible with each other (monotheistic and polytheistic religions have contrasting views of divinity, for example, and some Greek or Norse gods magnified human weaknesses). They argue that determining which god should be listened to remains a problem and that, even within a religion, contrasting views of God exist – the commands of God in the Old and New Testaments could seem to contradict each other.
== See also ==
Deontological ethics
Divine judgment
Divine right
Ethical subjectivism
Theocracy
Fideism
Might makes right
Euthyphro dilemma
Argument from authority
== References ==
== Bibliography ==
Adams, Robert Merrihew (2002). Finite and Infinite Goods: A Framework for Ethics. Oxford University Press. ISBN 0-19-515371-5.
Baggett, David; Walls, Jerry (2011). Good God:The Theistic Foundations of Morality. Oxford University Press. ISBN 9780199751808.
Chandler, Hugh (2007). Platonistic And Disenchanting Theories of Ethics. Peter Lang. ISBN 978-0-8204-8858-5.
Connolly, Peggy; Keller, David; Leever, Martin; White, Becky Cox (2009). Ethics in Action: A Case-Based Approach. John Wiley & Sons. ISBN 978-1-40517-098-7.
Cross, Richard (1999). Duns Scotus. ISBN 978-0195125535.
Evans, C. Stephen (2004). Kierkegaard's Ethic of Love: Divine Commands and Moral Obligations. Oxford University Press. ISBN 0-19-927217-4.
Geirsson, Heimir; Holmgren, Margaret (2010). Ethical Theory: A Concise Anthology. Broadview Press. ISBN 978-1-55481-015-4.
Harris, Michael (2003). Divine Command Ethics: Jewish and Christian Perspectives. Psychology Press. ISBN 978-0-415-29769-1.
Helm, Paul (1981). Divine Commands and Morality. Oxford University Press. ISBN 0-19-875049-8.
Kowalski, Dean (2011). Moral Theory at the Movies: An Introduction to Ethics. Rowman & Littlefield. ISBN 978-1-44221-455-2.
Langermann, Tzvi (2011). Monotheism & Ethics: Historical and Contemporary Intersections among Judaism, Christianity and Islam. BRILL. ISBN 9789004194298.
Martin, Michael (1993). The Case Against Christianity. Temple University Press. ISBN 978-1-56639-081-1.
Phillips, D. Z.; Tessin, Timothy (2000). Kant and Kierkegaard on Religion. Palgrave Macmillan. ISBN 978-0-31223-234-4.
Rae, Scott (2009). Moral Choices: An Introduction to Ethics. Zondervan. ISBN 978-0-31032-323-5.
Shermer, Michael (2005). Why People Believe Weird Things. Henry Hold & Company. ISBN 0-8050-7769-3.
Morris, Thomas (1988). Divine & Human Action. Cornell University Press. Being and goodness. ISBN 0-8014-9517-2.
Pojman, Louis; Rea, Michael (2008). Philosophy of Religion: An Anthology. Cengage Learning. ISBN 978-0-495-09504-0.
Quinn, Philip (2000). The Blackwell Guide to Ethical Theory. Blackwell Publishers. Divine command theory.
Swinburne, Richard (1977). The Coherence of Theism. Clarendon Press. ISBN 0-19-824410-X.
Wainwright, William J. (2005). Religion and morality. Ashgate Publishing. ISBN 978-0-7546-1632-0.
Williams, Thomas (2013). "John Duns Scotus". In Edward N. Zalta (ed.). John Duns Scotus. The Stanford Encyclopedia of Philosophy (Summer 2013 ed.).
Williams, Thomas, ed. (2002). The Cambridge Companion to Duns Scotus. ISBN 978-0521635639.
== External links ==
Divine Command Theory — Internet Encyclopedia of Philosophy
God and Morality — a defence of the Divine Command theory.
Moral Argument and Divine Command Theory — links to relevant on-line resources from Internet Infidels
Theological Voluntarism — Stanford Encyclopedia of Philosophy | Wikipedia/Divine_command_theory |
Christians in Science (CiS) is a British organisation of scientists, philosophers, theologians, ministers, teachers, and science students, predominantly evangelical Christians, concerned with the dialogue between Christianity and science. The organisation was started in the 1940s as one of the professional groups of IVF (now UCCF), and was known as the Research Scientists' Christian Fellowship from 1950 until it adopted the current name in 1988.
It took on financial independence from UCCF in 1996. The organisation has over 850 members and includes R. J. Berry and John T. Houghton as two of its more noteworthy members.
Along with the Victoria Institute, it publishes Science and Christian Belief twice yearly.
== Statement of Faith ==
Christians in Science is an "explicitly Christian society", and full membership is open only to those who can affirm the following "Statement of Faith", though it is possible for corporate bodies such as libraries and individuals who do not wish to make the declaration to become associate members.
I declare my belief in the triune God as creator and sustainer of the universe, and my faith in Jesus as Saviour, Lord of all and God.
I acknowledge the Bible as the Word of God and its final authority in matters of faith and conduct.
As a steward of God's world, I accept my responsibility to encourage the use of science and technology for the good of humanity and the environment.
I agree with the aims of Christians in Science.
== Aims of Christians in Science ==
Its aims are:
=== Science and faith ===
To develop and promote biblical Christian views on the nature, scope and limitations of science, and on the changing interactions between science and faith.
To bring biblical Christian thought on scientific issues into the public arena.
=== Faith and the environment ===
To stimulate responsible Christian attitudes and action towards care for the environment.
=== Students ===
To help Christians who are science students to integrate their religious beliefs and their scientific studies.
== See also ==
Christian Evidence Society
Victoria Institute
List of Christian thinkers in science
Relationship between religion and science
== References ==
== External links ==
Official website | Wikipedia/Christians_in_Science |
In cosmology, the steady-state model or steady-state theory was an alternative to the Big Bang theory. In the steady-state model, the density of matter in the expanding universe remains unchanged due to a continuous creation of matter, thus adhering to the perfect cosmological principle, a principle that says that the observable universe is always the same at any time and any place. A static universe, where space is not expanding, also obeys the perfect cosmological principle, but it cannot explain astronomical observations consistent with expansion of space.
From the 1940s to the 1960s, the astrophysical community was divided between supporters of the Big Bang theory and supporters of the steady-state theory. The steady-state model is now rejected by most cosmologists, astrophysicists, and astronomers.
The observational evidence points to a hot Big Bang cosmology with a finite age of the universe, which the steady-state model does not predict.
== History ==
Cosmological expansion was originally seen through observations by Edwin Hubble. Theoretical calculations also showed that the static universe, as modeled by Albert Einstein (1917), was unstable. The modern Big Bang theory, first advanced by Father Georges Lemaître, is one in which the universe has a finite age and has evolved over time through cooling, expansion, and the formation of structures through gravitational collapse.
On the other hand, the steady-state model says while the universe is expanding, it nevertheless does not change its appearance over time (the perfect cosmological principle). E.g., the universe has no beginning and no end. This required that matter be continually created in order to keep the universe's density from decreasing. Influential papers on the topic of a steady-state cosmology were published by Hermann Bondi, Thomas Gold, and Fred Hoyle in 1948. Similar models had been proposed earlier by William Duncan MacMillan, among others.
It is now known that Albert Einstein considered a steady-state model of the expanding universe, as indicated in a 1931 manuscript, many years before Hoyle, Bondi and Gold. However, Einstein abandoned the idea.
== Observational tests ==
=== Counts of radio sources ===
Problems with the steady-state model began to emerge in the 1950s and 60s – observations supported the idea that the universe was in fact changing. Bright radio sources (quasars and radio galaxies) were found only at large distances (therefore could have existed only in the distant past due to the effects of the speed of light on astronomy), not in closer galaxies. Whereas the Big Bang theory predicted as much, the steady-state model predicted that such objects would be found throughout the universe, including close to our own galaxy. By 1961, statistical tests based on radio-source surveys provided strong evidence against the steady-state model. Some proponents like Halton Arp insist that the radio data were suspect.: 384
=== X-ray background ===
Gold and Hoyle (1959)
considered that matter that is newly created exists in a region that is denser than the average density of the universe. This matter then may radiate and cool faster than the surrounding regions, resulting in a pressure gradient. This gradient would push matter into an over-dense region and result in a thermal instability and emit a large amount of plasma. However, Gould and Burbidge (1963)
realized that the thermal bremsstrahlung radiation emitted by such a plasma would exceed the amount of observed X-rays. Therefore, in the steady-state cosmological model, thermal instability does not appear to be important in the formation of galaxy-sized masses.
=== Cosmic microwave background ===
In 1964 the cosmic microwave background radiation was discovered as predicted by the Big Bang theory. The steady-state model attempted to explain the microwave background radiation as the result of light from ancient stars that has been scattered by galactic dust. However, the cosmic microwave background level is very even in all directions, making it difficult to explain how it could be generated by numerous point sources, and the microwave background radiation does not show the polarization characteristic of scattering. Furthermore, its spectrum is so close to that of an ideal black body that it could hardly be formed by the superposition of contributions from a multitude of dust clumps at different temperatures as well as at different redshifts. Steven Weinberg wrote in 1972:
"The steady state model does not appear to agree with the observed dL versus z relation or with source counts ... In a sense, this disagreement is a credit to the model; alone among all cosmologies, the steady state model makes such definite predictions that it can be disproved even with the limited observational evidence at our disposal. The steady state model is so attractive that many of its adherents still retain hope that the evidence against it will eventually disappear as observations improve. However, if the cosmic microwave radiation ... is really black-body radiation, it will be difficult to doubt that the universe has evolved from a hotter denser early stage."
Since this discovery, the Big Bang theory has been considered to provide the best explanation of the origin of the universe. In most astrophysical publications, the Big Bang is implicitly accepted and is used as the basis of more complete theories.: 388
== Quasi-steady state ==
Quasi-steady-state cosmology (QSS) was proposed in 1993 by Fred Hoyle, Geoffrey Burbidge, and Jayant V. Narlikar as a new incarnation of the steady-state ideas meant to explain additional features unaccounted for in the initial proposal. The model suggests pockets of creation occurring over time within the universe, sometimes referred to as minibangs, mini-creation events, or little bangs. After the observation of an accelerating universe, further modifications of the model were made. The Planck particle is a hypothetical black hole whose Schwarzschild radius is approximately the same as its Compton wavelength; the evaporation of such a particle has been evoked as the source of light elements in an expanding steady-state universe.
Astrophysicist and cosmologist Ned Wright has pointed out flaws in the model. These first comments were soon rebutted by the proponents. Wright and other mainstream cosmologists reviewing QSS have pointed out new flaws and discrepancies with observations left unexplained by proponents.
== See also ==
Jainism and non-creationism
Non-standard cosmology
Copernican principle
Large-scale structure of the cosmos
Expansion of the universe
== References ==
== Further reading ==
Burbidge, G., Hoyle, F., "The Origin of Helium and the Other Light Elements", The Astrophysical Journal, 509: L1–L3, 10 December 1998
Hoyle, F.; Burbidge, G.; Narlikar, J. V. (2000). A Different Approach to Cosmology. Cambridge University Press. ISBN 978-0-521-66223-9.
Mitton, S. (2005). Conflict in the Cosmos: Fred Hoyle's Life in Science. Joseph Henry Press. ISBN 978-0-309-09313-2.
Mitton, S. (2005). Fred Hoyle: A Life in Science. Aurum Press. ISBN 978-1-85410-961-3.
Narlikar, Jayant; Burbidge, Geoffrey (2008). Facts and Speculations in Cosmology. Cambridge University Press. ISBN 978-0-521-86504-3. | Wikipedia/Steady_State_theory |
The relationship between science and the Catholic Church has been both collaborative and contentious throughout history. Historically, the Catholic Church has served as a major patron of the sciences, playing an influential role in the establishment and funding of educational institutions, universities, and hospitals. Many members of the clergy have actively contributed to scientific research. Some historians of science, such as Pierre Duhem, attribute the origins of modern science to medieval Catholic scholars like John Buridan, Nicole Oresme, and Roger Bacon. However, the relationship has not been without conflict. Critics, including proponents of the conflict thesis, point to historical and contemporary tensions between the Church and science, such as the trial of Galileo, as examples of where the Church has opposed scientific findings that challenged its teachings. The Catholic Church, for its part, maintains that science and faith are complementary, as expressed in the Catechism of the Catholic Church, which addresses this relationship.
Catholic scientists, both religious and lay, have led scientific discovery in many fields. From ancient times, Christian emphasis on practical charity gave rise to the development of systematic nursing and hospitals and the Church remains the single largest private provider of medical care and research facilities in the world. Following the Fall of Rome, monasteries and convents remained bastions of scholarship in Western Europe and clergymen were the leading scholars of the age – studying nature, mathematics, and the motion of the stars (largely for religious purposes). During the Middle Ages, the Church founded Europe's first universities, producing scholars like Robert Grosseteste, Albert the Great, Roger Bacon, and Thomas Aquinas, who helped establish the scientific method. Today almost all historians agree that Christianity (Catholicism as well Protestantism) moved many early-modern intellectuals to study nature systematically. Historians have also found that notions borrowed from Christian belief found their ways into scientific discourse, with glorious results.
During this period, the Church was also a major patron of engineering for the construction of elaborate cathedrals. Since the Renaissance, Catholic scientists have been credited as fathers of a diverse range of scientific fields: Nicolaus Copernicus (1473-1543) pioneered heliocentrism, René Descartes (1596-1650) father of analytical geometry and co-founder of modern philosophy, Jean-Baptiste Lamarck (1744-1829) prefigured the theory of evolution with Lamarckism, Friar Gregor Mendel (1822-1884) pioneered genetics, and Fr Georges Lemaître (1894-1966) proposed the Big Bang cosmological model. The Society of Jesus has been particularly active, notably in astronomy; the Papacy and the Jesuits initially promoted the observations and studies of Galileo Galilei, until the latter was put on trial and forced to recant by the Roman inquisition. Church patronage of sciences continues through institutions like the Pontifical Academy of Sciences (a successor to the Accademia dei Lincei of 1603) and Vatican Observatory (a successor to the Gregorian Observatory of 1580).
== The theory of conflict between science and the Church ==
This view of the Church as a patron of sciences is contested by some, who speak either of a historically varied relationship which has shifted, from active and even singular support to bitter clashes (with accusations of heresy) – or of an enduring intellectual conflict between religion and science. Enlightenment philosophers such as Voltaire were famously dismissive of the achievements of the Middle Ages. In the 19th century, the "conflict thesis" emerged to propose an intrinsic conflict or conflicts between the Church and science. The original historical usage of the term asserted that the Church has been in perpetual opposition to science. Later uses of the term denote the Church's epistemological opposition to science. The thesis interprets the relationship between the Church and science as inevitably leading to public hostility when religion aggressively challenges new scientific ideas as in the Galileo Affair. An alternative criticism is that the Church opposed particular scientific discoveries that it felt challenged its authority and power – particularly through the Reformation and on through the Enlightenment. This thesis shifts the emphasis away from the perception of the fundamental incompatibility of religion per se and science-in-general to a critique of the structural reasons for the resistance of the Church as a political organization.
The Church itself rejects the notion of innate conflict. The Vatican Council (1869/70) declared that "Faith and reason are of mutual help to each other." The Catholic Encyclopedia of 1912 proffers that "The conflicts between science and the Church are not real", and states that belief in such conflicts are predicated on false assumptions. Pope John Paul II expressed the Catholic Church's position on faith and reason in the encyclical Fides et Ratio, describing them as "two wings on which the human spirit rises to the contemplation of truth". Papal astronomer Brother Guy Consolmagno describes science as an "act of worship" and as "a way of getting intimate with the Creator."
== Some leading Catholic scientists ==
Scientific fields with important foundational contributions from Catholic scientists include: physics (Galileo) despite his trial and conviction in 1633 for publishing a treatise on his observation that the earth revolves around the sun, which banned his writings and made him spend the remainder of his life under house arrest, acoustics (Mersenne), mineralogy (Agricola), modern chemistry (Lavoisier), modern anatomy (Vesalius), stratigraphy (Steno), bacteriology (Kircher and Pasteur), genetics (Mendel), analytical geometry (Descartes), heliocentric cosmology (Copernicus), atomic theory (Boscovich), and the Big Bang Theory on the origins of the universe (Lemaître). Jesuits devised modern lunar nomenclature and stellar classification and some 35 craters of the moon are named after Jesuits, among whose great scientific polymaths were Francesco Grimaldi and Giambattista Riccioli. The Jesuits also introduced Western science to India and China and translated local texts to be sent to Europe for study. Missionaries contributed significantly to the fields of anthropology, zoology, and botany during Europe's Age of Discovery.
== Definitions of science ==
Differing analyses of the Catholic relationship to science may arise from definitional variance. While secular philosophers consider "science" in the restricted sense of natural science, in the past theologians tended to view science in a very broad sense as given by Aristotle's definition that science is the sure and evident knowledge obtained from demonstrations. In this sense, science comprises the entire curriculum of university studies, and the Church has claimed authority in matters of doctrine and teaching of science. With the gradual secularisation of the West, the influence of the Church over scientific research has faded.
== History ==
=== Early Middle Ages ===
After the Fall of Rome, while an increasingly Hellenized Roman Empire and Christian religion endured as the Byzantine Empire in the East, the study of nature endured in monastic communities in the West. On the fringes of western Europe, where the Roman tradition had not made a strong imprint, monks engaged in the study of Latin as a foreign language, and actively investigated the traditions of Roman learning. Ireland's most learned monks even retained knowledge of Greek. Irish missionaries like Colombanus later founded monasteries in continental Europe, which went on to create libraries and become centers of scholarship.
The leading scholars of the Early Middle Ages were clergymen, for whom the study of nature was but a small part of their scholarly interest. They lived in an atmosphere which provided opportunity and motives for the study of aspects of nature. Some of this study was carried out for explicitly religious reasons. The need for monks to determine the proper time to pray led them to study the motion of the stars; the need to compute the date of Easter led them to study and teach rudimentary mathematics and the motions of the Sun and Moon. Modern readers may find it disconcerting that sometimes the same works discuss both the technical details of natural phenomena and their symbolic significance. In astronomical observation, Bede of Jarrow described two comets over England, and wrote that the "fiery torches" of AD 729 struck terror in all who saw them – for comets were heralds of bad news.
Among these clerical scholars was Bishop Isidore of Seville who wrote a comprehensive encyclopedia of natural knowledge, the monk Bede of Jarrow who wrote treatises on The Reckoning of Time and The Nature of Things, Alcuin of York, abbot of the Abbey of Marmoutier, who advised Charlemagne on scientific matters, and Rabanus Maurus, Archbishop of Mainz and one of the most prominent teachers of the Carolingian Age, who, Like Bede, wrote treatises on computus and On the Nature of Things. Abbot Ælfric of Eynsham, who is known mostly for his Old English homilies, wrote a book on the astronomical time reckoning in Old English based on the writings of Bede. Abbo of Fleury wrote astronomical discussions of timekeeping and of the celestial spheres for his students, teaching for a while in England where he influenced the work of Byrhtferth of Ramsey, who wrote a Manual in Old English to discuss timekeeping and the natural and mystical significance of numbers.
=== Later Middle Ages ===
==== Foundation of universities ====
In the early Middle Ages, Cathedral schools developed as centers of education, evolving into the medieval universities which were the springboard of many of Western Europe's later achievements. During the High Middle Ages, Chartres Cathedral operated the famous and influential Chartres Cathedral School. Among the great early Catholic universities were Bologna University (1088); Paris University (c 1150); Oxford University (1167); Salerno University (1173); University of Vicenza (1204); Cambridge University (1209); Salamanca University (1218-1219); Padua University (1222); Naples University (1224); and Vercelli University (1228).
Using church Latin as a lingua franca, the medieval universities across Western Europe produced a great variety of scholars and natural philosophers, including Robert Grosseteste of the University of Oxford, an early expositor of a systematic method of scientific experimentation, and Saint Albert the Great, a pioneer of biological field research. By the mid-15th century, prior to the Reformation, Catholic Europe had some 50 universities.
==== Condemnations of 1210–1277 ====
The Condemnations of 1210–1277 were enacted at the medieval University of Paris to restrict certain teachings as being heretical. These included a number of medieval theological teachings, but most importantly the physical treatises of Aristotle. The investigations of these teachings were conducted by the Bishops of Paris. The Condemnations of 1277 are traditionally linked to an investigation requested by Pope John XXI, although whether he actually supported drawing up a list of condemnations is unclear.
Approximately sixteen lists of censured theses were issued by the University of Paris during the 13th and 14th centuries. Most of these lists of propositions were put together into systematic collections of prohibited articles.
==== Mathematics, engineering and architecture ====
According to art historian Kenneth Clark, "to medieval man, geometry was a divine activity. God was the great geometer, and this concept inspired the architect." Monumental cathedrals such as that of Chartres appear to evidence a complex understanding of mathematics. The Church has invested greatly in engineering and architecture and founded a number of architectural genres – including Byzantine, Romanesque, Gothic, High Renaissance, and Baroque.
=== Roman Inquisition ===
In the Middle Ages of the Roman Church, Pope Paul III (1468-1549) initiated the Congregation of the Roman Inquisition in 1542, which is also known as the Holy Office. A large expansion of Protestantism began to spread all throughout Italy, which triggered Pope Paul III to act against it. He would be the first to create proactive reforms for the sake of Roman Catholicism. Evidently the reforms would be strict rulings against foreign ideologies that would fall outside of their religious beliefs. The Inquisition would soon be under the control of Pope Sixtus V in 1588.
==== View of outsiders ====
The Roman society was not very fond of outside beliefs. They would keep their borders up to religious foreigners as they felt other practices would influence and change their sacred Catholicism religion. They were also against witchcraft as such practices were seen in 1484 where Pope Innocent stated it was an act of going against the church. Any ideologies that was outside of their norm beliefs was seen as a threat and needed to be corrected even if it was through torture.
==== Inquisition tactics and practices ====
Pope Sixtus V put forth 15 congregations. The inquisition would imprison anyone who was seen as a threat towards the Catholic Church or placed onto house arrest. They kept a tight security and denied any other religious foreigners from coming inside their regions. Papal policies were implemented to stop foreigners from showing their practices to the public. The Index of Forbidden Books was used to prevent people from doing magic and to suppress books deemed heretical, politically disruptive, or threatening to public morals. To stray away from this would allow for one to not be "infected". Punishment was acceptable and torture tactics were used in order for one to confess their sins.
==== The fall of the inquisition ====
In the 18th century, witchcraft and other groups became less of a threat to the Catholic Church. The focus moved to conversos as the population grew. Conversos mainly impacted the Spanish Inquisition. Furthermore, by the 19th century, the Roman Inquisition was very minimal, however, some ideologies were still seen in 1965.
== Scientific Revolution and the Church ==
The Scientific Revolution began in 1543 with Nicholas Copernicus and his heliocentric theory and is defined as the beginning of a dramatic shift in thought and belief towards scientific theory. The Scientific Revolution began in Western Europe, where the Catholic Church had the strongest holding. It is believed that the Scientific Revolution began in Western Europe because of the freedom to pursue other ideas provided by most European Universities and which go against Church authorities. Western Europe was also a central 'melting pot' for foreign knowledge and cultural beliefs including ancient Chinese math, Islamic philosophy, and Arabic astrology. Posed by author Peter Dear, the revolution can be thought of in two parts: the Scientific Renaissance and the revolution. The renaissance is considered the actual rebirth of the ideas, where mathematics, philosophy, astronomy, and physics were all being rediscovered in a sense. Following this rediscovery, people began to question the ideas of the church (which could be considered antique). Dear also references the fact that when historians study the relationship between scientists and the Church, they are not taking the standpoint that either view is true, instead they look at it the reasons they believed their side and then "Find out; truth or falsity are determined by arguments and it is the arguments that can be studied historically."
The Scientific Revolution and its challenging of the Church's ideas were followed by the Period of Enlightenment where people not only question the Church's ideas but also began to question their authority. The central theme of this period is that human society "could be changed and improved by human action guided by reason" as stated by Marquis de Condorcet. These periods of changing thought eventually led to the prominent holdings of liberty, progress, tolerance, and scientific theories within the Church.
=== Development of modern science ===
==== Geology ====
Georgius Agricola (1494-1555), is considered the founder of geology and "Father of Mineralogy". He made important contributions which paved the way for systematic study of the Earth. A German Catholic who retained his faith through the Reformation, he also wrote on patristics (early church history). In 1546, he wrote De Ortu et Causis Subterraneorum which was the first book written on physical geology, and De Natura Fossilium (On the Nature of Fossils) which described fossils and minerals.
Nicolas Steno (1638-1686) is a Catholic convert who served as a bishop after making a series of important anatomical and geological innovations. His studies of the formation of rock layers and fossils was of vital significance to the development of modern geology and continue to be used today. He established the theoretical basis for stratigraphy. Originally a Lutheran, he did anatomical work in the Netherlands but moved to Catholic Italy and, in 1667, converted. Denied office in the Protestant north, he continued his medical and geological studies, but in 1675 became a priest and soon after was appointed a bishop, writing 16 major theological works.
==== Astronomy ====
The Catholic Church's interest and investment in astronomy before and during the scientific revolution played a significant role in developing related fields. While the Church supported many astronomical studies, this support was at times complicated by doctrinal conflicts, such as those involving the heliocentric theory proposed by Copernicus and supported by Galileo. Historian John L. Heilbron states, "the Roman Catholic Church gave more financial and social support to the study of astronomy for over six centuries, from the recovery of ancient learning during the late Middle Ages into the Enlightenment, than any other, and probably all, other Institutions."
The Church's interest in astronomy stemmed from issues surrounding the determination of the date for Easter, which was originally tied to the Hebrew lunisolar calendar. In the 4th century, due to perceived problems with the Hebrew calendar's leap month system, the Council of Nicaea prescribed that Easter would fall on the first Sunday following the first full moon after the vernal equinox. Thus, it became necessary that the Church have the capacity to predict the date of Easter with enough accuracy and forewarning to allow both for sufficient time to prepare for the feast as well as ensure the universal celebration of the holy day across all of the Church's dominion – a daunting logistical feat. This necessity fueled constant innovation and refinement of astronomical practice as the solar and lunar years diverge over centuries.
Between 1650 and 1750, four observatories run by the Catholic Church were among the best solar observatories in the world. Built largely to fix an unquestionable date for Easter, they also housed instruments that threw light on the disputed geometry of the Solar System.
The Church's dedication to ever-increasingly accurate astronomy led to developments in ancillary disciplines. In the 12th century, the church helped re-popularize and disseminate ancient Greek ideas and mathematical techniques across Europe by sponsoring the translation of newly available Arabic-language version of Greek texts into Latin. This was done in large part to aid in astronomical study. In the late 16th century, the Church encouraged the inclusion of pinhole cameras into the construction of churches. Pinhole cameras are among the best tools for measuring the time between solstices. The transformation of churches into solar observatories encouraged innovations in engineering, architecture, and construction, and fueled the careers of astronomers like Cassini.
By the 16th century, the date of the vernal equinox on the Julian calendar had receded from March 25 to March 11. The Council of Trent in 1562 authorized the pope to deal with calendar reform. The resulting Gregorian calendar is the internationally accepted civil calendar used throughout the world today. It was introduced by Pope Gregory XIII, after whom the calendar was named, by a decree signed on 24 February 1582.
When the Church sent Jesuit missionaries to spread the gospel in China in the 16th and 17th centuries, they were accepted into and valued by the Chinese Imperial court because of their astronomical and mathematical expertise. This channel of communication for dialog between China and Europe allowed not only for the propagation of European sciences into China but also the flow of Chinese technologies and ideas back to Europe. The introduction of Chinese ideas into European popular consciousness through this Jesuit channel is credited by modern historians with adding fuel to the scientific revolution and enlightenment. In many cases, Jesuits were specifically dispatched to China with a list of topics on which to collect information.
In 1789, the Vatican Observatory opened. It was moved to Castel Gandolfo in the 1930s and the Vatican Advanced Technology Telescope began observing in Arizona, USA, in 1995.
===== Copernicus =====
Nicolaus Copernicus was a Renaissance astronomer and Catholic canon who was the first person to formulate a comprehensive heliocentric cosmology which displaced the Earth from the center of the universe.
In 1533, Johann Albrecht Widmannstetter delivered a series of lectures in Rome outlining Copernicus' theory. Pope Clement VII and several Catholic cardinals heard the lectures and were interested in the theory. On 1 November 1536, Nikolaus von Schönberg, Archbishop of Capua and since the previous year a cardinal, wrote to Copernicus from Rome:
Some years ago word reached me concerning your proficiency, of which everybody constantly spoke. At that time I began to have a very high regard for you. ...For I had learned that you had not merely mastered the discoveries of the ancient astronomers uncommonly well but had also formulated a new cosmology. In it you maintain that the earth moves; that the sun occupies the lowest, and thus the central, place in the universe. ...Therefore with the utmost earnestness I entreat you, most learned sir, unless I inconvenience you, to communicate this discovery of yours to scholars, and at the earliest possible moment to send me your writings on the sphere of the universe together with the tables and whatever else you have that is relevant to this subject.
By then Copernicus' work was nearing its definitive form, and rumors about his theory had reached educated people all over Europe. Despite urgings from many quarters, Copernicus delayed publication of his book, perhaps from fear of criticism – a fear delicately expressed in the subsequent dedication of his masterpiece to Pope Paul III. Scholars disagree on whether Copernicus' concern was limited to possible astronomical and philosophical objections, or whether he was also concerned about religious objections.
At original publication, Copernicus' epoch-making book caused only mild controversy, and provoked no fierce sermons about contradicting Holy Scripture. It was only three years later, in 1546, that a Dominican, Giovanni Maria Tolosani, denounced the theory in an appendix to a work defending the absolute truth of Scripture. He also noted that the Master of the Sacred Palace (i.e., the Catholic Church's chief censor), Bartolomeo Spina, a friend and fellow Dominican, had planned to condemn De revolutionibus but had been prevented from doing so by his illness and death.
===== Galileo Galilei =====
Galileo Galilei was a Catholic scientist of the Reformation period whose support for Copernican heliocentrism was suppressed by the Inquisition. He is considered one of the inventors of modern science. Along with fellow Catholic scientist Copernicus, Galileo was among those who overturned the notion of geocentrism. Protestant and atheist critics of Catholicism's relationship to science have placed great emphasis on the Galileo affair. Galileo was ordered not to support Copernican theory in 1616, but in 1632, after receiving permission from a new Pope (Urban VIII) to address the subject indirectly through a dialogue, he fell foul of the Pontiff by treating the Church's views unfavorably, assigning them to a character named Simplicio— suspiciously similar to the Italian word for "simple".
Federico Cesi created the Accademia dei Lincei in 1603 as an Italian science academy, of which Galileo became a member. Galileo's championing of Copernicanism was controversial within his lifetime, when a large majority of philosophers and astronomers still subscribed to the geocentric view. Galileo gained wide support for his theories outside the universities by writing in Italian, rather than academic Latin. In response, the Aristotelian professors of the universities formed a united effort to convince the Church to ban Copernicanism.
Initially a beneficiary of Church patronage of astronomy, Galileo rose to prominence with the publication of Sidereus Nuncius, which included astronomical observations made possible by the 1608 invention of the telescope. He was feted in Rome, honoured by the Jesuits of the Roman College, and received by Pope Paul V and Church dignitaries. Galileo began to dismiss geocentrism and emerging alternative theories like that of Tycho Brahe. Galileo argued that the Bible needs to be re-evaluated to accommodate his teaching, quoting Cardinal Baronius: "The Holy Ghost intended to teach us how to go to heaven, not how the heavens go." He invited the Church to follow established practice and reinterpret Scripture in light of the new scientific discoveries. The leading Jesuit Theologian Cardinal Robert Bellarmine agreed this would be an appropriate response to a true demonstration that the Sun was at the center of the universe, but cautioned that the existing materials upon which Galileo relied did not yet constitute an established truth. Galileo also wrote a letter to an influential cardinal Carlo Conti, asking him if the Bible favoured Aristotelian physics. Conti wrote that while Aristotle's doctrine of heavenly unchangeability contradicts the Bible, "it will take some time to determine whether the new discoveries establish heavenly changeability". Regarding the motion of Earth, while Pythagorean and Copernican theories were not conforming to the scripture, Conti did argue that Job 9:6 could be referring to the motion of Earth as proposed by Diego de Zúñiga, but advised Galileo not to adopt such view "without great necessity".
Galileo's career coincided with the reaction of the Catholic Church to the Protestant Reformation, in which the Catholic Church struggled for authority in Europe, following the emergence of the Protestant Churches and nations of Northern Europe. Pope Paul III created the Roman and Universal Inquisition to stop the spread of "heretical depravity" throughout the Christian world. From 1571, the institution had jurisdiction over books and created the Index of Prohibited Books. Rome established the Sacred Congregation for the Propagation of the Faith in 1622. Science historian Jacob Bronowski wrote that "Catholics and Protestants were embattled in what we should now call a Cold War. ...The Church was a great temporal power, and in that bitter time it was fighting a political crusade in which all means were justified by the end." In this climate, Cardinal Bellarmine, himself a distinguished scholar, instigated inquiries against Galileo as early as 1613. Bellarmine's inquiries concerned Galileo's possible link with Cesare Cremonini, a philosopher often denounced as an atheist for his belief in mortality of the soul. When no connection was established between the two, charges were quietly dropped; Cremonini was never persecuted by the inquisition despite refusing to renounce his controversial views. William René Shea believes that "a check on anyone spreading novel ideas was in any case a routine matter in Rome during the Counter Reformation, and Galileo probably never heard that his name had cropped up at a meeting of the cardinal inquisitors."
By the time he returned to Rome in 1614 and 1615, Galileo published Discourse on Floating Bodies and Letters on the Sunspots, identifying sunspots as a type of clouds near the surface of the Sun. While this was in the opposition to the Aristotelian cosmology and vindicated Copernican theory, it was well-received. However, Galileo frequently cited the Bible and utilised theological reasoning in his writings, which worried papal censors that "it might give the impression that astronomers wanted to conquer a domain that belonged to theologians." As such, Galileo was to remove the Biblical passages and change religious wording, such as changing "divine goodness" to "favorable winds". Galileo's Copernican views were therefore accepted by the Catholic Church as long as he presented it as a scientific conjecture rather than a reinterpretation of the Bible. During this time, Galileo wrote essays and letters on philosophical and theological matters regarding his and Copernicus' theory. His Letter to the Grand Duchess Christina dealt with theological matters and the need to analyse the scripture differently, while Galileo's Considerations on the Copernican Opinions focused on epistemological issues. Galileo was staunchly supported by a Carmelite friar Paolo Antonio Foscarini, who published a book defending Galileo's heliocentrism and presenting it as compatible with the Bible.
However, as Galileo heavily engaged in philosophical and theological discussions, he was met with bitter opposition from some philosophers and clerics, and two of the latter eventually denounced him to the Roman Inquisition early in 1615, warning "that Galileo should not go outside mathematics and physics and should avoid provoking theologians by teaching them how to read the Bible". One of the philosophers who issued a complaint to the inquisition was Tommaso Caccini, who disregarded Galileo as a "mathematician" and strongly attacked him in his sermons, ordering him to withdraw from philosophy and citing Acts 1:10: "Ye men of Galilee, why stand ye gazing up into heaven?". Galileo defended his theories through the long-established Catholic understanding of Scripture, that the Bible was not intended to expound scientific theory and where it conflicted with common sense, should be read as allegory. Although he was cleared of any offense at that time, the report of inquisition consultants declared heliocentrism as "false and contrary to Scripture" in February 1616. However, Maurice Finocchiaro highlights that Copernicanism was never declared a formal heresy, as the Congregation of the Holy Office did not endorse the report and refused to follow through with an official declaration. Finocchiaro also observes that the wording of the inquisition's decree was "vague and unclear, which is a sign of having been some kind of compromise".
On 26 February, Cardinal Bellarmine visited Galileo and informed him of the inquisition's decision, explaining that although Copernicanism could be a viable theory, it was not proven true. As such, the church could not abandon the common interpretation of scripture for a hypothesis. Bellarmine argued that should a decisive proof of Earth's motion be found, the church would "admit that we do not understand them rather than say that something that has been proved is false." He then demanded Galileo to stop teaching and defending Copernican theory, to which Galileo agreed. Bellarmine met with the Pope on 3 March, and informed him of Galileo's compliance.
Despite the fact that the Congregation of the Holy Office did not declare Copernicanism a heresy, the Church's Congregation of the Index issued a decree in March 1616 suspending De revolutionibus until it could be "corrected", because the supposedly Pythagorean doctrine that the Earth moves and the Sun does not was "false and altogether opposed to Holy Scripture." The corrections to De revolutionibus, which omitted or altered nine sentences, were issued four years later, in 1620. The revision deleted or modified nine passages that contained religious references. Congregation of the Index did not mention Galileo at all, nor did it take action against his works.
In 1623, Galileo's friend Maffeo Barberini was elected as Pope Urban VIII. Urban VIII was an intellectual and patron of the arts and architecture, who had written poetry as a young man in praise of Galileo's astronomical writings. Galileo met with the new Pope, hoping to persuade him to lift the 1616 ban. Urban VIII had been an ally of Galileo ever since he became a cardinal, and provided funding for Galileo's work; Pope's correspondence also reveals that he was privately sympathetic to Copernicism, but did not wish to publicly admit so. Galileo was granted numerous audiences with the new Pope, with the conclusion that there "was no absolute condemnation of the Copernican theory; it did not enter the field of heretical opinions, but only those that were deemed bold". Galileo was permitted to publish a book on Copernican hypothesis, with the condition that it would be an objective analysis of the arguments for and against various cosmologies. The book, Dialogue Concerning the Two Chief World Systems, had pope's endorsement on its title page and was well-received across Europe, but explicitly endorsed the Copernican model, breaking the agreement. At the time, Copernicus' theory lacked necessary evidence to be universally accepted from either a scientific and theological viewpoint. Given the Pope's endorsement of the book, Galileo's explicit support for the theory compromised the position of Urban VIII, as it made it seem that the church publicly supported Copernicism. The book also offended the Pope as his own arguments were put into the mouth of the buffoon-like Simplicio in the dialogue. The Preparatory Commission for the trial of Galileo noted that the Pope's stated belief that it would be extravagant boldness to limit the power and wisdom of God to an individual's particular conjecture was put "into the mouth of a fool" in Galileo's text.
Galileo was summoned to Rome to be tried by the Inquisition in 1633. Galileo was accused of violating a precept issued by the inquisition in 1616 that forbade him from teaching or defending his theory; however, the memorandum presented by the inquisition is considered fraudulent as it lacked Galileo signature. Galileo was also accused of breaking his agreement with the Pope, as instead of following through the compromise of Urban VIII to present his theory as a hypothesis and an "instrument of prediction and calculation", Galileo presented his beliefs as "factual and unconditional". Moreover, Galileo's book received backlash for its "rhetorical excesses and biting sarcasm", including attacking several clerical figures. Galileo was found "vehemently suspect of heresy" for "following the position of Copernicus, which is contrary to the true sense and authority of Holy Scripture." Galileo was forced to recant, and was sentenced to house arrest, with the sentence being commuted in December 1633. Austrian philosopher Paul Feyerabend argues that the trial was a philosophical matter, as Galileo "advocated the uncritical acceptance by society of the views of experts, whereas the Church advocated the evaluation by society of the views of experts in the light of human and social values". The Catholic Church followed this principle, as shown by Cardinal Bellarmine's letter to Paolo Antonio Foscarini. Feyerabend concluded that "the Church would do well to revive the balance and graceful wisdom of Bellarmine, just as scientists constantly gain strength from the opinions of Galileo." Finocchiaro notes that the trial was focused on philosophy, and Galileo claimed to "have spent more years studying philosophy than months studying pure mathematics". Galileo was supported by several Catholic figures such as Monsignor Piero Dini, Carmelite Paolo Antonio Foscarini, and a Dominican Tommaso Campanella; his trial in 1633 made him gain sympathy from more clergy like Ascanio II Piccolomini and Fulgenzio Micanzio. Therefore, Finocchario believes that Galileo's trial was not a condemnation of heliocentrism, as Galileo's Two New Sciences that was published after the trial was allowed by the inquisition despite endorsing the Copernican theory, but rather a condemnation of Galileo's attempt to reinterpret the Bible, which was seen as especially dangerous amid Counter-Reformation. Galileo remained a practicing Catholic and continued to lead a luxurious life under house arrest; Gerard Marc Anthony Saint-Amant, who visited Galileo in Siena, remarked that he was "lodged in rooms elegantly decorated with damask and silk tapestries". There Galileo wrote his most influential work Two New Sciences – a book that was first published in Leiden by the House of Elzevir, and then was published in other countries such as France, Germany and Poland. Despite discussing the motion of Earth and endorsing Copernican theory, Galileo did not suffer any harm from the Inquisition for publishing this book, even though it reached Rome's bookstores in January 1639, and all available copies were quickly sold.
According to Maurice Finocchiaro, although Urban VIII himself sympathised with Galileo and wanted him to merely revision "Dialogue", Galileo's attacks on influential clerical figures and massive backlash forced him to act. The position of the Pope was also greatly endangered by the ongoing Thirty Years' War, which pressured him to reaffirm his authority. Finocchiaro states that many contemporary physicists objected to Galileo's theory as it lacked proof, which also affected the church's decision; Copernicus' argument was a hypothetical one regarding what phenomena would occur if Earth was in motion. Copernicus emphasised that he could not prove the motion of Earth, whereas Galileo strongly insisted on it being true, despite having no way to prove so. Jesuits Christoph Scheiner and Orazio Grassi are an example of astronomers who objected to Galileo's argument on scientific basis, such as his conclusions on sunspots and comets. William René Shea argues that Galileo attracted the interest of the inquisition by getting involved in theological matters - prior to 1616, several contradicting astronomical theories were permitted as they were treated as "tools for calculation". Galileo's stance was accepted as a conjecture that had yet to be proven, yet Galileo insisted that his theory was of "undoubted certainty" and demanded the scripture to be re-evaluated. Shea concludes that "had Galileo been able to demonstrate the truth of Copernicanism, all would have been well, but he did not have and was never to have such proof."
The Catholic Church's 1758 Index of Prohibited Books omitted the general prohibition of works defending heliocentrism, but retained the specific prohibitions of the original uncensored versions of De revolutionibus and Galileo's Dialogue Concerning the Two Chief World Systems. Those prohibitions were finally dropped from the 1835 Index.
The Inquisition's ban on reprinting Galileo's works was lifted in 1718 when permission was granted to publish an edition of his works (excluding the condemned Dialogue) in Florence. In 1741 Pope Benedict XIV authorized the publication of an edition of Galileo's complete scientific works which included a mildly censored version of the Dialogue. In 1758 the general prohibition against works advocating heliocentrism was removed from the Index of prohibited books, although the specific ban on uncensored versions of the Dialogue and Copernicus's De Revolutionibus remained. All traces of official opposition to heliocentrism by the Church disappeared in 1835 when these works were finally dropped from the Index.
Pope Urban VIII refused Galileo a stately burial upon his death, though later his bones were interred under a monument at the Church of Santa Croce in Florence. In 1980, Pope John Paul II ordered a re-examination of the evidence against Galileo and formally acquitted him in 1992.
===== Modern view on Galileo =====
In 1939 Pope Pius XII, in his first speech to the Pontifical Academy of Sciences, within a few months of his election to the papacy, described Galileo as being among the "most audacious heroes of research ... not afraid of the stumbling blocks and the risks on the way, nor fearful of the funereal monuments." His close advisor of 40 years Professor Robert Leiber wrote: "Pius XII was very careful not to close any doors (to science) prematurely. He was energetic on this point and regretted that in the case of Galileo."
On 15 February 1990, in a speech delivered at the Sapienza University of Rome, Cardinal Ratzinger (later Pope Benedict XVI) cited some current views on the Galileo affair as forming what he called "a symptomatic case that permits us to see how deep the self-doubt of the modern age, of science and technology, goes today." Some of the views he cited were those of the philosopher Paul Feyerabend, whom he quoted as saying: "The Church at the time of Galileo kept much more closely to reason than did Galileo himself, and she took into consideration the ethical and social consequences of Galileo's teaching too. Her verdict against Galileo was rational and just and the revision of this verdict can be justified only on the grounds of what is politically opportune." The Cardinal did not indicate whether he agreed or disagreed with Feyerabend's assertions. He did, however, say: "It would be foolish to construct an impulsive apologetic on the basis of such views."
On 31 October 1992, Pope John Paul II expressed regret for how the Galileo affair was handled, and issued a declaration acknowledging the errors committed by the Church tribunal that judged the scientific positions of Galileo Galilei; this was the result of a study conducted by the Pontifical Council for Culture. In March 2008 the Vatican proposed to complete its rehabilitation of Galileo by erecting a statue of him inside the Vatican walls. In December of the same year, during events to mark the 400th anniversary of Galileo's earliest telescopic observations, Pope Benedict XVI praised his contributions to astronomy.
===== Modern astronomers =====
Brother Guy Consolmagno, a Jesuit, became the first religious brother to be awarded the American Astronomical Society's Carl Sagan Medal for Excellence in Public Communication in Planetary Science in 2014. The judges noted his six books, and nominated his 'Turn Left At Orion' as having had an "enormous impact on the amateur astronomy community, engendering public support for astronomy." They described Consolmagno as "the voice of the juxtaposition of planetary science and astronomy with Christian belief, a rational spokesperson who can convey exceptionally well how religion and science can co-exist for believers." Consolmagno describes science as an "act of worship, ... a way of getting close to creation, to really getting intimate with creation, and it's a way of getting intimate with the creator."
==== Gessner ====
Conrad Gessner's zoological work, Historiae animalium, which appeared in four volumes and was published between 1551 and 1588. Under Pope Paul IV, it was added to the Roman Catholic Church's list of prohibited books as Gessner was a Protestant. He still maintained friendship with Catholics regardless of the religious animosities between Catholics and Protestants at that time. Gaining support for his work, Catholic booksellers in Venice protested the ban on Gessner's books but it was later on allowed for selling once it was revised and "freed" from doctrines contrary to the Catholic faith.
==== Evolution ====
In the years since the publication of Charles Darwin's On the Origin of Species in 1859, the position of the Catholic Church on the theory of evolution has slowly been refined. For about 100 years there was no authoritative pronouncement on the subject, though local church figures took on more prominent sides. In 1961, seven years after Francis Crick discovered the structure of DNA, Christian Henry Morris and John C. Witcomb published The Genesis Flood, which argued that there is scientific support for the bible creation story. In October 1996, Pope John Paul II outlined the Catholic view of evolution to the Pontifical Academy of Sciences, saying that the Church holds that evolution is "more than a hypothesis," it is a well-accepted theory of science and that the human body evolved according to natural processes, while the human soul is the creation of God. This updated an earlier pronouncement by Pope Pius XII in the 1950 encyclical Humani generis that accepted evolution as a possibility (as opposed to a probability) and a legitimate field of study to investigate the origins of the human body – though it was stressed that "the Catholic faith obliges us to hold that souls are immediately created by God." In contrast with Protestant literalist objections, Catholic issues with evolutionary theory have had little to do with maintaining the literalism of the account in the Book of Genesis, and have always been concerned with the question of how man came to have a soul.
Catholic scientists contributed to the development of evolutionary theory. Among the foremost Catholic contributors to the development of the modern understanding of evolution was the Jesuit-educated Frenchman Jean-Baptiste Lamarck (1744-1829) and the Augustinian friar Gregor Mendel (1822-1884). Lamarck developed Lamarckism, the first coherent theory of evolution, proposing in Philosophie Zoologique (1809) and other works his theory of the transmutation of species and drawing a genealogical tree to show the genetic connection of organisms. Mendel discovered the basis of genetics following long study of the inherited characteristics of pea plants, although his paper Experiments on Plant Hybridization, published in 1866, was famously overlooked until the start of the next century. The work of Catholic scientists like the Danish Bishop Nicolas Steno helped establish the science of geology, leading to modern scientific measurements of the age of the Earth. The Church accepts modern geological theories on such matters and the authenticity of the fossil record. Papal pronouncements, along with commentaries by cardinals, indicate the Church is aware of the general findings of scientists on the gradual appearance of life. The Church's stance is that the temporal appearance of life has been guided by God.
Modern Creationism has had little Catholic support. In the 1950s, the Church's position was one of neutrality; by the late 20th century its position evolved to one of general acceptance of evolution. Today, the Church's official position is a fairly non-specific example of theistic evolution. This states that faith and scientific findings regarding human evolution are not in conflict, though humans are regarded as a special creation, and that the existence of God is required to explain both monogenism and the spiritual component of human origins. No infallible declarations by the Pope or an Ecumenical Council have ever been made.
There have been several organizations composed of Catholic laity and clergy that have advocated positions both supporting and opposing evolution. For example:
The Kolbe Center for the Study of Creation operates out of Mt. Jackson, Virginia, and is a Catholic lay apostolate promoting creationism.
The Faith Movement was founded by Catholic Fr. Edward Holloway in Surrey, England. His book Catholicism: a new synthesis "argues from Evolution as a fact, that the whole process would be impossible without the existence of the Supreme Mind we call God."
Daylight Origins Society [3] was founded in 1971 by John G. Campbell (d.1983) as the "Counter Evolution Group". Its goal is "to inform Catholics and others of the scientific evidence supporting Special Creation as opposed to Evolution, and that the true discoveries of Science are in conformity with Catholic doctrines." It publishes the "Daylight" newsletter.
As in other countries, Catholic schools in the United States teach evolution as part of their science curriculum. They teach the fact that evolution occurs and the modern evolutionary synthesis, which is the scientific theory that explains how evolution occurs. This is the same evolution curriculum that secular schools teach. Bishop DiLorenzo of Richmond, chair of the Committee on Science and Human Values, said in a December 2004 letter sent to all U.S. bishops: "Catholic schools should continue teaching evolution as a scientific theory backed by convincing evidence. At the same time, Catholic parents whose children are in public schools should ensure that their children are also receiving appropriate catechesis at home and in the parish on God as Creator. Students should be able to leave their biology classes, and their courses in religious instruction, with an integrated understanding of the means God chose to make us who we are."
==== Genetics ====
Gregor Mendel was an Austrian scientist and Augustinian friar who began experimenting with peas around 1856. Observing the processes of pollination at his monastery in what is now the Czech Republic, Mendel studied and developed theories about the field of science now called genetics. Mendel published his results in 1866 in the Journal of the Brno Natural History Society. The paper was not widely read nor understood, and soon after its publication Mendel was elected abbot of his monastery. He continued experimenting with bees but his work went unrecognized until various scientists resurrected his theories around 1900, after his death. Mendel had joined the Brno Augustinian monastery in 1843, but also trained as a scientist at the Olmutz Philosophical Institute and the University of Vienna. The Brno Monastery was a center of scholarship, with an extensive library and a tradition of scientific research.
Where Charles Darwin's theories suggested a mechanism for improvement of species over generations, Mendel's observations explained how new species could emerge. Though Darwin and Mendel never collaborated, they were aware of each other's work (Darwin read a paper by Wilhelm Olbers Focke which extensively referenced Mendel). Bill Bryson wrote that "without realizing it, Darwin and Mendel laid the groundwork for all of the life sciences in the twentieth century. Darwin saw that all living things are connected, that ultimately they trace their ancestry to a single, common source; Mendel's work provided the mechanism to explain how that could happen." Biologist J. B. S. Haldane and others brought together the principles of Mendelian inheritance with Darwinian principles of evolution to form the field of genetics known as Modern evolutionary synthesis.
==== "Big Bang" Theory for early development of the universe ====
The Big Bang model, or theory, is now the prevailing cosmological theory of the early development of the universe and was first proposed by Belgian priest Georges Lemaître, astronomer and professor of physics at the Catholic University of Leuven, with a Ph.D. from MIT. Lemaître was a pioneer in applying Albert Einstein's theory of general relativity to cosmology. Bill Bryson wrote that the idea was decades ahead of its time and that Lemaître was the first to bring together Einstein's theory of relativity with Edwin Hubble's cosmological observations, combining them in his own "fire-works theory". Lemaître theorized in the 1920s that the universe began as a geometrical point which he called a "primeval atom", which exploded out and has been moving apart ever since. The idea became established theory only decades later with the discovery of cosmic background radiation by American scientists.
=== Sponsorship of scientific research ===
In ancient times, the Church supported medical research as an aid to Christian charity. The Church supported the development of modern science and scientific research by founding some of Europe's first universities in the Middle Ages. Historian Lawrence M. Principe writes that "it is clear from the historical record that the Catholic church has been probably the largest single and longest-term patron of science in history, that many contributors to the Scientific Revolution were themselves Catholic, and that several Catholic institutions and perspectives were key influences upon the rise of modern science." The field of astronomy is a prime example of the Church's commitment to science. J.L. Heilbron in his book The Sun in the Church: Cathedrals as Solar Observatories writes that "the Roman Catholic Church gave more financial aid and support to the study of astronomy for over six centuries, from the recovery of ancient learning during the late Middle Ages into the Enlightenment, than any other, and, probably, all other, institutions."
Scientific support continues through the present day. The Pontifical Academy of Sciences was founded in 1936 by Pope Pius XI to promote the progress of the mathematical, physical, and natural sciences and the study of related epistemological problems. The academy holds a membership roster of the most respected names of contemporary science, many of them Nobel laureates. Also worth noting is the Vatican Observatory, an astronomical research and educational institution supported by the Holy See.
In his 1996 encyclical Fides et Ratio, Pope John Paul II wrote that "faith and reason are like two wings on which the human spirit rises to the contemplation of truth." Pope Benedict XVI re-emphasized the importance of reason in his famous 2006 address at Regensburg. But the emphasis on reason is not a recent development in the Church's history. In the first few centuries of the Church, the Church Fathers appropriated the best of Greek philosophy in defense of the faith. This appropriation culminated in the 13th-century writings of Thomas Aquinas, whose synthesis of faith and reason has influenced Catholic thought for eight centuries. Because of this synthesis, many historians of science trace the foundations of modern science to the 13th century. These writers include Edward Grant, James Hannam, and Pierre Duhem.
==== The Catholic Church as a strategic and careful patron of science ====
The relationship between the Catholic church and science has been largely supportive in spite of the myth of conflict stemming from discomfort with divergence from a Biblical geocentric model of cosmology to a heliocentric one. The church and its Jesuit missionaries not only studied subjects such as astronomy, physics and math, they exchanged information with others such as the Chinese across the world. In 1616, the Qualifiers of the Holy Office formally disavowed heliocentric theory. However, when they needed assistance with a problematic Ecclesiastical calendar, they solicited the assistance of astronomers who inadvertently proved the validity of it. Two developments made the confirmation possible: the more accurate measurements of the sun and the moon, and the astronomical community's understanding of how to use language that was vague enough to avoid direct conflict with church doctrine. Words in Biblical scripture left some room for interpretation and when there were conflicts between the physical and the scriptural, both the church and the scientists engaged in exercises of hermeneutical accommodation.
===== Example of church sponsorship of astronomical research-ecclesiastical calendaring =====
One of the primary reasons that the church was so supportive of astronomical research was that the church needed astronomers to assist in resolving issues with the calendar—specifically in establishing a date for Easter. In 325 A.D., the Catholic theologians comprising the Council of Nicaea, set the date of Easter as the first Sunday after the first full moon of the vernal equinox where the vernal equinox was the point of equal daylight and darkness. The challenge in using astronomical observations for a religious celebration spanning great distances across the globe was that date was inconsistent and subject to errors in accuracy of observations. Beyond the challenge of Easter was the fact that the calendar was used for business that included payment schedules, etc. thus creating economic consequences every time days were removed for realignment purposes. By the sixth century, there was papal pressure to create a system for designating the date of Easter that was both accurate and consistent across the world. The church recognized that there had been a drift and that the date of Easter no longer seemed to align with heaven which created an urgent need to understand the movement of the Sun and Earth so that the calendar conflicts could be resolved. After reviewing the data from Aristotle to Ptolemy, they recognized that the problem centered on the period between successive Spring equinoxes. In 1514, Pope Leo X commissioned Dutch astronomer Paul of Middleburg to identify a resolution. Paul favored resetting the date of the vernal equinox to March 10 rather than eliminating days to correct the drift but the changes were not made. Copernicus, a contemporary of Paul, attributed the failure to inaccuracies in measurements of the Sun and Moon and he focused his attention on collecting more accurate data.
Accurate data about the vernal equinox required a large, dark space like a cathedral to measure a meridian line. A hole was cut into the roof of a cathedral and using a rod or line in the floor, they measured the time it took for a noon time image of the Sun to return to the same place. The accuracy depended on the quality of the laboratory set up for observation, including the location of the hole, the level of the floors and line placement. Cosimo I D'Medici a patron of the arts and supporter of the church, enlisted Egnatio Danti, a Dominican artist, for help with the calendar. Danti found the perfect location for his meridian in the Basilica di San Petronio in Bologna. Structural issues led to inaccuracy of Danti's meridian. Decades later, Giovanni Domenico Cassini, redid the meridian in the same basilica. His work resolved the apparent conflicts between Ptolemy's solar theory and Kepler's "bisection of eccentricity" using the diameter of the Sun's image as an inverse substitute for the Sun's distance from the Earth. His precise work ended up proving the validity of Copernican theory condemned by the church. After Galileo, scientists consciously identified ways to stay in alignment with the church as much as possible.
====== Avoiding conflict in sponsorship of scientific research-hermeneutical accommodation ======
Astronomers from Ptolemy to Cassini recognized potential conflicts between their observations and cosmology and it was often a challenge to cultivate a position in which science and scripture could both be true. Ptolemy saw the conflict between his model and the movement of planets. By interpreting the word orbit in both a geometric sense and in a way that could apply to the Sun or the Earth, Catholic scientists like Cassini could create enough distance from Galileo's theory to operate without condemnation from the church. Galileo himself felt that conflict between scripture and science could be resolved through hermeneutical accommodation. He believed that there could essentially be harmony between science or nature and scripture if one understood how to interpret scripture. Galileo was of the opinion that since God is responsible for every aspect of our world, including the sensory experiences that are an integral part of scientific observation, then if what we see differs from scripture, we should conclude that the observations are correct. Galileo references Cardinal Baronius who believed that the Bible is not meant to explain heaven or God's creation as much as it is meant to guide people's actions. With that being said, Andreas Osiander was a Lutheran theologian that used Copernicus's book De revolutionibus orbium coelestium to further emphasize Copernicus's astronomical system that was already being theorized. While Osiander would be coming from a Lutheran stance and Copernicus's system was in alignment with the Catholic canon. He found that Copernicus's system also coincided with Lutheran ideologies. The part that Osiander played in counteracting the critique was by writing the foreword or rather preface of Copernicus's book to refrain it from getting questioned, within the preface he essentially alluded to the fact that Copernicus's system may be mathematically accurate and therefore would be true, but states that it is all a theory. By Osiander writing the foreword and making this statement he was "saving the phenomenon" and was able to keep Copernicus's work from getting questioned to an extent ."Saving the phenomenon" was when scientists found reason to interpret or decode a theory in a more technical way and could further be contested with other theories. The part in which the foreword played further developed and helped bring to light the separation of both science and cosmology. Making that distinction furthered helped expand upon theories that would rub the Church in the wrong way, but avoided that because by focusing on the mathematical aspects and not making quick conclusions about how planets moved kept a boundary intact between the two and helped refrain a conflict from occurring.
The Church has, since ancient times, been heavily involved in the study and provision of medicine. Early Christians were noted for tending the sick and infirm, and priests were often also physicians. Christian emphasis on practical charity gave rise to the development of systematic nursing and hospitals after the end of the persecution of the early church. Notable contributors to the medical sciences of those early centuries include Tertullian (born A.D. 160), Clement of Alexandria, Lactantius, and the learned St. Isidore of Seville (d. 636). St. Benedict of Nursia (480) emphasised medicine as an aid to the provision of hospitality.
During the Middle Ages, famous physicians and medical researchers included the Abbot of Monte Cassino Bertharius, the Abbot of Reichenau Walafrid Strabo, the Abbess Hildegard of Bingen, and the Bishop Marbodius of Rennes. Monasteries of this era were diligent in the study of medicine. So too, convents: Hildegard of Bingen, a doctor of the church, is among the most distinguished of Medieval Catholic women scientists. Beyond theological works, Hildegard wrote Physica, a text on the natural sciences, as well as Causae et Curae. Hildegard of Bingen was well known for her healing powers that involved practical application of tinctures, herbs, and precious stones.
Charlemagne decreed that each monastery and cathedral chapter establish a school and in these schools, medicine was commonly taught. At one such school Pope Sylvester II taught medicine. Clergy were active at the School of Salerno, the oldest medical school in Western Europe. Among the important churchmen to teach there were Alpuhans, later (1058–85) Archbishop of Salerno, and the influential Constantine of Carthage, a monk who produced superior translations of Hippocrates and investigated Arab literature.
In Catholic Spain amidst the early Reconquista, Archbishop Raimund founded an institution for translations, which employed some Jewish translators to communicate the works of Arabian medicine. Influenced by the rediscovery of Aristotelean thought, churchmen like the Dominican Albert Magnus and the Franciscan Roger Bacon made significant advances in the observation of nature.
During the Bubonic Plague, the Franciscans tended to the sick, illustrating the Church's commitment to charity. However, while the Church supported medical studies, the development of medicine during the Renaissance was complex, with some religious authorities resisting certain practices, like dissection, due to doctrinal concerns. Still, in Renaissance Italy, somes Popes acted as patrons of anatomical studies, and artists like Michelangelo contributed to medical knowledge through their work.
The Jesuit order, created during the Reformation, contributed a number of distinguished medical scientists. In the field of bacteriology, Athanasius Kircher (1671) first proposed that living organisms enter and exist in the blood. In the development of ophthalmology, Christoph Scheiner made important advances about refraction of light and the retinal image.
In modern times, the Catholic Church is the largest non-government provider of health care in the world. Catholic religious have been responsible for founding and running networks of hospitals across the world where medical research continues to advance.
=== Pontifical Academy of Sciences ===
The Pontifical Academy of Sciences was founded in 1936 by Pope Pius XI. It draws on many of the world's leading scientists, including many Nobel Laureates, to act as advisors to the Popes on scientific issues. The Academy has an international membership which includes British physicist Stephen Hawking, the astronomer royal Martin Rees, and Nobel laureates such as U.S. physicist Charles Hard Townes.
Under the protection of the reigning Pope, the Academy aims to promote the progress of the mathematical, physical, and natural sciences and the study of related epistemological problems. The Academy has its origins in the Accademia Pontificia dei Nuovi Lincei ("Pontifical Academy of the New Lynxes"), founded in 1847 and intended as a more closely supervised successor to the Accademia dei Lincei ("Academy of Lynxes") established in Rome in 1603 by the learned Roman Prince Federico Cesi (1585–1630) who was a young botanist and naturalist, and which claimed Galileo Galilei as a member.
=== Vatican Observatory ===
The Vatican Observatory (Specola Vaticana) is an astronomical research and educational institution supported by the Holy See. Originally based in Rome, it now has headquarters and laboratory at the summer residence of the Pope in Castel Gandolfo, Italy, and an observatory at the Mount Graham International Observatory in the United States. The Director of the Observatory is Brother Guy Consolmagno, SJ. Many distinguished scholars have worked at the Observatory. In 2008, the Templeton Prize was awarded to cosmologist Fr. Michał Heller, a Vatican Observatory Adjunct Scholar. In 2010, the George Van Biesbroeck Prize was awarded to former observatory director Fr. George Coyne, SJ. The current director of the Vatican Observatory, Brother Guy Consolmagno, was awarded the American Astronomical Society's Carl Sagan Medal for Excellence in Public Communication in Planetary Science in 2014.
== Jesuits ==
The Society of Jesus (Jesuit Order) was founded by the Spaniard Saint Ignatius Loyola in 1540. Jesuits were leaders of the Counter-Reformation, who have contributed a great many distinguished scientists and institutions of learning, right up to the present. The role of some of its members like Robert Bellarmine, in the Counter-Reformation period and in defense of Papal teaching, show the constraints under which they operated. However, recent scholarship in the history of science has focused on the substantial contributions of Jesuit scientists over the centuries. Historian Jonathan Wright discussed the breadth of Jesuit involvement in the sciences in his history of the order:
[The Jesuits] contributed to the development of pendulum clocks, pantographs, barometers, reflecting telescopes and microscopes, to scientific fields as various as magnetism, optics, and electricity. They observed, in some cases before anyone else, the colored bands on Jupiter's surface, the Andromeda nebula, and Saturn's rings. They theorized about the circulation of the blood (independently of Harvey), the theoretical possibility of flight, the way the Moon affected the tides, and the wave-like nature of light. Star maps of the southern hemisphere, symbolic logic, flood-control measures on the Po and Adige rivers, introducing plus and minus signs into Italian mathematics – all were typical Jesuit achievements, and scientists as influential as Fermat, Huygens, Leibniz, and Newton were not alone in counting Jesuits among their most prized correspondents.
=== Jesuits in China ===
The Jesuits made significant contributions to scientific knowledge in China. Under the Qing Dynasty, the Jesuits' knowledge of observational astronomy and spherical trigonometry was welcomed by the imperial court. The Manchus who conquered the Ming Dynasty also welcomed the Jesuit scientists and employed their help due to their expert knowledge of mathematical astronomy, which aided the ruling class in predicting celestial events, thus, displaying that this dynasty retained the Mandate of Heaven. In addition to reinforcing the Mandate of Heaven, the Jesuits separated two fields of science that were thought by the Chinese to be the same, cosmology and cosmography. By doing so, they were able to avoid being restricted by the Book of Changes. The Jesuits' astronomical measurements were also more accurate than their Chinese counterparts. This factor, combined with the fact that the Jesuits also sympathized with the need of the Qing Dynasty to replace the old Ming calendar with a better one of their own enabled the Jesuits to make a significant impact on the Chinese Imperial Court. The Jesuits themselves each fulfilled different roles at the imperial court. Father Matteo Ricci served on a jury charged with filling high ranking positions in the imperial court. Father Johann Adam Schall von Bell was made president of the mathematics court of the Qing dynasty and contributed significantly to the reformation of China's calendar. Father Ferdinand Verbiest contributed to China's understanding of its geography and helped China define its border with Russia.
=== Matteo Ricci ===
Matteo Ricci was one of the most influential Jesuits that was sent to China. Matteo had been educated in math and science at the Collegio Romano with Christopher Clavius and also in Portugal at the University of Coimbra. Matteo went to China in 1581, where he resided in the city of Macau. He would then move to Beijing in 1601, where he hoped that the Ming would employ him and his order to correct their calendar. Ricci would also spread Euclidean Geometry to China by helping translate his works while using books prepared by Christopher Clavius. Ricci hoped to do this by earning the favor of the court and educated literati elites. In this, Ricci was successful. He was able to convert other Chinese scholars to Catholicism who would then subsequently help him spread both Christianity and more accurate astrological measurements. In one case, Ricci, along with Xu Guangqi and Li Zhizhao, both of whom he had converted, would translate both Euclid and Ptolemy's works into Chinese in 1607. These three would also go on to translate works from both Nicolaus Copernicus and Tycho Brahe. By doing this, they were able to introduce, however slightly new ideas into the Chinese astronomical system. Although the Ming court never took his work seriously while he was still alive, one of Ricci's converts, Xu Guangqi would later be called upon as a high-ranking member of the Ministry of Rites and he would go on to reform the Chinese astronomical system.
=== Johann Adam Schall von Bell ===
Johann Adam Schall von Bell was another influential Jesuit priest that was sent to China. During Schall's stay in China, the Ming dynasty was overthrown and replaced by the Manchu Qing Dynasty. Schall, along with many other Jesuits quickly adapted to the regime change and offered his services to the new Qing Emperor. The new Emperor accepted Schall's offer, and this could bring in a new age of Jesuit acceptance in China that contrasted with the Ming dynasty's indifference to Matteo Ricci's efforts. The acceptance of Jesuit help would go on to have drastic consequences, as the former Chinese and Muslim members of the Astrocaldendrical Bureau who were replaced by the Jesuits would join the anti-Jesuit faction in the court and seek to purge their influence. In the meantime, however, Schall and assistants would continue their work and in 1645, they unveiled their first work. They called it a "temporal model calendar". it heavily borrowed from Mathematical Astronomy According to the New Western Methods, which was a series of Western writings that were translated into Chinese by Xu Guanqi and past Jesuits. Schall, recognizing the importance of elaborate state rituals in China, offered the calendar to the Emperor in a complex ceremony involving music, parades, and signs of submission like kneeling and kowtowing. After this overwhelming success, however, Schall's legitimacy was quickly put into question by Yang Guangxian, who accused Schall of attempting to undermine the Qing dynasty by fomenting civil unrest. Schall and the Jesuits were also accused of secretly harboring illegal foreigners in their churches spread around China and were also accused of claiming that the Qing rulers relied upon their Western ideas for political legitimacy. Schall was imprisoned and died while in captivity in 1666 at the age of seventy-five. He was posthumously pardoned by Kangxi Emperor upon his ascension to the throne.
=== Ferdinand Verbiest ===
Ferdinand Verbiest was a Belgian Jesuit who was called upon by the Kangxi Emperor after his ascension to compete in a contest with Muslim astronomers. The contest involved predicting the length of a shadow that would pass over the imperial gnomon, which was a sundial in the Forbidden City. Verbiest won the contest and was subsequently placed at the head of the Astrocalendrical Bureau. As head of the Burea, Verbiest also shared his position with a Manchu, and this tradition would continue until the 1840s. Verbiest claimed that the studying of celestial patterns was of great practical importance to the dynasty and that whether the astronomer in question was Muslim, Jesuit or Chinese didn't matter. He argued that ensuring the observations were impartial and that applying Tycho's ideas to the observations to verify said observations were the two most important factors. Verbiest also claimed that Western ways of measuring data were the most accurate and dismissed the older findings of Chinese astronomers. While these claims did little to convince the Chinese that their old measurements were inaccurate, Verbiest's pushing of spherical trigonometry would go on to have the greatest impact on Chinese astronomy, as they saw it as being connected to when the Mongols brought Islamic astronomy to China during their conquest.
=== Christopher Clavius ===
Christopher Clavius was one of the most prolific members of the order. During his life, he made contributions to algebra, geometry, astronomy, and cartography. Most notable of his accomplishments was his work on the reform of the Gregorian Calendar. Having taught in the Collegio Romano for 40 years, he had a direct impact on the spread of scientific knowledge within the Jesuit order and, from there, an impact on the scientific knowledge of the places his students would visit in their missionary journeys. For example, the Jesuit priest Matteo Ricci translated Clavius' books into Chinese and shared the knowledge they contained with the people of China during his missionary work there. With the help of Clavius' books, Matteo and his fellow Jesuits were able to spread the West's knowledge of astronomy to China which, in turn, led to China's refinement of its calendar system.
=== Athanasius Kircher ===
Athanasius Kircher was a Jesuit priest who authored around 44 major works and is regarded by some scholars as the founder of Egyptology due to his study of Egyptian hieroglyphs. He is believed by many scholars to be the last "renaissance man" in light of his being a polymath and scholar of a wide range of disciplines including music, astronomy, medicine, geography, and more. Despite providing a wealth of knowledge in his books, Kircher did not contribute much in the way of scientific breakthroughs, but he is credited with the invention of the aeolian harp which was a popular instrument the 19th century One of many notable contributions Athanasius made to the world was his book, China Illustrata, in which he gives a detailed record of his observations of Chinese culture and geography—including numerous detailed illustrations plants, statues, temples, and mountains in the vast landscapes of China. Kircher wrote this book based entirely on his study of documents sent back to Rome from his fellow Jesuits in China which led to Kircher being recognized as an expert in China despite having never been there himself.
=== Pierre Teilhard de Chardin ===
Pierre Teilhard de Chardin was a Jesuit priest who took an interest in geology from a young age. After some time as a professor at the Catholic Institute of Paris, Chardin went on an expedition to China where he performed academic work concerning paleontology and geology. During his travels in China, he played a role in the discovery of the Peking Man's skull. After his research team discovered it, Chardin took part in the examination of the skull and discovered the geological time during which the Peking Man lived. During his time in China, Pierre was able to continue his research of fossils and expanded the scope of geological knowledge in Asia with the help of his fellow Jesuit, Pierre Leroy, who co-founded the Institute of Geobiology with him in Peking.
=== Pietro Angelo Secchi ===
Pietro Angelo Secchi became a Jesuit priest in 1833. He became a professor of astronomy at the Roman College and eventually founded an observatory where he would further his research in stellar spectroscopy, meteorology, and terrestrial magnetism. His observations and theories laid the foundation for the Harvard classification system of stars as he was the first to survey the spectra of stars and attempt to classify them by their spectral type.
=== Jesuit Observatories ===
Perhaps one of the greatest contributions made by the Jesuits to science is the large network of observatories they founded across the world. Between 1824 and 1957, 75 observatories were founded by the Jesuits. Though their main focus was astronomy, other fields the observatories were involved in include meteorology, geomagnetism, seismology, and geophysiology. In some countries in Asia and Africa, these observatories were the first scientific institutions they had ever had. The contribution of the Jesuits to the development of seismology and seismic prospecting has been so substantial that seismology has been called "The Jesuit Science". Frederick Odenbach, SJ, is considered by many to have been the "pioneer of American seismologists." In 1936, Fr. J.B. Macelwane, SJ, wrote the first seismology textbook in America, Introduction to Theoretical Seismology. In the 21st Century, Jesuits remain prominent in the sciences through institutions like the Vatican Observatory and Georgetown University.
== Popes ==
=== Paul IV ===
For being a Protestant, Conrad Gessner's work, Historiae animalium, was put on the Index of Prohibited Books by Paul IV.
=== Gregory XIII ===
The Gregorian calendar was introduced by Gregory XIII, after whom the calendar was named, by a decree signed on 24 February 1582.
=== Urban VIII ===
Urban VIII had Galileo's book put on the Index of Prohibited Books and had Galileo sentenced to lifelong house arrest for heresy for "following the position of Copernicus, which is contrary to the true sense and authority of Holy Scripture."
=== Leo XIII ===
On 18 November 1893, Leo XIII issued Providentissimus Deus. In it, he said that "no real disagreement can exist between the theologian and the scientist provided each keeps within his own limits. ...If nevertheless there is a disagreement ... it should be remembered that the sacred writers, or more truly 'the Spirit of God who spoke through them, did not wish to teach men such truths (as the inner structure of visible objects) which do not help anyone to salvation'; and that, for this reason, rather than trying to provide a scientific exposition of nature, they sometimes describe and treat these matters either in a somewhat figurative language or as the common manner of speech those times required, and indeed still requires nowadays in everyday life, even amongst most learned people."
=== Pius XI ===
The Pontifical Academy of Sciences was founded in 1936 by Pope Pius XI.
=== Pius XII ===
In 1939, Pius XII described Galileo as being among the "most audacious heroes of research ... not afraid of the stumbling blocks and the risks on the way, nor fearful of the funereal monuments."
In the 1950 encyclical Humani generis, Pius XII accepted evolution as a possibility (as opposed to a probability) and a legitimate field of study to investigate the origins of the human body – though it was stressed that "the Catholic faith obliges us to hold that souls are immediately created by God." In
=== John Paul II ===
John Paul II said, "faith and reason are like two wings on which the human spirit rises to the contemplation of truth; and God has placed in the human heart a desire to know the truth – in a word, to know himself – so that, by knowing and loving God, men and women may also come to the fullness of truth about themselves."
=== Benedict XVI ===
In his spiritual testament, Pope Benedict XVI said:
It often seems that science...are able to offer irrefutable results at odds with the Catholic faith...on the contrary, apparent certainties against the faith have vanished, proving to be not science, but philosophical interpretations only apparently pertaining to science;...with the succession of different generations I have seen theses that seemed unshakable collapse, proving to be mere hypotheses: the liberal generation (Harnack, Jülicher etc.), the existentialist generation (Bultmann etc.), the Marxist generation. I saw and see how out of the tangle of assumptions the reasonableness of faith emerged and emerges again.
=== Francis ===
In a July 2, 2021 video message, Pope Francis said that there "cannot and must not be any opposition between faith and science."
With the substantial increase in the proliferation and usage of large language models such as ChatGPT, Pope Francis expressed concerns about a "technocratic" future and transparency in the development of further artificial intelligence technologies at the 2024 G7 summit in 2024. He also addressed the topic in his October 2024 encyclical Dilexit nos. The Vatican City State enacted laws about the usage of AI on 1 January 2025. The doctrinal note Antiqua et nova was released on 28 January 2025.
== Current Church doctrine ==
In his 1893 encyclical, Pope Leo XIII wrote that "no real disagreement can exist between the theologian and the scientist provided each keeps within his own limits. ...If nevertheless there is a disagreement ... it should be remembered that the sacred writers, or more truly 'the Spirit of God who spoke through them, did not wish to teach men such truths (as the inner structure of visible objects) which do not help anyone to salvation'; and that, for this reason, rather than trying to provide a scientific exposition of nature, they sometimes describe and treat these matters either in a somewhat figurative language or as the common manner of speech those times required, and indeed still requires nowadays in everyday life, even amongst most learned people."
The Catechism of the Catholic Church asserts: "Methodical research in all branches of knowledge, provided it is carried out in a truly scientific manner and does not override moral laws, can never conflict with the faith because the things of the world and the things of faith derive from the same God. The humble and persevering investigator of the secrets of nature is being led, as it were, by the hand of God despite himself, for it is God, the conserver of all things, who made them what they are."
=== Providentissimus Deus ===
Providentissimus Deus, "On the Study of Holy Scripture", was an encyclical issued by Pope Leo XIII on 18 November 1893. In it, he reviewed the history of Bible study from the time of the Church Fathers to the present, spoke against what he considered to be the errors of the Rationalists and "higher critics", and outlined principles of scripture study and guidelines for how scripture was to be taught in seminaries. He also addressed the issues of apparent contradictions between the Bible and physical science, or between one part of scripture and another, and how such apparent contradictions can be resolved.
Providentissimus Deus responded to two challenges to biblical authority, both of which rose during the 19th century. The physical sciences, especially the theory of evolution and geology's theory of a very old Earth, challenged the traditional Biblical account of creation taking place 6,000 years ago. Pope Leo XIII wrote that true science cannot contradict scripture when it is properly explained, that errors the Church Fathers made do not demonstrate error in Scripture, and that what seems to be proved by science can turn out to be wrong.
The historical-critical method of analyzing scripture questioned the reliability of the Bible. Leo acknowledged the possibility of errors introduced by scribes but forbade the interpretation that only some of the scripture is inerrant, while other elements are fallible. Leo condemned the use that certain scholars made of new evidence, clearly referring to Alfred Firmin Loisy and Maurice d'Hulst, although not by name.
At first, both conservatives and liberals found elements in the encyclical to which to appeal. Over the next decade, however, Modernism spread and Providentissimus Deus was increasingly interpreted in a conservative sense.
This encyclical was part of an ongoing conflict between Modernists and conservatives. In 1902, Pope Leo XIII instituted the Pontifical Biblical Commission, which was to adapt Roman Catholic Biblical studies to modern scholarship and to protect Scripture against attacks. The Oath against Modernism was finally rescinded after Vatican II.
=== Humani generis ===
Humani generis is a papal encyclical that Pope Pius XII promulgated on 12 August 1950 "concerning some false opinions threatening to undermine the foundations of Catholic Doctrine." Theological opinions and doctrines are known as Nouvelle Théologie or neo-modernism and their consequences on the Church were its primary subject. Evolution and its impact on theology constitute only two out of 44 parts. Yet the position which Pius XII defined in 1950, delinking the creation of body and soul, was confirmed by Pope John Paul II, who highlighted additional facts supporting the theory of evolution half a century later.
=== Fides et Ratio ===
Fides et ratio is a Papal Encyclical that Pope John Paul II Promulgated on the 14th of September 1998, "On the Relationship between Faith and Reason". In the encyclical, Pope John Paul II addressed the relationship between faith and reason, the first to do so since Pope Leo XIII in 1879, with his encyclical Aeterni Patris. Pope John Paul II described the relationship between faith and reason as 'two wings on which the human spirit rises to the contemplation of truth'.
'This is why I make this strong and insistent appeal—not, I trust, untimely—that faith and philosophy recover the profound unity which allows them to stand in harmony with their nature without compromising their mutual autonomy. The parrhesia of faith must be matched by the boldness of reason.'
In his 1998 encyclical, Pope John Paul II gave an example to the faithful of how to defend faith, without shunning reason. Following and supporting the long tradition of Christian Theology and Philosophy. The Catholic Church has always purported a thesis of harmony between Science and Religion, despite the growing trend of conflict being purported between the two. Through Fides et ratio Pope John Paul II reinforced the Church's stance upon the relationship between Science and The Catholic Church. 'The Church remains profoundly convinced that faith and reason "mutually support each other"; each influences the other, as they offer to each other a purifying critique and a stimulus to pursue the search for deeper understanding.'
'Similarly, fundamental theology should demonstrate the profound compatibility that exists between faith and its need to find expression by way of human reason fully free to give its assent. Faith will thus be able "to show fully the path to reason in a sincere search for the truth. Although faith, a gift of God, is not based on reason, it can certainly not dispense with it. At the same time, it becomes apparent that reason needs to be reinforced by faith, to discover horizons it cannot reach on its own".'
== Ethics and science ==
The Catholic Church teaches that scientific research and conduct need to be informed by and put to the aid of Christian ethics. During recent pontificates, issues such as the implications of genetics and anthropogenic climate change have been important areas of focus. The Vatican draws on leading scientists to examine scientific literature in search of "moral and philosophical problems, either caused by science or which can be helped by science."
== Church and science as complementary ==
The Jesuit Teilhard de Chardin argued in an influential book The Phenomenon of Man (1959) that science and religion were two vital sides of the same phenomenon: a quest for perfect knowledge. Pope John Paul II in his 1998 encyclical Fides et Ratio wrote that "faith and reason are like two wings on which the human spirit rises to the contemplation of truth." In his spiritual testament, Pope Benedict XVI said:
It often seems that science...are able to offer irrefutable results at odds with the Catholic faith...on the contrary, apparent certainties against the faith have vanished, proving to be not science, but philosophical interpretations only apparently pertaining to science;...with the succession of different generations I have seen theses that seemed unshakable collapse, proving to be mere hypotheses: the liberal generation (Harnack, Jülicher etc.), the existentialist generation (Bultmann etc.), the Marxist generation. I saw and see how out of the tangle of assumptions the reasonableness of faith emerged and emerges again.
== Conflict thesis and "drastic revision" ==
The scientists/historians John William Draper and Andrew Dickson White were the most influential exponents of the conflict thesis between the Catholic Church and science. In the early 1870s, Draper was invited to write a History of the Conflict between Religion and Science (1874), a book replying to contemporary papal edicts such as the doctrine of infallibility, and mostly criticizing the anti-intellectualism of Roman Catholicism, yet he assessed that Islam and Protestantism had little conflict with science. Draper's preface summarises the conflict thesis: "The history of Science is not a mere record of isolated discoveries; it is a narrative of the conflict of two contending powers, the expansive force of the human intellect on one side, and the compression arising from traditionary faith and human interests on the other." In 1896, White published A History of the Warfare of Science with Theology in Christendom, the culmination of thirty years of research and publication on the subject. In the introduction, White emphasized he arrived at his position after the difficulties of assisting Ezra Cornell in establishing a university without any official religious affiliation.
More recently, Thomas E. Woods, Jr., asserts that, despite the widely held conception of the Catholic Church as being anti-science, this conventional wisdom has been the subject of "drastic revision" by historians of science over the last 50 years. Woods asserts that the mainstream view now is that the "Church [has] played a positive role in the development of science ... even if this new consensus has not yet managed to trickle down to the general public." Science historian Ronald L. Numbers corroborates this view, writing that "Historians of science have known for years that White's and Draper's accounts are more propaganda than history. …Yet the message has rarely escaped the ivory tower."
== See also ==
Christianity and science
Relationship between religion and science
Role of the Catholic Church in Western civilization
List of Roman Catholic scientist-clerics
List of Catholic scientists
List of Christian thinkers in science
List of Christian Nobel laureates
Science and the Popes
== References ==
=== Notes ===
=== Citations ===
Appleby, R. Scott. Between Americanism and Modernism; John Zahm and Theistic Evolution, in Critical Issues in American Religious History: A Reader, Ed. by Robert R. Mathisen, 2nd revised edn., Baylor University Press, 2006, ISBN 1-932792-39-2, ISBN 978-1-932792-39-3. Google books
Artigas, Mariano; Glick, Thomas F., Martínez, Rafael A.; Negotiating Darwin: the Vatican confronts evolution, 1877-1902, JHU Press, 2006, ISBN 0-8018-8389-X, 9780801883897, Google books
Harrison, Brian W., Early Vatican Responses to Evolutionist Theology, Living Tradition, Organ of the Roman Theological Forum, May 2001.
O'Leary, Don. Roman Catholicism and modern science: a history, Continuum International Publishing Group, 2006, ISBN 0-8264-1868-6, ISBN 978-0-8264-1868-5 Google books
=== Further reading ===
Bennett, Gaymon, Hess, Peter M. J. and others, The Evolution of Evil, Vandenhoeck & Ruprecht, 2008, ISBN 3-525-56979-3, ISBN 978-3-525-56979-5, Google books
Hannam, James (2009). God's Philosophers: How the Medieval World Laid the Foundations of Modern Science. Icon Books Ltd. ISBN 978-1848310704.
Johnston, George (1998). Did Darwin Get It Right?. Huntington: Our Sunday Visitor. ISBN 978-0-87973-945-4. (google books)
Küng, Hans, The beginning of all things: science and religion, trans. John Bowden, Wm. B. Eerdmans Publishing, 2007, ISBN 0-8028-0763-1, ISBN 978-0-8028-0763-2. Google books
Lindberg, David C.; Numbers, Ronald L. (October 2003). When Science and Christianity Meet. University of Chicago Press. ISBN 978-0226482149.
Olson, Richard, Science and religion, 1450-1900: from Copernicus to Darwin, Greenwood Publishing Group, 2004, ISBN 0-313-32694-0, ISBN 978-0-313-32694-3. Google books
Thompson, Phillip M (2009). Between science and religion. The engagement of Catholic intellectuals with science and technology in the twentieth century. Lanham, Md.: Lexington Books. ISBN 978-0-7391-4020-8. OCLC 659563600.
== External links ==
Christianity and Science in Historical Perspective (from the University of Cambridge)
Galileo Galilei, Scriptural Exegete, and the Church of Rome, Advocate of Science Archived 2011-06-08 at the Wayback Machine lecture (audio here) by Thomas Aquinas College tutor Dr. Christopher Decaen
"The End of the Myth of Galileo Galilei" by Atila Sinke Guimarães
Vatican Council I (1869-70), the full documents.
1913 Catholic Encyclopedia: Catholics and Evolution and Evolution, History and Scientific Foundation of
Herbermann, Charles, ed. (1913). "Vatican as a Scientific Institution" . Catholic Encyclopedia. New York: Robert Appleton Company.
The Vatican Palace, as a Scientific Institute, Catholic Encyclopedia, NewAdvent.org.
Herbermann, Charles, ed. (1913). "Geography and the Church" . Catholic Encyclopedia. New York: Robert Appleton Company.
Pope Pius XII, Humani generis, 1950 encyclical
Roberto Masi, "The Credo of Paul VI: Theology of Original Sin and the Scientific Theory of Evolution" (L'Osservatore Romano, 17 April 1969).
Pope John Paul II, general audience of 10 July 1985. "Proofs for God's Existence are Many and Convergent."
Cardinal Ratzinger's Commentary on Genesis "In the Beginning: A Catholic Understanding of the Story of Creation and the Fall".
International Theological Commission (2004). "Communion and Stewardship: Human Persons Created in the Image of God Archived 2013-05-26 at the Wayback Machine."
Mark Brumley, Evolution and the Pope Archived 29 June 2019 at the Wayback Machine, of Ignatius Insight Archived 27 January 2018 at the Wayback Machine
John L. Allen Teaching of Benedict XVI on Evolution before becoming Pope.
Benedict XVI's inaugural address.
Pontifical Academy of Sciences
Herbermann, Charles, ed. (1913). "Science and the Church" . Catholic Encyclopedia. New York: Robert Appleton Company. | Wikipedia/Catholic_Church_and_science |
The Marriage of Sense and Soul: Integrating Science and Religion is a 1998 book by American author Ken Wilber. It reasons that by adopting contemplative (e.g. meditative) disciplines related to Spirit and commissioning them within a context of broad science, that "the spiritual, subjective world of ancient wisdom" could be joined "with the objective, empirical world of modern knowledge". The text further contends that integrating science and religion in this way would inherently involve political aspects.
== Importance ==
Underscoring how important the relationship between science and religion is to our unfolding world, Wilber explains that science "has given us the methods for discovering truth, while religion is the force that generates meaning". To illustrate this point, the author enlists his AQAL model to show how varying understandings of Spirit, from romanticism to idealism through postmodernism have over time, predicated humanity's own development in relation to the Big Three cultural value spheres of art (Upper Left quadrant), morals (Lower Left quadrant), and science (Right hand quadrants).
== Overview ==
=== Part I: The Problem ===
Roger Walsh, in his review of the book, points out that despite significant differences among religions, there is broad consensus among scholars that the Great Chain of Being is central to nearly all major religions. He also notes that the Great Chain of Being was once humanity’s dominant worldview, but with the advent of modernity, the West became the first civilization to abandon it.
Wilber uses the term 'Great Nest of Being' to describe his concept of a holarchy, visualized as concentric spheres or circles. In this model, each level of existence, or "senior dimension," encompasses and transcends the previous level, which he refers to as its "junior." This hierarchical structure progresses from matter to mind to Spirit.
Wilber identifies a three-level scheme within this holarchy, which he argues is reflected in various cultural and spiritual traditions. He cites the example of "earth, human, and heaven" found in shamanic traditions, as well as the Hindu and Buddhist concept of the "three great states of being": the gross (matter and body), the subtle (mind and soul), and the causal (spirit).
Furthermore, Wilber argues that, traditionally, many religions, particularly those of antiquity and the classical period, viewed science as one valid way of acquiring knowledge among others, alongside approaches like theology and mysticism. This viewpoint, which Wilber identifies as epistemological pluralism, acknowledged that each method had its rightful place within the Great Chain of Being. He highlights Christian mystics such as St. Bonaventure and Hugh of St. Victor as proponents of this perspective, pointing to their belief in the "eye of flesh" (sensory perception), the "eye of mind" (reason), and the "eye of contemplation" (mystical insight) as evidence of their acceptance of multiple avenues to knowledge [emphasis added].
For this triple vision, man was endowed with a triple eye, as explained by Hugh of St. Victor: the eye of flesh, of reason, and of contemplation; the eye of flesh, to see the world and what it contains; the eye of reason, to see the soul and what it contains; the eye of contemplation, to see God and that which is within Him. Through the eye of the flesh, man was to see the things outside him; with the eye of reason, the things within him; with the eye of contemplation, the things above him.
As Wilber notes however, that prioritizing the "eyes of mind and flesh" obscures the "eye of contemplation." He clarifies that the "eye of flesh" is monological, the "eye of mind" is dialogical, and the "eye of contemplation" is translogical [emphasis added].
Likewise, but along with the Enlightenment, an entire set of values including "equality, freedom, and justice; representational and deliberative democracy, the equality of all citizens before the law; regardless of race, sex, or creed; political and civil rights (freedom of speech, religion, assembly, fair trial, etc.)"; all, gradually emerged. As a result, and because they'd "existed nowhere" on a large scale in "the premodern world", Wilber refers to these values and rights "as the dignity of modernity" [emphasis in original]. Subsequently, then, but pointing to the work of Max Weber and Jürgen Habermas, the book further contends that 'modernity' is chiefly defined by its "differentiation of the cultural value spheres" or the Big Three; "art, morals, and science; the Beautiful, the Good, and the True"; I (Upper Left quadrant), WE (Lower Left quadrant), and IT (Right hand quadrants) [emphasis added]. Yet, where this modern differentiation could be said to have begun "in earnest around the sixteenth and seventeenth centuries", "by the end of the eighteenth and the beginning of the nineteenth the differentiation was already drifting into a painful and pathological dissociation". Consequently, but in just this way, the Left-Hand or interior dimensions were ultimately "reduced to their Right-Hand or exterior correlates which utterly collapsed the Great Chain of Being, and with it, the core claims of the great wisdom traditions" [emphasis added].
=== Part II: Previous Attempts at Integration ===
Ascribing a recognition to Immanuel Kant of this "leveling and deadening of the modern monological collapse" however [emphasis added], Wilber chronicles the philosopher's subsequent attempt to integrate "moral we-wisdom with scientific it-knowledge" [emphasis added]. From this vantage point, Kant's Critique of Pure Reason is described as an affirmation that "science alone gives cognitive knowledge, "real" knowledge, and all else is nonsensical metaphysics." Likewise, his second installment, Critique of Practical Reason ferreted humanity's moral dimensions in concluding that while "(m)en and women are not free as empirical objects—in the world of ITS . . . as ethical subjects, men and women are indeed autonomous" [emphasis in original]. Further pursuing this line of thought, but utilizing the moral rationale of "ought", Kant's third critique, Critique of Judgement begins by examining the realm of aesthetics in route to ascertaining; as Wilber paraphrases it, "that the interior "ought" of moral reasoning could never get going in the first place without the postulates of a transcendental Spirit".
Consequently, but in the aftermath of Kant's contributions, the Romantics "began an intense effort to make the I-domain, the subjective domain—and especially the domain of aesthetics, sentiment, emotion, heroic self-expression, and feeling—the royal road to Spirit and the Absolute". However, because "romanticism was a philosophical revolt against rationalism" the movement "fell violent prey to" what Wilber has termed, "the pre/trans fallacy [emphasis in original], namely, the confusion of prerational with transrational simply because both are nonrational" [emphasis added].
Similarly, there also existed an ambiguity "between premodern and modern cultures" as to "the direction in which the universe" was said to be unfolding. Where a "time of creation" as recounted amongst premodern religions often entailed "a Great Spirit of one sort or another" creating "the world out of itself, or out of some prima materia", these traditions also commonly point to "a series of strange events" in which it was told, "either God began slowly to withdraw from humans, or humans withdrew from this God"; but generally depicting scenarios in which mankind inevitably "lost touch with the primal Eden". Sometime during the modern era however, this "idea of history as devolution (or a fall from God) was slowly replaced by the idea of history as evolution (or a growth toward God)". Thus, where history for premodern cultures was merely devolution, "one of the great announcements of the Idealists" asserted that "cosmic and human history" instead, was "most profoundly the evolution and development of Spirit".
Beginning then with Kant's assertion "that we can never know "the thing in itself", only the appearance or phenomenon that results when the thing in itself is acted on by the categories of the human mind" [emphasis added]; German Idealism shared much of its inception in "the notion that the world is not merely perceived but constructed." [emphasis in original] For them, "(n)ot naive empiricism, but mental idealism," was of essence in one's "perception of the world" [emphasis added]. In much this way, and to his credit, Johann Fichte is of special note in reasoning that "if you cannot know anything at all about the thing in itself" then ultimately, self-consciousness too is a social phenomena .
Everything that from eternity has happened in heaven and earth, the life of God and all the deeds of time simply are the struggles for Mind to know itself, to make itself objective to itself, to find itself, be for itself, and finally unite itself to itself; it is alienated and divided, but only so as to be able thus to find itself and return to itself.
Consequently, too, but in sublimating these same lines of thought, Wilber delineates three principal features of spiritual evolution:
1. Involution. This original "descent" of Spirit "is a forgetting, a fall, a self-alienation of Spirit".
2. Evolution. In this "second major stage of development, Spirit evolves from objective Nature to subjective Mind" [emphasis added].
3. Nondual Spirit. Spirit comes to know "itself objectively as Nature; knows itself subjectively as Mind; and knows itself absolutely as Spirit—the Source, the Summit, the Ground and the Process of the entire ordeal" [emphasis added].
Thus, he subsequently notes that "for both Schelling and Hegel, Spirit goes out of itself to produce objective Nature, awakens to itself in subjective Mind, then recovers itself in pure nondual Spirit, where subject and object are one pure act of nondual consciousness that unifies both Nature and Mind in realized Spirit" [emphasis added]. Unfortunately, yet underscoring Idealism's remarkable percipience in discerning "the integration of empirical evolution with transcendental Spirit" as reflecting "Spirit-in-action"; "it possessed no yoga—that is, no tried and tested practice for reliably reproducing the transpersonal and superconscious insights that formed the very core of the great Idealist vision". Furthermore, and "because the Idealists lacked a genuine spiritual injunction (practice, exemplar, paradigm), they were indeed, at least in this respect, caught in "mere metaphysics"". Consequently then, and "lacking the means of consistently delivering direct spiritual experience—Idealism in this regard degenerated into abstract speculations without the means of experiential confirmation or rejection" [emphasis in original]. Simply because "every holon has a Left- and a Right-Hand dimension, and therefore every holon without exception has an objective (Right) and an interpretive (Left) component" [emphasis added], postmodernism would ultimately assume "the great and nobel" aim of introducing "interpretation as an intrinsic aspect of the Kosmos" [emphasis in original].
Yet, and for "postmodernism, this moment of truth—every actual occasion has
an interpretive component—was taken to absurd and self-defeating extremes" leading to a facile reasoning that since "(t)here is nothing but interpretation", dispensing "with the objective component of truth" at times, merely serves as practical convenience. Disconcertingly though, "(t)his extreme denial of any sort of objective truth" has subsequently amounted "to a denial of the Right-Hand quadrants altogether, precisely the reverse disaster of modernity" [emphasis in original].
If we are to integrate the wisdom of yesterday with the knowledge of today—and that means, in the broadest sweep, the best of premodern, modern, and postmodern—we will have to look carefully at what the postmodern linguistic turn brought to our understanding of the Kosmos [emphasis added].
For this reason perhaps, Wilber cites the relevance of three core assumptions which underlie postmodern expression in the form(s) of constructivism, contextualism, and integral-aperspectival as all, coming "to the fore with the linguistic turn" [emphasis added]. Similarly too, and crediting Jean Gebser for coining the term 'integral-aperspectival', Wilber further elucidates the word's meaning as a "pluralistic or multiple-perspectives view" privileging "no single perspective" but which in turn, affords "a more holistic or integral" vantage point. Enlisting the same term somewhat interchangeably with "vision-logic or network-logic" [emphasis in original], Wilber recognizes Ferdinand de Saussure for taking vision-logic and applying "it to language, thus disclosing, for the first time in history, its network structure." Likewise, he further asserts "(t)he linguistic turn is, at bottom, vision-logic looking at language itself" [emphasis added].
Nonetheless, but "(s)tarting from the admirable reliance on vision-logic and integral-aperspectival awareness—yet still unable to escape the collapse of the Kosmos—these postmodern movements ended up subtly embodying and even extending the reductionistic nightmare". Serving as an example of this, and referring to William H. Gass's, The Tunnel as epitomizing what many claim "to be the ultimate postmodern novel", Wilber voices accord with RobertAlter's view that the book's defining strategy is reflected through the manner in which "everything is deliberately reduced to the flattest surface." Thus Gass's text is said to do this by "denying the possibility of making consequential distinctions between, or meaningful ranking of, moral or aesthetic values. There is no within: murderer and victim, lover and onanist, altruist and bigot, dissolve into the same ineluctable slime". Thus Wilber subsequently concludes that "under the intense gravity of flatland, integral-aperspectival awareness became simply aperspectival madness—the contradictory belief that no belief is better than any other—a total paralysis of thought, will, and action in the face of a million perspectives all given exactly the same depth, namely, zero" [emphasis added].
=== Part III: A Reconciliation ===
Consequently, and because "(a) modern and postmodern spirituality has continued to elude us," Wilber poses his vision for a spirituality capable of standing "up to scientific authority . . . by announcing its own means and modes, data and evidence, validates and verifications". Along these same lines, the author subsequently outlines what he regards as empirical science's two primary objections to an integration of science and religion:
That "there are no irreducible interior domains that can be studied by different modes of knowing, there are only objective ITS (atomistic or holistic) studied best by science. In short, interior domains have no reality of their own; thus there are no "interior" modes of knowing that cannot be explained away, literally."
"Even if there were other modes of knowing than the sensory-empirical, they would have no mean of validation and thus could not be taken seriously."
In addressing the first objection Wilber reasons that if "empirical science rejects the validity of any and all forms of interior apprehension and knowledge, then it" must also reject "its own validity as well". This is so because "a great deal" of this knowledge itself, already "rests on interior structures and apprehensions that are not delivered by" and hence can't be confirmed by, "the senses (such as logic and mathematics, to name only two)." Likewise, "(i)f science acknowledges these interior apprehensions, upon which its own operations depend, then it cannot object to interior knowledge per se. It cannot toss all interiors into the garbage can without tossing itself with it."
Similarly, Wilber asserts "(o)bjection number 2 can be answered by showing that the scientific method, in general consists of three basic strands of knowing (injunction, apprehension, confirmation/rejection). If it can be shown that the genuine interior modes of knowing also follow these same three strands, then objection number 2 . . . would be substantially refuted" [emphasis in original]. In this way, and "(w)ith the two major scientific objections to the interior domains undone", "a genuine reconciliation of science and religion (and the Big Three in general)" is afforded practical viability [emphasis added].
For these reasons, Wilber subsequently deduces that "sensory empiricism" cannot be included as one of "the defining characteristics of the scientific method", arguing that the "defining patterns of scientific knowledge" instead, "must be able to embrace both biology and mathematics, both geology and anthropology, both physics and logic—some of which are sensory-empirical, some of which are not." In this same regard however, he notes "there is sensory empiricism (of the sensorimotor world)" or empiricism in the narrow sense, "mental empiricism (including logic, mathematics, semiotics, phenomenology, and hermeneutics), and spiritual empiricism (experiential mysticism, spiritual experiences)" or empiricism in the broad sense. "In other words, there is evidence seen by the eye of flesh (e.g., intrinsic features of the sensorimotor world), evidence seen by the eye of mind (e.g., mathematics and logic and symbolic interpretations), and evidence seen by the eye of contemplation (e.g., satori, nirvikalpa samadhi, gnosis)" [emphasis in original].
Wilber then outlines what he states as believing "are three of the essential aspects of scientific inquiry"; referring to them as the "three strands of all valid knowing":
1. Instrumental injunction. "This is an actual practice, an exemplar, a paradigm, an experiment, an ordinance. It is always of the form "If you want to know this, do this."
2. Direct apprehension. "This is an immediate experience of the domain brought forth by the injunction; that is, a direct experience or apprehension of data (even if the data is mediated, at the moment of experience it is immediately apprehended)."
3. Communal confirmation (or rejection). "This is a checking of the results—the data, the evidence—with others who have adequately completed the injunctive and apprehensive strands" [emphasis added].
Advocating that science "expand from narrow empiricism (sensory experience only) to broad empiricism (direct experience in general) [emphasis added], Wilber similarly reasons that religion too "must open its truth claims to direct verification—or rejection—by experiential evidence." He subsequently asserts that "(r)eligion, like science, will have to engage the three strands of all valid knowledge and anchor its claims in direct experience" [emphasis added].
Authentic spirituality, then, can no longer be mythic, imaginal, mythological, or mythopoetic: it must be based on falsifiable evidence. In other words, it must be, at its core, a series of direct mystical, transcendental, meditative, contemplative, or yogic experiences—not sensory and not mental [emphasis in original], but transsensual, transmental, transpersonal, transcendental consciousness—data seen not merely with the eye of flesh or with the eye of mind, but with the eye of contemplation [emphasis added].
Likewise, Wilber contends that "in the modern and postmodern world", religion "will rest on its unique strength—namely, contemplation" or serve to merely "support a premodern, predifferentiated level of development in its own adherents: not (as) an engine of growth and transformation, but (as) a regressive, antiliberal, reactionary force of lesser engagements". He subsequently observes that "(i)f religion possesses something that is uniquely its own, it is contemplation" [emphasis in original]. Moreover, though, "it is the eye of contemplation adequately employed, that follows all three strands of valid knowing" [emphasis added]. "Thus religion's great, enduring, and unique strength is that, at its core, it is a science of spiritual experience (using "science" in the broad sense as direct experience, in any domain, that submits to the three strands of injunction, data, and falsifiability)" [emphasis in original].
In this same way, but "namely, to find some scheme that could accommodate both premodern and modern worldviews, and thus integrate religion and science"; because "the core of premodern religion was the Great Chain, and since the essence of modernity was the differentiation of the value spheres (the Big Three or the four quadrants)" [emphasis added], Wilber's text claims to accomplish a reintegration of religion and science by conjoining "the Great Chain with the four quadrants" [emphasis in original].
=== Part IV: The Path Ahead ===
Wilber similarly notes however, that "(w)hat needs to be integrated is not the dissociations but the differentiations of modernity, for not only do these define the dignity of modernity [emphasis added], they are an irreversible part of the evolutionary process of differentiation-and-integration" [emphasis in original]. Also, but by virtue of the likelihood that this "future evolution" proves to be a "process of collectively unfolding the yet higher stages of the Great Chain, as it has already unfolded the lower", Wilber envisions too that "real religion—genuine spirituality and the deep sciences of the interior" could subsequently serve "an unprecedented role as the vanguard of evolution, the growing tip of the universal organism, growing toward its own highest potentials, namely, the ever-unfolding realization and actualization of Spirit [emphasis added]".
For this reason too, and because "(t)raditional conservatism is "in many ways" adduced as being "anchored in premodern worldviews . . . whereas liberalism is largely anchored in the rational differentiations of modernity", Wilber envisages an integration of religion and science as opening "up the possibility of a significant reconciliation of conservative and liberal views". Prospects for this harmonization are further expressed as the means by which transrational awareness [emphasis added], "standing within the political freedom—the liberal freedom—offered by the Enlightenment . . . moves into its own higher estate by pursuing Spiritual Enlightenment, which it then offers, within that same political freedom, to any and all who desire to be released from the chains of space and time, self and suffering, hope and fear, death and wonder" [emphasis in original]. This "politics of meaning" then, in "its own spiritual realization" is "thoroughly transliberal, bringing together the Enlightenment of the East with the Enlightenment of the West" [emphasis added].
== Criticism ==
Reflecting an array of impassioned thought concerning a demarcation problem in the relationship between religion and science, The Marriage of Sense and Soul has spawned a range of intellectual response; both affirming and derogatory. Included among these many views was that of Dutch author Frank Visser who published an article addressing the book's detractors. From his perspective, Wilber's tome had "alarmed several critics, not too familiar with [the author's] works" even though (or perhaps, because) it represents "a view of reality which is large enough to absorb ANY conclusion of science—be it natural, human or spiritual—without giving science the last word" [emphasis added].
In response to Visser's piece, Wilber drafted a reply of his own saying that his "critics have completely missed" one "simple but essential point"; that was, by assuming "that in expanding science to include the higher realms", they'd inferred he was "somehow reducing the higher realms to science." This misconception is negated in the fact however, that "even with an expanded definition of science", he never reduces "the higher realms to science only, for there are the art and morals and science of the higher realms. And the art and morals have different specific methodologies than the sciences, as" he'd already explained in length [emphasis added].
== See also ==
Constructive empiricism
Constructivism
Contextualism
Integral theory
Integral (spirituality)
Involution
Jürgen Habermas
Phenomenology
Relationship between religion and science
Signifier (floating)
Validity (disambiguation)
== Notes ==
=== References ===
== External links ==
"The Development of Absolute Idealism"
The Marriage of Sense and Soul (book review) Archived 2011-06-02 at the Wayback Machine
"Unique Self Dialogue: Part 1, Ken Wilber & Marc Gafni | Wikipedia/The_Marriage_of_Sense_and_Soul:_Integrating_Science_and_Religion |
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