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Florida, which has a well-funded, sustained program, recently reported that its high school smoking rate fell to just 8.6 percent in 2013, far below national rates. Alaska, with another well-funded program, reported reducing high school smoking to 10.6 percent in 2013. From 2001–2010, the New York State Tobacco Control Program reported declines in adult and youth smoking rates that outpaced declines nationally.
In California, which has the nation's longest-running tobacco control program, lung cancer rates have declined four times faster than in the rest of the United States.
Studies have also found that tobacco prevention programs deliver a strong return on investment. A 2011 study in the American Journal of Public Health found that Washington state saved more than $5 in tobacco-related hospitalization costs for every $1 spent during the first 10 years of its program. A February 2013 study found that, from 1989 to 2008, California's tobacco control program reduced health care costs by $134 billion, far more than the $2.4 billion spent on the program. These results underscore how penny-wise and pound-foolish the states have been in shortchanging tobacco prevention and cessation programs.
Comprehensive state tobacco prevention and cessation programs include the following key components: (1) coordinated state and community interventions aimed at preventing youth and young adults from starting to use tobacco, promoting quitting among current tobacco users and eliminating exposure to secondhand smoke; (2) mass media campaigns and other public education efforts; (3) cessation interventions that encourage and help tobacco users to quit; and (4) surveillance and evaluation activities that monitor attitudes, behaviors and health outcomes to ensure the program is having the desired impact.
While the nation has made enormous progress in reducing smoking, tobacco use remains the number one cause of preventable death in the United States. Every one of these deaths is entirely preventable if we do what we know works. What's needed is the political will to fully implement proven strategies, including funding state tobacco prevention and cessation programs at CDC-recommended levels.
Pakistan did not adequately address the key US concerns, including the threat posed by the Haqqani Network and other terrorist groups including Jaish-e-Mohammed and Lashkar-e-Tayyiba that enjoyed safe haven with Pakistan.
Though Pakistan continued military operations to eradicate terrorist safe havens in the Federally Administered Tribal Areas, their impact on all terrorist groups was uneven, said the State Department report.
The US on Wednesday said the Jaish-e-Mohammed and Lashkar-e-Taiba militant groups continue to pose a regional threat and that Pakistan did not adequately address America’s concerns on terrorism in 2017.
Although al-Qaeda in Afghanistan and Pakistan has been seriously degraded, remnants of its global leadership, as well as its regional affiliate al-Qaeda in the Indian Subcontinent (AQIS), continued to operate from remote locations in the region that historically have been exploited as safe havens, the US State Department said in its annual Country Reports on Terrorism for the year 2017. “Pakistan-based Jaish-e-Mohammed and Lashkar-e-Tayyiba continued to pose a regional threat in the subcontinent,” it said.
The report notes that from August to December 2017, the Trump administration placed a pause on spending new Foreign Military Financing for Pakistan, holding these funds until Pakistan addressed key US concerns, including the threat posed by the Haqqani Network and other terrorist groups that enjoyed safe haven with Pakistan. “Pakistan did not adequately address these concerns in 2017,” said the report.
Although Pakistan’s National Action Plan calls to “ensure that no armed militias are allowed to function in the country,” several terrorist groups focused on attacks outside of the country continued to operate from Pakistani soil in 2017, it said. These groups included the Haqqani Network, besides the LeT and JeM which are directed against India.
According to the report, the Pakistani military and security forces undertook operations against groups that conducted attacks within Pakistan, such as the Tehreek-e-Taliban Pakistan.
Even as the Pakistani government pledged support to political reconciliation between the Afghan government and the Afghan Taliban it did not restrict the Afghan Taliban and Haqqani Network from operating in Pakistan-based safe havens and threatening US and Afghan forces in Afghanistan. “Pakistan did not take sufficient action against other externally focused groups such as Lashkar e-Tayyiba (LeT) and Jaish-e-Mohammad (JeM) in 2017, which continued to operate, train, organise, and fundraise in Pakistan,” the report said.
Pakistan detained Hafiz Saeed, leader of LeT and its front organisation Jamaat ud-Dawa (JuD), in January 2017, but a Pakistani court ordered his release from house arrest in November 2017, it said. In its report the State Department rued that progress remained slow on the Pakistan government’s efforts to implement UN sanctions related to designated entities and enforce anti-money laundering/countering the financing of terrorism (AML/CFT) controls.
The Financial Action Task Force (FATF), it said, continued to note with concern that Pakistan’s outstanding gaps in the implementation of the UN Security Council ISIS and al-Qaeda sanctions regime have not been resolved, and that UN-listed entities – including LeT and its affiliates – were not effectively prohibited from raising funds in Pakistan, nor were they denied financial services.
“Although Pakistan’s laws technically comply with international anti-money laundering/countering the financing of terrorism standards, authorities failed to uniformly implement UN sanctions related to designated entities and individuals such as LeT and its affiliates, which continued to make use of economic resources and raise funds,” it said.
Sybron Dental Specialties Inc. said it acquired Swiss company Hawe Neos Holding SA for $45 million to expand the Orange company's dental-products business in Europe.
Sybron, which was spun off from Apogent Technologies Inc. last year, said it expects the purchase to add one cent a share to its profit in fiscal 2002 and as much as 5 cents the following year.
The purchase will give Sybron a business that has about $17 million in revenue a year.
Sybron shares, which have risen 23% this year, fell 79 cents to $20.80 on the New York Stock Exchange.
Professor Douglas Melton introduces the astounding advances being made today to unlock the powerful potential hidden within our own cells.
I’m Doug Melton; I’m the Thomas Dudley Cabot Professor of Natural Sciences at Harvard University, and the Co-Director of the Harvard Stem Cell Institute.
Well, I’m glad to talk to you today about an exciting new biology in medicine. It’s what I call the biology of regenerative medicine and it’s going to change your life. It’s going to lead to longer and healthier lives for humans in a way that was really unimaginable just a few decades ago.
Let me put this in perspective. In the last century, infectious disease caused enormous suffering and harm to many millions of people. A simple infection like whooping cough or diphtheria or any kind of bacterial infection, led to millions of lost lives and suffering until the discovery of antibiotics. Once antibiotics were discovered, what now, for today is a simple infection would cause death. And now today with an antibiotic, we can eliminate that.
I’m going to talk to you about a biology that will similarly change our lives. It’s a biology based in stem cells and genetics and it has to do with understanding with how our bodies are made, maintained and replenished, and it will also teach us something deeply important about disease. Most interestingly perhaps, it will also open the door to manipulating our bodies in a way that we can change who we are and what our lives are like.
To put this in a little more perspective, let me remind you that in the last century, beginning with Mendel’s discovery of genes and genetic inheritance, we learned about the genes we inherit from our mother and father affect who we are. That was reduced to understand that genes are made of DNA, the chemical stuff of genes is DNA. And we now understand quite a bit about how genes encode the proteins that are found in our body. It however, can be an exaggeration, often appearing in the popular press that all we are is our DNA, and we’re much more than our DNA. Our DNA is merely a language or a code that tells our body or our cells what kind of proteins can be made, but the DNA doesn’t define who we are.
So what has been lost in this discussion up until now, is the idea that the real unit of biology is not DNA, but is instead a cell. Cells are alive, cells make more cells and cells are the units that allow us to harness the future of our bodies and regenerative medicine.
So let me move to this point by saying that I think in the 21st century, biology will usher in advances in regenerative medicine and stem cells will be at the center of discovery and application in that new field. In order to make sense of this, we have to dig into a little bit of a kind of biology called Developmental Biology. That’s the biology as shown here that has to do with answering a question, how does an egg become a human being? How does an egg make a human body?
In the last century there were two important advances in biomedicine. One was the discovery of antibiotics, which made it possible to then cure people of these what we consider to be common bacterial infections and led to so much disease and suffering.
The second major finding of the last century was an understanding of genes. This began with Mendel’s working on peas and understanding that our parents each give us some units of genetic inheritance which came to be known as genes. That led then to the finding that genes are made of DNA and that was concluded at the end of the last century with the decoding of all of the DNA, the sequence of the entire human genome.
But this, we should remember, is sort of like learning the letters of the alphabet or the words involved in a language. And language and books are much more than the letters of the alphabet or the words, it’s the way they’re combined. And that combination, to make the analogy with biology, occurs in cells. Therefore cells are really the units of life. Cells are alive, cells make more cells and it is cell biology that is going to change our understanding of our bodies and lead to new understandings of disease and development.
Let me explain that a bit more. I’m going to make the case that in this century, the 21st century, biology will usher in advances in regenerative medicine. Stem cells will be at the center of this discovery and application. To make sense of this, let’s remind ourselves what happens during normal human development. It is a great mystery and puzzle of how an egg becomes a human body. I’m going to show you some pictures of how this happens and talk a bit about the very early stages of human life.
In this picture here, you see the first spark that starts human development, that is fertilization. You see a large yellow egg there, a human egg, with many sperm trying to fertilize it. Only one sperm wins, one of those blue-headed sperm and that then leads to the first step, which will be cell division.
Cell division occurs rapidly over the first few days of development and as you see in this picture, there are two cells that are formed from the fertilized egg. Development proceeds a pace and forms an early stage of development called the blastocyst. This is quite an important stage and I’ll come back to it later, but the portion of this picture in the upper left is called the inner cell mass, and the few cells there out of the 100 cells at the blastocyst stage, it’s those few cells in the upper left that will give rise to the human body.
Within a few hours, development proceeds quite quickly and we can see here by one month later, the basic body form is already apparent. One can see the beginning of arms and legs, the heart, the eye and the facial cavities are starting to form. It’s just a short time after that, at 46 days, when it’s obvious then that an embryo is already formed. There’s an arm and a leg and you can see a kind of a cavity at the top in this picture where the brain isn’t fully formed, brain cells are being made, but they’re not completely developed yet.
To conclude then, by 70 days, you see something that’s clearly human. So within just 70 days, one has gone from a fertilized egg to something that’s clearly human, not yet fully developed, but clearly human. For me, this is one of the most mysterious and wondrous things about biology. How does that fertilized egg make this human in just 70 days?
Now, it’s not a human being yet, but it’s clearly on its way to being a human. And I like to sort of contrast this with things that we’re commonly amazed by in our life. Things like an iPod or a computer are not nearly as wondrous to me as how this fertilized egg made all of these body parts in just 70 days.
Well to look at that in a little bit more detail, let’s consider this picture where there are two aspects to human development. The first is obvious, is growth. Cells not only divide, but they have to increase in size and then growth occurs inside the womb of the mother. But the second and the one we’ll focus on today is a process called “differentiation” where cells become different from one another.
Here you see in the bottom of this picture, arrows pointing to the fact that different cells of the early embryo will give rise to different kinds of cells in the adult. The blue cells are representing nerve, the red cells there in the middle are blood cells and at the bottom is an organ, the pancreas, which makes insulin so that we can make use of our food. That process of “differentiation” proceeds until we make all of the different kinds of cells in the human body.
This picture shows, on the right, a fully formed cartoon of a human. It’s estimated that there are about 350 different kinds of cells in the human body. And as you see then, the puzzle is, how do these cells arise from a single fertilized egg?
In the last century, we’ve learned quite a bit about that. The first thing we know is that there are approximately 25,000 human genes, bits of DNA that code for proteins, that make up all of the proteins found in our cells. Now the puzzle then for a developmental biologist is to figure out how do those 25,000 genes get mixed and matched to make all the different kinds of cells?
We don’t understand that in detail yet, but that’s an exciting and important problem for the next generation of biologists. How do you take 25,000 genes and make all the different cells in the body? I sometimes think an interesting analogy for that is, when you go to a Chinese restaurant you can often see hundreds of dishes on the menu, but if you’re in the kitchen, you might only find 10 or 12 different pots. It’s the way things are mixed and matched that makes the different meals. Similarly, it’s the way our gene expression is mixed and matched at different times and amounts that makes all the different kinds of cells in our body.
Now, an important point discovered just in the last few decades is that while cells become different, they are differentiated as shown in this picture. They retain the capacity to do everything else. This is quite an amazing potential and it was demonstrated or identified by an important experiment called cloning. Many of you will have heard about cloning and I’m going to explain that to you in a bit of detail now because it establishes the very important principle that all of the cells in our body have this enormous potential locked inside of them.
This next picture then shows the result of the first cloned animal. On the right, you see 30 cloned adult frogs. These are genetically identical; it’s as if they are twins many times over. They were prepared from a mating of the two albino or white frogs shown in the middle part of the picture. And in that part of the picture, those two, a male and a female frog were mated to make an albino frog. And then nuclei were taken from that and injected into the egg of the donor shown on the left. That’s a wild type, or a normal frog. And that then gave rise, as I said, to this cloned animal, 30 times over. One could do this again and again and make many animals by this cloning procedure.
Let’s have a look in a little more detail with a cartoon of how that’s actually done because it’s an important experiment showing how one can reveal the potential of all of the genes in our cells. In this little cartoon movie, you’ll see a pipette and remove the nucleus that contains all of the genes from this… from the egg cell. So here comes the pipette, removing the nucleus leaving just the cytoplasm of the cell. The picture now shows taking the nucleus from a skin cell and injecting that into the egg cell. That sparks development, it goes on to proceed as shown in this cartoon where the nucleus is not receiving signals from the cytoplasm as to which genes should be turned on and off and development will proceed by cell division, it’ll then give rise to the blastocyst stage that I mentioned earlier. And you see in this picture the blue cells will appear shortly, those are the cells of the inner cell mass that will give rise to the whole embryo. So that’s the blue cells there at the top.
I thought it would be nice to see what does this look like in real life. So now I have a real life movie of a cloning experiment we’ve done with mice. It’s the same procedure, but in real life.
Here you see on the left, a holding pipette, which just provides a little suction to hold onto the egg. The egg is inside and the injection pipette on the right has to penetrate a membrane. That membrane looks sort of like the rings around Saturn. That egg has got this protective membrane and the pipette is drilling a little hole in there. It’s now drilled the hole and has removed the nucleus from the egg. You can see the nucleus is that sausage-shaped thing inside the pipette, which is going to be spit out.
So now we have the cytoplasm, which is the recipient for the cloning experiment. We’ll get that one out of the way. And now I’ll show in the next part of this picture a new egg coming in which has been nucleated, and now we’re going to inject a nucleus from a skin cell into that egg. Here again, it’s held with the holding pipette. The injection pipette drills a little hole through the membrane, spits out the unwanted stuff, and then watch as this sausage-shaped nucleus come in from the right. The pipette’s going to be pushed deep into the cytoplasm and squirt the nucleus into that egg.
We’ll do that again. We can line these up like a factor and do them one at a time and you can to tens of these at once and then reimplant the injected egg into a mouse to give rise to the cloned animal.
Now it looks relatively easy here. It’s not something you could do at home, but with practice, you can become quite an expert at this cloning procedure. As a result of that, at least one famous clone has been made, that’s the famous sheep, Dolly. You see here in the next picture, a picture of Dolly and her surrogate mother, the injected egg was put inside of the uterus of the sheep on the right, the black-headed sheep. And then Dolly, on the left, was born as you see here in this picture.
After that finding, it’s been possible to clone a number of kinds of animals. Here you see Dolly up on the top left in the picture, a horse cloned on the right, a dog on the bottom left, on the bottom right is a whole set of clones obtained from one cow. You might ask yourself, why would you close cows? Well, the answer to that is some cows are very good at milk production, can makes tens of gallons of milk a day, and rather than trying to breed them naturally to get more and more cows with an enormous capacity for milk production, one can clone them and then immediately in one generation get a whole herd of cows that are good at milk production.
So in this point of our understanding, scientists have been able now to clone quite a large number of animals. Shown in this picture is a list of those cloned recently: sheep, cow, goats, pigs, rabbits, horses, ferrets. I know of also common pets, cats and dogs.
What’s missing from this list is humans. I believe it’s possible to clone humans. It hasn’t been done, but that’s something we should think about and discuss is what would be the value on cloning humans and whether or not our society should allow that to occur.
For a biologist, however, cloning humans is not the interesting challenge. We’ve already learned what we want from the cloning experiment and that’s summarized here. What we can conclude from cloning is the following: the nucleus of the cells of your body, many, if not all, of the differentiated cells in your body can be reprogram by egg cytoplasm so that they can become fully potent stem cells and make an entire new animal. Another way of saying that is that during development from a fertilized egg to an adult human, there are no irreversible changes to the genes altogether called our genome during development.
So what I’d like you to remember from this is that many cells in your body have this astounding potential. They have locked in their nucleus the capacity to make any other part of your body. Regenerative medicine is all about harnessing that potential to make new cells and to treat and cure diseases.
Let’s go now to this problem of cell differentiation. We’re obviously not going to begin cloning people to make more cell types. What we have to do is make use of the conclusion from cloning to understand how we can harness and manipulate our own cells. That has to do with this issue of cell differentiation. So as I’ve said and is shown again in this picture, cells become different during development, but they don’t permanently lose the information that allows them to make any other kind of cell.
How might we get at that? Well the reason we want to get at it, of course, is if we could do that, we could replace damaged or diseased body parts. If one’s in an accident and loses some tissue or an organ or as is more common, suffering from a disease, a liver disease or a heart disease or a disease of the skin, one should be able to use our bodies own inherent capacity for development to replace or repair those lost tissues.
Now our bodies, as you may know, have the capacity to do some replenishment on their own. Not all parts of our body, but some of them are constantly replenished. You probably know, as shown here in this picture, that your skins turns over and is constantly renewed. When you got up in the mirror… or when you got up this morning and looked in the mirror, you of course recognized yourself, but if you were looking at the level of individual skin cells on your face, you’re looking at a completely new person, a person that wasn’t there three months ago. And that’s because our skin is sloughed off and new skin cells come back again and again.
That’s also true for our intestine, that is, our gut. Our gut cells are sloughed off at a very rapid rate and are constantly being repaired and replaced. So our body has the capacity to renew and replenish some of our tissues, but clearly, we don’t have an obvious capacity for major organ replacement. If you were to lose part of your brain or to lose a limb, your body doesn’t have the capacity to replenish or replace that. And yet I’ve told you that our cells have all that information inside. So this raises the challenge or the prospect of how could we learn about cell biology to do real regeneration or replacement?
So let me now talk a bit about regeneration. What is regeneration and what do we mean by it? This picture here is a painting from Rubens of a Greek myth. Zeus punished Prometheus for giving fire to humans. And as you see in this picture, they’ve chained Prometheus to a rock and then sent an Eagle to peck away at Prometheus’ liver every day. Well, it turns out; probably the only organ other than skin that our bodies are good at regenerating is the liver. So lucky for Prometheus that the Eagle was only interested at pecking at the liver. If it had been eating other organs, like his heart, he’d have been a goner.
We want to therefore understand really this process of regeneration, as I’ve said. Why is it that the liver can regenerate and other tissues don’t? So regeneration then is the reactivation of the normal process of development and we would like to use it to restore missing or damaged tissues.
Now as I’ve indicated and as you know, we as humans aren’t very good at regeneration. But there is one vertebrate, one animal with a backbone, which is extremely good at regeneration. It’s what I would call, the kind of regeneration, an expert. And here’s a picture of this species. These are salamanders. Common salamanders found in ponds all across the United States. These animals can do an enormous feat of regeneration. They can regenerate their tail. They can regenerate their limbs, their lower jaw and some of their internal organs. And I thought I’d show you a movie here, a cartoon of what we know about this and how it works.
So in this picture here, you’re going to see a cartoon of the normal process of regeneration sped up by time lapse photography. So here, a limb had been amputated and you see taking pictures every few days, a new limb growing back. Now a cartoon of what this looks like is shown here, and if you are a little queasy, you can avert your eyes when a little scissor comes into this cartoon. What we’re going to do is cut off the limb; here comes our scissors to remove it. That leads to a little bit of bleeding, the bleeding stops, that’s the worst part. And now a special skin, called the “wound epidermis” grows over the stump and now inside, a quite amazing process takes place.
You can see here, the bone in white and the muscle in red is starting to be changed to dedifferentiate, to become unspecialized, and create a mound of cells that will then go on to grow and recapitulate or reproduce a normal process of development. That takes a couple of months’ time. New cartilage and bone forms, there’s a new radius and ulna and all the carpels and the digits of the hand. So now our happy little Salamander has his limb back and he’s ready to go back and swim in the pond.
In real life, the time lapse pictures shown here in still form, shows that if one cuts through the upper arm, through the radius and ulna, or cuts here through the humerus, one can see that in both cases, by 70 days, the animal has regenerated its entire limbs.
The point I’d like to make here is that vertebrate animals have in their cells, the capacity to make any new part of their body and Salamanders have figured out how to do this on a large scale. A great challenge for us now is to figure out how we could learn to harness those processes to use them in human biology.
If we look forward to how that’s going to be done, it is, as I’ve indicated already, going to begin with learning about cell turnover. And that leads us to a very special kind of cell called a stem cell. I’ve already mentioned that cells in your body are not static, that they turn over. This picture here shows that our intestinal cells last a few days; blood cells last up to about 10 weeks and you sort of already know that because you may have donated blood at a blood drive. When you go to a blood drive, you are not permanently in deficit for the blood you donated, but your body tops up and makes new blood. The pancreas cells on the other hand, cells that are important for digestion and the use of food, live for months. Not as little as ten weeks, but for a much longer time. And your brain cells are nearly permanent. They don’t really turn over at any appreciable rate.
Well, what’s responsible for this turn over? How are these cells replenished? There are two ways our body does that. This slide shows that it’s done either with a stem cell or let’s look at the bottom of this picture at the division of fully differentiated cells.
In the bottom picture, let’s imagine a pancreas or a kidney cell which just divides to give rise to two more kidney cells. The top is really what I want to focus on today, which is a stem cell. These cells are very unusual because they have the capacity to make more of themselves, to self-renew, and to give rise to daughter cells that are fully differentiated.
So how our cells in out body are replenished. There are two ways this is done. One way is for a fully specialized differentiated cell to just divide and make two. That happens for cells in our pancreas and in the kidney, for example. But for many tissues in our body, there’s a special cell called a “stem cell.” That cell has two interesting properties. One is, it can make more of itself and the second important one is that some of the daughter cells can become specialized and do different things. A stem cell then has these two essential properties; self-renewal and the capacity to make specialized cells.
I want to focus a bit on this first one of self-renewal. I’ve been talking about how we renew our bodies, well, this stem cell does that on its own, that is one cell can make more of itself.
If we can understand how a stem cell makes more of itself that should deeply inform our thinking about how we can renew, not only a cell, but tissues and organs. So we’re very keen to understand this process of self-renewal.
A second thing a stem cell can do is make specialized or differentiated cells. Probably the best known of these is a bone marrow stem cell, a blood stem cell, which is given to cancer victims. And this cell makes all of the tissues of the blood, all of the… the picture here showing all the different kinds of blood cells.
Now among stem cells, there’s my favorite one, the one that has truly special abilities and that’s called an embryonic stem cell. An embryonic stem cell can not only self-renew like all other stem cells, but its special capacity is to make all different kinds of cells. Indeed, it can make blood, it can make nerve, it can make the whole pancreatic islet, the part of the part of the pancreas that makes the hormone insulin. So if one thinks about the significance of that, that means the discovery in the last couple of decades of stem cells has provided us with a reagent, a tool that can make any tissue in the body. It can make all of the skin, brain and nerve, what’s called the ectoderm of the body, the outside of our body. It can make all of the tissues on the inside, the mesoderm, which includes blood, heart, kidney, muscle and bone. And it can make the gut tube, the endoderm, the lung, the liver, the stomach, the pancreas, the intestine.
Now one thing I’ve skipped over here is, where do these especially interesting and important embryonic stem cells come from? Where do we get human embryonic stem cells? Let me show you that those are derived from a sort of complicated procedure making use of material from in vitro fertilization clinics. So as you probably know, some couples who want to have a baby are unable to do so by what we would call natural means. They go to their doctor at the IVF clinic, In vitro Fertilization Clinic, and donate an egg and a sperm, which is then fertilized in vitro. If that’s successful, some of those fertilized eggs are reimplanted into a woman and then after nine months, a baby is born. No matter what happens at the end of that procedure, if there is a baby and it’s successful or not, there are almost always leftover human fertilized eggs.
It’s estimated that there are about 400,000 such eggs in freezers in the United States. My colleagues and I use those to derive human embryonic stem cells. We derive them from fully informed consent, where the sperm and egg donor have said that rather than throw that material away; why not use it to try to find more about human development and disease.
So what you see is that we can take a human fertilized egg, allow it to develop to the blastocyst stage, which I’d mentioned before, in a petri dish, and then from the inside of that, culture out and derive human embryonic stem cells. The inner cell mass of this culture blastocyst is removed and put in a petri dish and then after some weeks of growing, we can isolate human embryonic stem cell colonies from it. A real life picture of that shows a blastocyst with its inner cell mass on the left and then the colonies of embryonic stem cells derived on the right. And over the last decade, we’ve gotten quite good at this and now we can isolate human embryonic stem cells with about a 50 percent efficiency.
It is worth noting that this has raised ethical questions which have important political implications and something for further discussion. Nonetheless, I believe that it’s perfectly justified, in fact, it’s something we should certainly do to try to alleviate human suffering by making use of this material which would otherwise be thrown away, to try to find treatments and cures for human disease.
I’m glad to say that in recent years there’s been another possibility of creating a human stem cell, what we call a pluripotent stem cell, which has many, but not exactly all of the properties of the human embryonic stem cell. And this one doesn’t have the ethical complications of beginning with a human fertilized egg. This method is to take a portion of skin, a skin biopsy, and then to add DNA or RNA genes that encode reprogramming factors to these skin cells. And we can make a patient-specific stem cell, shown here in multiple colors because of a florescent image, which is very similar, though not exactly identical to a human embryonic stem cell.
In the next few years, we may be able to find ways of turning these into a fully potent cell, just like a human embryonic stem cell. And that would be wonderful because it would then remove the need for dealing with these human fertilized eggs.
Well, what do we do with these stem cells? As I said, there are two kinds of things we want to think about using them for. One is to make tissues and organs, as I’ve already described with the human heart. But let’s talk about how we can use them to replace tissues in the diseased state and/or use them as tools to discover new drugs. So now I want to talk about why scientists are so excited about embryonic stem cells and stem cells in general and how we plan to use them.
This requires that I remind you where we are in biomedicine in this era. We’ve largely conquered the problem for many, but not all infectious diseases. What our society suffers from now, to a large extent is what I would call degenerative diseases. These are diseases where parts of our brain and our nervous system degenerate. For example, in Alzheimer’s, four brain basil neurons degenerate. In Parkinson’s it’s a cell that makes the chemical signal, Dopamine, right in the mid brain, which is lost. In a motor neuron disease, sometimes called Lou Gehrig’s Disease, can be abbreviated ALS for Amyotrophic Lateral Sclerosis, the nerves that innervate our muscles and make us move, allow us to breath, allow us to do all of our movement, degenerate. Cardiovascular disease is a disease, of course of the heart and the blood vessels. And the disease I am particular interested in and focused on is diabetes.
What all of these degenerative diseases have in common is that they have a genetic makeup that inclines the patient to get the disease, but doesn’t guarantee that they will get it. There’s another factor, an environmental factor, which you could say, pushes a person over the edge and causes them to get the disease. A good example would be of an environmental factor would be the sun for skin cancer, or smoking for lung cancer. A person may be inclined to get one of those diseases, one of those cancers, but it’s the environmental factor that pushes it over the edge.
We know this is true furthermore because there are many cases of identical twins, two people with the same genes, where one has one of these degenerative diseases and the other one doesn’t showing therefore that there is an as yet unknown environmental factor that therefore causes one to get juvenile diabetes.
So I’d now like to address the potential of stem cells to replace tissues and to use them as tools to discover drugs for degenerative diseases.
I haven’t talked much about degenerative diseases, so let me explain what I mean by them.
Degenerative diseases are diseases where a particular cell type in the body becomes dysfunctional or destroyed. In the case of neuro degeneration, that would be in the fore brain, basil neurons in the fore brain are lost in the disease known as Alzheimer’s. In Parkinson’s disease, it’s a different neuron. A neuron in the mid brain that makes a chemical signal called Dopamine. Another kind of neuro degenerative disease is sometimes called Lou Gehrig’s disease or Amyotrophic Lateral Sclerosis. It’s a real mouthful and we usually abbreviate it as ALS. That’s a disease where the nerves that innervate your muscles are degenerated and you can no longer move, you can’t breathe and you unfortunately die from that. There’s no treatment for it.
Another disease of the degeneration would be cardiovascular disease. A disease of the heart tissue or the blood vessels which degenerate over time leading to heart attacks and possibly death. The disease I work on, diabetes is one where our body’s metabolism can’t function anymore often because a cell in the pancreas that makes insulin is lost and therefore there is no insulin and we can’t make use of the food that we eat and it leads to the disease of diabetes.
I’d like to talk then about how we can treat these diseases with stem cells by focusing on the fact that in each of these cases, a single kind of cell is lost. In the case of diabetes, the cell which is lost is a cell in the pancreas called the beta cell, which makes insulin. There are two types of diabetes. There’s adult onset, usually related to obesity where people don’t initially use their insulin producing cells, but about 10 percent of that population eventually loses them and becomes insulin dependent. The type of diabetes that I work on is called juvenile or Type I diabetes, which is an autoimmune disease where the body’s own immune system wrongly identifies its own cells, its own pancreatic beta cells and kills them off leaving the patient without the ability to make insulin and therefore requiring regular insulin injections.
It might be worth pointing out that all of these degenerative diseases like diabetes have an enormous social and health consequence on the individual, but also a really enormous economic consequence on our society. It’s estimated, for example by the U.S. government, that the cost of treating diabetes in America runs on the order of about $178 billion, not million, billion dollars per year. So these are very important social and health problems that we would like to address.
So back to diabetes. ese islets, which contain the insulin producing cells within them.
In a Type I diabetic, as I’ve said, the body attacks those blue cells and eliminates them. In this picture here, you see that the blue cells are gone, there is no insulin producing cells and the patient is now entirely dependent on daily blood glucose checks and the insulin injections.
The way this can be treated now, which doesnLet’s talk about how we might use stem cells to treat diabetes. Well, if the cells in the pancreas are lost, they would look something like this. The blue cells here are cells that have been stained with an antibody for insulin. So they are the cells in your body that make the hormone, insulin. Every human has about 800,000 to a million of these little spheres, th’t work for a large number of people, but has been demonstrated to work, is that human islets can be isolated from cadavers, it usually takes two cadavers to prepare enough islets, those shown here in red are the insulin producing cells and they can be transplanted into a diabetic and that can make that person independent of insulin injections for many years.
What we’d like to do then is to make islet cells. That is the pancreatic insulin-producing beta cells from human embryonic stem cells. The way we go about doing that is to first understand how beta cells are normally made and then we try to recapitulate or reproduce that using human embryonic stem cells. So our starting material then is an ES cell, or the induced pluripotent stem cell, in both cases coming from a human. We then first have to instruct it, to tell it to become part of the gut tube, the endoderm. It needs other instructions to tell it to become part of the pancreas, within the pancreas it has to become endocrine, a hormone producing cell, and then finally we have to reach our target of the human beta cell.
We’re not there yet, but I’m confident that we’re going to be able to make bucket loads of these beta cells in the next few years. And as I’ve indicated before, this is just one application for human embryonic stem cells. If we go back to look at the list of these degenerative diseases, many investigators are working on how to make midbrain neurons to treat Parkinson’s patients, motor neurons for ALS, cardiac muscle cells, I’ve already shown and I just mentioned pancreatic beta cells for Type I diabetes.
So one big grand goal of the use of human embryonic stem cells is to make cells which are deficient in disease and use those for transplantation. In the next few years, I predict we will be able to see major advances in that for treatment of diabetes and some neurodegenerative diseases.
There is, however, another completely independent or parallel path where stem cells are used, not as products to put into people, but are used a tools for drug discovery. So drugs, of course, are small molecules of chemicals that you take to change your body’s Phenotype, your body’s activity. I’d like to describe an example where quite a lot of progress has been made. I’d like to describe an example where quite a lot of progress has been made in studying the neurodegenerative diseases, one in which motor neurons are lost.
The idea for this experiment is to take embryonic stem cells from a patient who suffers from Lou Gehrig’s disease, ALS, or a similar disease called spinal muscular atrophy. In both cases where motor neurons are lost. Turn those cells into motor neurons and then have a control or similar cell from a patient that doesn’t have the disease, from a volunteer. What we call control embryonic stem cells. The idea here then is to use those cells in petri dishes and then in plates, kind of like bingo cards where all of the cells are spread out and screen for chemicals or potential drugs that slow the degeneration, that stop the progression of this disease.
In the example I’ll give in this experiment is to use motor neurons that have been derived from stem cells. In one case from cells that have genes that cause a person to get the disease and in the other case not. The important point to see here is that if we use the control cells, the rate at which they die in a petri dish goes from the blue bars on the left to the right where you see the cells slowly dying. In the case where we use cells from a patient, the cells die much more quickly.
The red bars show that these motor neurons die very quickly in a petri dish. This allows us to set up an assay to look for a drug that will slow the progress of the disease. And tantalizingly, we’ve already found some examples where this could work. The green shows the amount of a protein that is important for motor neuron life for survival. And the minus sign, the drug has not been added. In the plus sign it has. And you can see much more green and red protein when we add the drug.