| 1 | Serious Science | Induced pluripotent stem cells - Rudolf Jaenisch | 16695 | 269 | 12 | 60.6 | positive | 11:45 | In use to report stem cells have a long history. What I learned at school was development is irreversible. So once a cell develops to a liver, it's a liver. It cannot become a brain. It cannot become an embryo. It's irreversible. This concept was shaken. Half a century ago by the seminal nuclear transplantation experiments of John Gerden. So what he did, he took the nucleus of a somatic cell, a cell of the intestine, and put the nucleus into the egg of a frog. And he reprogrammed, it wasn't called this, then, he reprogrammed this nucleus to become a whole frog. So development was not irreversible. So then in the 90s, when embryonic stem cells were discovered, nuclear cloning and stem cells were put together to the concept of a therapeutic cloning, which means you could make a embryonic stem cell from a patient. From a patient who want to generate cells for to a therapy. Like if you have a blood disease and you have sickle cell anemia, then you want to treat this with what's called autologous cells, autologous bone cells, which are not rejected. They have to come from the patient. How would you make that? You can't. But then you take the skin cells from this patient and reprogram it in the egg and the human egg. And then you get an embryonic stem cell. From this you can make a blood stem cell. That can be transplanted. Okay. The problem was for human consumption was human eggs are difficult to get and nuclear transfer in humans hasn't worked yet. So the problem was how do you do the reprogramming without eggs? And this was the invention of IPS cells, induced pluripotent stem cells. So what was discovered in 2006 by Yamannaka was you can use a few factors. Prescription factors. Put them into a fibroblast in a skin cell and induce this cell to undergo a reprogramming to a pluripotent state, which means these skin cells which normally are there to make hair and pigment but not brain and liver. There would become no pluripotent and these pluripotent cells could now make brain, liver, hair and skin, everything. So this was a major breakthrough because you could use now these cells potentially for studying diseases. I'll come to that later. You can study human development and it has an enormous scientific implication because you suddenly the concept of irreversibly of differentiation of being a liver cell, a brain cell or skin cell was shattered. It was not irreversible. It was fully reversible. There is nothing like an irreversible cell state. And indeed, following these discoveries of IPS cells, we are now able to convert fibroblast to an IPS cell and then the IPS cell to a liver cell or directly take the fibroblast and make directly a liver. It's called trans differentiation. So suddenly we had to realize things are much more flexible. So what is behind that? Well what's behind that is that first of all, which was in the original GERD experiment, nuclear transfer and frogs was the question, what's the difference between a liver cell and the brain cell? So it was clear liver cells would express different genes and brain cells. One way to achieve this would be you just delete the rid of the brain genes in the liver and the liver genes in the brain. So there would be genetic differences between brain and liver cells. If that was a case, nuclear transplantation should never have worked. Because it worked, it was clear this was not the case. So that was established. The IPS cells tell you know, well, it works pretty easy. You just have to culture the cells in a certain way, treat them in a certain way and you convert a skin cell to a liver cell and a skin cell to a brain cell. So that's really, so how does it work? That's of course great scientific interest. And what comes out, no, what sort of crystallizes is what we call epigenetic. It's the epigenetic state of the genes. So the genes are there in the liver, but they're not expressed. They're not expressed because they are packaged into chromatin, into histones. The DNA is modified, we call it epigenetic modification. So the genes are silent. The same genes, let's say brain genes, they're not silent in the brain because they're these genes are in a different epigenetic state and they can be expressed. So now we are able to switch that. Switch the different types of pattern of epigenetic modifications where cell types differ to one to each other. And I think the IPS, the IPS approach, led the way where we learned how to do that. And I could go into what one has to do, it becomes clear and clear, although there's much to learn. So I think it has a major developmental dimension, the IPS cells to learn what's the difference between two types of cells. It gives us the ability to convert one cell type to the other. And it will have, I think, enormous potential to study human diseases and potentially to call for therapies. So there are many, many issues here. So one issue is what is a good IPS cell? Because very easy to make bad ones. So what is a good one? What are the criteria? So in mouse, we work lots with mouse. That is rather easy because these cells of their good can make mice. So you take these skin cells, make an IPS or make a mouse. That's a pretty good system, right? I mean, imagine a skin cell makes a complex organism with eyes and a heart and hair. That's pretty amazing, right? If you think about it. Now, when you think about human IPS cells, you don't have that test. You cannot take human IPS cells and inject them into a human early embryo and make it what we call a camera. That's not allowed and not possible. And of course, that would be an nonsense experiment. So we have to rely on different criteria. And there is a lot of discussion and I think that's not resolved. For example, the gold standard, I embryonic stem cells, which come from an embryo. In mouse from a mouse embryo, a human from a human embryo. IPS cells come with this conversion process from a let's say skin cell or some other somatic cell. And it's clear there are differences. In mouse, we know these differences. In humans, we don't know. What is a gold standard? What do we have to try to aim to get? And so these are very important questions, which are not resolved at this point. And there comes together, they have to be analyzed by epigenetic confirmation, by genetic, by all sorts of means, and biologically. So I think there are many, many questions which have to be resolved. I think the biggest problem now, or the most unresolved problem, is how do you make specific cell types from an IPS cell? So the IPS cell can grow forever there in model, but you want to make mature liver cells, mature beta cells of the pancreas, for example, to study diabetes or neurons. And that's at the moment is still a problem. We want to learn how best to differentiate these cells to mature functional cells, which could be used to study the function of a liver cell, but also to provide cells, let's say, for therapy or liver disease. These are very important issues, they are really largely unresolved. I think we're getting, now, the methods in hand to begin to resolve those and to answer those. But I think that's a very active, it remains a very active topic of research, where we need progress. And the question really would be, can you make organs? Now, IPS cells or M-Ringstem cells are able to make organs in the embryo, in the context of developing embryo, sure. But that's not what we can do with human cells. So with human cells, we can ask the question, can you make a liver in the patronage? And the answer is no. You can make liver cells, but not a liver. You can make heart cells, but not a heart. It's a very complex organ like a heart, which only can develop in an embryo when all sorts of influence and all sorts of signals coming from different parts. So this is not possible, although people begin to try to use by engineering to make simple organs, they put a scaffold into this and make maybe an organ like a nurse of a ghost or a truck here, where you see cells on it and that's possible. But these are simple structures, of course. But a very complex structure like a kidney or a heart that is really at the moment not possible. But I don't think we need that for this technology to be highly useful for learning something about how organs function and how specific cells function. The future for this will be to resolve the technical issues which I outlined. Some of them was differentiation. So when we were, we go back ten years, when we had only nuclear transplantation to make this patient specific cells, for example, the biggest issue was to do it without cells, without eggs, and that's what's resolved. That was the biggest issue which hold back the field. This is resolved. I think these cells, now I think this is resolved. So I think we will have now getting into the more technical issues like differentiation and this will be probably resolved. There are so many people working on it within five to ten years, I think. Then we will have a very defined system where we can predict, you do this and this is the outcome and that's what you would like to have. | ↗ |