Scientist Stories: Doug Melton, The Promise of Stem Cell Science

Doug Melton is the Zander University Professor at Harvard and an investigator at the Howard Hughes Medical Institute. Additionally, he is the co-director of the Harvard Stem Cell Institute and the co-director of Harvard University Department of Stem Cell and Regenerative Biology. His current research interests include the directed differentiation of human embryonic stem cells particularly pertaining to type 1 diabetes. Twice in his distinguished career, Doug has been listed among Time magazine's 100 most influential people in the world. Today, he's here to influence us. He presents Standing on the Threshold: The Promise of Stem Cell Science. Thank you.

Thank you all for coming, and thank you, Frieda, for inviting me and the invitation. I'm going to talk to you in the next few minutes about the possibility that this new science, this stem cell science, will change the way we think about what it means to be human and will change drug discovery and treatment of major diseases. And moreover, I'm going to make the argument that it'll help you think in a different way about aging. Something I call healthy aging. Now to put this in context, I'll make a kind of superficial statement to say that much of biology in the last century concentrated, following Mendel and his work with peas, on DNA. The discovery of DNA as the genetic material, DNA as a double helix in 1953, culminating in the sequence of the human genome at the end of the last century. While some have argued that this has yet to really pay off in terms of finding drug targets, There is no doubt that the sequence of the human genome is a major, a monumental change in our understanding of biology. I, however, am going to remind you that DNA is not alive. Cells are alive, and cells are the units of who we are. And I'll therefore suggest to you, as it shows here in this slide, that in this century the focus will become on cells and regenerative medicine. Stem cells will be at the center of that.. And I'm going to try to illustrate that with 3 vignettes, 3 little stories about how stem cells are important. These 3 stories will be first to show you examples where stem cells can be used to replace tissues, tissues that are lost in injury or by disease. Secondly, and maybe more interesting to those here in the pharmaceutical industry, I'm going to make the argument that using human stem cells to screen for drugs on human cells will change that industry because it means no longer screening on rodent cells and no longer screening on the wrong cell type. Finally, I'll tell you about some exciting new work on stem cells for healthy aging. Now the background to this in the biology is relatively straightforward. It requires that I remind you that your body is not stable. It's not like building an automobile and then it just that slowly decays. Your body is constantly being renewed. The skin on the face you looked at in the mirror this morning wasn't there 3 months ago. Of course, you know that if you donate blood, which is a good thing to do, you're not in permanent deficit for that blood. Your blood stem cells top your body back up. I might give one example there. I'm going to talk to you for about 15 minutes. In that time, your body will make a billion new blood cells. So even if you're falling asleep, as we just heard, you're actually doing something. You're making new blood cells. Now here's a slide showing you that the rate of that cell turnover varies in our tissues. I mentioned skin. The intestine turns over rather quickly. The organ I'm most interested in, the pancreatic islet, is very slow to turn over. And unfortunately, you could argue that most of your brain does not turn over. The brain you had when you were young is the brain you have today. Well, what does it mean when that turnover is disrupted? That leads to these major degenerative diseases to which I alluded at the beginning. These are, as it were, the target, in my view, for stem cell biology and medicine. These are the diseases for which, in my view, there are no good treatments, there are no good cures on the horizon, and I'm going to make the argument that studying stem cell biology is a way forward. In the case of neurodegeneration, we have, of course, Alzheimer's, Parkinson's, ALS, and we've heard about that. Earlier today. Cardiovascular disease, which I'll give one example on, and I'll also show you something on diabetes. That's the sort of dark part of my talk, is we're all going to suffer from these diseases. What will we do about it? But I'm going to finish up with a more encouraging note on healthy aging. Let's take the case then of why are stem cells important for this. Well, stem cells have two properties. You've no doubt heard about them in previous political campaigns. For today, I just want to talk about their biology, which is they have two important properties. One, they can self-replicate, as shown in the top part of this slide, meaning they can renew or regenerate themselves. And that should make you think about understanding your own body's replenishment or renewal. Secondly, as shown on the bottom right, they can give rise to specialized cells. And Dr. Dimitri reminded you of this in the case of the blood system just a few minutes ago. Where if there's a mistake in that, it can give rise to a blood cancer. Now, human embryonic stem cells were discovered, you could say, about a decade ago, a little more. Mouse embryonic stem cells have been known for about 3 decades. And one way you can think about them is these are cells which can make any part of the body. So you can look at this chart and decide what's your favorite part and what you'd like to work on. I give that challenge to the undergraduates.. And I'm going to give you an example of two of the tissues here, the pancreas, which interests me, and also the heart. Let's take the case of diabetes, in particular type 1 diabetes. Here I'm showing you a confocal microscope image stained with different colors that is an image of the pancreatic islet. Your pancreas is about the size of a banana. It has about 800,000 of these little islets, like raisins in raisin bread, in it. And in type 1 diabetes, the blue cells, the cells that make insulin, are destroyed by an autoimmune attack. So now it's not so complicated to think about connecting the dots from what I've just told you. I told you that embryonic stem cells can make any part of the body. Here's a disease where one particular cell type is missing. To give you an update of where we stand on that, I'll just show you here in this cartoon, and then one result, what we've been doing to try to connect those dots. We begin with, on the left, a human embryonic stem cell, and then we try to instruct it by giving it external signals, or educate it to become a fully functional, mature pancreatic beta cell, shown here on the right. Now, of course, the reason for that is Type 1 diabetics don't have any pancreatic beta cells left, and as many of you will know in reading the newspapers about diabetes, while our nation is suffering from large financial deficits, we're also suffering from large beta cell deficits. There aren't enough beta cells in the population to manage their glucose control, leading to the epidemic of type 2 diabetes. Here's a picture then to just show you where we stand on that multi-year project. For scale, I'm showing you on the left the kind of vessel in which we grow these human embryonic stem cells. They start off as the picture in the middle,. And then over a period of weeks, they grow into spheres, homogeneous spheres, as shown on the right. And that vessel on the left is where we grow them, and there's an iPhone to give you its size. And the important point here is that we can now grow a billion of these cells in that vessel, and that's enough cells for one patient. Here is how far along we are, which is we're not at the end stage yet, but this is a section through one of those clusters., and you can see that about half of the cells are now making insulin. So one way to think about what I'm telling you is that we're more than halfway there of having an inexhaustible supply of human beta cells for diabetics. In the case of type 1 diabetes, this leaves the problem of the immune rejection, and you're going to hear about that in not the next talk, but the one after by Larry Turka, when he's going to talk to you about how we could think about transplanting things into patients and making them tolerant. I want to give you another example. This one here is about making human heart cells. So what you see in this little movie on the bottom right are human embryonic stem cells that have been allowed to specialize, and I'm just showing you 4 examples of them making human beating heart cells in a dish. Now, of course, that's not to scale or to size, and each one of those little clusters that's is about the size of a period in a sentence. But the important point here is these are not rodent cells, and they're not cells taken out of a person. They're cells that can be grown at will from an inexhaustible supply of human ES cells. So what are the things one might do with those? Well, one could think about screening for drugs, and I'm going to show you an example in a different tissue in a moment. But the other thing one can do is think about reconstructing tissues and organs.. So I'm going to give you an example of that now, of taking these cardiomyocytes that can be stem cell-derived and thinking about how you might use those to reconstruct the tissue or an organ. So this is not the endgame, but it's a halfway point where one begins with a rat heart shown here on the left, and then it's decellularized. All the living material is removed from it. This turns out to be a wonderfully simple process of just soaking Soaking it in, like, Joy or Dawn detergent. Takes a few hours. And you can see over at the right, we have what Harold Ott, who's done this work, would call the ghost, or the extracellular matrix of that heart which is left. That can then be seeded with these cardiomyocytes derived from stem cells. And here you will see that heart pumping. You can measure QT intervals, all the kinds of things you might want to measure. In fact, Harold has shown that he can keep a rat alive for 2 hours. With this, let's call it a reconstructed organ. Now, that's a long way from making a human heart, and I don't want you to conclude from this that we're about to make human hearts. But it shows the challenge of combining bioengineering with the stem cell biology to reconstruct tissues and organs. Let me now move to another area, which is not— the goal here is not to put cells back into the patient, but instead to use stem cell biology as a tool or a reagent to understand the root causes of degenerative diseases. So we're going to switch now and say, could we use stem cell biology to study degenerative diseases outside of the patient? And the advance here is to be studying human cells and to be studying the cells that are deficient in the patient. Now, I could give you a number of examples, But I'm just gonna remind you with this slide that in each of these major diseases I touched on at the beginning, they come crashing down in general on one particular kind of cell. I talked earlier about pancreatic beta cells. I now want to give you the example of motor neurons, the neurons or the nerve cells that are deficient in Lou Gehrig's disease, otherwise known as ALS. And I'm gonna show you what we've managed to do at the Stem Cell Institute by taking cells from a person, and that was shown here in this slide, skin cells, making a stem cell from them, then turning that stem cell into a motor neuron. So now I'm gonna show you a kind of real-life experiment where we have two dishes. One is a motor neuron that's been derived from a stem cell that was derived from a patient that has ALS, and the other case is the control. Person without the disease. The significance of this is that you are now going to watch, as it were, a marker or an example of the disease pathology in a petri dish instead of in a person. So let's see if I can make this work. You will be able to tell without me telling you which of these two is the patient, that is, the person suffering from the disease. What you're watching is the neurons send out their axons and survive over a 10-day period. Actually, it'll take a little bit too long, so I'm going to bring you to the end of this and just stop it in both cases. So there you see the difference between neurons that have grown up from a control person and neurons that have grown up from an ALS patient. That provides an assay, a test, for what's, what's screwed up on the right, what's wrong with those cells, why are they failing to make good neural connections, why are they dying sooner. And remember, this is the human cell and it's in a dish so you can do drug screening. Lee Rubin and his colleagues have been doing that. Here's just an example using molecular markers that are fluorescent where one's looking for more red or green, and it doesn't matter what the marker is, the minus or the plus of adding potential hits or leads for what could be turned into drug development. So this then is screening for drugs that increase motor neuron life. The goal here would then be, just to be clear, not to transplant these cells back into the patient, because remember the cells are defective, but instead to define a drug or treatment that will slow the degeneration. Now I've learned from giving talks like this before that it's very depressing for me to tell you all the things you're gonna suffer from, or your loved ones will, and that it's gonna take a long time to develop drugs. So I'm gonna tell you, I'm gonna finish instead by talking about healthy aging. Here the idea is, could you use the body's innate capacity for replenishment and renewal and juice it up, accelerate it, figure out what's causing it to happen, so that we would age at a slower rate? And the insights from this stem cell biology are aimed to forestall the natural process of aging. And they've come from work largely by Amy Wagers and her colleagues using parabiotic mice. So these are mice that are sewn together so that they share a common bloodstream. And I know this upsets some people. I'm showing you a real-life picture of it here, but I can just tell you the mice don't seem to mind. They feed, they live the same length of time, they try to mate. They're not really troubled by this sharing of a bloodstream. The experiment is one of my favorites because it's wonderfully simple. You take an old mouse and a young mouse, and you have them share their bloodstream, and you ask, is there something in old blood which is poisoning the young mouse that makes its physiological functions work more poorly? Or is there something present in young blood that is just missing in old people—old mice in this case—that could be replaced? I'm going to finish by showing you 3 examples that fortunately It's the latter which is true. We don't appear to accumulate poisons as we age. It's more that we lack things that were present in us when we were young. I'm going to give you 3 examples of that. The first is to show that young blood improves muscle regeneration in old mice. Young blood therefore contains factors that can stimulate muscle stem cells to repair more quickly. The experiment shown here is relatively simple. The lightning rod refers to giving the mouse a charley horse in its thigh, a strong bruise. The blue and red in the middle shows you the rate of muscle repair. So if you look on the left, you see two young mice, one is injured, and there's a lot of red new muscle cells. The next one over is old and young mice, O for old, Y for young. When you injure the young mouse, it shows the old mouse's blood is not poisoning that repair, repairs at the young rate. Two old mice, you can see, are rather pathetic at repairing muscle. Look in the key case, the last one, a young and an old mouse, injure the old mouse, it now repairs at the young rate. Amy has gone on to identify a factor in the blood that is stimulating old muscle stem cells to repair more quickly. And working with Rich Lee, she's done two more experiments I'm just gonna touch on. One is to show that to everyone's amazement, This can also have an effect on the elasticity and the size of the mouse's heart. On the right is the size in a section of an old mouse's heart, on the left a young heart. In the heterochronic pairing by parabiosis, you see that it shrinks the heart and increases the elasticity, and Rich Lee has gone on to show that this definitely improves heart function. Lastly then, what about our brain? Here's another example, maybe a little too detailed for I'm not going to show it today, but it's a toxin-induced test for remyelination. Again, the young mouse is capable of improving remyelination when the brain of an old mouse is injured. So what's my point here? The point is that I think we're now entering an area of regenerative medicine where we can think very exactly about how to use stem cells to replace damaged and injured tissues, how to use stem cells as reagents for drug discovery, And we should rethink about whether or not aging is absolutely inevitable. Can we find things to stimulate stem cells in old bodies that increase their repair? The final thing I'd like to say is how we sort of prosecute or do this. And I particularly like to thank someone who I'm not even sure is here, is Jeff Flier, who's been enormously excited and helpful about getting a new department started and supporting the Harvard Stem Cell Institute. The Harvard Stem Cell Institute connects all of the hospitals with a group of now more than 900 researchers, and Jeff has been particularly encouraging about this as a new approach to medicine. I wanted to thank him, but I'll have to thank him later. And I thank you all for coming to listen.

Thank you. We thank you. Very stimulating, very exciting opportunities for us. We heard a lot today about individualized or personalized medicine. How do you see stem cell research and regenerative medicine playing a role in advancing that area?

That's a great question, Freda. I showed the example of making motor neurons from one ALS patient. A different view of personalized medicine is not just the sequence of their DNA, but to have their personal cells in a dish that represent the disease from which they are suffering. So Kevin Egan has now done that experiment with 60 different patients. So think about like a bingo card where you're looking at 60 patients at once. They all have slightly different rates of motor neuron development and decay, but now one can run a screen on 60 patients at once, and that accounts for the personal differences between them. It's a good question.

And the other is there's— we've been talking about stem cell research and regenerative medicine for a while. What do you and your colleagues in in this area see as major barriers to the advancement of this work?

I think the things that have challenged us in the past, I'm glad to say, are largely dissolved, which are the political questions about whether or not this work was ethical. Now I see the challenges as combining what we're doing with the kind of good genomics work done here at the medical school and incorporating now more bioengineering approaches. We'll hear from Larry Terka soon about transplanting things back. But there is a connection. The distance between what he'll say and what I've said is how do we get more bioengineers involved in assembling these tissues for transplantation. So back to the collaborations that we've heard about over the course of the day. Absolutely. Fabulous.

Thank you.

Thank you so much. Much appreciated. Thank you. You're welcome. Thank you, Susan.