[Music] Scientists think they found the Fountain of Youth. What I think will become the cover story on magazines that humans have discovered the Fountain of Youth, and this will arise from Yamanaka factor-based cell reprogramming methods. It feels like a piece of technology that's fallen through a wormhole from the future. It does sound a little bit like science fiction. A $3 billion investment that was just made in Altos Labs, which is probably one of the biggest seed investments ever. He has made seminal contributions to understanding stem cell reprogramming. So at this time, it's my pleasure to introduce our recipient this year, Juan Carlos Espinosa. [Music] [Applause] [Music] Belante. Good afternoon. My name is Juan Carlos Belmonte. I'm going to start my participation with a rather provocative question, which is, can we rejuvenate an organism? And if so, what is the implication of that response for human health, for human disease? So the book of our lives is given to us when we are born. Our parent

past has this set of instruction, these millions and millions of letters that constitute our genome, and by and large, this is a very solid process. But every now and then, there are mistakes in these letters, and they may have importance for our life or may be irrelevant. Let me give you an example. For instance, you change, in this case, a C to a T. You're going to have a phenotype that is depe here. These kids, they are in the picture between 6 and 10 years old, but they look much older. They're really old, and they're not going to pass their teenage age, and just because of this small mutation, a C into a T. Now, fortunately, in the last few years, we scientists have developed methods by which we can reverse that change. We can fix that mistake. And, for instance, we have models in the lab. We have animal models. In this case, it's a mouse where we have created the same mutation, the C into a T. This mouse, a lab mouse, lives for about 2 years. This

mouse will live just for a couple of months, three to four months maximum, and it will have the same accelerated aging process of the human. But we can fix this. We can change this T back into a C, and we get this mouse, which has nothing to do with the previous mouse, is healthier, lives longer, and is able to regenerate some of their tissues that before it couldn't do it. The problem, as I was indicating before, is that this is a very small percentage of the mistakes that happen in our life. By and large, this is less than 1%. There are mistakes that generate diseases like this. By and large, we have many other diseases that are not due to a mutation in our genome. And if we look at this graphic that represents age and the possibility of death, you can see that after a certain number of years, around 40-45, the major risk factor for getting any disease is precisely that year's age. So the longer we live, the increased risk to get diseased, and around 40-45, we start to

develop all these diseases that you see at the top of the screen, and they are not related to changes into C or a t or a particular mutation. So how does this happen? How do these diseases appear, and what can we do about reversing these diseases? So let's go down to the cell level. Here you have two types of cells: a very young, healthy cell and an old, unhealthy cell. The healthy cell is very resilient in the presence of risk factors. It has a very strong buffer capacity, we call that, that can deal with these stresses. However, the old, unhealthy cell, in addition to the fact that it has been exposed because of time to more factors, excuse me, it has less buffer capacity. It's less resilient to these factors that damage the cell. And the question that I want to present today has to deal with this buffer capacity. And what is buffer capacity? Let's see if I can explain this well. So with time, as time passes, there are more risk factors during normal aging, there is more stress, and the buffering capacity, the resilience of

these cells go down, and when these two arrows, these two curves mix, the seas appear. And the question is, can we increase buffer capacity so that then the disease appears later, or it never appears? Can we increase the cell resilience to deal with the disease that appears with aging? When we are young, we really don't think about aging when we are old. A big percentage of our days is just thinking about how bad I feel and what can I do. So, can we increase this buffer capacity so that disease doesn't appear, it takes longer to appear, or we can even reverse it? And how can this be done? Just pause for a moment. What is aging? What makes that cell fragile, unhealthy? Many things. Our metabolism changes with age, our energy levels drop, our mitochondria don't produce that ATP that is needed for the cell to work properly, stem cells in our body die. Many things happen while we age, but I'd like to propose the idea that among all these things that happen during aging, there is one very important thing that could help to increase this

buffer capacity, and this has to do with what we call the epigenome. Epi comes from the Greek above, above our genome, above the instructions that we receive from our parents. And if we look at the cell and the genome, the DNA of any cell is very big. It will take approximately 6 ft if we were to extend it here, but we need to pack it inside a cell, and it has a special conformation bounded by specific proteins, which in a very basic way we can divide into a conformation that is open for business that we call open chromatin or closed for business, closed chromatin. And just this changing the conformation of the chromatin may have a huge effect on the health of the cell and the organism in the time when the disease appears. And the first and most important experiment to demonstrate this was done by Dr. S. Yamanaka, where what he did was a very simple experiment. He took four genes, added to an adult cell, a cell that is fragile, that is

unhealthy and make that cell an embryonic-like cell again. He did this by changing this confirmation of the chromatin. Now, can this help us, this experiment for which he was awarded the Nobel Prize? Can this help us deal with the problem I am trying to convey today: reverse disease, bring back time, and make the cell more resilient and healthy again? So, through a few years of studies, the message is this: that there is a correlation between the conformation of the chromatin, aging, and disease. When the epigenome, when the chromatin is closed, we call this heterochromatin. The cell is young, is healthy. When the chromatin is open, it leads to the increase, the loss of buffer capacity, and therefore disease and aging. And the question is, can we reverse that? Can we, this correlation, can we do something to alter the confirmation of this chromatin and demonstrate that just by bringing an open chromatin to a closed chromatin, we can rejuvenate a cell? And how do we do that? We took advantage of the initial ideas and studies of s

Yamanaka and using again this mouse model that I indicated before. This animal that has a mutation that has a C into a T that leads to an accelerated aging. You can see the animal here doesn't have hair, it's small, it's not going to live for too long. And what we did, we took these four factors, So-Cal Yamanaka factors, and put it inside this mouse, this old mouse. We're not fixing the mutation, remember at the beginning there is technologies by which we can fix the mutation. What we're doing here is just altering the chromatin. The mutation is still there in this mouse, the cause of the problem, that letter is still there, not fixed. But we're altering the chromatin, and we do this not continuously, we just do short pulses of the Yamanaka factors. We put just during the weekend, we put these factors, not during the entire week, to this mouse. And what happens is that we get a very different mouse, healthy mouse that is able to live longer. And remember, we have not fixed the mutation, the T is still there. So

Just by this small change in the chromatin, we can rejuvenate a mouse. And here is just an example of what I'm telling you. We can either, with very precise tools that we have developed, correct a specific mutation at the top, the C to a T, or without knowing the mutation, just that we know that this mouse has a problem. We just alter the status of the chromatin, and we practically get the same phenotype. We get rejuvenation on this mouse, either genome correction or epigenome buffering, increasing the capacity, the buffering capacity of this mouse. So, we have gone through from the initial point to a later point where the mouse will live longer and will have a healthier life. Now, anyone could tell me, Yes, you are telling me just about one case, this particular mouse that has this mutation. Does it work for something else, for other diseases? And the answer is yes. Let me tell you just one more example and a few others in a summary. Here we have another mutation. These mice have a mutation in a

gene called leptin, which makes these mice eat all the time, and as such, they get fat. They change their metabolism, they get older faster, etc. If we just give a short pulse of these Yamanaka factors, we get this mouse. The mouse still keeps eating because it has the mutation; we haven't corrected it. But the mouse now has less fat in the liver and can respond to glucose like a normal, young, and healthy mouse. And if we extend now, and I don't have time to go through this to many other diseases that we have tested in the lab: kidney disease, skin disease, liver disease, muscle disease, etc. The same thing happened; we can bring back this buffer capacity and make the cell younger and the mouse younger. There's a sentence there that says a deceased agnot this approach when you have a problem, you have a disease, you go to the doctor, and it gives you a medicine. But if you have another disease, it gives you another medicine. If we have a mouse with a mutation, we try

to correct that mutation, another mouse with another disease. We correct that mutation, but what I'm telling with this slide is that, independent of the disease, just by this small switch of changing the chromatin, we can increase the capacity of resilience of this mouse so that the disease takes longer or is even reversed. I think this is a very profound message that is not very precise. We are not touching the genome; we're touching the epigenome. But without this Deion, we can revert disease. Now, the key question is, This is great. I told you. Can we rejuvenate an organism? At the beginning, it seems that, based on this and other experiments in Rodin in the lab, the answer is yes. We take mice with different pathologies, we pass them through these short pulses of Yamanaka factors, and they're better. The disease takes longer to appear; they live longer. But even though in science, this animal is the one that we know more about health and disease, much more than humans, our interest is healthy people.

would this work in humans? And this is our mission in Aldos. Try to, by this cellular rejuvenation programming, increase the buffer capacity of a human cell so that the disease is reversed or can take longer to appear. We have done this in isolated human cells in the petri dish, but the next step is to move to a human being, an entire organism like the mouse. And this has to be done so that there is with all the safety and all the precautions so that we do not harm when this experiment is done. These mice are healthy, healthy, they're fine, there is nothing wrong with them, but we need to really be very cautious when touching a human cell. So rather than delivering these factors inside in vivo of a human being, what if we do it ex vivo? And here is an example, organ transplant. We know that organ donations save thousands and thousands of lives every year on our planet, but nonetheless, there are many thousands of organs that are discarded because of their quality, because they are old, the doctor when the organ

comes look at the organ and said, This is this organ is not good enough, doesn't have enough quality to be transplanted, and it just gets discarded. What if instead of going directly into a human being, we try to rejuvenate this organ that is discarded and see if the doctor now will say, Now this organ is ready to be transplanted, whatever conditions and quality required by this doctor, and we are making progress into this area. You can see here when we transplant ER, in this case, is still in Rodin, an old kidney into a young rat, and we compare this with the transplantation of a young kidney. The life of the horse is very different. You see these two, the green and the blue lines. So the blue line is with no treatment, the green line is after a short pulse of these factors that is given X Vivo to this organ before it's transplanted, and that led to an increase in the survival of the horse. So that's one way to start approaching of moving this technology.

that we are developing in the lab in mice into humans. But at the same time, there's one thing that, and I'm finishing, there is one thing that I would like to stress. It's not that all the cells of our organism go bad with time; otherwise, we'll be dead. There are just a few cells, and with time, there are more and more of these fragile, unhealthy cells that don't have enough buffer capacity. And you can see this in this diagram. The blue dots indicate that with time, we have more and more of these nonfunctional cells. But what we don't want to touch is what is working. We don't want to deliver these factors to cells that are healthy and that are functional. How do we deliver these factors just to those cells that are not working, to these blue cells? So, you see here the two H situation in a young tissue. You almost don't have any of these fragile and unhealthy cells. And how can we deliver the factors just in the age situation to the unhealthy cells, but we don't touch, we don't want to touch

the healthy cells. And this is what we have been doing. There are specific genes and markers that target and identify the unhealthy cell. And with these markers, we can guide our Yamanaka factors just to the unhealthy cell, and we obtain the same phenotype. You can see here an increase in lifespan just by targeting the unhealthy cell, increasing the buffering capacity of the unhealthy cell. And the last slide that I want to show you is, for instance, an organ like the skin. If we bring these factors to the non-healthy cell of the skin, you see phenotypes like this. For instance, an old mouse, like us, with time will get gray hair. It would just bring the factors to the unhealthy cells of the skin that produce this deterioration of function. Now you see that the gray hair doesn't appear. Or if we do a wound in the skin of an animal, of an animal and this in us after a certain age, the wound takes a long time to close, or even it doesn't close. You can see at the top the non-treated in red. There is there is a

wound there that has doesn't heal while the treated one even in a very very old mouth it just make a perfect Skin. So summary of what I have told you today is this that there is what we call Precision Medicine by which we can fix some of these mutations errors that our parent transmit into the book of our life but that's less than 1% of the diseases the majority of diseases correlate with age passing of the time and they don't have anything to do with particular mutations and without touching the genome with this Precision medicine just just modifying the conformational structure of the chromatin we can bring a disease and aged cell into a cell that is more resilient and more functional and certainly this type of experiment and the messages that it open up the question of can we rejuvenate a human being and can we reverse diseas in human thank you for your [Applause] right ju caros thank you for the presentation I want to I I don't I don't know if you can

overstate the significance of the discovery you have made, and it's funny to me how it's not popular knowledge at this point because of the results that you and other scientists have collected and the impact it will have to literally restore cellular health and deage an organism. The Yamanaka factors, or four proteins, just for Layman's conversation, are four proteins. That's what a factor is. It's a protein that causes a change in the epigenome and unwinds parts of the DNA. As a result, new genes get turned on, other genes get turned off, and the cell kind of revitalizes. It becomes young again. You discovered that you can actually—and they did this all—and made the cells go back all the way to being stem cells. But what you discovered was the ability to partially restore youthfulness in the cells through partial reprogramming. That's a dose factor. You put a smaller amount of the Yamanaka factors on the cells. What

how do you control it? And then I want to ask a question about if you put too much. Does it then, because I know there's been tests in mice where you end up with cancer because then the cells start multiplying too quickly. So maybe you can tell us a little bit about what it means to do partial reprogramming with the amak. What does partial mean? Very important question. Thank you for, let's see if I can clarify this. What Dr. S. Yamanaka did is something that no one in science in general could believe, that you can bring an adult cell to a start life again, become an embryo cell, embryol-like cell, an embryonic stem cell. Can be whatever. We have more than 250 cell types in our body. Our skin cell is different than our eye cell, is different than our brain cell, because different genes are turned on and off in each of those cells. They have the same DNA, but they have a different epigenome, different genes are turned on. Perfectly explained. Thank you.

So, and what I think it's so for people to get that. Yeah, what SAA did was just to delete, delete all that information, the identity of a skin cell, of a heart cell, and bring it back to the very beginning, to the very first time when we are born, to this type of cells. Now is when he was putting these factors, it's his factors, the Yamanaka factor for a long time, four proteins, four proteins, put them on the cell. This happens now. We don't want this. Imagine if we were to put this in the heart. The key cell in the heart is called cardiomyocyte, and what it does is beat. So, if we remove the identity, can't of that cell is not anymore a cardiomyocyte, and go back to an embryonic cell, the heart is not going to beat if we do that. In the liver, theoy is not going to do its function. So, doing this, going back in time to really the early stages, it will not do good to our bodies.

and then cancer arises. And then if you bring and lose the identity of a particular cell, then you are open for that cell to become something else, right? Like a cancer cell or a skin cell is transformed into many wrong things could happen. We want to maintain the identity of this cell, and the small switch here that we did, as you are asking me, is rather than having the factors for a long time, we just gave a short pulse. What that is doing is altering the chromatin, but for a very short time. It's a small shock, and then the chromatin gets close and maintains its identity. The cardiomyocyte is a cardiomyocyte, has not gone back to a different cell type, but its function is much better. This is so. The idea is just a short pulse of these proteins, which by the way, these are the proteins that Yamanaka discovered, but I'm convinced that there will be many other proteins. So that's organism. That's the next thing I wanted to ask you. So it

sounds like the search is on in various startups at Alto slabs for other proteins that can do this, but perhaps not protein, but smaller molecules, peptides, or small molecules, where theoretically you could take a pill, and it would do the same thing. Is that a reality? So, I think that one of the biggest inventions that we humans have made is the place we're here today, the university, the curiosity, the knowledge to advance in things that we don't understand, um, and discovering what other proteins, what other factors could do the same thing belongs to that domain of the curiosity and trying to increase our knowledge. But many times, we need to try to apply this knowledge, and you're asking me how are you going to deliver whatever factors you discover into a human being. You can do this in the lab with many other ways, but ideally, you would like to just put that into appeal. And so, here is where the other important thing comes, and that's industry, by mixing the Bas of Academia, this curiosity, this trying to

understand how we can close and open the chromatin with many other factors. With the experience, the drive, and the focus of industry, can we answer the question that you are asking? Can we put these factors or any other factors that alter the chromatin into appeal? This is precisely our endeavor: to try to make this safe and available to... Can I ask you a more, maybe a more basic question? Um, if this buffer capacity is essentially the insulation that we are born with that then decays, so young cell, good buffer capacity, old cell, no buffer capacity in very simple terms. Based on your side, what is the scientific community's understanding about how to minimize the rate of change and the decay by things that people in this room can control? Where we live, the things that we're exposed to, our food supply. Do any of those things, to your understanding, have an impact that's measurable and achievable by us today while we wait for altos and others to deliver more chemical manipulation of this huge impact? Incredible question and really huge impact. Just think of exercise. We

have compared what are the changes in the Cell between exercise and the short pulses of Y Mana factors, and you couldn't believe the similarities in the changes in gene expression that exercise th and how overlap these changes happen when we do the yamanaka the sh PES of yamanaka factors. So, things like exercise, but exercising what kind of exercise, how much, how often, why you want to know the answer too what don't laugh actually you know what don't answer the question you can tell us afterwards because they don't care don't it's [Applause] fine and exercise things that your mother will tell you eat less exercise H when I say stress I mean it stress to the cell that is going to alter the epigenome. So, until we really understand how these changes in chromatine happen, all these things that we do sometime with our life really improve the buffer capacity and has that been published or studied in a way that's digestible for Layman, meaning like whether it's intermittent fasting.

or whether it's the quantity of food or whether it's, you know, specific forms of exercise over another. Has that been well studied enough that we can, at a minimum, we can even just link to all of this so that you guys can get this information? But is it out there? This is, I would say, the last 10 years have been an incredible jump into these studies. So far, most of them have been done in animal models, in the lab, and we are starting to translate this to humans. For instance, I just finished. It's not, I think I can say that tomorrow it will be just one of these molecules that diabetic people take, metformin, to lower down their glucose. They can reprogram the cells so that all the cognitive function, or not just rodents, and this is the key thing, but of monkeys, which are 99% their book of life is very 99.9% similar to us, right? It can reprogram these cells and the cognitive abilities of monkeys, and their lifespan is increased. So this is coming. This is not

something that is just this small. Mouse in the lab where we know a lot about their health and disease, but I feel the next decade probably many of these discoveries with the caveat that it's a mouse and a mouse is not a human, might be translated to human. You put a slide up there where you had obviously a whole bunch of target markets. Some were autoimmune diseases, some were cancers, some were more just general aging. How do you decide or how do you figure out where there is the most real application today? Because part of it is there's obviously a market issue of making sure you continue to have capital and prove scientific value, but part of it is there may be some small wins today in rare diseases or something that could allow you to commercialize this faster. So how do you think about which problems should come first? Good question. I put up there the ex Vio example with the organ transplant. This is probably one of the most cautious and safest approaches where, say, acute liver disease, there's

nothing about this. You're going to die in 3 days, right? And if an organ is not there, you can do nothing. So, acute and deadly diseases that could happen could be an initial target for these types of approaches. But again, I want to say that even though we are trying to move as fast as we can into humans and we are doing this experiment in human cells in the Petri, a mouse is not a human, and this will need time to be replicated in a human being before we wrap. Can we just talk about how Altos Labs is set up? It's probably got more funding than any other private company in recent history. It's really incredible how the... Maybe you can tell us how you've organized this work, this mission. And again, reflecting on the importance that we know so little about the fundamental science of what is behind this big question. It's a question that we human beings have tried to approach since ever. How can we deal with disease with

aging so there are so many things we don't know. Basic sign is needed. So, as a startup, you raised billions of dollars to do a lot of core research as well as product development, and at the same time, in parallel, yeah, with all the safety approaches that we can think of. And we were talking about one possible example, perhaps without knowing every detail of how it works, provided it's safe and could have a positive effect, trying to move this forward. So, it's a combination of what we like to call the base of basic science and the base of industry. Yeah, well, look, I mean, I don't think there's a human on earth that will not benefit and does not appreciate the effort, and obviously, everyone hopes that you guys are extremely successful in both the scientific and commercial pursuits. I, it seems to me like as you guys have your breakthroughs, which I think you're going to have given the backing and people that are involved over time, partial cell reprogramming could be one of the most profoundly

impactful technologies that humans have ever discovered or invented. So, we appreciate the work that you do and thank you for being here with us. Thank you for thank you. [Applause]

Juan Carlos Izpisua Belmonte, Altos Labs | All-In Summit 2024

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