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

[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 A3 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 uh recipient this year Juan Carlos espia

[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 respon for human health for human disease so the 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 is 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 the these kids they are in the picture between 6 and 10 years old but they look much older they're really all and they're not going to pass their teenage H age and just because of this small mutation a c into a t now fortunately in the last few years we scientists have developed method 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 is a mouse where we have created the same mutation the C into a t and this mouse a

lab mouse lives for about 2 years this mouse will live just for a couple of month three 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 live 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 um this is a very small percentage of the mistakes that happen in our life by and large this is less than 1% there is 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 represent age and the possibility of death you can see that after certain number of years around 4 45 the major risk factor for getting any disease is precisely that years 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 this happen how 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 type of cells a very young cell healthy cell and an all an unhealthy cell the healthy cell is very res resilien in the presence of risk factors it has a very strong buffer capacity we call that that can deal with these these stresses however the all an unhealthy cell in addition to the fact that 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 reach 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 is more risk factors during normal aging there is more stress and the buffering capacity the resilient of these cells goes go down and when these two arrows these two curve mix the Seas appear and the question is can we increase buffer capacity so that then the disease appears later or it never appear can we increase the cell resilience to deal with the disease that appearing with aging when we are young we really don't think about AG when we are all a big percentage of our days is just thinking 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 metab po change with ag 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 Poe 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 epig genome 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 The genome the DNA of of any cell is 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 the specific proteins which in a very basic way we can divide it in in a confirmation that is open for business that we call open chromatin or close for business close chromatin and just this changing the conformation of the chromatine may have huge effect in 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 embrionic like cell again and he did this by changing this confirmation of the chromatin now can this help us this experiment for which he was awarded the Noel price 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 chromatine 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 chromatine to a closed chromatine 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 te that leads to an accelerated aging you can see the animal here doesn't have hair it's small it's not going to leave 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 happen 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 te is still there so just by this small change in the chromatin we can rejuvenate a mouse and here is the just example of what I'm telling you we can either with very precise tools that we have developed correct bre 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 chromatine

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 leptine which make 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 but the mouse now has less fat in the 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 test in the lab kidney disease skin disease liver disease muscle disease Etc the same thing happen 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 are you have a problem you have a disease you go to the doctor and it give you a medicine but if you have another disease it give 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 reverse 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 they're better the the disease takes longer to appear they live longer but even though in science this 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 Sease is reversed or can take longer to appear we have done this in isolated human cells in the petrides 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 inv Vivo of a human being what if we do it ex Vio and here is an example organ transplant we know that organ donations save thousands and thousands of lives every year in our planet but nonetheless there are many thousands of organs that are discarded because their quality because they are all 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 get 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 requir 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 all 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 lead to an increase in the survival of

the hor so that's one way to start approaching of moving this technology that we are developing in the lap 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 just a few cells and with time there is 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 work work into these blue cells so you see here the two H situation in a y tissue you almost don't have any of these fragile and healthy 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 we have been doing there is a specific genes and markers that Target and identify by 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 life span just

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 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

nontreated 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 uh knowledge at this point because of the results that you and other

scientists have collected and the impact it will have to literally restore uh cellular health and and deage an organism and um the yamanaka factors or four proteins just just for Layman's conversation there are four proteins that's what a factor is it's a A protein that causes a change in the epigenome and unwinds parts of the DNA and as a result new genes get turned on other genes get turned off and the cell kind of revitalizes it becomes young again um you discovered that you can actually and and they did this all the 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 and that's a dose Factor you put a smaller amount of the yanaka factors on the cells what how do you control it and then I want to ask a question um 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 we no one in in science in general could believe that you can bring an adult cell to a start life again become an

embryo cell embryol likee 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 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 for four prot 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 cardom myosite and what it does is beat so if we remove the identity can't of that cell is not anymore a cardom myosite 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 in time to really the earli

stages it will not do good to our bodies and then and 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 aite 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 get

close and maintain its identity the cardiomyocyte is a cardom myosite has not gone back to a different cell typee but its function is much better this is so the idea is just a short P of these proteins which by the way these are the proteins that s 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 come 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 chromatine into appeal this is precisely our Endeavor 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 compare 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 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 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 um for instance I just finish it's not I think I can say that tomorrow it will be just one of these molecules that diabetic people take metformine 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 a obviously a whole bunch of Target markets some were autoimmune diseases some were cancers some were more just general aging um how do you decide or how do you figure out where there is the uh most real application today because I part of it is there's a obviously Market issue of making sure you continue to have capital and prove scientific

value but part of it is there may be some small winds 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 safest approach where say uh acute liver disease there's nothing about this you're are going to die in 3 days right and if an organ is not there you can do nothing so acute and and deadly diseases that could happen could be an initial um target for these type of approaches um but again I I want to say that even though we are trying to move

as fast as we can into humans and we are doing this experimen 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 altto Labs is set up it's probably got more funding than any other private company in recent history it's really incredible how the the maybe you can tell us how how you've organized this this work this Mission um and again is reflecting on the importance that we know so little and about the fundamental science of what is behind this big question is a question that we human

beings have have tried to approach since ever how can we deal with disease with aging so there is so many things we don't no 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 is 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

uh not benefit and does not appreciate the the effort and and obviously everyone hopes that you guys are extremely successful in both the scientific and Commercial uh Pursuits I it seems to me like as you guys have your breakthroughs which I think you're uh you're going to have given the backing and people that are involved over time uh 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 and thank you for being here with us thank you for thank you [Applause]