00:00:00
[Music] scientists think they found the Fountain of Youth what I think will become the
00:00:04
cover story on magazines that humans have discovered the Fountain of Youth and this will arise from yamanaka Factor
00:00:11
based cell reprogramming methods it feels like a piece of technology that's fallen through a wormhole from the
00:00:17
future it does sound a little bit like science fiction A3 billion investment that was just made in Altos Labs which
00:00:23
is probably one of the biggest seed Investments ever he has made seminal contributions to understanding stem cell
00:00:30
reprogramming so at this time it's my pleasure to introduce our uh recipient this year Juan Carlos espia
00:00:39
[Music] [Applause] [Music] belante good afternoon my name is Juan Carlos Belmonte I'm going to start my
00:00:54
participation with a rather provocative question which is can we rejuvenate an organism and if so what is the
00:01:07
implication of that respon for human health for human disease so the the book of Our Lives is
00:01:19
given to us when we are born our parent past has this set of instruction these millions and millions of letters that
00:01:28
constitute our genome and by and large this is a very solid process but every now and then
00:01:37
there is mistakes in these letters and they may have importance for our life or may be
00:01:45
irrelevant let me give you an example for instance you change in this case a c to a
00:01:54
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
00:02:04
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
00:02:15
small mutation a c into a t now fortunately in the last few years we scientists have developed method by
00:02:27
which we can reverse that change we can fix that mistake and for instance we have models in the lab we have animal
00:02:36
models in this case is a mouse where we have created the same mutation the C into a t and this mouse a
00:02:46
lab mouse lives for about 2 years this mouse will live just for a couple of month three four months maximum and it
00:02:55
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
00:03:05
we get this mouse which has nothing to do with the previous Mouse is healthier live longer and is able to regenerate
00:03:15
some of their tissues that before it couldn't do it the problem as I was indicating
00:03:23
before is that um this is a very small percentage of the mistakes that happen in our life by
00:03:33
and large this is less than 1% there is mistakes that generate diseases like this by and large we have many other
00:03:43
diseases that are not due to a mutation in our genome and if we look at this graphic
00:03:50
that represent age and the possibility of death you can see that after certain number of years around 4
00:04:01
45 the major risk factor for getting any disease is precisely that years age so the
00:04:12
longer we live The increased risk to get diseased and around 40 45 we start to develop all these diseases that you see
00:04:21
at the top of the screen and they are not related to changes into C or a t or a particular
00:04:29
mutation so how this happen how these diseases appear and what can we do about reversing these
00:04:39
diseases so let's go down to the cell level here you have two type of cells a very young cell healthy
00:04:51
cell and an all an unhealthy cell the healthy cell is very res resilien in the presence of risk factors
00:05:03
it has a very strong buffer capacity we call that that can deal with these these stresses however the all an
00:05:14
unhealthy cell in addition to the fact that has been exposed because of time to more factors excuse me it has less
00:05:24
buffer capacity it's less resilient to these factors that damage reach the cell and the question
00:05:35
that I want to present today has to deal with this buffer capacity and what is buffer capacity let's see if I can
00:05:44
explain this well so with time as time passes there is more risk factors during normal aging there is more stress and
00:05:55
the buffering capacity the resilient of these cells goes go down and when these two arrows these two curve mix the Seas
00:06:07
appear and the question is can we increase buffer capacity so that then the disease appears later or it never
00:06:18
appear can we increase the cell resilience to deal with the disease that appearing with aging when we are
00:06:27
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
00:06:35
what can I do so can we increase this buffer capacity so that disease doesn't appear it takes longer to appear or we
00:06:43
can even reverse it and how can this be done just pause for a moment what is aging what makes that cell fragile
00:06:56
unhealthy many things our metab po change with ag our energy levels drop our mitochondria don't produce that ATP that
00:07:07
is needed for the cell to work properly stem cells in our body die many things happen while we
00:07:16
age but I'd like to Poe the idea that among all these things that happen during aging there is one very important
00:07:25
thing that could help to increase this buffer capacity and this has to do with what we call the epig
00:07:34
genome Epi comes from the Greek above above our genome above the instructions that we receive from our
00:07:43
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
00:07:55
ft if we were to extend it here but we need to pack it inside a cell and it has a special
00:08:03
conformation bounded by the specific proteins which in a very basic way we can divide it in in a confirmation that
00:08:12
is open for business that we call open chromatin or close for business close chromatin and just this changing the
00:08:24
conformation of the chromatine may have huge effect in the health of the cell and the
00:08:33
organism in the time when the disease appears and the first and most important experiment to demonstrate this was done
00:08:42
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
00:08:54
is fragile that is unhealthy and make that cell an embrionic like cell again and he did this by changing this
00:09:06
confirmation of the chromatin now can this help us this experiment for which he was awarded the
00:09:15
Noel price can this help us deal with the problem I am trying to convey today reverse disease bring back time and make
00:09:24
the cell more resilient and healthy again so through a few years of studies the message is this that there is a
00:09:33
correlation between the conformation of the chromatin aging and disease when the
00:09:39
epigenome when the chromatine is closed we call this heterochromatin the cell is Young is
00:09:46
healthy when the chromatin is open it leads to the increase the loss of buffer capacity and therefore disease and aging
00:09:58
and the question is can we reverse that can we this correlation can we do something to alter the confirmation of
00:10:06
this chromatin and demonstrate that just by bringing an open chromatine to a closed chromatine we can rejuvenate a
00:10:14
cell and how do we do that we took advantage of the initial ideas and studies of s
00:10:25
yamanaka and using again this mouse model that I indicated before this animal that has a
00:10:34
mutation that has a c into a te that leads to an accelerated aging you can see the animal here doesn't have hair
00:10:42
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
00:10:52
put it inside this mouse this old mouse we're not fixing the mutation remember at the beginning there is Technologies
00:11:00
by which we can fix the mutation what we're doing here is just altering the chromatin the mutation is still there in
00:11:08
this mouse the cause of the problem that letter is still there not fixed but we're altering the
00:11:15
chromatin and we do this not continuously we just do short pulses of the yamanaka factors we put just during
00:11:23
the weekend we put these factors not during the entire week to this mouse and what happen is that we get a very
00:11:29
different Mouse healthy mouse that is able to live longer and remember we have not fixed
00:11:37
the mutation the te is still there so just by this small change in the chromatin we can rejuvenate a
00:11:48
mouse and here is the just example of what I'm telling you we can either with very precise tools that we have
00:11:57
developed correct bre a specific mutation at the top the C to a t or without knowing the mutation just that
00:12:07
we know that this Mouse has a problem we just alter the status of the chromatine
00:12:13
and we practically get the same phenotype we get Rejuvenation on this mouse either genome correction or
00:12:21
epigenome buffering increasing the capacity the buffering capacity of this mouse so we have gone through from the
00:12:29
initial point to a later point where the mouse will live longer and will have a healthier
00:12:37
life now anyone could tell me yes you are telling me just about one case this particular mouse that has this mutation
00:12:46
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
00:12:56
others in a summary here we have another mutation these mice have a mutation in a
00:13:02
gene called leptine which make these mice eat all the time and as such they get fat they
00:13:11
change their metabolism they get older faster Etc if we just give a short pulse of these yamanaka factors we get this
00:13:20
mouse the mouse still keeps eating because it has the mutation we haven't corrected but the mouse now has less fat
00:13:28
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
00:13:38
have time to go through this to many other diseases that we have test in the lab kidney disease skin disease liver
00:13:46
disease muscle disease Etc the same thing happen we can bring back this buffer capacity and make the cell
00:13:55
younger and the mouse younger there's a sentence there that says a deceased agnot this approach when you
00:14:05
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
00:14:14
disease it give you another medicine if we have a mouse with a mutation we try to correct that mutation another mouse
00:14:22
with another disease we correct that mutation but what I'm telling with this slide is that independent of the disease
00:14:30
just by this small switch of changing the chromatin we can increase the capacity of resilience of
00:14:40
this mouse so that the disease takes longer or is even reverse I think this is a very profound
00:14:49
message that is not very precise we are not touching the genome we're touching the epigenome but without this Deion we
00:15:00
can revert disease now the key question is this is great I told you can we rejuvenate an
00:15:06
organism at the beginning it seems that based on this and other experiments in Rodin in the lab the
00:15:15
answer is yes we take mice with different pathologies we pass them through these short pulses of yamanaka
00:15:22
factors and they they're better the the disease takes longer to appear they live
00:15:28
longer but even though in science this this animal is the one that we know more about health and disease much more than
00:15:37
humans our interest is healthy people would this work in humans and this is our mission in Aldos try to by this
00:15:51
cellular Rejuvenation programming increase the buffer capacity of a human cell so that the Sease is
00:16:00
reversed or can take longer to appear we have done this in isolated human cells in the
00:16:09
petrides but the next step is to move to a human being an entire organism like the
00:16:16
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
00:16:26
this experiment is done these mice are healthy healthy they're fine there is nothing wrong with them but we need to
00:16:32
really be very cautious when touching a human cell so rather than delivering these
00:16:42
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
00:16:55
organ donations save thousands and thousands of lives every year in our planet but nonetheless there are many
00:17:05
thousands of organs that are discarded because their quality because they are all the doctor when the organ
00:17:14
comes look at the organ and said this is this organ is not good enough doesn't have enough quality to be transplanted
00:17:22
and it just get discarded what if instead of going directly into a human being we try to
00:17:30
rejuvenate this organ that is discarded and see if the doctor now will say now this organ is ready to be
00:17:38
transplanted whatever conditions and quality requir by this doctor and we are making progress into this area you can
00:17:47
see here when we transplant ER in this case is still in Rodin an all kidney into a young rat and we compare
00:18:00
this with the transplantation of a young kidney the life of the horse is very different you see these two the green
00:18:08
and the blue lines so the blue line is with no treatment the green line is after a short pulse of these
00:18:19
factors that is given X Vivo to this organ before it's transplanted and that lead to an increase in the survival of
00:18:28
the hor so that's one way to start approaching of moving this technology that we are developing in the lap in
00:18:36
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
00:18:46
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
00:18:57
with time there is more and more of these fragile unhealthy cells that don't have enough buffer capacity and you can
00:19:05
see this in this diagram the blue dots indicate that with time we have more and more of these nonfunctional cells but
00:19:14
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
00:19:23
that are functional how do we deliver these factors just to those cells that are not
00:19:28
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
00:19:37
these fragile and healthy cells and how can we deliver the factors just in the age situation to the unhealthy cells but
00:19:47
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
00:19:55
genes and markers that Target and identify by the unhealthy cell and with these markers we can guide our yamanaka
00:20:04
factors just to the unhealthy cell and we obtain the same phenotype you can see here an increase in life span just
00:20:12
targeting the unhealthy cell increasing the buffering capacity of the unhealthy cell and the last slide that I want to
00:20:20
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
00:20:31
phenotypes like this for instance an old mouse like us with time will get gray hair it would just bring the factors to
00:20:41
the unhealthy cells of the of the skin that produce this deterioration of function
00:20:50
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
00:21:02
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
00:21:09
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
00:21:19
mouth it just make a perfect Skin So summary of what I have told you today is this that
00:21:28
there is what we call Precision Medicine by which we can fix some of these mutations errors
00:21:37
that our parent transmit into the book of our life but that's less than 1% of the diseases the majority of diseases
00:21:46
correlate with age passing of the time and they don't have anything to do with particular
00:21:55
mutations and without touching the genome with this Precision medicine just just modifying the conformational
00:22:04
structure of the chromatin we can bring a disease and aged cell into a cell that
00:22:12
is more resilient and more functional and certainly this type of experiment and the messages that it open up the
00:22:21
question of can we rejuvenate a human being and can we reverse diseas in human thank you for your
00:22:28
[Applause] right ju caros thank you for the presentation I want to I I don't I don't
00:22:44
know if you can overstate the significance of the discovery you have made and it's funny
00:22:51
to me how it's not popular uh knowledge at this point because of the results that you and other
00:23:00
scientists have collected and the impact it will have to literally restore uh cellular health and and deage an
00:23:09
organism and um the yamanaka factors or four proteins just just for Layman's conversation there are four proteins
00:23:17
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
00:23:25
result new genes get turned on other genes get turned off and the cell kind of revitalizes it becomes young
00:23:32
again um you discovered that you can actually and and they did this all the and made the cells go back all the way
00:23:39
to being stem cells but what you discovered was the ability to partially ReStore youthfulness in the cells
00:23:45
through partial reprogramming and that's a dose Factor you put a smaller amount of the yanaka factors on the cells what
00:23:52
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
00:23:58
been tests in mice where you end up with cancer because then the cells start multiplying too quickly so maybe you can
00:24:02
tell us a little bit about what it means to do partial reprogramming with the amak what does partial mean very
00:24:09
important question thank you for let's see if I can clarify this what Dr s yamanaka did is something that we no one
00:24:18
in in science in general could believe that you can bring an adult cell to a start life again become an
00:24:30
embryo cell embryol likee cell an embryonic stem cell can be whatever we have more than 250 cell types in our
00:24:40
body our skin cell is different than our eye cell is different than our brain cell because different genes are turned
00:24:46
on and off in each of those cells they have the same DNA but they have a different epigenome different genes are
00:24:52
turned on perfectly explained thank you so and what I think it's so for people to get
00:24:59
that yeah what SAA did was just to delete delete all that information the identity of a skin cell of a heart cell
00:25:08
and bring it back to the very beginning to the to the very first time when we are born to this type of cells
00:25:16
now is when he was putting these factors it's his factors the yamanaka factor for
00:25:22
a long time four proteins for four prot four proteins put them on the cell this happens now we don't want this imagine
00:25:30
if we were to put this in the heart the key cell in the heart is called cardom myosite and what it does
00:25:37
is beat so if we remove the identity can't of that cell is not anymore a cardom myosite and go back to an
00:25:46
embryonic cell the heart is not going to beat if we do that in the liver theoy is
00:25:54
not going to do its function so doing this going back in in time to really the earli
00:26:03
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
00:26:12
particular cell then you are open for that cell to become something else right like a cancer cell or a skin cell is
00:26:21
transformed into aite many wrong things could happen we want to maintain the identity of this cell
00:26:29
and the small switch here that we did as you are asking me is rather than having
00:26:35
the factors for a long time we just gave a short pulse what that is doing is altering the
00:26:44
chromatin but for a very short time it's a small shock and then the chromatin get
00:26:49
close and maintain its identity the cardiomyocyte is a cardom myosite has not gone back
00:26:59
to a different cell typee but its function is much better this is so the idea is just a short P of these proteins
00:27:07
which by the way these are the proteins that s yamanaka discovered but I'm convinced that there will be many other
00:27:15
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
00:27:21
startups at Alto slabs for other proteins that can do this but perhaps not protein but smaller molecules
00:27:30
peptides or small molecules where theoretically you could take a pill and it would do the same thing is
00:27:40
that a reality so I think that one of the biggest inventions that we humans have
00:27:48
made is the place we're here today the university the Curiosity the knowledge to advance in things that we don't
00:28:00
understand um and discovering what other proteins what other factors could do the same thing
00:28:08
belongs to that domain of the Curiosity and trying to increase our knowledge but
00:28:14
many times we need to try to apply this knowledge and you're asking me how are you going to deliver whatever factors
00:28:22
you discover into a human being you can do this in the lab with many other ways but ideally you would
00:28:29
like to just put that into appeal and so here is where the other important thing come and that's
00:28:39
industry by mixing the Bas of Academia this curiosity this trying to understand how we can close and open the
00:28:49
chromatin with many other factors with the experience the drive and the focus of
00:28:57
Industry can we answer the question that you are asking can we put these factors
00:29:02
or any other factors that alter the chromatine into appeal this is precisely our Endeavor try to make this safe and
00:29:12
available to can I ask you a more maybe a more basic question um if this buffer capacity is essentially the insulation
00:29:25
that we are born with that then decays so young cell good buffer capacity old cell
00:29:31
no buffer capacity in very simple terms based on your side what is the scientific community's understanding
00:29:40
about how to minimize the rate of change and the Decay by things that people in this room can control where we live the
00:29:49
things that we're exposed to our food supply do any of those things to your understanding have an impact that's
00:29:57
measurable and achievable by us today while we wait for altos and others to deliver more
00:30:03
chemical manipulation of this huge impact incredible question and really huge impact just think of exercise we
00:30:11
have compare what are the changes in the Cell between exercise and the short pulses of Y Mana
00:30:20
factors and you couldn't believe the similarities in the changes in gene expression that exercise
00:30:28
th and how overlap these changes happen when we do the yamanaka the sh PES of yamanaka factors so things like exercise
00:30:40
but exercising what kind of exercise how much how often why you want to know the answer
00:30:45
too what don't laugh actually you know what don't answer the question you can tell us afterwards because they don't
00:30:50
care don't it's [Applause] fine and exercise things that your mother will tell you eat less
00:31:00
exercise H when I say stress I mean it stress to the cell that is going to alter the epigenome so until we really
00:31:10
understand how these changes in chromatine happen all these things that we do sometime with our life really
00:31:18
improve the buffer capacity and has that been published or studied in a way that's digestible for Layman meaning
00:31:25
like whether it's intermittent fasting or whether it's the the quantity of food or whether it's you know specific forms
00:31:31
of exercise over another has that been well studied enough that we can at a minimum we can even just link to all of
00:31:37
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
00:31:44
an incredible jump into into these studies so far most of them have been done in
00:31:53
animal models in the lab and we are starting to translate this to humans um for instance I just finish it's not I
00:32:06
think I can say that tomorrow it will be just one of these molecules that diabetic people take metformine to lower
00:32:15
down their glucose they can reprogram the cells so that all the cognitive function or not just rodents and this is
00:32:23
the key thing but of monkeys which are 99% % their book of life is very 99 9% similar to us right it can reprogram
00:32:34
these cells and the cognitive abilities of monkeys and their lifespan is increased so this is coming this is not
00:32:44
something that is just this small Mouse in the lab where we know a lot about their health and disease but I feel the
00:32:53
next decade probably many of these discoveries with the caveat that it's a mouse and a mouse is not a human might
00:33:01
be translated to human you put a slide up there where you had a obviously a whole bunch of Target markets some were
00:33:08
autoimmune diseases some were cancers some were more just general aging um how do you decide or how do you
00:33:18
figure out where there is the uh most real application today because I part of it
00:33:26
is there's a obviously Market issue of making sure you continue to have capital and prove scientific
00:33:32
value but part of it is there may be some small winds today in rare diseases or something that could allow you to
00:33:39
commercialize this faster so how do you think about which problems should come first good question I put up there the
00:33:51
ex Vio example with the organ transplant this is probably one of the most cautious and safest safest approach
00:34:02
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
00:34:11
not there you can do nothing so acute and and deadly diseases that could happen could be an
00:34:20
initial um target for these type of approaches um but again I I want to say that even though we are trying to move
00:34:34
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
00:34:42
this will need time to be replicated in a human being before we wrap can we just
00:34:47
talk about how altto Labs is set up it's probably got more funding than any other
00:34:53
private company in recent history it's really incredible how the the maybe you can tell us how how you've organized
00:35:00
this this work this Mission um and again is reflecting on the importance that we
00:35:07
know so little and about the fundamental science of what is behind this big question is a question that we human
00:35:17
beings have have tried to approach since ever how can we deal with disease with aging so there is so many things we
00:35:27
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
00:35:35
product development and at the same time in parallel yeah with all the safety approaches that we can think of and we
00:35:43
were talking about one possible example perhaps without knowing every detail of how it works provided is safe
00:35:53
and could have a positive effect trying to move this forward so it's a combination of what we like to call the
00:36:01
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
00:36:08
uh not benefit and does not appreciate the the effort and and obviously everyone hopes that you guys are
00:36:15
extremely successful in both the scientific and Commercial uh Pursuits I it seems to me like as you guys have
00:36:22
your breakthroughs which I think you're uh you're going to have given the backing and people that are involved
00:36:29
over time uh partial cell reprogramming could be one of the most profoundly impactful technologies that humans have
00:36:38
ever discovered or invented so we appreciate the work that you do and and thank you for being here with us thank
00:36:43
you for thank you [Applause]