[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]