December 6, 2022 • 25 mins
We're highlighting a breakthrough moment - this summer, Dr. Jacob Hanna, a professor at the Weizmann Institute of Science published a paper demonstrating that synthetic mouse embryos could be grown outside the womb, without an egg or sperm. This is a major advance that was covered by Nature, The Washington Post, The New York Times, and others. Today, the head of NFXBio Omri Amirav-Drory is sitting down with Dr. Hanna to discuss how we reached this milestone, what it means for science, and how entrepreneurship can help bring this technology out of the lab.
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(00:08):
They're seeing a heartbeat, you know, it isvery exciting because really Beller you this is
no longer hand waving.
You know, you're you're getting an organ filledembryo
Yeah.
And and as you know, just recently, we got anemail from a young twenty two year old Morgan
that very emotionally wrote to us that, shelost the ability to to appropriate because she
was diagnosed with cancer, and she didn't havetime to freeze her egg before she had to
(00:32):
undergo chemotherapy.
Pete, you know, people want to have their ownbabies.
And, and it's very emotional.
And, hopefully, we can solve this problem oneday.
If you've listened to this podcast before, youknow that NFX is interested in edge case
solutions to big problems.
We'd like to explore what's happening on themargins of the network before it gets huge.
(00:53):
So today, we're highlighting a landmarkscientific moment, the ability to grow
synthetic embryos without a sperm or eggoutside the womb.
This breakthrough was published in thescientific journal's cell and was covered by
the New York Times, Washington Post, BusinessInsider, and many more.
To explain what this means for the future oftech bio, NSX bio general partner, Amar Omri,
sat down with the lead author of this work andfounder of Renewal Bio, Doctor Jacob Hannah of
(01:16):
the Weisman Institute science in Israel.
We hope you enjoy this conversation.
Hello, everyone.
My name is I'm a Pete in FX.
And today, we're going to talk aboutbreakthrough science, and we have with us,
Professor Yako Pshana, from the WeitzmanInstitute Hello, Jacob.
Hi.
So we just started a new company called RenewalBio based on the breakthrough technology from
(01:40):
your lab.
And the world is buzzing about the, theresearch which was just published.
And this podcast is an FX podcast.
It's usually a guilt word.
Entrepreneurs and in founders.
So maybe they don't want to send biology much,but, you know, this is quite amazing, and I
believe one day we'll win the Nobel Prize.
(02:02):
So you heard it first year.
So today, I want to discuss your your journey,towards, you know, creating synthetic embryos
that was a paper that was published in Bellerjust a month ago.
So maybe we can start by, you know, yourbackground, you know, where do you start and
how did you get to to be a professor at Watson?
(02:25):
Yeah.
Well, thank you for the Morgan few of theenthusiasm.
We're very excited.
We hope, you know, we believe that you know,this can become something important.
So I'm already trained as a physician.
I'm a licensed physician in Israel, but I, dida PhD in immunology, actually.
And after that, I did a postdoc on stem cellsat MIT, right at the time where there was a
(02:48):
breakthrough that you can actually take a skincell or a blood cell and completely reverse it
back to become a stem cell.
So you don't need to have embryo derived stemcells.
And, we've been working on that since, youknow, my postdoc from 2007 for 15 years.
And overall, we're trying to tackle this bigquestion which faces modeling society and the
(03:13):
challenge is really how do we come up with asource for organ transplants and for cell
transplant from the that are identical to thepatient.
As you know today, if you want to Pete adisease and find an organ donor, it's very
difficult to find one.
And even if you do, the DNA is never identical.
So there's always gonna be a rejection and youneed immune suppression and so forth.
(03:35):
So, you know, this the the sense discovery ofthis IPS was 15 years ago, the the idea is that
now we now we have stem cells that areidentical to the patient, the challenge remains
how do we move forward and make organs andcells for transplantation from them.
It is important to emphasize that we cannottake embryonic or these IPS them to the
(04:01):
patient.
You know, if you put them in the lung, they'renot gonna become lung cells just by learning
from their neighbors.
You actually have to differentiate them.
You have to make cells that are mature, definedpopulation, and only those you can, transplant
them.
And that actually, has proven a very difficultchallenge, and that's what we've been trying to
solve for for the last 12 years.
(04:25):
So last year, you published a reallyinteresting paper in nature where you show you
can take now charl, mouse, embryos, and goldenX Utero, today, 8a half.
And again, mouse, pregnancy is only 20 days.
So it's a big part of the pregnancy.
Can you tell us more about the that research?
(04:46):
Yeah.
So I think things in Puerto Rico is what is whywe Pete doing this and why this is leading up
to this.
So we're not just like, you know, one Morgan,let's start growing memories and so forth.
But actually, as I mentioned, we're trying wewant stem cells to become Morgan.
And to do that, we need to understand andimitate the embryo.
(05:09):
How does the embryo makes its organs?
But the challenge, for this really is that theembryo does this process what's called gas
relation, which is making the organ progenitorsand organogenesis, which is mature organ
formation, happens right when an small embryo,which is just a Beller of stem cells enters the
uterus.
So in the mouse, this happens within 5 days,you get entire embryos then becomes a fetus
(05:33):
because it has its all its organs.
And the uterus is not transparent.
We cannot see what's happening.
And also at these late stages, even if you takean embryo out, you cannot put it back.
So for example, you cannot take it Pete turbotand watch what is the outcome.
And this is even in mice.
If you're talking about human beings, it's justBeller completely in the dark because usually
(05:56):
you're talking about stages in pregnancy thatare so early that usually a woman doesn't know
she's pregnant at all.
So that's why we decided to really think can wegrow make basically mammalian embryos like
zebrafish or frogs, meaning grow outside theuterus?
And and this is also a fundamental question.
You know, can you get capture, gastrication,and organogenesis outside the mammalian users?
(06:21):
Is it possible at all?
And what we published last year really was thethe end result of a very long 8 year study
where we basically developed a platform whichconsists of a electronic device and also the
media conditions to grow these embryos becauseyou don't have a uterus and maternal blood
supply.
And the system is basically you can think of itas a ventilation machine.
(06:43):
We're not ventilating the mouse lung, butactually then Flint the environment of embryo.
And and we learned over the years, what are theparameters that are critical to really get the
embryos growing, such as, for example,pressure, control the exposure to exposure to
light and so forth, and also what are thenutrients in the media that need to make this
embryo grow.
(07:04):
Really, what what that paper really showedthat, this was a big, jump from before we grow
embryos maybe for one day and embryos wereactually abnormal.
You can go from day 5 to day 11 in the mouseembryo.
So this is 6 days.
Which is about 3rd mouse pregnancy.
But again, this is the critical phases thatwe're after because this is exactly from Pete
(07:26):
gastrulation to late Morgan Genesis.
We can really see the entire continuum of thishappening outside the uterus.
So this taught us as a principle, really, thatthat really you can capture entire organ
formation in mammals outside the uterus.
It shows you that the embryo is self organizingin a way.
(07:48):
So the pattern or what's called the morphogens,which makes the morph meaning in the shape of
the embryo, is dictated by the embryo itselfand not by the uterus.
And then the uterus, of course, is veryefficient and important, but it's actually more
about metabolic supply which we can substitute,in that regard.
So that was really the the study last year, butalso it constituted, I would say, the
(08:11):
bottleneck for for the entire field becauseit's also bottleneck, which led us to the
current study where you actually what happens,you know, if you put aggregates of stem cells.
We can call them organoids or embryoids fromstem cells.
What if you put them in this device?
What would happen?
(08:31):
Because you can think of the field of this,what's called synthetic embryos.
So they are cell embryos that are made fromstem Beller.
Unlike, you know, what we call naturalmemories, which are made after fertilization of
permanent egg, that field was really stuckbecause you had you know, a lot of great papers
making, you know, small aggregates of stemcells, like very, very early embryos that do
(08:52):
not have any Morgan.
But you couldn't know all these real embryos,can they become Morgan filled embryos,
basically?
And that is because, well, if you cannot grow anatural embryo outside, you know, how are you
going to be able to to to grow syntheticembryos?
So basically, what we did last year becomeswhat they call the positive control or the
(09:14):
reference control.
So now we know what it takes.
We know what are the conditions that are neededto allow a mouse embryo in this case to go
through gas station organigens.
So we know what it takes And the question waswhat happens if we put stem cells and the
question which type of stem cells in thissetting and would they make something that is
(09:36):
similar to an embryo or not?
So last year really was the the the technologyand the platform the bottleneck and now is
which I guess is the most important result inthe current study, which really allowed which
showed actually quite simply that the samecondition, the same device, the same media, the
same parameters, if you take stem Beller, whatwe call them naive in a naive state.
(09:59):
Really the stem cells that are grown in thestate that is very similar to the earliest
stages in the in the embryo.
They can start growing.
We start with like a club of 25 Beller.
And alone over a process of 8 days, they startMorgan, themselves, into an embryo like
structure.
And if we if we learned last year that embryosare self organizing to make their organs, now
(10:23):
we're learning that stem cells are selforganizing to be make embryo like structures
which are self organizing to develop, and makeorgans.
And in this context, I think, we can reach, asI mentioned, day 8a half, an 8a half in
development, it is after gas station, post gasstation, and already well into organ
(10:43):
formations.
There are these embryos have brains includingthe anterior region, the mid region, They have
noiltube.
They have a heart with chambers that isbeating.
They have blood stem cells.
They have the intestinal tube and and they havethe tail.
And we did a lot of characterization.
We need to show, I would say, that theseembryos are not totally normal.
(11:04):
I would say about perhaps 19 95% similar tonatural embryos.
But definitely they are by far the mostsophisticated, the most advanced,
differentiation entities because they reallycapture the the sequence of events and the way
that organs are, placed inside the embryo andrelation to each other is very, very
(11:27):
physiological state.
So that's so super siding.
Can you remember how you felt going to the labday after day looking at the result?
Like, oh my god.
This is actually working.
Can you remember that?
Unfortunately, no.
I think that I know that this is perhaps adisappointing, answer.
And I would say because this is, for tworeasons.
(11:49):
This is as I said, like, perhaps a very longprocess of of working, for 12 days where we
every time we actually got one more day andincrease the efficiency and increase the
quality.
And, a bad habit that we have is, you know, ofcourse, we get excited, but within within 1
hour, we're actually thinking, what about thenext step?
So that's really, of course, it has been veryexciting.
(12:12):
And, you know, yes, the the other hand, they'reseeing a Pete, you know, it is very exciting
because it really tells you this is no longerhand waving, you know, you're you're getting an
organ filled embryo.
But but the the the I think really the magicwas, which is great, has been, you know, just
continuous slow, but persistent, progress inseeing how this developed, whether it's natural
(12:34):
embryos, whether it's synthetic embryos, fromthe mouse, and, you know, we work on other
species, for example, from rabbits and soforth.
So really seeing this expanding, has been veryexciting.
And also as I Flint, as what's also beenexciting is really seeing different aspects
that we did do research in the lab mergetogether really to culminate into this this
(12:55):
this one climax.
In other words, So it's not about hasn't beenonly, as I mentioned, about how to grow embryos
and build a device, but actually learning howto make what we call naive stem Beller.
Particularly in humans and other species.
So naive stem cells are really the highestlevels of stemness.
And and and and for years, people, you know,when we were working on these naive stents, it
(13:18):
was like, oh, why should we care?
We have conventional stem Beller.
They're good anyways.
But we now, you know, we showed before thatconditional sensors are limited in their
potential And now actually we show that thiscan only work by using naive stencils.
And so this, you know, this is kind of themerger between the the the those two paths was
(13:39):
perhaps, you know, not always clear, is initself also very exciting for us and and and
and and also gives us a lot of knowledge andcontrol, we need to make our results better
because we've, you know, we're we're, very wellversed in both aspects of this stem cell field.
So currently, you published fully syntheticmouse embryos.
(14:01):
So no sperm, no end, no uterus, from day 0 today, 8 a half out of 20 days.
Why just 8 a half?
Why not 9 a half?
Why not 20 days?
You think in the future you can get syntheticembryos growing all the weight?
So that's an excellent question.
So as as I mentioned, in natural embryos, wepublish we can reach day 11a half.
(14:23):
I can share with you, actually, we now alsoreach day 13a half.
And it is interesting why in synthetic embryos,we could reach only 8 a half versus if we went
one day later, they became not normallydeveloping, so we couldn't call them, you know,
an embryo or an equivalent embryo.
And, we believe that this is, you know,perhaps, I assume it's, suboptimal way of the
(14:45):
protocol.
I think that I have no reason to believe thatthese embryos cannot go further because I think
Once you already finished gastrication, you cansee all the the Morgan.
They should proceed further.
I think what's happening in the embryo becauseas I mentioned, they are, there are some subtle
malformations, for example, perhaps in someembryos, the heart is too big or too small, or
(15:06):
the brain is slightly too big or too small.
And that actually adds up and and the embryodoesn't grow further.
And the challenge is really how can we perhapsbetter confine the embryos and and do some
tricks to really make them aggregate in abetter way.
And I believe they can't catch up with naturalambiance.
Whether we can, you know, get entire, let's saywe talked about in mouse pregnancies, more of
(15:30):
an entire pregnancy outside the uterus, hasn'tbeen a, I must say, a major focus of of our lab
is because as I mentioned, we're trying to lookat how organ formation happens.
We are now starting to work on this on mice.
And one advantage is that although there's nomaternal blood supply here, but these embryos
have an umbilical cord and have a and haveplots applied.
(15:52):
So basically, you already have what you callit, the highway roads to really try perhaps and
to use circulation on these Now I would thinkthis is, you know, for mouse because mouse is
very small and for 20 days of pregnancy.
And when you're talking to larger animals,you're talking about Bovine monkeys, even
humans when they, I don't think this is reallypossible.
(16:13):
I think we're we're we're it's it's theirembryos are too big.
It's too long as far fetched at the moment.
And, we prefer actually at the moment to focuson their early stages from different Pete,
including humans, because we we what's moreabout understanding how organ progenitors are
formed and perhaps even, you know, using theseorgan projections that emerge in this process
(16:37):
for transplantation, and research.
So let's talk about that part because I think,you know, people think about company formation.
You start a company to commercialize thetechnology and to create products.
For people that suffers.
So what kind of diseases or indication?
What kind of suffering can we prevent in theworld using this technology if we just imagine
(17:01):
how the future can look like.
Yeah.
So I think, this is a very important question.
I think, you know, it's it's it's it's veryimportant to all remember and remind ourselves
that this is this is our goal in the end thatwe're trying to make early Beller for janitors
that are for their useful transplantations.
And the scenario that we are really facing, youknow, you can think of, an adult woman who's
(17:27):
infertile either because of unknown causes orfrom undergoing chemotherapy at a younger age
or women, you know, in modern society, perhapsif, you know, at the day after age of thirty
eight, the the quality of eggs reallydeteriorates.
That's one one one scenario.
You can think of other scenarios where you havea patient who needs bone marrow transplant or
liver transplant, and he cannot find a matcheddonor, Pete with these ones.
(17:52):
And that's why what we want to explore in thecompany and and we think there is, merit and
there is rationale based on what we know frommouse experiments and also what we know with
conventional differentiation of stem cells thatwe can envision a scenario where such a
patient, will come and just donate Beller it'sa drop of blood or a hair we can make we
(18:16):
already know how to make these IPS cells.
We then put them and make them in this naivestate that I mentioned, which is really the
most pristine and most potent Beller.
And then try to push them to self organize towhat we call the synthetic hole embryo.
You can model what we call them in briefswings.
You know, this kind of early differentiationfor about, let's say, 20 or 30 days, which we
(18:38):
already know, for example, germ cells or or orblood steps is already found such early stages.
And in this case, well, these cells can betaken, perhaps expanded or modified if needed,
and then transplant it back to that thatpatient.
That is the scenario, that we're we're tryingto do, and I think this is what has the field
(19:01):
been after.
So that could be, you know, in in thisscenario, it could be an easy way where you can
have a genetically man matched patient specificstem cells that self organize into complex,
authentic, differentiated cells that can beused Currier, either as I said, for
transplantation or drug discovery and so forth.
(19:23):
Yeah.
And and as you know, just recently we got anemail a young twenty two year old woman that,
you know, very emotionally wrote to us that shelost the ability to to appropriate because she
was diagnosed with cancer, and she didn't havetime to freeze her egg before she had to
undergo chemotherapy.
Pete, you know, people want to have their ownbabies, and it's very emotional.
(19:48):
And, hopefully, we can solve this problem oneday.
No.
No.
Something, you know, as I said, I've seen inthe clinic from my physician training as a
physician, but as I mean, I've I've been, youknow, getting such emails and, for years about
this.
And there are, in other ways, and in general,in the field, and I think, you know, the stem
cells, when it says, oh, there's stem cellpromise and, you know, where, why has it been
(20:12):
so much progress?
So I would say, actually, there has been a lotof progress.
And I think the Beller can do it.
And I think there's very, you know, when yousee these cells Morgan that you remember, you
realize that the cells can do the job is thatwe need to learn how to control them in a way,
and use them for this benefit.
So that's so this is I think it provides a newpath of getting at this problem.
(20:35):
I think it's a very strong and valid Pete, andit's a very unique one.
And and that's what we would like to explore inmany different directions and see what it can
be good for.
Amazing.
Really, truly amazing.
And, in NSFacts, we like to support scientistsfounders.
And then in this company, you know, there are 2kind of scientists of course, you are a
(20:59):
scientist, in Weitzman Institute.
You are staying at Weitzman.
You're still doing a lot of amazing basicresearch Beller while helping the company.
So I'd love to hear what's your experience beenso far.
And then your students, you know, they went tothe video, their PhD, they feed postdocs.
Some of them went to industry, some to Academyand out there.
Many of them are coming back to to work on thisproject you know, what do you think about this,
(21:24):
journey of the scientist founder?
Yeah.
Well, yeah, I think, you know, you must sayit's a very exciting one.
You know, this is the first company that I'minvolved with.
And I think Paul is the last one.
And for me, the reason is that, you know, we,for me, is starting trying to make something.
(21:45):
This is something I'm very, very committed to.
I think this has been a goal after, and I thinkand this is high time Beller to try to push
this in the company is not.
So, of course, about trying tocommercialization, the company can also push
the science very much forward.
Then, so I'm, you know, this is a learningexperience for me.
It's been, you know, very, very good one sofar.
(22:06):
And really challenging and putting the plan.
But really what's what's, as you mentioned,what has been more special is that, you know,
that being able to recruit former students fromfrom my lab that went on and actually became
experts in other fields.
You know, one of them is actually now become avery expert in hematopoietic stem cells.
(22:27):
One of those is really, expert intransplantation in pigs of certain Morgan.
So actually that's really exciting because, youknow, it's it's watching them not sure.
They they have even knowledge in things thatfar beyond what I do have, and it's and we know
each other, and it's nice to kind of, you know,kind of Pete, work together at a higher level
(22:48):
and some some end.
And a different and and and this kind ofenthusiasm and many, many ideas together.
And so I think it's also a very healthy way infun way of doing it.
Yeah.
In some places like the Weitzman Institute are,like, the bastions of, like, basic science and
all the ethics, you know, all the setting upthe scientists to focus just on basic science
(23:14):
with my experience in companies like sensewhere Jennifer Dona is the co founder that
obviously you can still be an amazing curiositydriven basic scientist and start companies.
And some of your students can go startcompanies, and some of your students can go
become amazing scientists And your companiescan give you resources back to the lab so you
(23:37):
could do more science.
And so I think for my experience, it's a winwin for for scientists.
Actually, I mean, I can you can add one whenyou were talking about the Weizmann Institute
about the basic issues.
I think maybe so I think you know, I think thatthe wise men actually, you know, that it's you
can do research whatever you want, whether it'sbasic, whether applied, and and and these
(23:58):
things.
And this is very curiosity driven.
But, you know, what what always proves itselfagain and again, as you mentioned, whether it
was a crisp battle from before and that basicscience typically goes hands and hands and and
this understanding leads to development thatare highly applied.
And I think in our example, really learningabout what what does it mean to be a naive cell
(24:18):
and what is the signaling pathway for us innaive cell and really trying to be curious why
you can't then grow an embryo at Pete latestages.
And then, of course, that develops into anapplied thing which helps you go back and
answer a basic thing.
So particularly in the stem cell, you know, Ithink we are lucky because we're we're always,
you know, going, you know, we're, go together,you know, we're doing two things most of the
(24:43):
time.
You know, it's both of the coins.
We're we're advancing basic knowledge thathelps advance technology technology that goes
back again and feeds in and increasing ourknowledge of basic research.
And I think, this is what's happening in, forus in this case and, very helpful for us.
And we we will continue in this way to answerbasic questions on this process.
Amazing.
Thank you so much for being here today.
(25:05):
Thank you very much.
It'll be exciting.
They're seeing a heartbeat, you know, it isvery exciting because really Beller you this is
no longer hand waving.
You know, you're you're getting an organ filledembryo
Yeah.
And and as you know, just recently, we got anemail from a young twenty two year old Morgan
that very emotionally wrote to us that, shelost the ability to to appropriate because she
was diagnosed with cancer, and she didn't havetime to freeze her egg before she had to
(00:32):
undergo chemotherapy.
Pete, you know, people want to have their ownbabies.
And, and it's very emotional.
And, hopefully, we can solve this problem oneday.
If you've listened to this podcast before, youknow that NFX is interested in edge case
solutions to big problems.
We'd like to explore what's happening on themargins of the network before it gets huge.
(00:53):
So today, we're highlighting a landmarkscientific moment, the ability to grow
synthetic embryos without a sperm or eggoutside the womb.
This breakthrough was published in thescientific journal's cell and was covered by
the New York Times, Washington Post, BusinessInsider, and many more.
To explain what this means for the future oftech bio, NSX bio general partner, Amar Omri,
sat down with the lead author of this work andfounder of Renewal Bio, Doctor Jacob Hannah of
(01:16):
the Weisman Institute science in Israel.
We hope you enjoy this conversation.
Hello, everyone.
My name is I'm a Pete in FX.
And today, we're going to talk aboutbreakthrough science, and we have with us,
Professor Yako Pshana, from the WeitzmanInstitute Hello, Jacob.
Hi.
So we just started a new company called RenewalBio based on the breakthrough technology from
(01:40):
your lab.
And the world is buzzing about the, theresearch which was just published.
And this podcast is an FX podcast.
It's usually a guilt word.
Entrepreneurs and in founders.
So maybe they don't want to send biology much,but, you know, this is quite amazing, and I
believe one day we'll win the Nobel Prize.
(02:02):
So you heard it first year.
So today, I want to discuss your your journey,towards, you know, creating synthetic embryos
that was a paper that was published in Bellerjust a month ago.
So maybe we can start by, you know, yourbackground, you know, where do you start and
how did you get to to be a professor at Watson?
(02:25):
Yeah.
Well, thank you for the Morgan few of theenthusiasm.
We're very excited.
We hope, you know, we believe that you know,this can become something important.
So I'm already trained as a physician.
I'm a licensed physician in Israel, but I, dida PhD in immunology, actually.
And after that, I did a postdoc on stem cellsat MIT, right at the time where there was a
(02:48):
breakthrough that you can actually take a skincell or a blood cell and completely reverse it
back to become a stem cell.
So you don't need to have embryo derived stemcells.
And, we've been working on that since, youknow, my postdoc from 2007 for 15 years.
And overall, we're trying to tackle this bigquestion which faces modeling society and the
(03:13):
challenge is really how do we come up with asource for organ transplants and for cell
transplant from the that are identical to thepatient.
As you know today, if you want to Pete adisease and find an organ donor, it's very
difficult to find one.
And even if you do, the DNA is never identical.
So there's always gonna be a rejection and youneed immune suppression and so forth.
(03:35):
So, you know, this the the sense discovery ofthis IPS was 15 years ago, the the idea is that
now we now we have stem cells that areidentical to the patient, the challenge remains
how do we move forward and make organs andcells for transplantation from them.
It is important to emphasize that we cannottake embryonic or these IPS them to the
(04:01):
patient.
You know, if you put them in the lung, they'renot gonna become lung cells just by learning
from their neighbors.
You actually have to differentiate them.
You have to make cells that are mature, definedpopulation, and only those you can, transplant
them.
And that actually, has proven a very difficultchallenge, and that's what we've been trying to
solve for for the last 12 years.
(04:25):
So last year, you published a reallyinteresting paper in nature where you show you
can take now charl, mouse, embryos, and goldenX Utero, today, 8a half.
And again, mouse, pregnancy is only 20 days.
So it's a big part of the pregnancy.
Can you tell us more about the that research?
(04:46):
Yeah.
So I think things in Puerto Rico is what is whywe Pete doing this and why this is leading up
to this.
So we're not just like, you know, one Morgan,let's start growing memories and so forth.
But actually, as I mentioned, we're trying wewant stem cells to become Morgan.
And to do that, we need to understand andimitate the embryo.
(05:09):
How does the embryo makes its organs?
But the challenge, for this really is that theembryo does this process what's called gas
relation, which is making the organ progenitorsand organogenesis, which is mature organ
formation, happens right when an small embryo,which is just a Beller of stem cells enters the
uterus.
So in the mouse, this happens within 5 days,you get entire embryos then becomes a fetus
(05:33):
because it has its all its organs.
And the uterus is not transparent.
We cannot see what's happening.
And also at these late stages, even if you takean embryo out, you cannot put it back.
So for example, you cannot take it Pete turbotand watch what is the outcome.
And this is even in mice.
If you're talking about human beings, it's justBeller completely in the dark because usually
(05:56):
you're talking about stages in pregnancy thatare so early that usually a woman doesn't know
she's pregnant at all.
So that's why we decided to really think can wegrow make basically mammalian embryos like
zebrafish or frogs, meaning grow outside theuterus?
And and this is also a fundamental question.
You know, can you get capture, gastrication,and organogenesis outside the mammalian users?
(06:21):
Is it possible at all?
And what we published last year really was thethe end result of a very long 8 year study
where we basically developed a platform whichconsists of a electronic device and also the
media conditions to grow these embryos becauseyou don't have a uterus and maternal blood
supply.
And the system is basically you can think of itas a ventilation machine.
(06:43):
We're not ventilating the mouse lung, butactually then Flint the environment of embryo.
And and we learned over the years, what are theparameters that are critical to really get the
embryos growing, such as, for example,pressure, control the exposure to exposure to
light and so forth, and also what are thenutrients in the media that need to make this
embryo grow.
(07:04):
Really, what what that paper really showedthat, this was a big, jump from before we grow
embryos maybe for one day and embryos wereactually abnormal.
You can go from day 5 to day 11 in the mouseembryo.
So this is 6 days.
Which is about 3rd mouse pregnancy.
But again, this is the critical phases thatwe're after because this is exactly from Pete
(07:26):
gastrulation to late Morgan Genesis.
We can really see the entire continuum of thishappening outside the uterus.
So this taught us as a principle, really, thatthat really you can capture entire organ
formation in mammals outside the uterus.
It shows you that the embryo is self organizingin a way.
(07:48):
So the pattern or what's called the morphogens,which makes the morph meaning in the shape of
the embryo, is dictated by the embryo itselfand not by the uterus.
And then the uterus, of course, is veryefficient and important, but it's actually more
about metabolic supply which we can substitute,in that regard.
So that was really the the study last year, butalso it constituted, I would say, the
(08:11):
bottleneck for for the entire field becauseit's also bottleneck, which led us to the
current study where you actually what happens,you know, if you put aggregates of stem cells.
We can call them organoids or embryoids fromstem cells.
What if you put them in this device?
What would happen?
(08:31):
Because you can think of the field of this,what's called synthetic embryos.
So they are cell embryos that are made fromstem Beller.
Unlike, you know, what we call naturalmemories, which are made after fertilization of
permanent egg, that field was really stuckbecause you had you know, a lot of great papers
making, you know, small aggregates of stemcells, like very, very early embryos that do
(08:52):
not have any Morgan.
But you couldn't know all these real embryos,can they become Morgan filled embryos,
basically?
And that is because, well, if you cannot grow anatural embryo outside, you know, how are you
going to be able to to to grow syntheticembryos?
So basically, what we did last year becomeswhat they call the positive control or the
(09:14):
reference control.
So now we know what it takes.
We know what are the conditions that are neededto allow a mouse embryo in this case to go
through gas station organigens.
So we know what it takes And the question waswhat happens if we put stem cells and the
question which type of stem cells in thissetting and would they make something that is
(09:36):
similar to an embryo or not?
So last year really was the the the technologyand the platform the bottleneck and now is
which I guess is the most important result inthe current study, which really allowed which
showed actually quite simply that the samecondition, the same device, the same media, the
same parameters, if you take stem Beller, whatwe call them naive in a naive state.
(09:59):
Really the stem cells that are grown in thestate that is very similar to the earliest
stages in the in the embryo.
They can start growing.
We start with like a club of 25 Beller.
And alone over a process of 8 days, they startMorgan, themselves, into an embryo like
structure.
And if we if we learned last year that embryosare self organizing to make their organs, now
(10:23):
we're learning that stem cells are selforganizing to be make embryo like structures
which are self organizing to develop, and makeorgans.
And in this context, I think, we can reach, asI mentioned, day 8a half, an 8a half in
development, it is after gas station, post gasstation, and already well into organ
(10:43):
formations.
There are these embryos have brains includingthe anterior region, the mid region, They have
noiltube.
They have a heart with chambers that isbeating.
They have blood stem cells.
They have the intestinal tube and and they havethe tail.
And we did a lot of characterization.
We need to show, I would say, that theseembryos are not totally normal.
(11:04):
I would say about perhaps 19 95% similar tonatural embryos.
But definitely they are by far the mostsophisticated, the most advanced,
differentiation entities because they reallycapture the the sequence of events and the way
that organs are, placed inside the embryo andrelation to each other is very, very
(11:27):
physiological state.
So that's so super siding.
Can you remember how you felt going to the labday after day looking at the result?
Like, oh my god.
This is actually working.
Can you remember that?
Unfortunately, no.
I think that I know that this is perhaps adisappointing, answer.
And I would say because this is, for tworeasons.
(11:49):
This is as I said, like, perhaps a very longprocess of of working, for 12 days where we
every time we actually got one more day andincrease the efficiency and increase the
quality.
And, a bad habit that we have is, you know, ofcourse, we get excited, but within within 1
hour, we're actually thinking, what about thenext step?
So that's really, of course, it has been veryexciting.
(12:12):
And, you know, yes, the the other hand, they'reseeing a Pete, you know, it is very exciting
because it really tells you this is no longerhand waving, you know, you're you're getting an
organ filled embryo.
But but the the the I think really the magicwas, which is great, has been, you know, just
continuous slow, but persistent, progress inseeing how this developed, whether it's natural
(12:34):
embryos, whether it's synthetic embryos, fromthe mouse, and, you know, we work on other
species, for example, from rabbits and soforth.
So really seeing this expanding, has been veryexciting.
And also as I Flint, as what's also beenexciting is really seeing different aspects
that we did do research in the lab mergetogether really to culminate into this this
(12:55):
this one climax.
In other words, So it's not about hasn't beenonly, as I mentioned, about how to grow embryos
and build a device, but actually learning howto make what we call naive stem Beller.
Particularly in humans and other species.
So naive stem cells are really the highestlevels of stemness.
And and and and for years, people, you know,when we were working on these naive stents, it
(13:18):
was like, oh, why should we care?
We have conventional stem Beller.
They're good anyways.
But we now, you know, we showed before thatconditional sensors are limited in their
potential And now actually we show that thiscan only work by using naive stencils.
And so this, you know, this is kind of themerger between the the the those two paths was
(13:39):
perhaps, you know, not always clear, is initself also very exciting for us and and and
and and also gives us a lot of knowledge andcontrol, we need to make our results better
because we've, you know, we're we're, very wellversed in both aspects of this stem cell field.
So currently, you published fully syntheticmouse embryos.
(14:01):
So no sperm, no end, no uterus, from day 0 today, 8 a half out of 20 days.
Why just 8 a half?
Why not 9 a half?
Why not 20 days?
You think in the future you can get syntheticembryos growing all the weight?
So that's an excellent question.
So as as I mentioned, in natural embryos, wepublish we can reach day 11a half.
(14:23):
I can share with you, actually, we now alsoreach day 13a half.
And it is interesting why in synthetic embryos,we could reach only 8 a half versus if we went
one day later, they became not normallydeveloping, so we couldn't call them, you know,
an embryo or an equivalent embryo.
And, we believe that this is, you know,perhaps, I assume it's, suboptimal way of the
(14:45):
protocol.
I think that I have no reason to believe thatthese embryos cannot go further because I think
Once you already finished gastrication, you cansee all the the Morgan.
They should proceed further.
I think what's happening in the embryo becauseas I mentioned, they are, there are some subtle
malformations, for example, perhaps in someembryos, the heart is too big or too small, or
(15:06):
the brain is slightly too big or too small.
And that actually adds up and and the embryodoesn't grow further.
And the challenge is really how can we perhapsbetter confine the embryos and and do some
tricks to really make them aggregate in abetter way.
And I believe they can't catch up with naturalambiance.
Whether we can, you know, get entire, let's saywe talked about in mouse pregnancies, more of
(15:30):
an entire pregnancy outside the uterus, hasn'tbeen a, I must say, a major focus of of our lab
is because as I mentioned, we're trying to lookat how organ formation happens.
We are now starting to work on this on mice.
And one advantage is that although there's nomaternal blood supply here, but these embryos
have an umbilical cord and have a and haveplots applied.
(15:52):
So basically, you already have what you callit, the highway roads to really try perhaps and
to use circulation on these Now I would thinkthis is, you know, for mouse because mouse is
very small and for 20 days of pregnancy.
And when you're talking to larger animals,you're talking about Bovine monkeys, even
humans when they, I don't think this is reallypossible.
(16:13):
I think we're we're we're it's it's theirembryos are too big.
It's too long as far fetched at the moment.
And, we prefer actually at the moment to focuson their early stages from different Pete,
including humans, because we we what's moreabout understanding how organ progenitors are
formed and perhaps even, you know, using theseorgan projections that emerge in this process
(16:37):
for transplantation, and research.
So let's talk about that part because I think,you know, people think about company formation.
You start a company to commercialize thetechnology and to create products.
For people that suffers.
So what kind of diseases or indication?
What kind of suffering can we prevent in theworld using this technology if we just imagine
(17:01):
how the future can look like.
Yeah.
So I think, this is a very important question.
I think, you know, it's it's it's it's veryimportant to all remember and remind ourselves
that this is this is our goal in the end thatwe're trying to make early Beller for janitors
that are for their useful transplantations.
And the scenario that we are really facing, youknow, you can think of, an adult woman who's
(17:27):
infertile either because of unknown causes orfrom undergoing chemotherapy at a younger age
or women, you know, in modern society, perhapsif, you know, at the day after age of thirty
eight, the the quality of eggs reallydeteriorates.
That's one one one scenario.
You can think of other scenarios where you havea patient who needs bone marrow transplant or
liver transplant, and he cannot find a matcheddonor, Pete with these ones.
(17:52):
And that's why what we want to explore in thecompany and and we think there is, merit and
there is rationale based on what we know frommouse experiments and also what we know with
conventional differentiation of stem cells thatwe can envision a scenario where such a
patient, will come and just donate Beller it'sa drop of blood or a hair we can make we
(18:16):
already know how to make these IPS cells.
We then put them and make them in this naivestate that I mentioned, which is really the
most pristine and most potent Beller.
And then try to push them to self organize towhat we call the synthetic hole embryo.
You can model what we call them in briefswings.
You know, this kind of early differentiationfor about, let's say, 20 or 30 days, which we
(18:38):
already know, for example, germ cells or or orblood steps is already found such early stages.
And in this case, well, these cells can betaken, perhaps expanded or modified if needed,
and then transplant it back to that thatpatient.
That is the scenario, that we're we're tryingto do, and I think this is what has the field
(19:01):
been after.
So that could be, you know, in in thisscenario, it could be an easy way where you can
have a genetically man matched patient specificstem cells that self organize into complex,
authentic, differentiated cells that can beused Currier, either as I said, for
transplantation or drug discovery and so forth.
(19:23):
Yeah.
And and as you know, just recently we got anemail a young twenty two year old woman that,
you know, very emotionally wrote to us that shelost the ability to to appropriate because she
was diagnosed with cancer, and she didn't havetime to freeze her egg before she had to
undergo chemotherapy.
Pete, you know, people want to have their ownbabies, and it's very emotional.
(19:48):
And, hopefully, we can solve this problem oneday.
No.
No.
Something, you know, as I said, I've seen inthe clinic from my physician training as a
physician, but as I mean, I've I've been, youknow, getting such emails and, for years about
this.
And there are, in other ways, and in general,in the field, and I think, you know, the stem
cells, when it says, oh, there's stem cellpromise and, you know, where, why has it been
(20:12):
so much progress?
So I would say, actually, there has been a lotof progress.
And I think the Beller can do it.
And I think there's very, you know, when yousee these cells Morgan that you remember, you
realize that the cells can do the job is thatwe need to learn how to control them in a way,
and use them for this benefit.
So that's so this is I think it provides a newpath of getting at this problem.
(20:35):
I think it's a very strong and valid Pete, andit's a very unique one.
And and that's what we would like to explore inmany different directions and see what it can
be good for.
Amazing.
Really, truly amazing.
And, in NSFacts, we like to support scientistsfounders.
And then in this company, you know, there are 2kind of scientists of course, you are a
(20:59):
scientist, in Weitzman Institute.
You are staying at Weitzman.
You're still doing a lot of amazing basicresearch Beller while helping the company.
So I'd love to hear what's your experience beenso far.
And then your students, you know, they went tothe video, their PhD, they feed postdocs.
Some of them went to industry, some to Academyand out there.
Many of them are coming back to to work on thisproject you know, what do you think about this,
(21:24):
journey of the scientist founder?
Yeah.
Well, yeah, I think, you know, you must sayit's a very exciting one.
You know, this is the first company that I'minvolved with.
And I think Paul is the last one.
And for me, the reason is that, you know, we,for me, is starting trying to make something.
(21:45):
This is something I'm very, very committed to.
I think this has been a goal after, and I thinkand this is high time Beller to try to push
this in the company is not.
So, of course, about trying tocommercialization, the company can also push
the science very much forward.
Then, so I'm, you know, this is a learningexperience for me.
It's been, you know, very, very good one sofar.
(22:06):
And really challenging and putting the plan.
But really what's what's, as you mentioned,what has been more special is that, you know,
that being able to recruit former students fromfrom my lab that went on and actually became
experts in other fields.
You know, one of them is actually now become avery expert in hematopoietic stem cells.
(22:27):
One of those is really, expert intransplantation in pigs of certain Morgan.
So actually that's really exciting because, youknow, it's it's watching them not sure.
They they have even knowledge in things thatfar beyond what I do have, and it's and we know
each other, and it's nice to kind of, you know,kind of Pete, work together at a higher level
(22:48):
and some some end.
And a different and and and this kind ofenthusiasm and many, many ideas together.
And so I think it's also a very healthy way infun way of doing it.
Yeah.
In some places like the Weitzman Institute are,like, the bastions of, like, basic science and
all the ethics, you know, all the setting upthe scientists to focus just on basic science
(23:14):
with my experience in companies like sensewhere Jennifer Dona is the co founder that
obviously you can still be an amazing curiositydriven basic scientist and start companies.
And some of your students can go startcompanies, and some of your students can go
become amazing scientists And your companiescan give you resources back to the lab so you
(23:37):
could do more science.
And so I think for my experience, it's a winwin for for scientists.
Actually, I mean, I can you can add one whenyou were talking about the Weizmann Institute
about the basic issues.
I think maybe so I think you know, I think thatthe wise men actually, you know, that it's you
can do research whatever you want, whether it'sbasic, whether applied, and and and these
(23:58):
things.
And this is very curiosity driven.
But, you know, what what always proves itselfagain and again, as you mentioned, whether it
was a crisp battle from before and that basicscience typically goes hands and hands and and
this understanding leads to development thatare highly applied.
And I think in our example, really learningabout what what does it mean to be a naive cell
(24:18):
and what is the signaling pathway for us innaive cell and really trying to be curious why
you can't then grow an embryo at Pete latestages.
And then, of course, that develops into anapplied thing which helps you go back and
answer a basic thing.
So particularly in the stem cell, you know, Ithink we are lucky because we're we're always,
you know, going, you know, we're, go together,you know, we're doing two things most of the
(24:43):
time.
You know, it's both of the coins.
We're we're advancing basic knowledge thathelps advance technology technology that goes
back again and feeds in and increasing ourknowledge of basic research.
And I think, this is what's happening in, forus in this case and, very helpful for us.
And we we will continue in this way to answerbasic questions on this process.
Amazing.
Thank you so much for being here today.
(25:05):
Thank you very much.
It'll be exciting.
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