They're seeing a heartbeat, you know, it is very exciting because really Beller you this is no longer hand waving. You know, you're you're getting an organ filled embryo Yeah. And and as you know, just recently, we got an email from a young twenty two year old Morgan that very emotionally wrote to us that, she lost the ability to to appropriate because she was diagnosed with cancer, and she didn't have time to freeze her egg before she had to undergo chemotherapy.
Pete, you know, people want to have their own babies. And, and it's very emotional. And, hopefully, we can solve this problem one day. If you've listened to this podcast before, you know that NFX is interested in edge case solutions to big problems. We'd like to explore what's happening on the margins of the network before it gets huge. So today, we're highlighting a landmark scientific moment, the ability to grow synthetic embryos without a sperm or egg outside the womb.
This breakthrough was published in the scientific journal's cell and was covered by the New York Times, Washington Post, Business Insider, and many more. To explain what this means for the future of tech bio, NSX bio general partner, Amar Omri, sat down with the lead author of this work and founder of Renewal Bio, Doctor Jacob Hannah of 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 about breakthrough science, and we have with us, Professor Yako Pshana, from the Weitzman Institute Hello, Jacob. Hi. So we just started a new company called Renewal Bio based on the breakthrough technology from your lab. And the world is buzzing about the, the research 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. 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 Beller just a month ago. So maybe we can start by, you know, your background, you know, where do you start and how did you get to to be a professor at Watson?
Yeah. Well, thank you for the Morgan few of the enthusiasm. 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, did a PhD in immunology, actually. And after that, I did a postdoc on stem cells at MIT, right at the time where there was a breakthrough that you can actually take a skin cell or a blood cell and completely reverse it back to become a stem cell.
So you don't need to have embryo derived stem cells. And, we've been working on that since, you know, my postdoc from 2007 for 15 years. And overall, we're trying to tackle this big question which faces modeling society and the challenge is really how do we come up with a source for organ transplants and for cell transplant from the that are identical to the patient. As you know today, if you want to Pete a disease 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 you need immune suppression and so forth. So, you know, this the the sense discovery of this IPS was 15 years ago, the the idea is that now we now we have stem cells that are identical to the patient, the challenge remains how do we move forward and make organs and cells for transplantation from them. It is important to emphasize that we cannot take embryonic or these IPS them to the patient.
You know, if you put them in the lung, they're not gonna become lung cells just by learning from their neighbors. You actually have to differentiate them. You have to make cells that are mature, defined population, and only those you can, transplant them. And that actually, has proven a very difficult challenge, and that's what we've been trying to solve for for the last 12 years.
So last year, you published a really interesting paper in nature where you show you can take now charl, mouse, embryos, and golden X 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? Yeah. So I think things in Puerto Rico is what is why we 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 we want stem cells to become Morgan. And to do that, we need to understand and imitate the embryo. How does the embryo makes its organs? But the challenge, for this really is that the embryo does this process what's called gas relation, which is making the organ progenitors and 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 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 take an embryo out, you cannot put it back. So for example, you cannot take it Pete turbot and watch what is the outcome. And this is even in mice.
If you're talking about human beings, it's just Beller completely in the dark because usually you're talking about stages in pregnancy that are so early that usually a woman doesn't know she's pregnant at all. So that's why we decided to really think can we grow make basically mammalian embryos like zebrafish or frogs, meaning grow outside the uterus? And and this is also a fundamental question. You know, can you get capture, gastrication, and organogenesis outside the mammalian users?
Is it possible at all? And what we published last year really was the the end result of a very long 8 year study where we basically developed a platform which consists of a electronic device and also the media conditions to grow these embryos because you don't have a uterus and maternal blood supply. And the system is basically you can think of it as a ventilation machine. We're not ventilating the mouse lung, but actually then Flint the environment of embryo.
And and we learned over the years, what are the parameters 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 the nutrients in the media that need to make this embryo grow. Really, what what that paper really showed that, this was a big, jump from before we grow embryos maybe for one day and embryos were actually abnormal. You can go from day 5 to day 11 in the mouse embryo.
So this is 6 days. Which is about 3rd mouse pregnancy. But again, this is the critical phases that we're after because this is exactly from Pete gastrulation to late Morgan Genesis. We can really see the entire continuum of this happening outside the uterus. So this taught us as a principle, really, that that really you can capture entire organ formation in mammals outside the uterus. It shows you that the embryo is self organizing in a way.
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 itself and not by the uterus. And then the uterus, of course, is very efficient 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, but also it constituted, I would say, the bottleneck for for the entire field because it'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 from stem cells. What if you put them in this device? What would happen? Because you can think of the field of this, what's called synthetic embryos.
So they are cell embryos that are made from stem Beller. Unlike, you know, what we call natural memories, which are made after fertilization of permanent egg, that field was really stuck because you had you know, a lot of great papers making, you know, small aggregates of stem cells, like very, very early embryos that do 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 a natural embryo outside, you know, how are you going to be able to to to grow synthetic embryos? So basically, what we did last year becomes what they call the positive control or the reference control. So now we know what it takes. We know what are the conditions that are needed to allow a mouse embryo in this case to go through gas station organigens.
So we know what it takes And the question was what happens if we put stem cells and the question which type of stem cells in this setting and would they make something that is similar to an embryo or not?
So last year really was the the the technology and the platform the bottleneck and now is which I guess is the most important result in the current study, which really allowed which showed actually quite simply that the same condition, the same device, the same media, the same parameters, if you take stem Beller, what we call them naive in a naive state. Really the stem cells that are grown in the state 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 start Morgan, themselves, into an embryo like structure. And if we if we learned last year that embryos are self organizing to make their organs, now we're learning that stem cells are self organizing to be make embryo like structures which are self organizing to develop, and make organs.
And in this context, I think, we can reach, as I mentioned, day 8a half, an 8a half in development, it is after gas station, post gas station, and already well into organ formations. There are these embryos have brains including the anterior region, the mid region, They have noiltube. They have a heart with chambers that is beating. They have blood stem cells. They have the intestinal tube and and they have the tail. And we did a lot of characterization.
We need to show, I would say, that these embryos are not totally normal. I would say about perhaps 19 95% similar to natural embryos. But definitely they are by far the most sophisticated, the most advanced, differentiation entities because they really capture the the sequence of events and the way that organs are, placed inside the embryo and relation to each other is very, very physiological state. So that's so super siding.
Can you remember how you felt going to the lab day 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 a disappointing, answer. And I would say because this is, for two reasons. This is as I said, like, perhaps a very long process of of working, for 12 days where we every time we actually got one more day and increase the efficiency and increase the quality.
And, a bad habit that we have is, you know, of course, we get excited, but within within 1 hour, we're actually thinking, what about the next step? So that's really, of course, it has been very exciting. And, you know, yes, the the other hand, they're seeing a Pete, you know, it is very exciting because it really tells you this is no longer hand waving, you know, you're you're getting an organ filled embryo.
But but the the the I think really the magic was, which is great, has been, you know, just continuous slow, but persistent, progress in seeing how this developed, whether it's natural embryos, whether it's synthetic embryos, from the mouse, and, you know, we work on other species, for example, from rabbits and so forth. So really seeing this expanding, has been very exciting.
And also as I Flint, as what's also been exciting is really seeing different aspects that we did do research in the lab merge together really to culminate into this this this one climax. In other words, So it's not about hasn't been only, as I mentioned, about how to grow embryos and build a device, but actually learning how to make what we call naive stem Beller. Particularly in humans and other species. So naive stem cells are really the highest levels of stemness.
And and and and for years, people, you know, when we were working on these naive stents, it was like, oh, why should we care? We have conventional stem Beller. They're good anyways. But we now, you know, we showed before that conditional sensors are limited in their potential And now actually we show that this can only work by using naive stencils.
And so this, you know, this is kind of the merger between the the the those two paths was perhaps, you know, not always clear, is in itself also very exciting for us and and and and and also gives us a lot of knowledge and control, we need to make our results better because we've, you know, we're we're, very well versed in both aspects of this stem cell field. So currently, you published fully synthetic mouse embryos. So no sperm, no end, no uterus, from day 0 to day, 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 synthetic embryos growing all the weight? So that's an excellent question. So as as I mentioned, in natural embryos, we publish we can reach day 11a half. I can share with you, actually, we now also reach 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 normally developing, 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 protocol. I think that I have no reason to believe that these embryos cannot go further because I think Once you already finished gastrication, you can see all the the Morgan.
They should proceed further. I think what's happening in the embryo because as I mentioned, they are, there are some subtle malformations, for example, perhaps in some embryos, the heart is too big or too small, or the brain is slightly too big or too small. And that actually adds up and and the embryo doesn't grow further. And the challenge is really how can we perhaps better confine the embryos and and do some tricks to really make them aggregate in a better way.
And I believe they can't catch up with natural ambiance. Whether we can, you know, get entire, let's say we talked about in mouse pregnancies, more of an entire pregnancy outside the uterus, hasn't been a, I must say, a major focus of of our lab is because as I mentioned, we're trying to look at how organ formation happens. We are now starting to work on this on mice.
And one advantage is that although there's no maternal blood supply here, but these embryos have an umbilical cord and have a and have plots applied. So basically, you already have what you call it, the highway roads to really try perhaps and to use circulation on these Now I would think this 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 really possible. I think we're we're we're it's it's their embryos are too big. It's too long as far fetched at the moment.
And, we prefer actually at the moment to focus on their early stages from different Pete, including humans, because we we what's more about understanding how organ progenitors are formed and perhaps even, you know, using these organ projections that emerge in this process 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 the technology and to create products.
For people that suffers. So what kind of diseases or indication? What kind of suffering can we prevent in the world using this technology if we just imagine 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 very important to all remember and remind ourselves that this is this is our goal in the end that we're trying to make early Beller for janitors that are for their useful transplantations.
And the scenario that we are really facing, you know, you can think of, an adult woman who's infertile either because of unknown causes or from undergoing chemotherapy at a younger age or women, you know, in modern society, perhaps if, you know, at the day after age of thirty eight, the the quality of eggs really deteriorates. That's one one one scenario.
You can think of other scenarios where you have a patient who needs bone marrow transplant or liver transplant, and he cannot find a matched donor, Pete with these ones.
And that's why what we want to explore in the company and and we think there is, merit and there is rationale based on what we know from mouse experiments and also what we know with conventional differentiation of stem cells that we can envision a scenario where such a patient, will come and just donate Beller it's a drop of blood or a hair we can make we already know how to make these IPS cells.
We then put them and make them in this naive state that I mentioned, which is really the most pristine and most potent Beller. And then try to push them to self organize to what we call the synthetic hole embryo. You can model what we call them in brief swings. You know, this kind of early differentiation for about, let's say, 20 or 30 days, which we already know, for example, germ cells or or or blood steps is already found such early stages.
And in this case, well, these cells can be taken, perhaps expanded or modified if needed, and then transplant it back to that that patient. That is the scenario, that we're we're trying to do, and I think this is what has the field been after.
So that could be, you know, in in this scenario, it could be an easy way where you can have a genetically man matched patient specific stem cells that self organize into complex, authentic, differentiated cells that can be used Currier, either as I said, for transplantation or drug discovery and so forth.
Yeah. And and as you know, just recently we got an email a young twenty two year old woman that, you know, very emotionally wrote to us that she lost the ability to to appropriate because she was diagnosed with cancer, and she didn't have time to freeze her egg before she had to undergo chemotherapy. Pete, you know, people want to have their own babies, and it's very emotional. And, hopefully, we can solve this problem one day.
No. No. Something, you know, as I said, I've seen in the clinic from my physician training as a physician, but as I mean, I've I've been, you know, 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 cell promise and, you know, where, why has it been so much progress? So I would say, actually, there has been a lot of progress. And I think the Beller can do it.
And I think there's very, you know, when you see these cells Morgan that you remember, you realize that the cells can do the job is that we 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 new path of getting at this problem. I think it's a very strong and valid Pete, and it's a very unique one. And and that's what we would like to explore in many different directions and see what it can be good for. Amazing.
Really, truly amazing. And, in NSFacts, we like to support scientists founders. And then in this company, you know, there are 2 kind of scientists of course, you are a scientist, in Weitzman Institute. You are staying at Weitzman. You're still doing a lot of amazing basic research Beller while helping the company. So I'd love to hear what's your experience been so far. And then your students, you know, they went to the video, their PhD, they feed postdocs.
Some of them went to industry, some to Academy and out there. Many of them are coming back to to work on this project you know, what do you think about this, journey of the scientist founder? Yeah. Well, yeah, I think, you know, you must say it's a very exciting one. You know, this is the first company that I'm involved 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. This is something I'm very, very committed to.
I think this has been a goal after, and I think and this is high time Beller to try to push this in the company is not. So, of course, about trying to commercialization, the company can also push the science very much forward. Then, so I'm, you know, this is a learning experience for me. It's been, you know, very, very good one so far. 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 from from my lab that went on and actually became experts in other fields. You know, one of them is actually now become a very expert in hematopoietic stem cells. One of those is really, expert in transplantation in pigs of certain Morgan. So actually that's really exciting because, you know, it's it's watching them not sure.
They they have even knowledge in things that far 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 and some some end. And a different and and and this kind of enthusiasm and many, many ideas together. And so I think it's also a very healthy way in fun 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 up the scientists to focus just on basic science with my experience in companies like sense where Jennifer Dona is the co founder that obviously you can still be an amazing curiosity driven basic scientist and start companies.
And some of your students can go start companies, and some of your students can go become amazing scientists And your companies can give you resources back to the lab so you could do more science. And so I think for my experience, it's a win win for for scientists. Actually, I mean, I can you can add one when you were talking about the Weizmann Institute about the basic issues.
I think maybe so I think you know, I think that the wise men actually, you know, that it's you can do research whatever you want, whether it's basic, whether applied, and and and these things. And this is very curiosity driven. But, you know, what what always proves itself again and again, as you mentioned, whether it was a crisp battle from before and that basic science typically goes hands and hands and and this understanding leads to development that are highly applied.
And I think in our example, really learning about what what does it mean to be a naive cell and what is the signaling pathway for us in naive cell and really trying to be curious why you can't then grow an embryo at Pete late stages. And then, of course, that develops into an applied thing which helps you go back and answer a basic thing.
So particularly in the stem cell, you know, I think 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 time. You know, it's both of the coins. We're we're advancing basic knowledge that helps advance technology technology that goes back again and feeds in and increasing our knowledge of basic research. And I think, this is what's happening in, for us in this case and, very helpful for us.
And we we will continue in this way to answer basic questions on this process. Amazing. Thank you so much for being here today. Thank you very much. It'll be exciting.