Theories of Everything with Curt Jaimungal - Alfonso Arias: Richard Dawkins, Morphogenesis, Epigenetics, Genes, Cell Biology

Episode Date: June 4, 2024

Alfonso Martinez Arias is ICREA Research Professor in the department of systems bioengineering of the Universitat Pompeu Fabra in Barcelona. The recipient of numerous awards, he is co-author of the biology textbook Principles of Development, which was awarded the Royal Society of Biology book prize.Please consider signing up for TOEmail at https://www.curtjaimungal.org  Support TOE: - Patreon: https://patreon.com/curtjaimungal (early access to ad-free audio episodes!) - Crypto: https://tinyurl.com/cryptoTOE - PayPal: https://tinyurl.com/paypalTOE - TOE Merch: https://tinyurl.com/TOEmerch  Follow TOE: - *NEW* Get my 'Top 10 TOEs' PDF + Weekly Personal Updates: https://www.curtjaimungal.org - Instagram: https://www.instagram.com/theoriesofeverythingpod - TikTok: https://www.tiktok.com/@theoriesofeverything_ - Twitter: https://twitter.com/TOEwithCurt - Discord Invite: https://discord.com/invite/kBcnfNVwqs - iTunes: https://podcasts.apple.com/ca/podcast/better-left-unsaid-with-curt-jaimungal/id1521758802 - Pandora: https://pdora.co/33b9lfP - Spotify: https://open.spotify.com/show/4gL14b92xAErofYQA7bU4e - Subreddit r/TheoriesOfEverything: https://reddit.com/r/theoriesofeverything  

So, Professor, why don't you give us the cliff notes of how you got to where you are in your research, so your worldview or, as I say, your biological Weltanschaung on this channel? The Weltanschaung is a word I like very much. We can get to that. I grew up in Madrid, and under very difficult times, we had the dictator leaving. It was a very difficult society. There was not a lot of culture. My parents were journalists and we had books at home. And it was a time, and I think this will explain something to you,

that where you learn rather than being taught. I mean, practically any books that you could pick up, that's where you learn because the university was very busy with a lot of social unrest and a lot of protests like they are now with other issues, but we had that issues then. And I came across biology as one of the great and very interesting mysteries. I was very, very interested in, I had seen some pictures in magazines about the embryos, human embryos that fascinated me, and I wondered where that was coming from. How old were you at that point?

About 13, 14. I was quite interested in this. And I started studying biology in the university because I was interested in this. As I said, at that time, the teaching was not very interesting. We were interrupted. We had a lot of interruptions, but two books came into my hands that I think were very fascinating to me. One, it's Chance and Necessity by Jacques Monod. That's an absolutely central book in the history of biology because it presented a very materialistic view. This is the beginnings of molecular biology. Jacques Monod is one of the most important

and great heroes of molecular biology. People know Watson and Crick everywhere. Everybody has heard, but it's surprising that they haven't heard of Jacob and Monod, who from my point of view, they did much more for biology than Watson and Crick. And this book of Monod, which tried to explain life in a very materialistic

basis and looking at proteins, he was very interested in proteins and the activities and the philosophy of proteins, Chance and Necessity is a philosophy book that really grabbed me. The other book that I found fascinating, it was a collection of essays called Towards Theoretical Biology, which was edited by someone, Conrad Waddington. Conrad Waddington was a very interesting character, English character, who was very interested and way ahead of his time, particularly on theory in biology, and assembled a group of people, largely physicists, mathematicians, and some biologists, to try to understand in the 60s, if there could be a theory of biology as there is a theory of physics.

And this collection of essays actually completely took me over and I felt that physics, maybe one could do theoretical biology or one did theoretical physics. Through that path, I came to someone that you probably know, which is Ilya Prigozhin and his thermodynamics. And I was very fascinated by dissipative structures, the connections that they have with biology. And that led me through a coup of luck to go to the University of

Chicago to do a PhD in the Department of Biophysics at the University of Chicago. This was the late 1970s, and it was very hard because I was no mathematician. And at that time, we really didn't know enough biology, enough of the elements of biology to actually do any theory or to relate physics to biology. So you went into biophysics with solely a background in biology? Well, in the final years in the university, I got very bored with biology and I took a lot of courses on physical chemistry. I was very interested in physical chemistry and chemistry. So I had a little bit of a background,

particularly in the physical chemistry aspects. At Chicago, I took a lot of courses in quantum mechanics. I took ordinary differential equations, calculus, and that was, but I realized I was a very good professor there, Jack Cowan is a very famous theoretical neurobiologist, pointed out to me that I was a very good professor there, Jack Cowan, he's a very famous theoretical neurobiologist, pointed out to me that I was not, in those times, the only theoretical biology that you could do, serious and useful one, was theoretical neurobiology. And I was interested in development, I was interested in how the organ is built.

Jack introduced me to Turing's paper, which was the most important and most important and Turing paper on the chemical basis of morphogenesis. But after two years trying to become a theoretical biologist, I realized that A, it was too mathematical and too abstract for me, and second, that we didn't know any biology. So I turned into finishing my PhD in a more experimental source. And I started gene regulation, which at the time was coming to the fore. We were starting to understand the genes that control development. Finished my PhD and I went to England to do a postdoc in developmental biology. I never forgot my interest in the connection between physics and biology. And in Cambridge, I worked with a famous developmental biology,

geneticist Peter Lawrence, at the time where really we were starting to see where were the genes that control development. And I spent almost 20 years looking at this. And in the year 2000, I assisted to a lecture by Michael Elowitz. And that really bowled me over. I always kept my eye on anything that had to do with physics. One of the things that I always admired in physics was statistical mechanics. Statistical mechanics was for me a very fantastic edifice created by people.

And I thought that that was one of the problems with biology, the same way that you could explain pressure, volume, and temperature on the basis of the kinetic and potential energy of the molecules, we should be able to do that in biology. But we needed to know what was the velocity and the position and the momentum of the different particles. This is what it was missing. Michael Elobits, who many people that are listening probably know, is the poster child of systems biology. I really like his approach. He was starting to work with bacteria, trying to understand noise,

trying to understand heterogenesis, and that really changed my mind. At the time I had been doing a lot of developmental genetics of Drosophila, trying to link genes to processes of patent formation. It was very, very, I mean, that allowed me to know genetics very deeply and the connection between genetics and phenotype. But Drosophila always sends that I needed a system

where self-organization and emergent properties would work. Drosophila is a very deterministic system. You would get the impression that it's built by genes, if you wanted. I discovered some things that maybe suggested that no, but it was not a good system to study the things that I was interested in. And I was very lucky at the time that embryonic stem cells were coming into the fore. I thought that there were a very good system to do that because they had an interesting property. In a dish you could differentiate them into all the cell types of an organism, but would not make an organism.

So I wonder why that is. Either there is something magic here, or maybe we can build an organism out of all these ES cells. And I set out to see if we could coax these embryonic stem cells into making an embryo. And I'm very glad to say that we succeeded in some way, and we've learned a lot along the way. The last 10 years have been very exciting. I'm sure we to say that we succeeded in some way, and we've learned a lot along the way. The last 10 years have been very exciting. I'm sure we can get to it.

But also for a while, I organized a series of symposium in Cambridge called the Physics of Living Matter. I organized the first 13 ones in which I promoted the interactions between physics and biology. It was a little bit selfish on me because this was, now it was the time to actually do that.

Biology has becoming a very good pose for physicists. They've been coming very much into the fore with quantitative analysis. Biology has changed enormously in the last 15 years and now it's a very good priority for physicists to work on very interesting problems and to contribute very interesting things to biology. So during this series that I organized in Cambridge, I learned a great deal. This is a community now that is extraordinary. I am not part of it because in the course of our work,

I discovered things that we need to understand before I can model the things that I want to understand. Sometimes I feel that I'm too early into too many things, but now the physics-biology interface is tremendous. They just had, you may have heard a month ago, they had the first Solvay Conference on Physics and Biology that was very, very exciting. I heard that I wasn't there,

but this is a field that now is very mature. I follow it on the site. I have many friends that I've accrued through this symposium that I organize. And I'm very glad that I've accrued through this symposium that I organized. And I'm very glad that now we are in a place in biology where we can apply a lot of physical methods to biology. I like to say that biology is the unwritten chapter of statistical mechanics. When you get to non-equilibrium processes, now that's particles and self-organization, you are in an area of biology.

Prigojing was right that there were dissipative structures, but now we know so much that we can actually see what things we can explain rather than just, you know, try to do theories abstract as people did in the late 70s or early 80s. So do you believe that life is just the inexorable consequence of thermodynamics? Yeah, I think of remember, I mean, it's in a way what Boltzmann would say, right? We are decaying fluctuation in a very small part of the large phase space.

And as we are returning to the maximum state of entropy as a dissipated set of structures, we are creating order. But I concur with that view of life. Professor, please explain to me what led you to oppose Dawkins' selfish gene concept. Well Kurt, I think it's not so much to oppose. I think one has to dig into the history of biology in the 20th century to understand that perhaps the selfish GMB of Dawkins is incomplete. And I think what led me, as you say, to oppose, not so much to oppose, but to appreciate or to identify some weaknesses in that theory theories my background in developmental biology. I am interested

in how animals are built and they are built from the zygote. And you might recall that a very important tenet in the views of Dawkins about the selfish genes is that organisms are instruments that genes built in order to travel through time in a way. They are just structures that are a direct consequence of the genes so that the genes can compete with each other to travel in time. But I think that the problem with that view is that it ignores completely developmental biology. I don't think there is anything wrong with the selfish gene view of

Dawkins other than it's very limited in what it explains of biology. The selfish gene view of biology, which is the gene side view of biology, it's a consequence of the developments in the 20th century to explain biology in terms of genes. If you look at the history of biology, it starts the 20th century with the discovery of the gene, which becomes a very powerful concept that one can use to explain a great deal of things, okay? It's interesting that for 50 years, people don't know anything

about the material basis of the gene. And the gene comes into being as a contradiction, actually, to Darwin's ideas of evolution. Because Darwin describes an evolution that is continuous, in which the phenotype that is continuous variation and selection acting on that continuous variation, it's what starts creating the shapes and the structures that we see around the world. He didn't have an explanation for the material basis of this continuous variation. When the genes come, they provide something

of an explanation, but they create a problem. And that problem is that they are discrete units. And the question is, how can you bring together, how can you bridge the gap between a set of discrete units and continuous variation? And that is the great triumph of population genetics and what is called the modern synthesis, which some people today are trying to challenge and say that it needs to be overturned. But it creates a connection

between these discrete entities, which are genes, and the continuous variation which occupies the world. Can you explain the difference between cell biology, population genetics, and then developmental biology? Yes, I'll try. Are these different views? You mentioned there's a gene-centric view, and I assume that that's what you're opposing or that's what you're disputing as incomplete? That is, I'm not, I'm not, I'm not, I'm disputing that that is the whole explanation for biology.

We live in a time where wherever you look, and I'm sure you will agree with me, everybody, you open the papers and everything is about our genes, is about our DNA. There is personalized medicine which measures the genes and will give you medicines according to your genes. People talk about the DNA of a company. People talk about it is in your genes. I mean, it's absolutely pervasive, okay? And actually, there is a whole bunch of things that are not in the genes. I mean, and I can tell you, Saman will come to that in a minute. So the gene view of the world is that this molecule that is called DNA, where there are these stretches, which are called genes, which code for proteins, is all there is that if you know the genes of a person, you know that person. That is really what they are telling you. 23andMe, for example, will sequence your DNA and will tell you a lot of things about yourself that you might believe or might not believe. So the view of biology from the gene

is that if you know the genome of a person, you know everything about that person. In fact, it's been said, now there are some people that are backtracking, that if the genome contains a blueprint of the organism, that all you have to do, there are instructions there to build an organism. It's nothing of the like, okay?

So genetics, genes, they just look at the sequence of DNA. There is a blueprint in DNA is to make another molecule of DNA. That's about it. That's because there is a template, you know, there is the double strand and one strand can code for the other and that's about the only blueprint. Cell biology, it's an old discipline and what it tries to understand is the structure and function of cells. Cells are very complex structures, particularly what we call eukaryotic cells. We are made of cells that are eukaryotic cells. Prokaryotic cells are bacterial cells,

which are much simpler. They are not so complicated. Cells have an enormous repertoire of behaviors and an enormous complexity. Cells are really an emerging structure. They emerge their behaviors. They really, you cannot predict from their components. In fact, one of the points that Dawkins always makes and the people that suggest Dawkins is that DNA is a great replicator. It replicates itself and passes from one organist to another.

It is the only thing that can replicate. But actually, there are many structures in the cell that cannot be made out of genes only. They have to be replicated in order to be themselves. Membranes, for example, you cannot create. If you put together all the genes that are supposed to be involved in making membranes, they will not make membranes.

A cell needs another cell in order to recreate. So cell biology is about this emergent structure that we call a cell, which has a number of properties that are not in the genes. It can interact with other cells. It can divide. It can grow. It uses the genes as tools to do all this. But it's not.

A lot of its properties are not encoded in the genes. They are emergent from the interactions of these structures that appear from the genes that are the proteins. And to finish, developmental biology, what it does is studies how cells interact with genes in order to build organisms. Those would be the three elements. Whereas in a very gene-centric view of the world, genes have a blueprint in your DNA, there is a blueprint for the organism. The way I would think it is that the genes are coding for a number of tools and materials that the cells actually deep into in order to build organisms. They are constantly deepening in those cells. And I think the understanding of these emerging properties and how cells interact with each other is something that is now coming into the fore,

which can explain many things that the gene-centric view of the world, it can't. Professor, when people say that there's just nature and then there's nurture, is there a third option? Is there more than that? Or is it just this dichotomy? Or is there only one? I suppose nurture is part of nature. I mean, I find it difficult. It's one of those things you're presenting me

with a dichotomy and asking me there is something else, but each of those terms encompasses so much that it would be very difficult. Nurture is what fits nature, but it's usually part of nature. I don't think you can separate them. I think if you want to say when we think about an organism, if the organism is driven by internal forces, or it requires something else that comes from the outside, I think obviously it needs something from the outside. As we were talking, we are dissipative structures. So this is something that needs

to be addressed. And I think now there is people because, sorry, because we can do measurements, people are able to start, they're starting starting but they're able to do thermodynamics of certain developmental events and doing measurements. There's a concept called genetic determinism so would you say that you disagree with that? Completely I think I think this is one of the errors if you talk to geneticists, nobody will own that concept. They will say that nobody, but actually when you look at their actions, and I think actions is what matters, this is a very extended view and I'll give you some examples. Please. And I think this is where I think we need to think at this moment. Genetic determinism is the notion that we are determined by our genes.

In a way, if you wish, it's an extreme consequence of the selfish gene hypothesis. We are nothing but our genes. I am not refuting. I want to stress that there is anything wrong, that the genes have something to do with us. I'm just saying that they don't explain everything and that we have to extend this and to think a little bit deeper.

The idea of genetic determinants leads to eugenics in the early part of the 20th century, which is the fact that having decided that we are our genes, we can decide who is the fact that having decided that we are our genes, we can decide who is the perfect human being and get rid of those whose genes defined in a very abstract manner in the connection between genotype and phenotype, we can get rid of those people. And that's what the practice of eugenics was, particularly in the United States, where it reached the point that even certain immigrants groups were

set to have bad genetics and they were judged to be able to enter or not in the United States, depending on this. So genetic determinism, the first incarnation in the beginning of the 20th century leads to all the horrors of eugenics, which now everybody will abhor and they don't want to to to abstain. Then we enter into a phase where we now agree that we cannot characterize an individual by one gene or by one or a small group of genes. But with the emergence of the Human Genome Project with all this ability of getting genes in a very cheap way, having

accepted that there is not one-to-one correspondence between a gene. And I'd like to qualify what do you mean by a gene now. A gene is a stretch of DNA that has many different forms that is called alleles. People sometimes talk about having one gene or having, we all have the same genes. The variance of those genes is what creates the differences. So somebody that has sickle cell anemia is not because they have the gene for sickle cell anemia. It's because the gene that goes for myoglobin or hemoglobin is defective. So this idea sometimes that people have a gene for a disease is a misunderstanding.

We all have the same genes. It is the versions that we have of those genes that can be faulty or can be different, let's call like that. Just a moment. So for an analogy, would it be akin to saying, look, this is a blue cup and we all have the same cup, but we have different colors of cups. You may have a green one.

Exactly, exactly. But you're reading the press very often and I can see that you have a colors of cups. You may have a green one. Exactly, exactly. That's, but you're reading the press very often and I can see that you have a blue cap now. Yes. And you know, you're reading the press, this person has the gene for cancer or this person has the gene for diabetes. We all have the same genes.

It's the variance, it's the colors of those genes that are different between us. And some of those colors can cause disease on some occasions. The number of diseases that are monogenic that can be linked to a gene, to one gene, there are many, but they are not very representative. Given the number of diseases that we have, there are not that many. So what people have done is create this notion that is called the polygenic risk score.

I'm not gonna go into the details because it can get a bit- The polygenic what? Polygenic risk scores. Risk score, got it, okay. It's a statistical quantity that tries to identify the genetic contribution to a particular trait in the population. Okay? I'm not going to go into the technical details, but this is now very important because people are sequencing genomes,

and on the basis of your sequence, for example, recently they got very excited because they found the number of genes that they have to measure to determine height. And they call that they have a thousand, 10,000 genes. To me that doesn't make any sense. They are translating a genetic determinism based on one gene to say, now we can make a statistical measure over thousands of alleles and now give you a probability of you having being 170 or having diabetes or having, and I think this is very serious because usually

what is called the heritability, the contribution of the genetics to this character is very, very low. But this is now a new form of genetic determinism in my view, okay? It's a form of now rephrasing instead of one gene, we are going to find the statistical measure that gives us a number to say how much of a genetic contribution is for you. And we can tell whether you're gonna be sick or not. That sounds like a natural extension of statistical mechanics applied to the genes.

To cheat. Why do you not like that? In a way it is, but not to phenotypes, it's to genetics. And these polygenic risk scores, now they are all the rave. In fact, last year, there was a very famous book in the States called the Genetic Lottery. There is these people called behavioral geneticists, which claim that on the basis of these measurements, by sequencing the DNA of a child, they can determine what their school attainment is

going to be. And somebody in a book called the Genetic Lottery proposed to reorganize the school system in the United States based on polygenic risk scores that they can assign to possible attainment. To me, this is genetic determinism. This is a second version of genetic determinism and one that is very, very dangerous. In the UK now they are sequencing the DNA of about hundreds of thousands of children in order to try to assess the probability that they are going to have diseases on the basis of these thousands

of alleles or colors or shades of gray, and then you can intervene or not. I think that there is a danger in this because we don't understand. As I said, this is in a way an extreme form of the dockings that the individual, the organism, is a linear consequence of the genetic makeup. And this is very dangerous because between the gene and the organism there is the cell. There is a great integrator, there is a great worker, there is a great architect. I wrote this book, The Master Builder, which is all about this dichotomy and about highlighting the things that genes cannot explain. Nowhere is written that we have two arms or we have five fingers. There is nothing in the genome that says that.

There is nothing in the genome that positions our eyes. As I tell in the book, you know, our fingerprints, we have 10 different fingerprints. That is the same DNA. That's why you can only open your phone with one finger. The one of the other hand will not do because your fingerprints on this hand are unique. They all have the same genes. It's what you're referring to right now, morphogenesis or morphogenetics? Exactly. What would be the difference between those two?

Well, they are the same. Morphogenesis is the process. Morphogenetic process is the process whereby you create form, you create shape. And I think we know very little about this process. But we know that it's not in the genes only, that the genes are being used to create forms. So, speaking about morphogenesis, on page 438, I believe, but from your book called The Principles of Development. Oh, yes.

Oh, wow. You talk about the imaginal disc, which comes from ectoderms of insects. So what are imaginal discs? So imaginal discs is in a way, it's very fascinating in the history of developmental biology or biology. It's a remarkable thing. Insects are very weird the way they develop. Imaginal disks, everybody has seen the chrysalid, the pupa of a butterfly or of a... So normally out of the egg of an insect comes a little kibik crawly, a little slug that feeds for a few days. And hidden in that little worm-like structure, there are very small bags of cells,

which are called imaginal discs because of the meaning, we are not going to get into the meaning of the word. And those little cells that are growing as this little creepy crawly is feeding itself, and they are growing, okay? And there are about 10 of these discs, and every one of them is the seed of a part of the adult butterfly, or the adult life. When this creepy crawly goes into form in the chrysalid, many people must have had silk worms, for example. People that like biology, they grow. So they can see that all of a sudden the worm goes into this chrysalid, which is what is used to make silk. And then there a fantastic transformation occurs in which the cells of the creepy crawly die, and these things become like a Lego.

They become assembled into the butterfly, or into the fly. The imaginal disk, so there is a little group of cells that will give rise to one wing, another group of cells that will give rise to the other wing. There are six legs, and every leg comes from a group of cells that sort of grows and has instructions to make a leg. And in that pupa, in that chrysalid that you know,

this assembly is happening. And then it closes and you get this wonderful animal. And that's the imaginal discs. It's the basis of a lot of the insects that we know, particularly these insects like butterflies and flies that we have around. And they are remarkable because you wouldn't think that an organism is made like a Lego. And you might ask, how do the cells know how to assemble together, you know?

Because in the in the creepy-crawly, they are completely separated from each other. And all of a sudden in that pupa that you must have seen in many, many places and that some of our audience will have seen when they make the seal worms, everything magically and now we can film these processes and we can see how the cells, because you know, part of the every leg comes from a totally different imaginal disc, which is these clusters of cells and they all come together in a fantastic manner during the formation of the adult organism that is that fly. When you look at the development of animals, what you find, it's a big variety of modes

of operation of development. One of the things that we have learned over the last 20 years is a fantastic story, which I think we don't yet understand, which is that the genes that make us are not very different from the genes, well, that make us, sorry, I don't want to recant myself. The genes that we have are not very different from the genes of the fly. It's how the cells use those genes that create the difference between a fly and a human.

It's not the genes. We are not very different in terms of a gene repertoire. So the genes will give the raw material to the cell and the cell then has to do something with it? That's my view. That's the way, that's what I'm suggesting. A change of perspective that we need to look not at the genes as the masters, but as the servants if you wish to the cells.

I see. So again, just to make an analogy, a video game analogy for people who play survival games, there's crafting in those games. And what that means is you go out in the world and you find some corn and then you find some steel and you find some wood and then you can make various objects with them. Okay. So would it be that the genes are like what's providing you the corn and the wood and the steel, and then you as the crafter are the cell? They are the corn. They are. Yeah. They are. They are the corn.

Exactly. They are the corn. They are the steel. They are. That's, that's what they are. They code for those things. That's very clever. The way evolution has created this. And the cell,

there is a very interesting relationship between the two. If the cell wants to make another cell, it's going to go into the genome and pick up, as you said, the corn or the silk or the rope that it needs, and it's going to then make a... Yeah, silk and the rope would be better analogies because corn itself is a living organism. Well, it's food, but the corn is food and the cell also needs food, so it has to create food. Right, right, right. So I think that the cell, there is a very interesting symbiotic relationship between

the two, but the cell controls the genome in ways that we are starting to see. Cells are able to sense how many cells they have around. They are able to sense pressure. cells they have around. They are able to sense pressure. They are, I mean, they create shape. They use genes to do that, but the genes are not, as I said, there is nothing in the genes that say that we have to have two eyes or five fingers. Again, for people who are listening or watching,

you have a book that's for the general audience called The Master Builder, correct? Correct, thank you. Okay. And then there's another watching, you have a book that's for the general audience called The Master Builder, correct? Correct. Thank you. Okay. And then there's another book that you have with some other people like Walpart, which is published by Oxford University Press called Principles of Development. That's a more academic book.

Yes. Yeah. On page 586 or so, you talk about the development and regeneration of a neurogenic limbs something like that a neurogenic and you also talk about amphibians which remind me of michael levin so i want you to talk about. Where do you see harmony with what you're doing and michael levin's work. And where do you see discord. Where do you see discord? I am, I know Michael Levin and I think he's a very good spokesperson for certain aspects of the work, emphasizing certain aspects which I would agree with, you know, about the need to go beyond genes. I think he goes a bit farther than I go because I think maybe I go stepwise.

I think we have to go beyond genes as we've been discussing and we can have the reasons. But I think we need to understand cells, how cells work, what is the relationship with genes. I don't think we can throw genes out of the window. We need to understand what is the role because there is a lot of evidence that, and I discuss this in the book in a manner that I hope people will understand. But I think Michael has a tendency to go a bit far off the realms of what we can do at the moment and what we can think.

I think his ideas are very appealing, particularly to people that don't know biology. So in that sense, it is good that he calls attention on some holes in biology. But I find him a little bit wanting in some of the details of how we bridge this gap. So he has two main bones of contention. One of them, I think it is indeed important. The other we can discuss in a minute. He's very interested in the role of bioelectricity in development and we come to regeneration in a minute.

And I think that, so electricity, as many of the people that are listening know, it's the key element in the functioning of a nervous system. I mean, this has been known since Volta and Galvani, and there is no question. Great advances have been made in understanding our brain. I would say that neurobiology is by far the best understood and most deeply known part of our biology at the moment. I am not to the point that that's why we can imitate it

with neural networks, we can do a lot of stuff. We don't understand very much, but, and that's driven by electricity. Mike goes and says something that many people know, that there is also electrical signals outside the nervous system. And I think many people will agree with that. The question is, what do those signals do? and what is the role that they play in the makeup and in the development of an organism?

He makes statements which in my view is going to take time to prove in terms of the experimental evidence to support some of his claims. For example, he claims that he can induce regeneration with electric currents as a response to genetic defects. I have read the papers, I have listened to him talk, and I have difficulty seeing the sound evidence for that kind of statement. So they haven't been replicated? They haven't been. I mean, this is one of the important things in science, right? That other people do the same experiment and get the same thing. And I'm afraid that for now, let's put it that he hasn't convinced people, people that have tried have not seen the same, but he hasn't convinced enough people to, that this has become a field or that people are

doing those experiments. You can say that that's because he's thinking too far ahead of his time, it is possible, but it's clear that this is not a mainstream area. The issue of bioelectricity and regenerative ability of bioelectricity is not something that for now has been accepted, and people that have tried those experiments at a smaller scale, I don't think they have gone very far. As I said, I've been again, I follow the field because I think he has an interesting point. I think bioelectricity in my view probably doesn't play a major role in the shaping of the organism. I think it plays a minor role in adjusting, in fine adjustments or in the physiology of many cells.

There is evidence coming for the role of bioelectricity with very fine experiments, but I think he has a tendency to do very bold experiments that perhaps because of that, they are difficult to replicate. I mean, this is one of my problems. Regeneration is a very fascinating field, but not all animals regenerate. I mean, this is the other thing, you know, people, certain frogs and certain fish, you know, you can cut the tip of your finger, the tip of your finger will regenerate, but if you cut a bit farther,

you could lose the tip of the finger. It's a fascinating field. Many people are very interested in that. I think the future of that field lies in the embryonic stem cells and the discoveries that many of us have, I mean, I've been very glad to participate in that over the last few years.

The embryonic stem cells are being harnessed to create mimics of organs in culture. And in some cases, they are promising a great deal, guts, livers, very fascinating stuff. This is also where I think Mike, this idea of the xenobots, which I have to say that the frog developmental biologists have known those structures for 80 years. And it's a bit curious that he discovers them and gives them the name.

And I know that some people in the field get a bit miffed about this, because these things that you create, these ciliated epidermal things, and they move around, I mean, this has been known, there is plenty of studies of that. But if you want to regenerate, to create organs for regeneration, the organoid field, what we do, which is starting with embryonic stem cells, we can create the very early beginnings of embryos and create structures that have the three axes and that

reproduce very well a lot of the early embryonic stages. And that can be used at the moment to understand how those early stages occur. It is where the field lies. And as I say, people are being able to recreate guts, for example, that they are being used to put in mice and do experiments of transplantation of these guts created in vitro from embryonic stem cells. And that's where I think the field is going to be in the use of the stem cells to create these organs through the emergent properties of the cells. This is the other important thing. But Mike Levine, I think, is very good that he makes these statements about But Mike Levine, I think is very good that he makes these statements about the fact that we need to go beyond genes and creating an impulse for people to think beyond that. So in other words, let's say there's an axis of genes, of gene-centric and then what lies beyond genes, it would be Dawkins, and then it would be you, and then it would be you and then it would be Michael Levin. Yeah, Michael is a bit closer to the mainstream if you wish.

Because I think I'm an experimentalist and I... So what lies beyond Michael Levin? Who is even outside Levin himself but is still a researcher and academic? Yes. What I'm saying is like, look, there's Dawkins, then there's you, then there's Michael Levin himself, but is still a researcher and academic. Yes. What I'm saying is like, look, there's Dawkins, then there's you, then there's Michael Levin, and then is there another person outside that who is also a professor? I think Mike is very, reaches out very far, you know, he talks about agency, he talks about the consciousness topics that I would never dare with, you know, I,

I was thinking sometimes I think that I am, I am more a materialist than a reductionist. I have difficulty with words. You can get into the realm of words. And in biology that's very easy because you can do philosophy in physics for quantum mechanics, for relativity, but you have to know the maths. If you don't know the maths, you cannot really get into those realms. In biology, because everything is still very early and is very loose, you can play with words. And I think that that's what happens sometimes when you go very far from the biological reality, from the materialism. I think you could say that Mike is very holistic and is very philosophical. I am less so. I see. So what's something that you believe to be true that most of your colleagues in your field don't?

And you can get as granular as you like when talking about what your field is in this question. So it could be developmental biologists, it could be biologists in general, but I would like it to be something that your collaborators, they're close to you, so close that they're your collaborators and you disagree with them. You've put me a big challenge there, Kurt. that there are features of the makeup of an organism that are not in the genes is something that I get into arguments because as I've said, the biology is very dominated by a gene centric view. And I think what I find interesting, I've mentioned earlier that there is a new catered of people that are basic physicists coming into the field,

and they are much more prepared to think about these emergent properties and look for the cost of these emergent properties in a manner that I would agree with. But if you talk to the card carrier biologists, they would tell you that there is nothing that is not in the genes, that everything is in the genes. This is something that if I was to get into a room with 10 biologists, nine of them would be very much against me, and we would find a very interesting discussion that I don't know what it would ensue, but I've been thinking. Something else that people sometimes get confused with what I say because they don't understand is this notion of epigenetics, which these days are very popular. Epigenetics, you know, it's a concept that has evolved

a little bit. It was first mentioned by Waddington that I mentioned earlier, who was interested in theoretical biology and was interested in doing that. But the term, the way he expressed epigenetics was exactly in the term of needing to understand beyond genes and needing to understand the sort of emergent properties that are the consequence of the gene's activity. Today, epigenetics has become a proxy for modifications of the DNA that control transcription, which is a totally different concept. I call it the genetics of genetics. Yeah, so you classify epigenetics as still under genetics when you're, when we're talking about the concept of genetic determinacy that

we referenced earlier. Right, yes. Yeah. And these days, actually, many people want to transfer all the things that genetics cannot explain to epigenetics, which, as I say, is just transferring, kicking the can down the road. I mean, this is what it is. But I do feel that epigenetics, in the original sense of Waddington, it's a very interesting concept that refers to the sort of emerging properties of the systems. Either they are systems of cells or they are of cells, or they are systems of tissues,

or they are systems of organisms. As I say, if you got me into a room with a lot of my colleagues, they're not the very close ones who I think, I believe and are willing to understand these things, but in most people will argue that there is nothing that is not in the genes, that everything in the end maps to the genes. Whereas I think that there is nothing that is not in the genes, that everything in the end

maps to the genes. Whereas I think that there is a whole world out there, this is something that I probably would share with Mike Levine, that we need to explore. I just maybe, being a bit reductionistic and being a bit materialistic, I want to understand the basis of that. I think there is, at the end of my book,

I discuss a very famous paper by Mark Kishnet and some of his colleagues from Harvard, which they call, they try to advocate the need to explore in deep detail these emerging properties. They call it material vitalism. Vitalism is the idea that there was some missing force. I think today we have a lot of evidence that these emergent properties exist in biological systems and we need to understand how they work and how to harness them for medicine. So there is something to vitalism in that there's something called material vitalism.

I mean, I discussed this paper, I refer to it at the end of the book. It's a very, very interesting paper because vitalism sometimes is used to an ad hoc explanation for things that we don't understand. But today, actually, we can see how things that we didn't understand emerge from the activities of cells or from the activities of molecules within cells. And this is something. I think that this is a very exciting century because I think the cells, understanding the cell and what it does and how it interacts with other cells, it's gonna revolutionize not only our understanding of biological systems, but it's gonna provide points of view to do with health and to do with a lot of the regenerative medicine.

It's not gonna come from genes. I think even cancer, now people are starting to realize that cancer, which in many places is the genetic disease par excellence, it's clear that it's not just the genes that can create cancer. In many situations, the gene are responding to the activity of cells. People would like to understand the cell of origin, as they call it. It's not just simply that you get a mutation in a gene or two genes or three genes and

you get cancer. There is something else that changes in the cell that we still don't understand that leads to the changes in gene function. I can understand how a cell can respond to a gene, but how does a gene respond to a cell? So as I said, very, very simple. I'll give you a good example from our work and I hope I can make it clear. If not, I'll try another one. So we can culture these embryonic stem cells in a dish in flat, okay? And we can tell them to do something, you know?

To create all the elements of an early embryo from anterior to posterior, okay? We are very organized. The embryo is very organized in the way it does it. So we can tell them to do that, to activate genetic programs that do that, these genetic programs exist in flat, in a flat situation, they will do that. But they will do that in a highly disorganized manner. Okay? Everything will be chaotic.

All the programs will be there. We can measure them. We can see them. We can look at the temporal sequences of expression. Now, and this is part of our work and what really bowled me over. You can make a ball of cells now that is about a thousand cells, of these embryonic stem cells, and trigger the same program, okay? And if there are a thousand cells, they will activate this program again very chaotically, very, very chaotically. Now we take 300 cells, 200, 300 cells, and it has to be very precise. We activate now the programs in those 300 cells, and they make an embryo, perfectly proportioned, everything. They are the same cells, they are the same genes.

So what information have they got? And we know that the number is very precise. If we go by 100 cells or even by 50 cells, the thing doesn't work. So the cells are able of measuring somehow. We don't know if it's space, if it's numbers, what it is. We don't know what it is, but they are now starting to use the genome in a much more organized manner

that if they are very many of them or if they are disorganized. This observation, which is one we made 10 years ago and is the basis for our research over the last 10 years, I find it fascinating. And I think we have systems to understand what is that the cells are reading. They are reaching now into the genome,

but in a very organized manner, right? Because the numbers seem to be able to influence. How do they do that? This is totally, I mean, I'm really bolt over. And the programs now become perfectly synchronized. They were very, very well organized. I don't know what you mean by programs. Oh, so a genetic program,

it's that when your development starts, you know, when development starts, the cell doesn't know anything and it activates a gene cascade, you know. This is what happens during development. You get a genetic program is like a program. I mean, the analogies with computers, many people would jump to me if I make the analogy, but in a way it's not that different. So you get one cell, it becomes two cells. And now in those two cells, you activate now a genetic program in one cell. So a gene is activated in one cell

and a gene is activated on the other. That gene now will activate a set of genes downstream from it, because the gene in one cell is different from the gene in the other. Now the genes that are activated, then you you unroll a program depending on those genes. That's what I call a genetic program. In fact, in the book I discuss, but I think it's a vision that I have to help me. Genes create time in development. This is also very interesting, you know.

Genes create time. Yeah, genes, gene networks, these gene programs create time because there are sequences of gene expression, right? And we know that they are very well timed. When we develop the great precision, these gene regulatory networks, as they are called, can create time. Cells create space. You see, genes cannot create, and I think it is this dialogue between the two, but in which the cells have a very big say, that we are seeing in these structures that we generate in the lab. That's super interesting. Now, do you mean that more than just a metaphor? Do you mean that maybe in physics? I think it's more that, for me, of course there is...

I mean, the notion of timing, the notion of timing biology right now, it's very, very important. And it's very, people are discussing where the timing development comes from, you know? Meaning in the development of an organism. Because that's a very fundamental question. We have the same genes as a mouse, pretty much, but the mouse develops

faster than we do. The events are very, very fast. In NASA, they are very, very slow, but they are the same genes. So what is determining these different tempos? Okay, this is something that now, over the last three or four years, has become a very important focus of research. How does time emerge in the development of an organism and what controls time? I think we know that it's in the gene regulatory networks, but we don't know how, but the timings are very, very precise.

When you follow these embryos very early in development, very precise, the changes in events, the emergence of structures, and what we see in the structures that we create in the lab from the embryonic stem cells, they recapitulate these timings, which is very surprising. Okay. So what constitutes a time step?

Usually it's a continuum, but when the cells are growing, for example, they are growing in a state, let's call it state A, they are trying to make a muscle, for example. So they go through a series of stages and it's those stages until they make muscle, and in the end they make muscle and they will stay. The process of changing from a cell that is naive to a cell that will make muscle, the different steps are highly controlled. The time is always the same,

and the switches in the program, the transitions from one gene regulatory network to another, they are very, very controlled. What it's interesting is that in a mouse, a mouse is using the same program, but the timing is totally different. And the same for every mouse, you know? So we don't know what the control of time it's in.

I mean, maybe the control of time it's related to our aging too. After all, aging has a component of time. Yes. So then, okay, well, you said maybe. So I'm about to ask you a question that's well, skeptical by nature. Yes. I understand that you don't want to deal with the concept of or with the topic of consciousness. However, when it comes to perception and time, is it, are you making the argument that a mouse, let's say a mouse's lifespan is a 20th of hours, or

maybe it's a 30th of hours that they then experience time 30 times quicker? Oh, that's a, you know, consciousness time. Yeah, you're right. Because I don't think I have much to say. Okay. And one of my brothers asked me a lot about this, and our conversations are very short. Not because I don't think it's interesting, it's because I find fascinating, for example, and I think we've all experienced what I'm going to say, that you go to sleep,

and all of a sudden, sometimes you wake up and you think the whole night has passed by, and you look at the watch and you've been sleeping for half an hour. Right. And other times, you think you've been sleeping for a very short time, and you've at the watch and you've been sleeping for half an hour. Right. And other times you think you've been sleeping for a very short time and you've passed the night. I think the perception of time is very subjective. I think maybe one question that you're asking, which is interesting, is how do cells perceive time? I mean, this is definitely very interesting. I think maybe this is maybe a rephrasing of your question.

Yeah, it's a superior phrasing. Because time is passing in the cell, you know. I mean, cells have clocks, for example. You are familiar with the circadian clocks, which is what allows us to run through the day. It's what changes when you are jet-lacked, is your circadian clock needs to be adjusted. We know the mechanism of those clocks very, very well. This is clear. But those are repeated, you know?

As we get older, that network that is controlling the circadian clock breaks down. That's why old people have problems that they lose, or we lose as one is aging. We lose our control over our circadian clock. But so for that particular clock, we do know how the cells are perceiving it because there is this system that is working. But as the organ is aging, time is passing, absolutely. And the cells must be perceiving time. So Michael Levin had a question when he passed on to me about Dennis Noble.

So Dennis Noble had a theory that there is no single privileged level of causation in biology and Michael wanted to know what are your thoughts on that? My thoughts are that I know well the ideas of Noble. I think that again, he's one of these individuals with whom I agree that we need to go beyond the gym. But I think the difference with Dennis Noble, I hope I have expressed it, that doesn't mean that what we know is wrong or that is or Dawkins is wrong.

We need to extend these ideas. I think the idea he talks about multilevel. Dennis Noble is the one who talks about multilevel. Yes, yes. I mean, because you know, what we are talking here about is about evolution again, that's what he's talking about. And he's saying that there is many levels of description. I think one of the criticisms that have been made of Denis Noble's view by the more hardcore

evolutionary biologists is that he's not concrete. He's not concrete. He's unable of pointing out what these levels are and how they impinge on the biology of a system. I agree that there are many levels at which one can act, but I think the cell is central to those levels because the cell is the linchpin between the genetic programs and the large phenotypic programs that he's talking about. Dennis Noble is a physiologist and likes to talk a lot about the central role of physiology in a lot

of ideas. Sure, the physiology of an organism is not a simple readout from the genes. I agree with that, but I think we need the physiology of an organism is the output of its cells. And I think we are back onto the situation, whereas I agree that there is many levels, I think the cell is central. I actually think that Michael Levine would not disagree with this point of view. My object is to understand the cell

and to understand the emergent properties from which it arises and the emergent properties that it generates. To me, the cell is absolutely the central element of biology. And from the perspective, cell-cell biobiology is going to give us a lot of surprises, interesting things to do research, and really a satisfaction of a new vantage point of biology. So would you say then that there are emergent properties? Oh yes, there is no question. I've said about that in a way. Sorry, what I mean to say is a new vantage point of biology. So would you say then that there are emergent properties?

Oh yes, there is no question. I've said about that in a way. Sorry, what I mean to say is there's a concept called weak emergence and then strong emergence. I don't know if you know the distinction. Yes. Okay. So are you suggesting that there are strong emergent properties? Yes, in biology, I would say there are.

Uh-huh. Well, explain, sir. Yeah. I think first probably we should revise the notions because I think sometimes physicists and biologists don't talk about the same things, okay? Sure. And I'm also thinking about, so if you can remind me

what is the perspective of the physicist so that I'm not misled, then I will be able to answer the question without engaging in a dialogue of fools. Sure. It would be more of a philosophical distinction. I don't know if physicists make this, but okay. So in reductionism, the lowest levels give rise to everything at the higher levels. And sure, there could be emergence, but it's more emergence at the level of what we can't calculate and so we just say that okay something comes about and maybe it's a chaotic

effect but in principle it was determined by the lower levels and the higher levels don't cause anything to occur at the lower levels. Whereas in strong emergence the lower levels can give rise to something which then at this layer, at the top layer or middle layer, just a non-low layer, causes something to occur at the low layer. Absolutely. That is absolutely at the center of biology, particularly in the development of an organism. Basically, that's why I said that I thought that that's what you were saying. I thought that's also another element of another element of that strong emergencies is downward causation. I mean downward causation is a very important part of biology. In fact, I don't know enough physics to see if a strong emergence in the way you have described

how many physical systems exhibited in biology is absolutely a standard that, you know, the gene regulatory networks code for proteins, okay? The proteins all of a sudden are able to create the networks, to modify the activity of the networks, to modify the connections, all right? If those networks occur in a dish, you can get them to operate in a dish, and they will work in a way. But if they occur within a cell, they're going to be spatially organized, and that is going to change the protein networks, and that's going to change the activity and

the organization of the gene networks. When the cells are organizing a tissue, the tissue level now changes the properties of the cell, that changes the properties of the proteins and that changes the properties of it. So at every time that you go to a new level, the organization of that level has a knockdown effect, a downward causation on the activities of all the other levels. And this is why you cannot predict what's going to happen, what a cell is going to do

from its genetic makeup. Yes. Okay. I should have been clear when at one of the levels, say the cellular level, when it's causing something to occur at the genetic level, that causation from a higher level to a lower one has to be such that it's not reducible to the lower one, such that it's as if this higher level is autonomous. Exactly, that is what I mean. You can't. You can't predict it. You cannot describe it in terms of genes. Can you tell me about cellular autonomy? So, the fact that a cell is its own individual unit, because if you can say, if you can objectively

say that a cell is its own individual unit, which it seems like you can, then I'm wondering if there's some objective way to say that we are an individual unit. So that is you aren't merely the collection of cells, that you you're experiencing this right now some unified experience experience and that there's something distinct about that but it's always tricky to define you philosophically it's tricky to define you but what i'm wondering is if it's not tricky to define a cell can we use some similar mechanism to define us i don't know i'm thinking about about how to respond this this in a manner that is not too long, because I think you've opened up a very interesting window, which I think is very important as a first

step to understand that we are multicellular organisms, and we are derived from single cell organisms. There is a lot of work these days, not a lot, but has been known for a while about the possibilities of single cell organisms as individuals. Okay. I could give you some in the stentor, for example, it's a very interesting single cell organism that some people are studying because it exhibits behaviors that would be of an organism. One of the big questions in biology this day, I would say, is the transition from unicellular to multicellular. We don't know how that happened. Some people would say that

it's an enlargement of the genetic repertoire of the cell. That would be more of a Dawkins type, you would say that? Yeah, exactly. But there is a lot of work now that a lot of the genes that we think even are involved in development or in multicellular, they already exist in the single cell organism. The kingdom of single cell organisms is enormous. So we don't know how that jump happened, but it's not simply a question of getting more genes that are going to do more things. So all of a sudden there you have a very interesting example of all of a sudden you get in the evolution of the world these very interesting structures that all of a sudden do things that all these unicellular organs even when they come together they don't know because the cells

now are working as a coherent unit and are doing interesting things. In the evolution of that you get the nervous system. The nervous system is something that that is totally autonomous in many ways, you know, but it's it's it results from the assemble of many different cells. Okay. So I think that that one thing that I can say is that contrary to a lot of what we are led to believe today, we are not our genes. We are the product of ourselves. I should also point out to you that you are not the same person that you were

20 years ago in the material basis. You know, I mean, every day turns out you may not realize that, but every week you get a totally new gut. Every month you get a totally new skin. Every 10 years you get a totally new skeleton. Every day you are making 2 million red blood cells per second. So you are in a constant flux and your genes are, for all practical purposes, the same.

And your neurons are changing because they are working all the time. So I think our individuality is who we are, is something that is also moving along in time. We are changing because our material, in fact, the actually structure that we are is changing. This is something that many people are not aware of. And I find very, very interesting that aspect of ourselves.

The genes, there are some differences, but they are the same. And yet we are very, very different. I think the one that I'm always very amused is the bones. Because you might not think very amused is the bones because you might not think, you think that the bones are gonna be the same and they are changing.

And also, you know about questions, you think about interesting questions. What sets up these renewal processes with these precise times? I mean, you know, interesting questions in biology. The blood has a very good balance of cells, 100,000 platelets, I mean, 40,000 white blood cells, millions of red blood cells, all in perfect balance. Because if you break that balance, you get a leukemia or you get a blood

disease. What keeps that balance of cells? What ensures that the intestine, you know, any change in this balance is going to create a tumor in your intestine. And yet it's changing in a very, what controls that? I mean, we don't know that, and that's very, very important. I find the creation of shape and form and progressive changing. So I think what defines us are our cells, and there are all these processes that are

keeping us as we are, and we need to explore that beyond the genes, because to blame a gene for all this and to blame a gene for who we are is really not seeing what is in front of our eyes, which is that we are our cells. Well, in some way, you made an argument that is in favor of genes having to do with the identity of us because the genes are the only ones that remain constant in that. Like you said, the bones are replaced and the teeth are replaced or the eyes are the cells. Okay, until I tell you that every cell in your body has a different genome and that that genome is changing. I didn't want to go into these details, but this is now a great discovery over the last few years. That every cell is changing its genome all the time in a very small manner. And by the time, in fact, in the entity's thought that

we have more, when you take together all the DNA in our body, we have more mutations than cells in our body. And that to me is a very sovereign thought. It's a very sovereign thought. This is work that is coming out now from our ability to sequence the DNA of single cells. And we are learning a great deal. So we are changing all the time. It's very important now. What is the self? I think we're entering back into philosophical terrain into which I don't have much to say, not because I don't think

it's interesting, it's simply because I don't have much to say. So what's another important question you mentioned, well what is regulating this balance that if you go off of it? Oh that's a very that's a fascinating question I think, I mean we have no idea idea what regulates the proportions. You and I are different sizes, but we are equally proportioned. That is a very strange thing. What regulates that? What determines that?

How do cells know? Our two arms, they have never met. They develop independently from each other, and yet they are more or less the same length. Not the genes? The genes don't regulate that? The genes have to do with that, but we don't know what regulates that. I mean, other questions.

So I think to me, this is one of the very important and solved questions in biology. Issues of what determines the proportions, issues of what determines this. You know, we said what regulates the size of the gut, the skin, because if it goes off for a little bit, you get a very bad condition. You can even die from that condition.

So something we don't know very much about this control of proportion growth. That is one of the great outstanding questions in biology. The other, as I say, you wanted some interesting questions is the origin of multicellularity. You know, that's another interesting question. And of course, I think one of the most fascinating ones is the inventions of novelty, the origin of novelty in evolution. You know, what is the origin of novelty? You know, how do wings appear? How do eyes appear? How do, I mean, it's very, very intriguing.

Why is that not solved when Richard Dawkins was at the Royal Institute, I believe, and he showed how an eye can develop just with gradual changes? No, no, wait, wait. That is, once you, this is back to the famous, what we mentioned in the beginning about the difference between natural selection and evolution, you know? Once you have a structure that can give an eye, you can see how that changes. I mean, that is very well understood,

how selection can drive the perfection or the modification of a structure, okay? This is really central to Darwin's tenet, is descent with modification. This is the phrase that he used. But the novelty, the appearance of new structures, it's sometimes more of a challenge in evolution, you know? And we have some ideas,

we can see these gradually appearing, but all of a sudden, how the vertebrates appear in a very remarkable bone, all of a sudden appears in our life history. It's a very interesting thing. If we had time, we could get into our history and an evolutionary history and how we are just, we carry so much baggage from our evolutionary

history and that's a fascinating thing. But the appearance of bones, for example, that's a very, all of a sudden. I mean, this is the thing about dockings. I always say that if life was what dockings would like it to be, I think we would all be viruses and bacteria because all you need is DNA replicating itself and finding. I think that something happened that when cells were invented, particularly the eukaryotic cells, something happened. A creative ability was unleashed that we are just trying to understand. And I find that very, very interesting, particularly that transition from unicellularity to multicellularity. I think it's right now a very big and interesting

problem. And then the appearance of different groups, you know, there is a very remarkable process and one that raises many exciting questions. I'm not understanding the difference between selection and evolution. So it's my understanding that evolution is selection, variance, and replicability, or reproducibility. But is that what you mean that natural selection is just one of the ingredients? No, evolution has a very important component of what you've said. Evolution has a very important component of what you say.

But that's exactly what you said. If you have a structure, now you can turn it into a different structure. You know, the fins of a fish, we can see how they are transformed through a slow modification into our arms or into wings, or how wings, you know, the limbs can become wings and how wings can be varied in a bat or in a squirrel or in a... So all those things are fine. And that natural selection can explain, okay. That is not a problem, but the appearance of bone, for example, it's a very remarkable thing. So professor, I'm confused.

Is this an open question? Yeah. In the field. So that is to say, if you were to poll other evolutionary biologists, what they say, we don't know how novel structures emerge. Are you saying that to you and maybe to some of your colleagues, it's unclear how novel structures emerge, evolutionarily that is? I think you will find, Kurt, that there is people that feel that simple descent with

modification and variation can also explain that, okay? In terms of genes, this is, you will find a very strong component of that. I would say that there are things that that can, you will then find another group of people that would say that you cannot explain that simply with the genes driving the process. I'm not saying that the genes are not involved, simply with the genes driving the process.

I'm not saying that the genes are not involved, but with the genes driving the process. So modification of structures into other structures, we probably can explain by switches in allelic frequencies and in genes. But novelty is something completely different, okay? Which in the end, you may be able to map to genes, but I think at the moment, we need to think about this. And I think the cell as a very important element in the process also even of selection, it's a consideration that we need to include. I think that that's, as I said, a missing link that we need to explore now that we need to include. I think that that's, as I said,

the missing link that we need to explore. Now that we are understanding a lot about cells, and it's what I told you, how do cells know how to count? How do the cells know how many cells are they in an aggregate in order to build an embryo? Embryos have length scales. They are very small, all for a reason. So all those things are influencing

the ability of genes. So it could be they could say, well, yes, we get a new gene that involves a protein that can sense. Yeah. But I think there is no one gene, one particular protein. I think these emergent properties are a bit more complicated. I think, as I said, you would find two camps if you were to discuss with evolutionary biologists. Ones that say we can explain everything with genes. I think there is a danger in using a hammer to try to see everything in a nail. I think sometimes we just have to admit there is no problem. I'm not saying that there is anything magical.

I'm not saying like Dennis Noble that we need a new theory of evolution, we need to incorporate the cell into our current theory of evolution. That's what I would say. What the heck is neo-Darwinism and what's the difference between that and Darwinism? Well, it's what I said in the beginning, that is a crucial moment. Darwinism, what Darwin saw that you could explain that descent with modification as a continuous process was a very important element in the creation of variation on the earth. What type of modification you said? you can take the fin of a fish and the arm of a mammal, and you can see how through slow processes, you can transform the bone structure

that give rise to the fin. You can see how by small changes, little by little, it will be transformed into the limb of a vertebrate, of us, of a tetrapod, as they are called. So, the fin, you can see how slowly, slowly, slowly will- I understand. And that's continuing.

For Darwin, this was a continuous process. Now, the problem that Darwin had is that he couldn't find the material basis for that. He was very frustrated. He made many mistakes. When they discovered the genes in the beginning, it was not clear what genes had to do with evolution, but slowly it became, well, very quickly it became clear that they could be the material basis for Darwinist, but they

had a problem. The genes are discrete units. But I don't see what's wrong with that. No, the problem is how, the problem was, how can you create continuous variation from discrete units? Well, the reason why I don't have a problem with that is that I don't see how even Darwin himself could have concluded that the variation is continuous in the physics sense of continuous, that you can take a small epsilon and you'll always be able to find a change between where you were before and where you are after because you only have a fine you

Only have discrete amount of children Well, but that is no well That's why the the survival of the fetus and this is where Dawkins Dawkins does a lot of his work with insects with invertebrates Which are very large progenies. Okay This is we are a bit of an exception in many ways human beings in terms of the progeny The progenies are huge in terms of evolutionary time scale. And I think exactly what you've described, a bit of an extreme version of it, of the epsilon that requires another epsilon, this is the way evolution was seen. I mean, this is the way most evolutionary biologists will see the progress. This is the same with modification,

that is to say that in the next generation, some tweaks are going to have been produced by a random mutation that is going to change the structure. If the structure is good, those variations in the alleles will be kept. And then epsilon by epsilon, evolutionary epsilons, you will transform one structure into another. Now, for you, it might not be a problem to see how these discrete units that people didn't know what they were really physically, they could measure their effects, how could they link to a continuous change. And it was Fisher, in fact, the whole world of statistics is founded by Ronald Fisher

when trying to solve these problems. And he's the one that shows that by adding alleles and doing a lot of algebra and statistics, out of these individual elements that were discrete, you could create a continuum. Neodarwinism is the process whereby these people, particularly Huxley and Fisher, they put together this idea that they could reconcile the genetics that they had discovered with these changes that were continuous. That is neo-Darwinism. It's called neo-Darwinism because they felt that they had updated Darwinism.

I see. I see. So neo-Darwinism is not the same as genetic determinacy or genetic determinism? Genetic determinism is something hanging on the wings of all these, okay? But neo-Darwinism and the modern synthesis is that. Now, the genetic determinism is something that some people advocate, other people don't. It's a totally different story.

Now there is people claiming that we need to, that Darwin didn't explain everything, that Neo-Darwinism doesn't explain everything. And as I've said to you, I agree with that, but I don't think we have to throw everything that we have learned from genetics and population genetics and evolutionary genetics. I think we have to build on that and try to develop that further. And I think Dennis Noble, for example, is one that would throw the baby and the bath out of the window. And I don't think you can do that. I think there is no question that genes play a role.

My question is, what is that role exactly relative to the cell in the building of an organism? Those are the questions that I'm interested in. So professor, your first major publication was 1987 or so, something called the developmental genetics of drosophila, which you referenced earlier. Tell me what was that experience like emotionally to see your work finally in print? Well, I think that that was interesting.

It was an embryology, a paper on embryology. I think that was exciting at the time because in fact, when I look at my life, I've spent a lot of my life linking cells to genes. This is what I've done and maybe this is why I'm interested in that connection. I think I was very young and I saw a structural organization of the Drosophila embryo that had not seen before and that allowed people to frame the gene expression patterns that were being unveiled at the time, okay? Because without understanding the structure of the embryo, there were patterns of expression

that didn't make sense. And my job and what I found was a way of putting the two together. Let's put it like that. And I think this is something that now has occupied me a lot of time. And I think we were talking before that the genes generate time, because through these cascades and through these cells generate space. And now that's becoming very, very clear to me. And evolution plays with these two variables as independent things that brings together in a manner. So at that time, I wasn't aware of what was light ahead.

I was just excited to have seen something. People had been looking at these Drosophila embryos for a hundred years, and I saw a structure that didn't make sense, but that then it made sense in terms of the genes and surface as a ruler to put the genes there. Most interesting one when we saw these structures that we can generate out of embryonic stem cells,

that was about 10 years ago, which we call gastroloids because they imitate the process of gastrulation, which is the way- Gastroloids, right. That was very exciting. That was very exciting because all of a sudden we could see a structure that resembled an embryo emerging from a collection

of cells. And this is what I told you that it actually required a very precise number of cells. I was bowled over by that observation that if we had the precise number of cells, these cells would react in a way that they would create a coordinate system, would organize themselves with regard to this coordinate system, would grow in very specific, and that actually resembled a very important part of an embryo. That, I have to say, it took me completely by surprise.

I didn't expect this to happen. And I was very concerned that maybe this was... I mean, I'm very glad that now there is many labs around the world doing the same observation as we talked before. This is the important thing, that maybe this was, I mean, I'm very glad that now there is many labs around the world doing the same observation as we talked before. This is the important thing and this is becoming a tool that people are using to study emergence in biological systems, others to study biophysics, and many of us also to study the development of, because we can do it with mouse cells and with human cells.

And that is very important because then we can have an access to the earliest stages of human development in a dish. How do you want to be remembered? That's always, I'd like to be remembered by someone that, by my family, I'd like to, in terms of science, by someone who raised questions and left a good progeny of students and scholars. I think with rigorous scholars and rigorous the rest, as they say, it's a very good sentence of a Belgian or French developmental biologist called Jean Rostand, theories pass, the frog

remains. I really like that one. You can theorize over the frog, the theories, there will be many theories over time and the frog will remain. We are just adding little things and if what I can do, it helps the new generations to understand, that's a good thing. I think that that's the most important thing. I mean, the most valuable thing I do as an academic

and as a researcher is to raise new questions that feed the curiosity and the intellect of younger people. I think to me, that is the big satisfaction and where I draw more of what I really like to do. I think this is a very exciting time in biology. I've been very lucky to do my career in a topic that I was interested in from a time where we didn't know what genes involved in development to a time that now we can see that there is more than the genes that control development.

And also brings me back to my interest in physics when I went to the University of Chicago and tried to bring that interest into the thing. So very simple by the progeny that they will remember. And he said, yeah, it was good. He made us think in interesting ways. That's really what I would like. So professor, before we close, I want to know what are some of the questions that you are toying with now, especially some of the questions that you hope either you can address or someone else can address, can solve? Well, I think two very simple questions. How do these cells, it's interesting because these number of cells that initiate that with which we can initiate the organization of these embryo-like structures in the dish is approximately the same number that the real embryo has.

So what is it in that number? How do cells read that number in a precise manner? We are working on that, you know, to organize themselves. Is that called gastrulation? Gastruloids. Gastrulation is the process that takes the mass of cells. Yes, yes. you talked about that. And then transforms it through an origami. I mean, my friend Louis Wolpert used to say that the most important moment in your life is not when you're born, when you marry, when you're dead, but when you undergo gastrulation. And I'd like gastrulation to be because that's the moment where you acquire the shape and the organization that is going to give rise to you.

So yes, we use gastrointestinal studies as so many other people now in the world. And I'm pleased for that. You see, it's a good thing that we generated a tool of study, I think, to generate. That's one thing. The other thing that I'm curious about, I don't think I'll have the time to do it, is what we were talking about. Why? How the same genes generate different tempos, different structures. I mean, what are cells reading? How are they generating time?

But this is a question that I don't think I'll ever get to it. Kuwait, can you please expand on that question just so that you can leave it open for people who are younger biologists. And you could also use this as a time to state what your advice is for people who are entering the field. So restate the question about time. No, the question, the question, the question about time, as I say, there is people now, there is people now, a small group of people that are tackling this process. How cells keep time? group of people that are tackling this process. How cells keep time? I mean, you know, and also a mouse and a human embryo, for example, they have the same genes, they have the same programs running, but they run at different times. Where is the source of that question?

I think this is a very, very important question. The other question, I mean, those are questions that if I had time, I would look into now. The origin of multicellularity is another one, but that one of the time, how do cells perceive time? How do they create time and how do they perceive time? I think those are very, very interesting questions. Advice to young people is very, the world in which we live is very, very complicated. I think science is not something that you do if you want a job.

I think you have to be passionate and obsessive. And I think there are good questions there. I think don't fall into the trap of simply technology development or use. Think of the questions, because there are good questions out there. They are hard, but I think there is a reward in trying to

answer them, even if you don't answer them all the time. Is that something that you advise your PhD students on, or your graduate students? Yeah, I think these days PhD students, they have to have a very big motivation. I think over the last few years, we are entering into a sensitive territory. I think when I started doing science 40, 50 years ago, there was not that many people doing science because the educational systems were not mass producing science majors. I think those of us who were doing science, and even you, you, and I know you major in physics and all that, we were driven by curiosity.

And I can see that in your program, the way you interview people. I think today there is a lot of people, and I have, sometimes when I meet students, I ask them a very, a question that surprises them. I ask them, have you ever been bored? And they don't understand that question. And I think being bored at some point in your life

is very important to find out what you want to do. I said at the beginning that I grew up in a country and at a time where we were not on to anything because there were other priorities. There were social unrest, there was a dictatorship. So I had to find out by reading, by following my hunches what I was interested in. I think today people from very early on are drawn into getting a CV, into one thing after another. They don't have time to think.

I think it's very important that you get a time to figure out what is that you want to do. Don't get into science simply because you think you're going to get a career or this is where you're schooled. Get into science because you want to answer a question or you are curious about nature. Uh-huh. And for that sometimes being bored is very, very useful.

Professor, thank you for spending so much of your time with me. Thank you, Kurt. Thank you. I think you're very open-minded, man. Oh, thank you. You're very open-minded. Firstly, thank you for watching.

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