Welcome to this first seminar of a list of seminars that we organized in IHP. So this list of seminars are entitled fundamental questions on amazing logic of molecular biology. And in fact, this list of seminars, all these seminars will be about

very interesting topics in molecular biology and are linked to a book that we are currently writing with Misha Gromov present here on François Kepes which co-organized this series of seminars. And this book is about amazing and brilliant ideas

that shaped and did very good breakthroughs in molecular biology. And so every seminar will be linked to a chapter of this book. And we will start today with Michel Morange,

which probably for most of you already know. So Michel Morange is a professor at ENS at the University of Paris 6. He is the director of the Centre of Caliesse. And he did his PhD in anthropology,

but also in Paris he did a PhD in philosophy of science. And ever since he had a double competence, he was a molecular biologist and also a historian of science. And since a few years, he stopped his activity of molecular biology

and is now really into history and philosophy of science. And he is an author of a numerous books. The last one is called Histoire de la Biologie. I'm sorry to present to you today the meetings of molecular evolution in Michel Morange.

Can you switch off the light? Okay, thank you. Thank you very much to the organizer. I must say that somehow it was difficult for me first because I did not know exactly what you were expecting.

Second, because I didn't know who will be the people attending this seminar. And so my starting point was a kind of discourse, these statements done on molecular biology.

For instance, molecular biology was a reductionist approach of biological phenomena. It was even a sad chapter in the history of biology. As Ernst Mayr said at the end of his life, somehow nothing was changing other biological disciplines

like evolutionary biology, by the development of molecular biology, or what is very commonly said is that molecular biology is an ensemble of techniques. Okay, so I'm somehow tired by these kind of simplistic statements.

First, for many reasons. The first, because it's already an 80-year event. The history of molecular biology started in the 1920s and 1930s. So already more than 80 years,

and it was obviously a very long process with different facets. And it's what I want to do today just to show you the successive transformation of molecular biology. Second, because words like reductive or reductionist are not so simple,

what does exactly it mean to be a reductionist? And it's among the issues I will address during this lecture. So it will be somehow chronological starting from the beginning, trying to show what were the origins of molecular biology,

and following the different steps up to now and to raise some issues at the end. So I'm afraid maybe it's far too simple and far too general from some of you, sorry,

but it depends probably also on your background in biology and molecular biology. So, beginnings of molecular biology, the development of molecular biology from the 1930s,

which is often seen as a convergence or encounter between genetics and biochemistry. Just, and it will be one of my messages, beginning were not so reductionist, especially in one group which was very active at the beginning of molecular biology,

which was the American Phage Group headed by Max Delbrück. Probably some of you know Max Delbrück and know his role in the development of molecular biology. He chose a system which was a bacteriophage because it was a simple system,

but the objective of Max Delbrück was to find laws of reproduction of organisms from the study of this simple model system. And Max Delbrück was not fond of chemistry. He hated, in some sense, chemistry. He found it, especially biochemistry.

And so one of the origins of molecular biology is at least very different. The second thing, on the opposite, I will now turn to microbiology because it's interesting also to see microbiology, bacteriophage, as we have seen, but also bacteria, played a major role in the development of molecular biology.

But when you look now at the long way from the characterization of this microorganism, end of 19th century, beginning of 20th century, and today with the molecular revolution,

what is striking is to observe that in fact this movement to understand at a lower level what was happening started from the beginning. Even at the end of 19th century, it was discovered that many microorganisms were in fact pathogens because they were secreting toxins, which were proteins.

And so the reduction of a complex process, a disease, to the action of a toxin was already there at the end of the 19th century. And in this case, molecular revolution was not a dramatic change in this kind of studies. And in fact, when you observe what happened in the 1940s, 50s,

where progressively the notions of molecular biology entered into microbiology, you can see how progressive it was. I mentioned here, for instance, the famous Hershey Chase experiment, an experiment of the phage group showing that in bacteriophage, it's only DNA that enters bacteria

and is responsible for reproduction of bacteriophage. This experiment was clearly a step towards reduction of bacteriophage to its chemical components, but it was a part of a smooth process. Another example is another phenomenon, which is temperate bacteriophage, or lysogeny.

The possibility of phages to remain silent within bacteria. It was a very important phenomenon because it was essential for the emergence of the models of regulation,

gene regulation, regulation of gene expression. And when you look at this problem, okay, you have a bacterium, nothing happens, and suddenly bacteriophage is released from this bacterium. So, how is the bacteriophage within the bacterium? In the 1950s, you can follow the progressive transformation in this notion of prophage

in the following drawing from the group of Andre Lvoie, Francois Jacob, Elie Valman. Here, for instance, in 1950, you have a representation and you see silent bacteriophage, prophage are represented by a small circle, like a small organism.

Nobody knows exactly what they are. Some years later, in Andre Lvoie, it's a line. You say it's not different. Yes, it is, because line is linear, so it means it's more similar to genetic material. And the same year, Elie Valman goes slightly further and asks the issue,

what are the relations between the genetic material of the prophage and the genetic material of the bacteria, which is represented by a long line? And he considered all the possibilities. You see different amounts of the bacteriophage, genetic material,

an attachment or not to the chromosome of the bacterium. And in fact, the right model is not represented, unfortunately, because the right model is that the genetic material of the phage

is inserted into the genetic material of the bacterium, which is not the case, which is represented in this slide. But just to show you how progressively silent bacteriophage was converted into a molecule and a DNA molecule, in fact, some years later.

Another important aspect of the rise of molecular biology was the emergence of the studies on macromolecules. The notion of macromolecules, the emergence of this notion was parallel to the early development of molecular biology.

But what is interesting, once again, first, is that the debate was not about reduction or not, it was about what kind of reduction. Because there was an alternative model, which was a colloid model, telling that at a certain level of matter, you had the colloid states,

aggregates, which were responsible for new properties. And so the emergence of molecular biology was an emergence in favor of existence and role of macromolecules opposed to the existence of these colloids. But it was no more reductionist, no less, than the study of colloids.

It was different, once again. And second, I wanted to add something which is, I think, important also. It still remains that it was noticed by Wolfgang Ostwald,

the physical chemist, in the beginning of the 20th century, that when you were looking at the different levels in the universe, different sizes, the chemist was studying simple molecules, but there was a limit. Under the light microscope, you were observing structures,

but there was a limit at a low level. And between the two, there were absolutely no tools to study what happened, levels of colloids or macromolecules. And the rise of molecular biology was also somehow parallel or linked

with the development of this new technology, and in particular, for instance, electrophoresis, which is probably one of the most characteristic of molecular biology, and even today of molecular studies, just to show you that it was exactly as for the computer.

I enjoyed this slide for this reason. The first machines were enormous, very expensive, very difficult to manipulate, and today in the biological labs, you have very simple machines on each bench. So this is a part of the progress in technology,

this reduction to simpler devices. Okay, so it's another part of this movement towards molecular biology. Last point I want to discuss very briefly. As I told you, it's an overview,

but in the discussion we can come back and ask many issues on each of these points, if you like. Last point is that you add another form of reductionism in the same year, which was the genetic reductionism, and I think it's important to note that you had always a type of confusion

between genetic reductionism and molecular reductionism. Genetic reductionism means that in the organism, you can cut somehow the organism into different parts, characters, and each of these characters is controlled by your gene. So organics can be reduced to genes, an ensemble of genes,

but it's something very different of a chemical, biochemical, or molecular reductionism because the gene remains an abstract object and nobody knows what is its precise nature. I will come back on this point because the relations between genetics and molecular biology

are complex and they are still somehow at the origin probably of many difficulties or misinterpretation about what is molecular biology and what it tells about things and so on.

Okay, so it was my first part on the origin. So now the second part, the 1960s, molecular biology, becomes a well-recognized new scientific discipline. So what did it bring? Plenty of things, but I have made a very short list.

A relation between different classes of macromolecules, DNA, proteins, genetic code, of course, but also you have regulatory mechanisms operating at the molecular level and I think there is something more in molecular biology.

It was evidence for its founders that maybe not all, clearly, but many explanations of biological phenomena can be found at the level of macromolecules. Not all, I think, except probably for some molecular biologists

and I will come back on this extreme case of reductions, but many phenomena will find their explanation at this level. Okay, so now I will discuss a few points of this now period of molecular biology.

Molecular biology has become a discipline. The first is once again the relations between genes on one side and DNA on the other. In fact, with the rise of molecular biology, you had two different movements.

The first was to say genes correspond to DNA, so molecular reduction. The second was to say genes correspond to uninformation and the genome is a program, for instance, for the organism.

It's two things which are highly different. One is reductionist, the other is absolutely not reductionist. Let's now focus to the reduction to DNA, one gene, one DNA fragment. As you know, this reduction is not so simple

and the difficulties appeared in the 1960s because, okay, must you include regulatory sequences in the DNA fragments or regulatory sequences present upstream of a gene must be included or not? Okay, you include them, but in some organisms regulatory sequences are very far from the gene

and they are shared with other genes and so on. So we have plenty of difficulty to say one gene corresponds to this precise fragment of DNA. In fact...

Not one fragment, maybe, combination of fragments maybe also like a gene. Okay, but in the case for instance where one element like an enhancer controls different genes, this element will be shared between different genes so the gene will be this fragment which is common and another fragment which is specific

but it creates other issues because it means that you have in fact interaction between the genes and so it's not at least it's a reduction but with many interactions. So it's not so simple. It was my point to say that reduction in this case was not so simple from a genetic point of view.

From the point of view of geneticists. And it's even I think more serious concerning genetic determinism. You know that in classical genetics the genes were responsible for this, this, this.

It was very clear genes were responsible for the color of the eyes, for the shape of the wings and so on. Strong determinism, a specific form of a gene is there. You will have the characteristic, special characteristic. Okay, when you enter into molecular mechanism this kind of determinism is no longer possible.

Why? Because when you look at molecules, a molecule is not isolated. It interacts with other molecules, it can be modified, it can be controlled and so on. So you can no longer keep this very simple form of determinism.

Molecular determinism is much more complex than genetic determinism. And for less strong than genetic determinism, it cannot be as strong as genetic determinism, I think.

Okay, so just to show you that this transition to molecular biology was from the point of view of genes, genetic reduction, genetic determinism, not so simple. Okay, so now the characterization of proteins, it's another important part of molecular biology.

But some interesting things about that. The first is that it was something very progressive. It's not the same story as DNA. DNA 1953, genetic code 1961, regulatory mechanism 1961, very simple, and we have a very beautiful model.

Concerning proteins, I think I have just... No, it's Linus Pauling, just to mention because he was so active in this process. This is the first model of a protein in 1957, myoglobin. At C-sanction resolution, it was the first protein structure.

In 1970, so 13 years later, there were only about no more than 10 proteins that had been characterized at high resolution.

And the progress in the characterization of the structures came later with different steps, genetic engineering, which permitted the preparation of huge amounts of proteins, progress in x-ray diffraction sources, progress in computers, of course, and so on and so on.

And so you have a real exponential growth of structures of proteins up to now, and the progresses have not found an end. But now you can obtain a three-dimensional structure of a protein in a very limited amount of time compared to what happened at the beginning.

And what is the consequence? The consequence, I think, is that the situation has dramatically changed because this three-dimensional structure of proteins is what is important for the design of new drugs. Because by knowing the structure, you can imagine inhibitors,

allosteric or competitive inhibitors, and you can after test them. So, from the point of view of molecular biology, this structural part of molecular biology, it has never been as brilliant, as powerful, than today.

Whereas probably the other informational part of molecular biology is that the results were updating rapidly, and there were more doubts appearing after the existence of programs and notions like this. So, very different histories of the two.

Just one word on regulation, discovery of regulation, regulation of enzymes, regulation of the control of gene expression. Just to tell you that, in fact, with this regulation,

it was clear that molecular biology was entering a new era, because it means that you have loops, you have feedbacks, events, and some systemic vision of molecular phenomena becomes necessary.

So, we probably will realize this later, but some people, like Denis Tefri here at the Ecole Normale, says that the beginning of systems biology was in the opera model, and the people who exploited it immediately after, like René Thomas,

I think he is not totally wrong. It was the beginning of another vision of living organisms, with the existence of these regulations. Okay, so it was the opera model.

So, conclusion of this part. Once again, you see reductionism. Yes, I come back on this issue. There were strong forms of reductionism, precisely trying to reduce a huge process to one molecule and the structure from one molecule only.

And one good example was the existence of what was called memory molecules of molecules of memory, the idea that the behaviors or souvenir's memories were encoded into macromolecules directly,

and that by transferring these macromolecules, you could change in a recipient animal the behaviors or the memories. And there were in the 1970s famous experiments and studies about which macromolecule was doing that. And this kind of experiment, sorry, it's in French,

but it's not, I guess, a problem, but the experiment of George Ingard, he ordered a rat. The rat was trained to have a certain behavior, for instance, to avoid the black part of the labyrinth. And the animal was killed, the brain was taken, crashed, and extracts of macromolecules were done.

They were transferred to a recipient animal, and immediately the animal behaved properly. He has learned the behavior of the dead animal. So these experiments disappeared, but it was clearly totally reductionist.

You have a complex behavior and you say it's due to one macromolecule. All is in the structure of one macromolecule. Who was there already produced? This kind of experiment? There were many people offering this type of experiment. It never came to applications, but there were plenty of papers

in best journals like Science and Nature, published this kind of observations. But when the last? Last, it's middle of the 1970s. And interestingly, it's when Ondorphine and Ankephaline were discovered.

I think that from the beginning there were some people who were not happy with these experiments of transfer. But when Ankephaline and Ondorphine were discovered, it was possible to say, okay, the experiments were not faked. But some people had illusion.

They had in fact extracted peptides having non-specific effect on the nervous system, and they misinterpreted their experiment. So it was a way to explain past observation without telling that the people have invented data, which probably was okay for some of them. Or self illusion, which is another problem in science, which can happen also.

May I also make a comment that some rare diseases can be brought back to a single mutation. So they can be explained on a very reductuous basis, and even treated sometimes with the letters that you just mentioned.

What kind of process, what kind of phenomena can be reduced to one macromolecule? A number of rare diseases. Yeah, of course. Just to the... Yeah, yeah, yeah, no, no. Others are much more complicated, I agree. Yeah, yeah, no, no, I absolutely agree. In some cases, and in genetic disease,

you have one single mutation, one effect, and you can explain with that all the effects. No, no. Once again, there were abuses of reductionism in some cases, but some other reductionist approach was powerful.

Yeah, yeah. My message is that it doesn't work in all cases. Not at all. Not at all. I reassure you. No, and I think I will even show some examples. OK, next step was genetic engineering. And once again, probably because it's now nearly 40 years ago that it happened,

it has been forgotten that during, let's say 15 years, molecular biology has provided big schemes, big explanations, but no tools in particular to study higher organisms.

So it was a period with very few results, and the opposite complex results because the technology was not correct. But things changed in the middle of the 1970s, and you had after a rapid accumulation of molecular descriptions.

OK, so what were the first results with this molecular description? The first one was to characterize, for instance, message exchange between cells and the cell signaling pathways and the growth factors,

the action of growth factors, and the emergence of the theory of cancer, which is somatic mutation theory. I want to pinpoint two points. The first is that once again you see that molecular biology did not lead to a reductionist view because it was a reductionist,

but in some sense it shows that interactions were a very important interaction between cells, communication, and so on, even to understand disease. So what does mean a reductionist? Yes, it was a reductionist because you described components, but the effect was not reduced to one single component.

That was my point. And the second, OK, there are discussions today about the theory of cancer, but nevertheless, whatever, maybe it's not sufficient, maybe it has to be changed and so on, but it's clear that this description of the signaling pathways

was once again to break through and explain many of the phenomena concerning cell division, control of cell division, and so on. So first result, it was a period of focus on DNA and a kind of genocentrism.

If you look at technologies, genetic engineering, you manipulate eventually DNA. But there is one point which is not understood by people outside biology. It's that if people manipulate DNA,

it's because it's much more easy to manipulate DNA than anything other macromolecules. If you want to change something in a cell, it's much more easy to introduce a modified form of DNA and to synthesize, for instance, altered forms of proteins than to inject these altered forms of proteins.

So to act on living organisms, to modify them, DNA is the best way to do it. It's a path to modification of organisms. And for one very simple reason, I think, which is not because, as sometimes you read biologists are focused on DNA,

they were obsessed by DNA and so on. It's simply because DNA structures have been selected because it can easily transmit information from one generation to another generation. So there is something specific in the structure of DNA which allows a simple manipulation of DNA.

Biologists have used a trick that has been forged by natural evolution. But it was nevertheless true that for many people, they saw DNA coming back, modification of organisms by DNA,

genetic modification. And what we were discussing previously, for instance, isolation of genes involved in genetic disease. So a kind of return of a certain form of genetic determinism. Okay, so in some cases it works well,

like for instance sickle cell anemia, others you have a simple mutation and you can explain the effects of the disease by this simple mutation. In some other cases, it's slightly more complex. Of course, the modification is responsible for, but the path to the phenotype is a very complex one.

Like even, for instance, cystic fibrosis, which was a great discovery of the gene. Nobody was known about the origin of the disease when the gene was isolated at the end of the 1980s. But from the progressive knowledge of the gene and of the protein,

the way was known to understand all the complexity of the disease. Okay, but I think the problem was there were, once again, and I don't say that these today were not useful,

but when you look at, you have exactly at the same time, many groups starting to isolate genes involved in behaviors. And I think, okay, because a gene can be responsible for one disease, why your gene would not be responsible for a specific behavior, conceived as a disease, for instance, at that time,

like, for instance, sexual behaviors. And you know that it was a period where people said they have isolated genes involved in mental pathologies, in some specific behaviors, in aggressivity, and so on and so on.

I don't want to say there was a plethora of articles going in this direction. Most of these articles were shown later to be non-viable, not really confirmed by later experiments.

But I think it reinforces, and it's a paradox, because as I mentioned, molecular biology, in fact, for me, it's the beginning of the end of genetic determinism, in the sense that it cannot be so simple as geneticists had imagined.

But in these years, it was clear that it permitted a kind of burst, again, of genetic determinism, the idea that we are controlled by our genes, totally controlled by our genes, and so on. And it also supported the idea that, okay, but molecular biology,

it's a technique. And there was an identification between molecular biology and genetic engineering, which is not the case. Genetic engineering are techniques, but they are techniques, too, for projects different and a project of a science,

which has a vision of what is important is an organism. Okay, the last word in the last period, we can say, not last, before the present,

but the Human Genome Sequencing Program, launched in 1986 and achieved in 2000, 2003. Okay, just a few words about it. It's always possible to ask a question,

was it the right time to launch it, and so on. It has no historical sense, it happened. But in any case, I think it was obvious that once the structure of DNA was known and once it was accepted that genes were formed of DNA,

sequencing the whole DNA content of a cell, like human cell, was something which was reasonable. So, but, as you know, the way this project was presented

was probably not absolutely adequate. And for instance, you had these kind of sentences like, we will read the book of life, or we will know who we are by reading the book of life. So, there were oppositions,

but oppositions were more on the form, a new form of science engendered by this program, or the fact that Monet was now devoted to sequencing and not to more interesting projects, and so on. But in fact, the idea is that immediately, this program will bring huge results to biology.

I think this idea remains strong. Which explains that in 2001, when the sequences were published, I think there was an immense disappointment.

Because when you read the two articles in Science and Nature, you have plenty of data, but it's difficult to isolate, take on messages. If I say that, it's not to say that it was useless to sequence a genome. I think that retrospectively, it's clear that it was,

in fact, it changed the work of biologists, the way they are working. It was an extraordinary resource to find sequences, to compare sequences, and we know all these tools now. And I think also, something which was not anticipated,

it opened to comparisons. What was important was not somehow the sequences, but the comparison between sequences. And through comparison of sequences, you opened the door to evolutionary questionings about transformations and so on.

So an absolutely new aspect. But somehow it didn't change. It's my point of view. We enter into points that deserve to be discussed. It didn't change the nature of the questions asked by biologists. My point of view. We can discuss this later.

Okay, now come to postgenomics and systems biology epigenetics. I think that to understand the discourses, the statements that accompanied the rise of these two disciplines,

one must understand the previous events, the program, sequencing program, and somehow the initial disappointment. It was necessary to say, okay, but it's now that it becomes important. And there was a mini statement which flourished that now we will put things together

and it will be something radically new. Just to give a quotation of that time by David Botstein and Patrick Brown, describing what can be done with DNA chips and transcriptomics in particular. As you can see, in the first part they say

we have discovered plenty of genes which were unknown. It's like a new continent, like the discovery of America some centuries ago. And as the discovery of America changed a lot, all the Western countries and all the world in general,

it will be the same for biology. This knowledge will totally change. And as you see, new technology will make that now it's no longer necessary to have a hypothesis or to somehow new vision,

new logics will emerge spontaneously from the accumulation of this data. I really think that it was in part a strategy to say, okay, maybe there was a program, we said that we will understand who we are at the end of the program,

we have not understood, but okay, now starts the important thing, so it was strategic. But I don't think that all these statements have a strong meaning. For instance, I am not convinced that you have this dramatic movement

from balance between a reductionist approach and now a global systemic approach or something radically new and so on. I think the transition was more progressive than that. This is more political discourses of politics in science

and scientific discourses and scientific statements for me. Okay, just before closing, I want to show you that now if we take one discipline and to show you that the difficulty somehow of relation between molecular biology and other disciplines

evolved and evolved quite positively, very rapidly, and I will conclude after. First, when you look at evolutionary biology and molecular biology, as I mentioned at the beginning, evolutionary biology is considered that molecular biology

was physics and chemistry and not biology. It was very clear in Ernst Mayr that molecular biology is not biology. But because he knew nothing of this, I guess, he was completely ignorant of molecular biology or anything else except for onetology. He was onetologist or he used birds and the rest he was competitive. I would not be as strong as you are,

but I think he clearly was not a specialist in biochemistry and so on, and he was not interested and he considered that it was not essential. I think he said a thing about molecular biology, and that was wrong. He never said anything right, except for the leakage of birds. But the problem is that he had the feeling that,

in fact, for instance, he said that in 2009. I think this is wrong, absolutely wrong, that evolutionary biology has not been changed at all by molecular biology. And this is wrong, I think. You cannot say that. He never said anything right. I read what he said, everything came from him. Let's change to another discussion.

Okay, what were the problems, I think? When you consider evolutionary biologists, they pay more attention to natural selection. When you are a molecular biologist,

you are interested by variations because you are looking for variation, you are seeing variations between organs. So you have from the beginning, there was a disagreement. What is the most important in evolution? Variations or natural selection? It's not so. It's an important issue, I think. And naturally, molecular biology said it's variation.

And when you look at variations, it's obvious that you have plenty of types of variations. Gene duplication is not the same as at-the-point mutation. Genome duplication is something even more significant and so on. And also because, for instance, if you mutate a gene involved in development,

it will have a strong effect on development and so on, the morphology of the organism and so on. So there were plenty of discrepancies, differences, between the vision of evolutionary biologists and molecular biologists at the beginning.

But finally, in fact, there were, now the situation is much more peaceful, I think. The first, for instance, at the beginning, there were also the arguments that molecular phylogenies will learn nothing about true phylogenies, because true phylogenies are interested by important characteristics of organisms,

and molecular characteristics are not important. Okay, now, who is not using molecular phylogenies? All people working in classification work molecular phylogenies. Second, evolution and in vitro evolution now has combined with molecular evolution.

I've just mentioned the experiment of Richard Lenski, which I think are fantastic, because when he started his long-term culture of bacteria in very simple environments, he had not the techniques to look at the variations. The techniques came 20 years later, 30 years later,

with high throughput sequencing techniques, but he has kept samples of the cultures at different times, so it was possible to use them again and to characterize the different mutations. And just to show you here, for instance, in 50,000 generations,

and he observed the different types of mutation along the time which has occurred in his culture. So simply to tell you that... Which years? What kind of message?

The days, what period of time? Which year? When did he start, because he's not finished? When he started. He started in the 1980s. 1980s. I think. 1989?

1980s, about. At the time, it was another possibility of sequencing rapidly. Okay, so to come back to other transformations, there are now also possibilities to do the evolutionary studies of isolated proteins.

For instance, you can reconstitute ancestral forms of proteins, study their properties, and so on. It has been done in some cases. It's a huge work, but something fantastic, I think. And molecular studies and evolutionary studies are combined. And, okay, and now the idea is that, okay, variation is important.

Molecular biology can tell you the type of variation, but it does not mean that environment and natural selection is not an actor in the process. For instance, the gene mutation can be there, and they will be only important if there is a change in the environment.

So, somehow, there is a combination between these. Just to tell you, okay, when you look at the details, all conflicts have somehow vanished. I think this is okay. This is experiments on proteins. You reconstitute the ancestor. You try to understand how the ancestor progressively was modified during evolution,

which kind of event, aleatory event, and so on. I have no time, but we can come back to the discussion. So, conclusions. Molecular biology's reduction is okay, so I've tried to show you that it must be distinguished from genetics,

that DNA-centered vision is a methodological bottleneck, in some sense more that the real decision of biology is to say that DNA is more important or more significant, but technically, when you manipulate a living system, it's much more easy to manipulate DNA.

The anti-reductionist discourse, which is often seen, for instance, in post-genomics, was many times a strategy, more than probably a reality. It's my point of view. But, okay, it opens to discussion.

Is there, at the end of molecular biology, so there have been dramatic changes in technologies recently in biology, that's true, but my feeling, but okay, open to discussion, that the interpretative framework has not dramatically changed.

And, as a structural part of molecular biology is concerned, it still provides a huge of data, for instance, for the design of new drugs and so on. So, it remains a firm pillar of molecular biology. And the last slide is something new emerging, which is a stupid question because we never know what will emerge.

So, but nevertheless, what I would say in this debate is, it's clear that I think among biogies, sometimes there is a feeling that the accumulation of data is very rapid, but the change in conception and so on is more slow now than it has been in the past,

as if there was something maybe lacking to really be able to put all this, to interpret all this data, but it's a feeling. Second, also, that it's something like cancer, for instance. Okay, you can continue accumulating mutations,

but you have the feeling that you can, you will obtain results, but will it lead to really understand four better cancers than before? There are doubts, but at the same time, I think, are there alternatives?

Is there something radical and new emerging? Loads of complexity, that's a question I think so far, but you will discuss. Many biogies must be somehow reluctant to think that something essential,

like loads of complexity, are lacking. I think I have the feeling. It doesn't mean that plenty of important results will not emerge, showing dynamics of behaviours and so on, but the question is, are we at the origin of a change as dramatic as was the molecular revolution in the 1930s?

That's a question, and as I mentioned, there is no answer, and if there is an answer, we will know it in 20 or 30 years, probably. So it was only my bad answers. Okay, thank you.

I have a question, because you mentioned evolution as, the fact that biology had changed in the late, in the 1990s, and with the genome, the human genome sequencing, that it had changed the work of biologists,

and it had opened up to evolutionary questions, and I just wanted to raise the issue and have your comments on this aspect, because in some sense, it's important how we see ourselves, indeed.

The discovery, the sequencing of Neanderthal, for instance, has led Homo erectus, as well, has led to the notion that Homo sapiens had, in Eurasia, had some DNA from Neanderthal,

and in, where is it, no, actually in Europe, and in Asia, some DNA from Homo erectus. So far, this course of scientists to the general public have been, we are a single race.

Homo sapiens is a single race. Now, the fact is that these new developments lead to the idea, perhaps, that we are metis, how do you say this in English? Metis? Metis, yeah.

And so it's not the theory of replacement, which actually has been very popular this last week in France, but it's not the theory of replacement that holds, but it's the theory of metis, metisim, metishing, I don't know. Hybridization. Hybridization, yeah, which holds,

and so it changes the view of how we see ourselves, and also changes, perhaps, the discourse of the scientists to the general public, potentially. No, no, it's an interesting question, and my feeling, but it's a feeling,

this comparison are very important. Once again, it was something that was not anticipated, that it would be possible to sequence DNA from fossils of nearly 100,000 years old, so something unexpected.

And the results are puzzling, because I think, yes, apparently these flux of genes were not equally equal in different parts of the world,

and so it means that it's not of full homogeneity. My feeling is that if this result had been obtained, let's say, 70 years ago, it would have probably been exploited by many people to show that human races are different,

some are higher than others, and so on. My feeling is that, okay, there was a long period when it was clearly said that there is one human race, full exchange, so these results have not been interpreted in this way, saying, no, you see, we are not the same, we are different, we have a different genetic background.

Hopefully. Otherwise, yes, it's true that medicine and this exchange are important, and it's all,

but one must be also very cautious against rapid interpretations of the data. I think when, for instance, crossing between Neanderthals and modern humans, it's presented like good Neanderthals and Homo sapiens, who was more aggressive

and transmitted the genes of aggressivity, whereas Neanderthal transmit. I think this kind of interpretation must be done with, we must be very cautious because they are probably very naive, and maybe one day we will never know exactly what was the character of the Neanderthal, for instance.

But it's interesting, and you are right, it's ambiguous because it can be read from different points of view, this new data, as showing differences between humans and the opposite, showing the importance of mixing and exchange, depending upon what you...

It's clear that I think it raised a lot of interest among scientists and among people, but my message would be, be very cautious for the interpretations, because...

Perhaps this would be very cautious when you talk to a wider audience? Yeah, yeah, yes. Yeah, no, no, because... And to say that Homo sapiens is, for instance, is intelligent but aggressive,

not very honest and so on, I think, OK, genes will never tell us this kind of thing, so it's really an interpretation which is... But you read that now today, and the poor modern Neanderthal was kind and so what, he was eliminated,

but OK, that's beautiful stories, but once again, because we expect too much from Barge in this case, in some sense. I think there's always a reason, you can estimate a much fewer of them, yeah? There is a kind of obvious rule, the large group usually wins, by all this reason,

maybe 10% probably. Yeah, but there are plenty of reasons why this ought to happen. For instance, it's clear that Homo Neanderthalis was probably best adapted to cold weather and at the end of the glaciations, probably was less adapted than Homo sapiens.

So, you do not need to have these dimensions of violence, of goodwill or bad will, to explain maybe the replacement of... The accident could be other way around, yeah? Yes, and there can be accidents, there can be stochastic events

and privileging one group instead of another, yeah. So, once again, to be very cautious not to... It's a problem, I think it's always the same. Some people want to have the answer to the question. Why Homo sapiens said no to Homo Neanderthalis? Because, and you have one sentence and everything is explained.

That's a danger.

quite agree that there's more in ancient genes. But all the same, they're still incredibly mechanism-oriented, so if you really want to understand something, you have to know the mechanism. So what about this distinction that we were talking earlier about, the distinction between proximate and ultimate causes, if you want to understand why there's

something going on? Okay. For genocentric, it was after I mentioned the expression after the beginning of genetic engineering, so at the beginning of the expansion of molecular biology, because it was genocentric. I agree that epigenetics has changed its vision of genocentric. Even

I think something which must be reminded is that you have epigenetics because you have genetics, and epigenetics cannot exist without genetics. No, but nevertheless, in gene history of organ is probably also something to keep in mind. But it's mechanistic, yes. Molecular

biology remains mechanistic, and explanation remains, so far, mechanistic, dominant types of explanations. But biochemistry was mechanistic, and my feeling is that epigenetics is close to biochemistry. So it's also mechanistic, as can…

So we need also to consider them as the ultimate causes of things that we… Evolution is typically about the ultimate causes of that. Yeah, but what exactly… Okay, I agree, this form of mechanistic explanation is

strong, but… It's successful as well, isn't it? To a certain degree, at least. Sorry? It's successful as well, to a certain degree, at least. The mechanistic explanation. I mean, I always come with my own point of view. No, no, no, no. We are obliged to look for molecular basis of the diseases without an understanding

of the molecular diseases. We can't start a program. But what can be said is that mechanistic explanation is nevertheless typical of chemistry, biology, but less typical of physics, for instance, where in physics you have other

types of explanations, like by the existence of laws, of relations, of symmetries and so on, which are different types of explanations. Mechanistic explanation has become characteristic of, at least, biology. You use something like physical, if you use that molecular dynamics or something,

you apply physical law to actually your own mechanism. Yeah, yeah. No, you are right. And it's always difficult because biology has no frontiers. And when you are doing molecular dynamics, you are entering physics and using concept and notion of physics. And so in this case, yes, you have different ways of explaining.

But precisely, if I may, the example of proteins, the mechanistic conception of protein was very strong at the end of the 1990s with nanomachines, micromachines. And then you have the dramatic change, I think, in the study of proteins,

with the rise of molecular or development of molecular dynamics. It anticipated, but there were new tools, new ways. And now you have a vision of protein which is totally different, I think, far less mechanistic, you are right. But up to the point that sometimes I wonder whether this field is still fully biological in some sense.

The study of proteins now, when you see the models, it's very different from the model found in other branches of biology. You have energetics, you have population of molecules, statistical mechanisms. Well, most biologists are not familiar with that.

And you work in this field? I work in this field, yes. But when you speak with a traditional biologist,

you probably see that, for instance, the concept of molecular dynamics are not easy to introduce. Just to follow on this thing, it's sometimes, when you are talking about wave function in science or wave T approach in science, especially in genetics, the idea of 1G, sometimes you do not want to put biology, different sub-science in different classes,

it's not qualitative, too, because we look at system biology, scientific biology, there are a bit of evolution of molecular biology and genetic engineering. It's difficult to see. Do we not wish to just separate too much things by making a department of biology,

or just look at big data? No, no, no. I agree that it's bad to separate, but my starting point was more to oppose some strong statements like molecular biology was too deductionist. Precisely attributing one specific characteristic

to molecular biology in 80 years. But I would agree with the opposite. In fact, you have different disciplines where one aspect is more important than another, and for instance, system by system view is more significant. So you have not one discipline with one precise type of approach,

but you have different disciplines where one approach is more important than another. The other more interesting is when you mix. Yeah, yeah, yeah, yeah. Absolutely. I don't know whether there are

probably some encounters lead to nothing because the fields were not mature, it was not ripe for an interaction. It's difficult to know also when two different approaches or two fields will interact fruitfully or well, okay.

Yeah, yeah. It's difficult to anticipate this, I think. But yeah, no, no. You have different approaches with different emphasis put on different aspects and a permanently changing spectrum of relations.

That's my feeling. So I think I totally relate to basically your main point about reductionism and also the fact that this systemic discourse is mainly political. But I also feel that

compared to the biology of the 90s, the framework, at least the way I see it, is very different in biology. I can isolate to try to be more specific three areas where this might be the case. One is I think evolutionary genomics

and you mentioned it in these investigations on for example protein universe, genome duplication. So there was sort of I guess population genetics was born without any data

and now we're forced to have data to deal with so that all the theory that we have to use is to be sort of constrained by this data as to explain this data. So the framework is more similar to quantitative sciences. Now of course there's people from different

backgrounds because like you say, a biologist does not know molecular dynamics but these are areas where people converge from different fields. So another area like this maybe is this quantitative physiology where people are trying to define laws for cell growth and in this case

I think it's interesting because they're going back to before the molecular biology revolution where there were other approaches like this companion school and they're trying to they say that this is in their discourse probably but they say that they want to sort of

link their research to these guys and also maybe this single cell gene expression, single cell physiology single cell genomics stuff where people are forced to deal with again some of these are technological but I think it's not only technological it's really areas where

people have a different way of asking because one of the things you said for me was I don't know is that the main questions are the same as for example in the 90s I don't know No no no I would not like to leave this

feeling there are plenty of new things and new approaches I just wanted to say I'm doing a sense of different framework maybe it's not like a molecular biology revolution but I see this as a tense of shifting the framework

not worse or more reductionism No no but you are absolutely right just what I wanted to tell is that if you look at for instance DNA, RNA, protein relations between macromolecules or respective roles of macromolecules even if RNAs have a new function and so on but nevertheless

this framework remains but after nobody is testing in Newton's law and those are things you really don't but it has not been replaced in something different because some people have said that molecular biology was dead and so I think it's not dead

it's still there this message but you have plenty of new developments and some of them in fact pre-existed, anticipated and were somehow forgotten during one period of time and developed slightly later At the same time when you said

for instance population genetics emerged at a time when the gene was not known so it was normal to be abstract now we know what is a gene, what is a mutation and we can bring and articulate this new information with population genetics. It's not always simple because

it forces to totally change of course there are things that population genetics have remained true but then you have to describe the process of mutations, the constraints of the process of mutation the different kinds of mutations Yes but because also some people I think in this case consider

that these limitations are not limitations for instance during a while many population geneticists said it's not a problem if you don't know the nature of the gene the nature of mutation, the theory is still valid whatever this limitation and somehow it's not always easy to say no it can bring you

yes there was a yeah it was not so so obvious to do but yes you have plenty of exchange new fields appearing but it's up to you I didn't have this in the 90s like in the 2000s

and now you have this and if I compare between the 80s and the 90s I don't see this change so I see more change between the 90s and the 2000s than between the 80s and the 90s between the 80s and the 90s and now I see a straight line and that and now I see a lot of branches

yes but it's true or synthetic biology, system biology and so on, it was new but nevertheless I maybe I'm wrong it's difficult still to say what will be the one which will become dominant

yeah no no, you are right but also it's difficult to distinguish between discourses, statements and reality because many are made to push new approaches or to say that it's radically new, a new vision

for instance just we didn't mention it but precision medicine which is quite fashionable today, personally I don't see exactly what will emerge why? why I don't see? because for instance precision medicine

you look at genes, susceptibility genes and you see that for one disease for instance like autism you have more than 300 genes with like okay what can you do with such type of information you have to stratify patients

yes, but you have one patient who has among these 300 genes 20 genes with a slightly higher probability to develop autism and maybe 20 forms of genes with a lower probability okay and so on but what we are trying to do is

to classify patients and then develop treatments for different okay, but in a very simple yes, I agree, in a very simple at the same time it's impossible, but if you have let's say 3 or 4 you can still treat the problem with a combination treatment

but the problem remains what will be the significant rears the significant disease, the significant markers which can be really useful in practice so it's not a general principle, precision may seem okay but what is important what kind of markers what kind of genes

what kind of will be really useful in the future and this I think is not so simple so far no? once I have the let me just come back a little bit from the to the beginning to reductionism I have already discussed it with you

over the course I think we can attach 2 or 3 more errors to this and then we arrive to the systems biology approach of today so beyond reductionism there is also robustness which is a consequence of

redundancy of the different pathways that connect targets of molecular biology so from reductionism via redundancy and robustness we can get to complex systems which we can try to treat with the network approaches of today I think we can link

molecular biology which is still a very very important approach to what we are trying to do today to treat systems as a whole but that's also a reductionist approach that's more global but it's also reductionist there are only 2 ways to do

reductions you should do nothing you just stop why is there somewhere you have to deal it's because it's so complex language if you have no reductionist it's so expressible in the language language structural language everything is used to work easily

in interacting with special rules nothing which is not reductionist is expressible in the language no no reductionist is just absolutely never ever anything came from that we don't like it so we go to philosophy after science language is reductionist

this essence of our thinking is reductionist there is no other thinking just bubble bubble bubble there is no point we are skeptical of being reductionist yes but I would say more analytical in the sense of it means that what we do in science is to reduce the problem there are many components

and we try to see after how it works together so it's not reductionist it's the same place when you have something complex you try to decompose the problem less complex components try to understand the components and have to come back to the

whole issue I would prefer to speak about analysis and I think in science we do that because as you said the languages we analyse we separate in the language also but in science we do that we analyse, we take a huge problem and decompose it into parts

and try to understand the different parts and after we try to see how the parts interact there is a point in physics something is not a part when you have interaction of object it's not a part but there is no counterpart it's not that this is a reduction there is underlying new structure

discovered in physics in biology they are not discovered it's something else they are not objectively different in nature so that's the fact that's a difficult thing you don't expect it but you do some other problems I think the major problem now the general obvious problem that you don't know how to handle large data

you have large data, they are amorphous we don't know how to pacify them computers don't help and this is an obvious technical problem which has to be solved this is a very technical problem you have huge data, they are very amorphous how to systematise them make them available to everybody because most things going to data banks you cannot read them because in the language you don't understand

and then there is no standard in biology you need standard like what happens to chemistry you need standard and of course not for people but for computers this is a very technical but absolutely necessary thing you need tools which are technical and logical before you can discover new biology

immediately but not indirectly you can count on new things it's a bit what synthetic biology tries to do it's analyzing the data because they are not standard before you start creating new things you have to understand what you have and that's very difficult because you produce much more data in biology

than computers can handle and if computers of course can't organize it there is no way, no idea how to organize all that in biology which people don't know how to perhaps it's possible that you don't know all of it this is under way isn't it? people try to do it of course but it's not done yet very difficult it's a technical way

it's a technical problem it's a real thing you have to be solved 30 years ago statistics was about to get the maximum amount of information about the minimum of beta now my statistic is the good filter it's the minimum for nature thank you

your last slide you mentioned, you had a question what is new? and you talked about the laws of complexity I'm wondering whether the introduction of synthetic approaches in biology

may not be something that goes into the direction of changing the way we ask questions and have some different true change in a way we think biology should be working

so I would like to have your comment no no I will say something maybe please everybody among the young new biological disciplines I have the feeling that synthetic biology is probably one of the most significant I would say probably because

for one major reason because the idea is that it will allow really to check the state of our knowledge on biological objects and it's something I think which is new not so much for the application which is another side of synthetic biology and also understanding

yes and testing that we have understood the principles of life or we have a good description of living systems I would say even I'm not testing but having the possibility to answer questions by synthesis rather than analysis and the complementarity

between analysis and synthesis may have the potential to disrupt our concepts in biology and the second change which will maybe follow is that the activity of biologists will no longer be to observe what exists in organisms and how they behave but to build organisms

like chemists in the 19th century changed from observing to synthesizing new and new molecules and new because if you look at the evolution of chemistry it's clear that the introduction of synthetic approaches that are just in their infancy in biology but this introduction of synthetic

approaches really changed the concepts in the field of chemistry and the role of emergence of new theories so I was wondering whether you considered synthetic approaches in biology may have the same capacity of raising new models

or new theories a new way of thinking what biology is and even if it doesn't work I think that's what is strong with synthetic biology because failure can be very instructive but you have probably

your own answers to this issue what you see I was asked by Mr. Gromov to see what is the most important discovery in the last five years I don't know but you have probably each of you has different answers it would be interesting to share

because if you see it in the last five or ten years what is the most significant result that will change the face of biology in the next coming decades it's not easy but it's a good way to you can say discovery of fluorescent proteins

would be so crucial when they came up how long it took the discovery of fluorescent proteins so that was in the 1980s was that true? yes

no, no, it's true it was also in the that allowed how long it took how long did it take to be appreciated and to become a major I don't remember at least ten years I think twenty-first

the most technical of the things is the rise of cryo-EM microscopy allow us to reach a mechanistic level of protein and soon we can imagine we will see on symbology

also the possibility to activate for instance nerve cells by light optogenetics which is also something for the neurobodist I think quite radically new nothing came from that

the people do that zero before zero after no, because now they have the possibility it's like synthetic biology I think they have the possibility to activate one gene circuit and see what happens it doesn't seem to you there was a problem in the physiology

for the last twenty years they have data they completely are not not consecutive misinterpreted these new techniques don't help because they don't know what to look for it's very different from molecular biology this goes and really develops it doesn't develop it's very interesting to compare

they are blocked by something and we don't know where but maybe in general yes for neurobiology there are some specific questions for instance in the role of cells in the hippocampus that can be really solved with this technology so maybe not at the high level of how the nervous system

is organized there will be immediate answer but I guess a new technology can be used for very precise some of the technology are coming there but that's very interesting to compare it's really developed at the same time in molecular biology in neurobiology the progress of molecular biology in that is incomparable you need to put a lot of effort

because they learn as little as you learn in half a year the problem is probably more difficult no, all the people are not smart enough they have wrong ideas what they look for many things they say what they want to find is not right yes, but it's a part of the fact

that it's more difficult if you have a wrong idea people of course doing before and after molecular biology is incomparable to what you were saying you can't really see the man and like you were saying that's what happens when you work on neurons right, outside the field

perhaps you do the same so but we all mentioned more technological tools, I can mention another one but these are not really scientific we allowed some scientific breakthroughs, but we all mentioned no, no, no, scientific is great stuff great ideas, but scientific is very good and best thing

the great ideas great phenomena scientific is a wrong word you use it as a sign it becomes just knowledge and it's fundamental discovery yes, in the case I mentioned CRISPR when I answered so I imagine that you mentioned it but I think in this case

really the sentence of it was understand the physicist more is different because I think with CRISPR okay, got DNA it was already existing but it wasn't very efficient now it's more efficient more precise simpler, less expensive but I think it opens possibilities

that did not exist before in some sense probably it's after what will happen and maybe the modification of the germline is not what will happen there will be plenty of other use of this tool different from what those which were discussed

earlier but the fundamental discovery of the immune system which yeah yeah, exactly