 Bienvenue à cette première séminaire de la liste de séminaires que l'on organise en IHQ. Cette liste de séminaires est intitulée sur la question fondamentale et la logique de molecular biology. En fait, cette liste de séminaires sera très intéressante pour les topics de molecular biology et est liée à un livre que vous avez présenté avec Michel Grumhoff, présent ici en François K.P.S., qui organise cette série de séminaires. Et cette liste est très intéressante sur les idées que l'on a créées dans la logique de molecular biology. Donc, chaque séminaire sera lié à une chapter de ce livre. Et nous allons commencer aujourd'hui avec Michel Morange, qui probablement, pour la plupart d'entre vous, connaît. Donc Michel Morange est professeur de l'ENS de l'Université Paris VI, directeur du Centre de Calais. Il a fait son PhD dans l'Anthiologie, mais aussi, par exemple, il a fait son PhD dans la philosophie de la science. Et depuis qu'il avait une compétence de développement, il était un biologiste et aussi historien de la science. Et depuis quelques années, il a établi son activité de molecular biologiste et il est venu de l'histoire et de la philosophie de la science. Et c'est l'autor de ce livre, le dernier, qui s'appelle Histoire de la Biologie. Et je suis désolé de vous présenter aujourd'hui les signes de molecular biology à Michel Morange. Est-ce qu'il peut changer de lumière ? Ok, merci. Merci beaucoup à l'organisateur. Je dois dire que, à un moment, c'était difficile pour moi. D'abord, parce que je ne savais pas exactement ce que vous étiez attendu. Deuxième, parce que je n'en savais pas. Ce sera les gens qui attendent cette seminar. Et donc, mon point d'essence était un genre de discours, des statements de molecular biologie. Par exemple, molecular biologie était une réduction de l'approche de la phénomène biologique. C'était même une chapter de l'histoire de la biologie. C'est-à-dire qu'à la fin de sa vie, il n'y a pas de changement de disciplines biologiques, comme la biologie évolutionnaire, par le développement de la biologie. Ou ce qui est très communement dit, c'est que la biologie est un ensemble de techniques. Ok. Donc, je suis en train de parler de ces types de statements simplistiques. D'abord, pour beaucoup de raisons. D'abord, parce que c'est déjà un événement de 80 ans. L'histoire de la biologie de molecular biologie a commencé, c'est difficile, c'est déjà plus que 80 ans. Et c'était évidemment un processus très long de différentes façons. Et c'est ce que je veux faire aujourd'hui, juste pour vous montrer la transformation successive de la biologie. D'abord, parce que les mots réductifs et réductionnistes ne sont pas si simples. Qu'est-ce qu'il signifie exactement pour être réductionniste ? C'est l'issue que je vais adresser pendant cette lecture. Donc, il sera un peu chronologique, à partir du début, tenter de montrer ce que sont les origines de la biologie de molecular et de suivre les différents steppes à partir de maintenant et de créer des sujets à la fin. Donc, j'ai peur, peut-être, que c'est trop simple et trop général d'autres de vous. Mais ça dépend probablement aussi de vos backgrounds dans la biologie et dans la biologie de molecular. Donc, le début de la biologie de molecular, le développement de la biologie de molecular depuis le 1930, qui est souvent vu comme une conversion ou un rencontre entre la génétique et la biochemistry. Juste, et ce sera un de mes messages, le début n'était pas si réductionniste, surtout dans un groupe qui était très actif au début de la biologie de molecular, qui était le groupe américain qui était dirigé par Max Delbrouc. Probablement, quelqu'un de vous connait Max Delbrouc et connaît son rôle dans le développement de la biologie de molecular. Il a choisi un système qui était un bacteriophage parce que c'était un système simple. Mais l'objectif de Max Delbrouc était de trouver des lois de reproduction des organismes du stade de ce système simple model. Et Max Delbrouc n'était pas fondé de la chemistry, il l'a acheté, en un sens de chemistry, il l'a trouvé, surtout de la biochemistry. Donc, l'origine de la biologie de molecular est au moins très différente. La deuxième chose, à l'extérieur, je vais maintenant retourner à la biologie de micro-biologie. Parce que c'est intéressant aussi de voir la biologie de micro-biologie, un bacteriophage, comme l'on l'a vu, mais aussi de la biologie. Il a joué un gros rôle dans le développement de la biologie de molecular. Mais quand vous regardez maintenant dans le long de la caractérisation du micro-organisme au début du 19e siècle, du 20e siècle, et aujourd'hui, avec la révolution de la molecularité, ce que j'ai essayé, c'est d'observer que, en fait, ce mouvement, d'understand, à un niveau bas, ce qui s'est passé, a commencé depuis le début. Même à la fin du 19e siècle, il a été découvert que beaucoup de micro-organismes étaient en fait pathogènes parce qu'ils se sont secretés des toxins, qui étaient les protéines. Et donc, la reduction d'un processus complexe, pour l'action d'un toxin, était déjà là à la fin du 19e siècle. Et dans ce cas, la révolution de la molecularité n'était pas un change dramatique dans ce genre de études. Et, en fait, quand vous observez ce qui s'est passé dans les années 1950, progressifement, les notions de la biologie de molecular s'entendent dans la microbiologie, vous pouvez voir comment progressif c'était. Je veux juste mentionner, ici, par exemple, l'expérience de l'expérience de l'expérience de Jean-Claude Fégel qui montre que dans le bacteriophage, il n'est que un DNA qui entraîne les bacteries et qui est responsable pour la production de la bacteriophage. Ce sont ces expériments qui étaient bien plus au niveau de la reduction de la bacteriophage dans ses compétences chimiques. Mais c'était un part du processus smooth. Un autre exemple est un autre qui est la bactérie de l'esprit, ou l'hyzogenie. La possibilité de l'esprit est de rester silencieuse avec l'esprit. C'était un phénomène très important parce que c'était essentiel pour les modèles de régulation, la régulation de la génération. Quand vous regardez ce problème, ok, vous avez une bactérie, rien ne se passe, et tout de suite, la bactérie de l'esprit est élevée par cette bactérie. Alors, comment est la bactérie de l'esprit dans la bactérie ? Dans le 1950, vous pouvez suivre la transformation progressive dans cette notion de professeur. Dans le suivi, les drawings de la groupe de François Jacques, Bélie Vollmann, ici, pour exemple, en 1950, vous avez une représentation et vous voyez que la bactérie de l'esprit sont représentées par un petit cercle, comme un petit organisme. Personne ne sait exactement ce qu'ils sont. Certains ans plus tard, en Andrel Voff, c'est une ligne. Vous avez dit que ce n'est pas différent. Oui, c'est parce que la ligne est légère, donc cela signifie que c'est plus similaire à un matériel génétique. Et en même année, Bélie Vollmann va un peu plus tard et demande la question de la relation entre le matériel génétique de la professeur et le matériel génétique de la bactérie, qui est représenté par une longue ligne. Et il considère toutes les possibilités, vous voyez, différentes... différentes quantités de la bactérie génétique et de l'attachment de la bactérie génétique ou pas de la chromoseuse de la bactérie. Et en fait, le modèle correct n'est pas représenté, infortunement, parce que le modèle correct est que le matériel génétique de la professeur est inserté dans le matériel génétique de la bactérie, ce qui n'est pas le cas, qui est représenté dans ce slide. Mais juste pour vous montrer, progressivement, la bactérie silencieuse qui a été convertie dans un molécul et le molécul DNA, en fait, il y a quelques années plus tard. Ok, donc, un autre aspect important du rise de la bactérie génétique était l'imagination des études et des molécules macromolecules. C'est une motion de molécules macromolecules. L'imagination de cette notion a été comparée à l'éveloppement de la bactérie génétique. Mais ce qui est intéressant, encore une fois, c'est que le débat n'était pas sur la réduction ou pas, mais sur ce genre de réduction. Parce qu'il y avait un modèle alternatif, qui était le modèle colloïde, qui disait qu'à un certain niveau de matière, vous avez les études colloïdes, les agrigates, qui étaient responsables de nouvelles propriétés. Et donc, l'imagination des molécules macromolecules était une image en faveur de l'existence et d'un rôle de molécules macromolecules opposées à l'existence des colloïdes. Mais il n'était pas plus de réduction, il n'était plus qu'un étudiant des colloïdes. C'était différent, encore une fois. Et second, j'ai voulu ajouter quelque chose qui est, je pense, important aussi. C'est à dire que c'était fait, c'était observé par Wolfgang Ostwald, le chemiste physique, au début du 20e siècle, qu'en regardant les niveaux différents dans l'univers, les niveaux différents, le chemiste étudiait des molécules simples, mais il y avait un limiter. Dans le micro-scope, vous étiez observé des structures, mais il y avait un limiter bas, à un niveau bas. Et entre les deux, il n'y avait absolument pas d'études pour étudier ce qui s'est passé, le niveau des colloïdes ou des molécules macromolecales. Et le rise de la barbe moléculaire était aussi, à un moment, parallel ou linked avec le développement de cette nouvelle technologie et en particulier, par exemple, l'électrophoresis, ce qui est probablement l'un des plus caractéristiques de la barbe moléculaire et même aujourd'hui, de la barbe moléculaire, c'est juste pour vous montrer que c'était un lait de glace pour la compétition. Je l'ai apprécié pour cette raison. Les premières machines étaient énormes, très expensives, très difficiles à manipuler et aujourd'hui, dans les laboratoires biologiques, vous avez des machines très simples sur chaque manche. Donc, c'est la partie de la technologie progresse, cette reduction de la technologie. Ok, donc c'est une autre partie de ce mouvement de la biologie moléculaire. La dernière point, je veux discuter très rapidement. Comme je l'ai dit, c'est un overview mais dans la discussion, nous pouvons revenir sur beaucoup de problèmes à chaque point, si vous voulez. La dernière point, c'est que vous avez une autre forme de reductionisme dans le même année et je pense que c'est important de noter que vous avez toujours un type de confusion entre le reductionisme génétique et le reductionisme moléculaire. La reduction de la génétique signifie que dans l'organisme, vous pouvez couper l'organisme dans différents parts, les personnages et chaque de ces personnages est contrôlée par votre génie. Donc, l'organisme peut être réduit pour les gènes et un symbole mais c'est quelque chose très différent de le reductionisme moléculaire parce que la génétique reste un objet abstract et personne ne sait comment est-ce sa nature précise. Je vais revenir à ce point parce que les relations entre la génétique et la biologie moléculaire sont complexes et elles sont toujours à l'origine probablement interprétations sur ce qu'est la génétique moléculaire et ce qu'est les choses, etc. Ok, c'est mon premier part sur l'origine. Maintenant, la deuxième partie du 1960, la génétique moléculaire devient une nouvelle discipline de scientifique. Qu'est-ce qu'elle a fait ? Plein de choses que j'ai fait une très petite liste de relations entre différentes classes de moléculaires de l'RNA protéines, de la génétique bien sûr, mais aussi vous avez un mécanisme régulatoire opérant au niveau moléculaire et je pense qu'il y a quelque chose plus dans la biologie moléculaire. Il y avait une évidence que peut-être pas toutes clairement, mais beaucoup de explications des phénomènes biologiques peuvent être trouvées au niveau des moléculaires macro pas toutes, je pense d'accord, probablement pour des moléculaires biologiques et je vais revenir sur ce cas extreme de réduction. Mais beaucoup de phénomènes vont trouver leur explication à ce niveau. Ok, donc maintenant juste, je vais discuter quelques points de cette période de moléculaire biologiques de moléculaires biologiques la première, c'est, encore une fois, les relations entre les genes sur l'un côté et le DNA sur l'autre. En fait, avec le risque de moléculaire biologiques vous avez deux mouvements différents la première, c'est de dire que les genes correspondent au DNA, donc la réduction moléculaire la deuxième, c'est que les genes correspondent à une information et le genome est un programme, par exemple, pour l'organisme il y a deux choses qui sont très différentes l'un est réductionniste l'autre n'est absolument pas réductionniste. Let's now focus 1 gene, 1 fragment DNA 1 gene, 1 fragment DNA As you know this reduction is not so simple and the difficulties appeared in the 1960s because ok must you include regulatory sequences in the DNA fragments or regulatory sequences present upstream of the gene must be included or not ok you include them but in some organismes regulatory sequences are very far from the gene and they are shared with other genes and so on. So if you have plenty of difficulty to say 1 gene correspond to this precise fragment of DNA in fact ok but in the case for instance where 1 element like an ananser control 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 issue 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 geneticist and it's even I think more serious concerning genetic determinism you know that in classical genetics the gene were responsible for 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 there you will have the characteristic special characteristic ok 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 ok 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 ok 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 1953 genetic code 1960 one regulatory mechanism 1961 very simple and we have very beautiful model concerning proteins I think I have just no it's Linus Pauling just to mention because it was so active in this process this is the first model of a protein in 1957 myoglobin at C. Sanktrum 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 a high resolution and the progress in the characterization of the structure came later with different steps genetic engineering which permitted the preparation of huge amount of proteins progress in extreme 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 progress is not have not found an end but now you can obtain a structure of a protein in a very limited amount of time to compare to what happened at the big and what is the consequence the consequence I think is that the situation has dramatically changed because this three-dimensional structure of proteins or 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 barges this structural part of molecular barges it has never been as brilliant as powerful than today rather probably the other informational part of molecular barges the result were happening rapidly and there were more doubts appearing after the existence of programs and notions like this so very different stories of the two just one word on regulation discovery of regulation regulation of enzymes regulation of 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 we realized this later but some people like Denis Tiefry here Michael Normand says that the beginning of systems of biology was in the operand model and in ok the people who exploited it immediately after like René Tomas I think he is not totally wrong it was the beginning of another vision of living organism with this existence of these regulations ok so it was the operand model so conclusion of this part it's 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 in the structure one molecule only and one good example was the existence of what was called were called memory molecules of molecules of memory that behaviors or souvenirs 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 they were in the 1970s famous experiments and studies about which macromolecules was doing that and this kind of experiments sorry it's in French but I guess a problem but the experiment of George Ungard you are the rat the rat was trained to to have a certain behavior for instance to avoid a black pot of labyrinth and the animal was killed the brain was taken, crushed 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 this kind of experiments there were many people offering un type of experiments it never came to applications but there were plenty of papers in best journals like science, nature publicist kind of observations when the last last in the middle of the 1970s and interestingly it's when Andorphine and Ankephalin were discovered I think that from the beginning there were some people who were not happy with these experiments of transfer but when Ankephalin and Andorphine were discovered it was possible to say ok, 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 experiments, so it was a way to explain past observation without telling that the people have invented the data which probably was ok 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 equation so they can be explained on a very reductionist basis and even treated sometimes that you just mentioned what kind of process what kind of phenomena can be reduced to one more macromolecule a number of rare diseases ah yeah, of course no no 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 there were abuses of reductionism in some cases but in 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 result with this molecular description first one was to characterize un 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 sometimes she chose that interactions were very important interactions 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 theory of cancer but nevertheless whatever maybe it's not sufficient maybe it has to be change and so on but it 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 focus 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 any other molecule if you want to change something in a cell it's much more easy to introduce modified form of DNA and to synthesize for instance altered forms of proteins that to inject these altered forms of proteins so to act on living organism to never defy them DNA is the best way to do it's a path to modification of organism and for one very simple reason I think which is not because as sometimes you read barges that 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 an information from one generation to another generation so there is something specific in the structure of DNA which allows a simple manipulation of DNA barges have used a trick that has been forged by natural evolution but it was nevertheless it's true that for many people they saw DNA coming back modification of organism 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 ok so in some cases it works well like for instance you have a simple mutation and you can explain the effects of the disease by the 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 the gene nobody was known about the origin of the disease when the gene was isolated at the end of 1980s but from the knowledge progressive knowledge of the gene and of the protein the way was long to understand all the complexity so ok 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 ok 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 I don't want to say there was a plethora of article going in this direction most of this article were showed later to be non viable not really confirmed by later experiments but I think it reinforced and it's a paradox because as I mentioned molecular 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 this years it was clear that it permitted a kind of burst gain 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 molecular biology it's a technique and there was an identification between molecular biology and genetic engineering which is not the case but there are techniques too for projects different and a project of science which has a vision of what is important is an organism of a last word on last period we can say or not last before the present but the human genome sequencing program launched in 1986 and achieved in 2000-2003 ok 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 ok but as you know the way this project was presented was probably not absolutely adequate and for instance you had this 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 new form of science engendered by this program or the fact that money was now devoted to sequencing and not to more interesting project and so on but in fact the idea is that immediately this program will bring huge results to Bargi 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 taken messages if I say that it's not to say that it was useless to sequence a genome think that retrospectively it's clear that it was in fact it changed the work of Bargist the way they are working it was an extraordinary resources resource to find sequences to compare sequences and we know all these tools now and it 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 open the door to evolutionary questionings about transformations and so on so absolutely new aspect but somehow it didn't change it's my point of view it didn't change the nature of the questions asked by Bargist my point of view we can discuss this later ok now come to post genomics and systems biology epigenetics I think that to understand the discourses the statements that combine 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 ok but it's now that it becomes important and there was a many 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 Butstein and Patrick Brown describing what can be done with DNA chips and transcriptomics in particular as you can see in first part they say we have discovered in the genome plenty of genes which were unknown it's like a new continent like the discovery of America 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 hypotheses or to somehow new vision new things will emerge spontaneously from the accumulation of this data I really think that it was a part in part a strategy to say ok maybe there was a program we said that we will understand we are at the end of the program we have not understood but ok now start the important thing so it was strategic but I don't think that all these statements are have a strong meaning for instance I am not convinced that you have this dramatic movement from balance between reductionist approach and now global systemic approach or something radically new and so on think the transition was more progressive and that this is more political discourses of political politics in science and scientific discourses and scientific statements for me ok 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 bargy and other disciplines evolved quite positively very rapidly and I will conclude after first when you look at evolutionary bargy and molecular bargy as I mentioned at the beginning evolutionary bargy considered that molecular bargy was physics and chemistry and not a biology it was very clear in Ernst Meyer molecular bargy is not bargy parce qu'il n'y a rien de physics parce qu'il est ignorant de molecular bargy d'exemple ornithology ornithology or his birth and the rest he was compact I would not be as strong as you are but I think he clearly was not a specialist of biochemistry and so on and he was not interested and he considered that it was not essential he said I think about molecular bargy but the problem is that he had the feeling that in fact for instance he said that in 2009 I think this is wrong that evolutionary bargy has not been changed at all by molecular bargy and this is wrong I think you cannot say that let's change to let's change to another discussion ok what were the problems I think when you consider evolutionary bargy they paid more attention to natural selection when you are a molecular bargy you are interested by variations because you are looking for variations you are seeing variations between organs so you are from the beginning there was a disagreement what is the most important in evolution variations or natural selection so it's an important issue I think and naturally molecular bargy 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 the point mutation genome duplication is something even more significant and so on and also because for instance if you in evo devo if you mutate a gene involved in development it will have a strong effect and development and so the morphology of the organism and so on so there were plenty of discrepancies differences between the vision of evolutionary bargy and molecular bargy 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 molecular phylogenies will learn nothing about true phylogenies because true phylogenies are interested by important characteristics of organism and molecular characteristics are not important ok now who is not using molecular phylogenies all people working in classification work molecular phylogenies second evolution and in vitro evolution now combine with molecular evolution I've just mentioned the experiment of Richard Lenski which I think are fantastic because when he started this long term culture of bacteria in very simple environment he had not the techniques to look at the variations the techniques came 20 years later 30 years later with IFU put sequencing techniques but he kept samples of the cultures at different time so it was possible to use them again and to characterize the different mutations and just to show you here for instance and 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 what period of time the word was done by Lenski it's which years what kind of message the days, what the period of time which year when he started when he started I started in 1980s 1980s I think 1989 oh no 1980s about I met with another possibility of sequence so rapidly ok so to come back to other transformation there are now also possibility to do the evolutionary studies of isolated proteins for instance you can reconstitute ancestral form of proteins studies of 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 ok and now the idea is that ok 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 genes 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 ok when you look at the details the old conflicts has somehow vanished just this is ok this is experiments on either proteins you reconstitute the ancestor you try to understand out the ancestor progressively was modified during evolution which kind of event, aleatory event and so on I have no time but to come back discussion so conclusions molecular biologist reduction ok so I tried to show you that must be distinguished from genetics that DNA centered vision is a methodological bottlenecks in some sense more that the real decision of biologist to say that DNA is more important or more significant but technique when you manipulate 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 ok it happens to discussion is there at the end of molecular biology so there have been dramatic change in technologies recently in biology that's true but my feeling but ok open to discussion that's interpretative framework has not dramatically changed and as I structural part of molecular biology concern 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 biologists sometimes there is a feeling that the accumulation of data is very rapid but the change in conception so on slow now that 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 in some feel like cancer for instance ok you can continue accumulating mutations but you have the feeling that you can, you will obtain results but will it lead to really understand far better cancer than before there are doubts but at the same time I think are there alternatives is there something radical and new emerging laws of complexity that's a question I think so far but you will discuss many biologists, biologists are somehow reluctant to think something essential like laws of complexity are lacking I think I have the feeling doesn't mean that plenty of important result will not emerge showing dynamics of behavior and so on but the question is are we at the origin of change as dramatic as was the molecular revolution in the 1930s that's the 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 ok thank you I have a question you mentioned evolution as the fact that biology had changed in the late in the 1990s with genome at human genome sequencing that it had changed the work of biologists and it had opened up to evolution and I just wanted to raise the issue and have your comments on this aspect because in some sense it's important on how we see ourselves indeed the discovery that the sequencing of Neanderthal for instance has led the homolectus 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 so far this course of scientists to the general public had been we are a single race Homo sapiens 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 so it's not the theory of replacement which actually has been very popular these last weeks in France but it's not the theory of replacement that holds the theory of metis I don't know hybridisation which holds and so it changes the view about how we see ourselves and also changes perhaps the discourse of the scientists to the general public just no no it it's a interesting question and my feeling but it's a feeling ok this comparison are very important once again it was something that was not anticipated that it would be possible to sequence DNA from four seals of nearly 100,000 years 100,000 years old so something unexpected and the results are puzzling because I think yes apparently these flux of genes were not equal in different parts of the world and so it means that all 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 ok there were long periods when it was clearly said that there is one human race fully changed but the 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 ok it's true that the medicine and this exchange are important and 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 so and transmitted the genes of aggressivity whereas Neanderthals transmit I think this kind of interpretation 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 Neanderthals for instance but it's interesting and you are right it's ambiguous because it can be read from different point of view this new data as showing differences between humans and the importance of mixing and exchange depending upon what you it's clear that I think it raises a lot of interest among scientists and among people but my message would be be very cautious for the interpretations because you have to be very cautious when you talk to a wider audience yes yes 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 interpretation which is but you read that now today the poor modern Neanderthalis was carrying and so he was eliminated but ok that's beautiful stories but once again because we expect too much from bulge in this case all this reason there are much fewer of them the larger group usually wins by all this reason 10% ok but there are plenty of reasons why this ought to happen for instance it's clear and homo Neanderthalis was probably best adapted to cold weather and at the end of the glacations probably was less adapted than homo sapiens so you do not need to have these dimensions of violence of good will to explain maybe the replacement accident could be otherwise yes and there can be accidents there can be stochastic events and privileging one group instead of another so once again to be very cautious 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 not homo Neanderthalis you have one sentence and everything is explained that's a danger to continue on this thing so I work in an institution at the moment quite close here where people would agree with your statement that things have become too genome centered because many of them they quite agree there's more in ancient genes but all the same they're still incredibly sort of 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 approximate and ultimate causes if you want to understand why is something going on for genome centric 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 genome centric it is that epigenetics has changed this vision even I think something which must be reminded is that you have epigenetics because you are genetics epigenetics cannot exist without genetics never the less and the history of organ is probably also something to keep in mind but it's mechanistic yes molecular barges 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 I can we need also to consider the ultimate causes of things that we have evolution is typically about the ultimate causes yes but what exactly ok I agree this form of mechanistic explanation is strong but it's successful as well to a certain degree at least 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 we need to look for molecular basis of the diseases without understanding the molecular diseases we can't start a program but what can be said is that mechanistic explanation is never the less typical of chemistry bargy but less typical of physics for instance where in physics there are other types of explanations like by the existence of laws of relations of symmetries and so on which are different types of explanation mechanistic explanation has become characteristic of at least bargy yeah yeah no you are right and it's always difficult because bargy has no frontiers and when you are doing molecular dynamics you are entering physics concept and notion of physics and so in this case yes you have different ways of explaining but it's precisely me but the example of proteins the mechanistic conception of proteins was very strong at the end of the 1990s with nanomachines, macromachines and then you were the dramatic change I think instead of proteins with the rise of molecular or development of molecular dynamics but there were new tools, new ways and now you have a vision of protein which is totally different I think for 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 you are very different from the model found in other branches of bargy you have energy, you have population of molecule statistical something well most bargy I'm not familiar with that and you probably you work in this field but when you speak with traditional bargy you always see that for instance concept of molecular dynamics are not easy to introduce Just to follow on this sometimes when you are talking about reduction in science or relative approach in science especially in genetics the sometimes you do not want to put biology in different sub-science in different class because if you look at system biology, synthetic biology there is a bit an evolution of molecular biology and genetic engineering difficult to see we don't risk to just separate too much things by a department no no but they will just look at big data no no no but I agree that it's bad to separate but my starting point was more to oppose some strong statements like molecular bargy was to deduction precisely attributing one specific characteristic to molecular bargy in 80 years but I would agree with the opposites that in fact you have different disciplines where one aspect or is more important than another and for instance system biology system view is more significant so you have not one discipline with one precise type of approach but you have different discipline more important than another the ones that are more interesting is when you mix absolutely and yeah it can be I don't know whether they are probably some encounters to nothing because the fields were not match or it was not right for an interaction it's difficult to know to approaches different approaches or to fields will interact fruitfully or well ok yeah yeah it's difficult to anticipate this I think but yeah no no you have a poly different approaches with different emphasis put on different aspects and the permanently changing spectrum of relations that's my feeling so I think I totally relate to basically a main point about reductionism and also the fact that 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 is very different in biology and I can isolate to try to be more specific three areas where this may be the case and one is I think evolutionary genomics and you mentioned it in these investigations on for example protein universe genome duplications so there was sort of I guess population genetics was born without any data and now we are forced to have data to deal with so all the theory that we use to be sort of constrained by this data has 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 biologists that does not know more like aerodynamics but these are areas where people converge from different fields so another area like this may be this quantitative physiology where people are trying to define laws for cell growth and in this case I think it's interesting because they are going back to before the molecular biology revolution where there were like other approaches like this companion school and they are trying to recite these papers they say that this is the end of this course problem 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 evidence where people will have a different way of asking because one of the things you said that for me was I don't know is that the main questions are the same as for example in the 90's I don't know I would not like to leave this feeling there are plenty of new things and new approaches I just wanted to say but you're in a sense of different framework maybe it's not like a big molecular biology revolution but I see this as a tense of shifting the framework not worth less or more actionism but you're absolutely right just what I wanted to tell is that if you look at for instance DNA protein relations between macromolecules or respective roles of macromolecules even if RNA a found new function but nevertheless this framework remains but after nobody is questioning Newton's law but then I mean those are just like but it has not been replaced on something different because some people have said that molecular biology was dead and so on so I think it's absurd, it's not dead it's still there, this message but you have plenty of 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 say for instance population genetics emerge at the 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 okay we can bring and articulate information with population genetics it's not always simple but again it forces to totally change of course there are things that population genetics that remain tool but then you have to describe the process of mutations the constraints of the process of mutations the different kinds of mutations the global world yes but because also some people I think in this case 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 the 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 yes it was not so so obvious to do yes you have plenty of exchange new fields appearing but it's up to you I don't... in the 2000s and now you have this 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 yeah between the 80s and the 90s I see a straight line et now you see a lot of branch oh yes but it's true synthetic margin system margin 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 and 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 and you see that for one disease for instance like autism you have more than 300 genes with like ok what can you do with such type of information what can you do you have to classify 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 23 forms of genes with a lower probability ok and so on what we are trying to do is to classify patients and then develop treatments for different classes ok but in a very simple, yes I agree in a very simple 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 real, the significant disease the significant markers which can be really useful in practice no general principle precision ok 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 to the beginning to reductionism I have already discussed it with you I think we can attach 2 or 3 more adverts to this and then we arrive to the sister biology approach of today 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 by 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 they are trying to do today to treat systems as a whole but that's also a reductionist approach just more global but it's also a reductionist there are only 2 ways of reductionism but we should do nothing to just stop like somewhere we have to be just because he's so complex no, because language language by nature reductionism if you give one reductionism it's an expression of the language language, structure of the language everything is used to work with this grid in interaction with such special rules nothing which is not reductionism except for English, either normal or mathematical so no reductionism is just empty word absolutely never, ever, anything care from that just don't like to be vulnerable so you want to follow such a proper size language is reductionism this essence of our thinking is reductionism there is no other thinking out in bubble, bubble, bubble there is no reductionism yes, but I would say more in the sense of Descartes it means what we do in science is to reduce a problem there are many components we characterize the components and we try to see after how it works together so it's not reductionist it's the same place that when you have something complex you try to decompose a problem into less complex components try to understand the components and after come back to the world issue I would prefer to speak about analysis and I think in science we do that because as you said the language is we analyze we separate in the language also but in science we do that we analyze, we take a huge problem and decompose it into parts and try to understand the different parts and after we try to see other parts interact it's important in physics something not a part when you have interaction of object when you have to refuel it's not a part but there is no counterpart on disability that's the problem it's not that this is a reduction there is a underlying new structure discovered in physics in balance they are not discovered it's something else they are not of different nature so that's the fact ok, that's the difficulty you don't expect it but you do some other problems you analyze data they are amorphous we don't know how to classify them computers don't help and this is an obvious technical problem which has to be solved I mean it's not philosophical very technical problem huge data they are amorphous how to systematize them makes them available to everybody because most things go into it but data banks can't read them because in the language you don't understand so you need to understand and wish of course not for people but for computers very technical but absolutely necessary you need tools which are technical kind of logical you can discover your biology immediately but not indirectly you can come to new things it's a bit what synthetic biology try to do no, it's analyzing the data because there are no standard attacks before you start creating new things you have to understand what you have and that's very difficult because you know computers can handle and computers of course can't organize there is no way, no idea how to organize all data in biology people don't know how perhaps it's possible for the gene ontology this is under way isn't it this is under way before try to do it of course but it's not done yet it's technical very difficult technical problem it's a real thing 30 years ago statistics was about to get the maximum amount of information about the minima of data not the statistics on the filter that was the minimum of information I go is there a question yes your last slide you mentioned you had the 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 the way we we think biology should be working I will say something that will not please everybody among the young new biological discipline I have the feeling that synthetic budge is probably one of the most significant I would say probably because there is for one major reason because the idea that it will allow really to check the state of our knowledge on biological object and it's something I think which is new not so much for the application which is another side of synthetic budge yes and testing that we have understood the principles of life or we have a good description of living systems because we having the possibility to answer question by synthesis rather than analysis and the complementarity between analysis and synthesis may have the potential to destroy our concepts in biology and the second change which will maybe follow is that the activity of biologist will no longer be to observe what exist in organism and how they behave but to build organism like chemist in the 19th century change from observing to synthesizing new and new molecules and new because if you look at the evolution of chemistry it's clear that introduction of synthetic approaches that are just in their infancy in biology but this introduction of synthetic approaches really change the concepts in the field of chemistry and a role emergent of new theories so I was wondering what you already said that synthetic approaches in biology may have the same capacity of raising new molecules or the 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 and but ok but after 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 5 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 5 or 10 years what is the most significant result we will change the face of the next coming decades it's not easy but it's a good way to you can say discovery of fluorescent proteins so it's crucial when they came up how long it took discovery of fluorescent proteins so that was in the 1980s yes no no it's true it was also in me that's a lot yeah how long it took how long it took to be appreciated to become the major I don't remember at least more than 10 years 5-10 years from the 5 years it's much more technical than the thing it's the rise of Huawei and Microsoft which mechanistique level of protein and soon we can imagine we will see anzimology in a visual way you have also the possibility to activate for instance nerve cells by by light opto genetics and which is also something for no budgist I don't think quite radically new nothing came from that the people do that they look at the brain they understand zero before more or less no because now they have the possibility it's like synthetic budgie I think they have the possibility to activate one gene circuit and see what happens it doesn't seem to me there was an improvement in the physiology for the last 20 years whatever they were doing no no no consecture in some misentoflite 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 it develops it doesn't develop it's very interesting compare why they've lost the something and we don't know by what but maybe in general yes for neuro budgie but there are some specific questions for instance in the hippocomposal that can be really solved with this technology so maybe not at the high level of how the nervous system is organized there would be immediate answer but I guess a new technology can be used for very precise technology are coming there but it's very interesting to compare it's good development at the same time of molecular biology and neurovisology incomparable the progress of molecular biology and in that it's incomparable why as little as you know the problem is probably more difficult the problem is probably more difficult no all my people smile now they have wrong ideas what they look for many thing they say what they want to find they look not right yeah but it's a part of the fact that it's more difficult if you have wrong idea if you have wrong idea yeah I guess it's people doing the point after the act of molecular biology comparable to what you're saying you're actually a superman you're saying Mr. Pincis that's why you work on your words I'll send you a few I'll send you a few but we all mentioned more technological breakthroughs I can mention another one but these are not really scientific we allowed some scientific breakthroughs but we all mentioned you get great stuff and great ideas but scientific is very kind of it's good and bad things they have great ideas how to call them material scientific is their own work usually they are assigning a way but you just know it it's a mental story in the case I mentioned Chris Bay when I answered Mr. Grumov so I'm happy that you mentioned it but I think in this case it's really the sentence of physicist more is different because I think Chris Bay ok cut 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 so it's really after what will happen maybe the modification the germline is not what will happen there will be plenty of other use of this tool different from what those who were discussed which were discussed earlier what the fundamental discovery or the linear system which yeah yeah yeah exactly