 I think it's a vision series. And today we are welcoming a talk from Lucille Abelat. So Lucille Abelat is a CNFS researcher in Paris, NPTRIF. She's at the same time a philosopher and working in a real experimental laboratory on cancer research. And she, if you don't know her work, we have a presentation today. She's the author of a wonderful book in the Harvard University Press on the Hans-Them-Selves, which is a very, very impressive work showing how philosophy and analytic conceptual investigation can be useful for understanding conceptual, understanding perishable theories. And I suppose we're going to have a part of this today. So I think I've said everything. And so we're going to talk today about that. So this is it. No, I just, I need to say that this is a, this session seminar is in collaboration with Airella Project, which is a European project for the ethics of oncology and technology. It's going to be one of the applications of stem cells. And so we are hosting this seminar as a collaboration between, to this life-changing seminar that exists. And on your site, Airella Project, where we are investigating organoids as is basically the case of stem cells in it. So it seems like this is it. So please. So thanks a lot for inviting me and super happy to be here today. So thank you for the introduction. Should I keep my mask or should I leave it? It's as you wish. You are more permitted to take it off if you want according to the local rules. It's entirely up to you. Okay. So maybe I'll, if everybody is comfortable. So maybe the first thing I should tell you is a little bit more about my curriculum. So I started my PhD working on this notion of stem cell. So I started reading the scientific literature. Then I went to a few labs to see the practice behind the theory. And then I started to realize that in fact I need more. So in the middle of my PhD, I did a master in stem cell biology, which included a six months lab internship. And that really bent the way I see philosophy and the way I want to do philosophy. So after I finished my PhD, I decided that I want to work in science lab, which I do ever since. And I do want to mix the scientific approach with the philosophical approach. And I'm going to try to illustrate why I think these two things need to be integrated. So the first thing is there are many ways of doing philosophy. So in my case, something that is really important for me is the aim I follow is I want to use philosophy to make a contribution to science. And that will involve a mixture of using philosophical tool, but also sometimes doing some experiment myself, or doing some bioinformatic analysis. So with Thomas Brader, we wrote a paper which was on why we think science needs philosophy. And he also has a lot of work trying to characterize this way of doing philosophy, which he calls philosophy in science. So the idea is that in the case of philosophy of science, the main characteristic is you start with a scientific problem, then you address it with philosophical tools, and that gives a philosophical answer to the science. So it's a philosophy making a scientific contribution. In my case, it's even a bit more complex than that because I'm not just doing philosophy, so sometimes I address scientific questions with philosophical tools and the scientific answer it gives raise new philosophical questions that I might in fact answer to using scientific tools. So it's a mix of all these approaches. The main thing you have to understand is it's really important for me to drive a driver for my work to contribute to the science. So this is the outline of the talk. So today I'm going to illustrate this mix of philosophy and science in the context of the stem cell science. So the first part of the talk, I will show what are the conceptual issues that are discussed in the scientific community around what stem cells are. Then I do a philosophical analysis of what stem cells are, so that will be the second part. And here I will show that in fact, stem cells, the property of being a stem cell, can be of four different types, categorical, dispositional, relational, or systemic. I will explain each of them. Philosophy really helps clarifying these four possibilities. And after that, this will open three different questions. The first one is, does this philosophical analysis matter for the science? And the second one is, if stem cells can be of different type of properties, is it stable or can a cell move on one to another? And the third is, if stem cells can be of different type of things, then are we right to keep having one category with what is stem cell in it, or should we split it into four? So those two last parts are ongoing projects. So it's really open questions. So let's start with what stem cells are. So the first thing to know is that we have stem cells everywhere. So for each of your tissues, you have a bunch of stem cells that ensure the production of your... So you have stem cells producing your blood every day. You have stem cells producing your skin, your muscle. For each of your tissues, except for the liver, you have a pool of stem cells that keep producing the daily cells that you need to renew your tissue. And the traditional view of what stem cells are goes this way. So the main idea is that for each tissue, you have this small pool of stem cells. They can set renews so they can produce more stem cells. This allows to maintain this pool of stem cells through your entire life. And they can differentiate so they produce all the cells of your tissue throughout your life. This view of stem cells comes with three main characteristics. The first one is the idea that stem cells are cell type. So the idea is if you look at a bunch of cells, you should be able to say those are stem cells and those aren't. The second thing is stem cells are defined by too many properties. So the ability to self-renew and to differentiate that I have just explained. And the third big idea is that this differentiation, it goes only one way. So once the stem cells start to differentiate, there is no return to a stem cell state. That's the traditional view of what stem cells are. But today, all of this is being questioned in the scientific community. So first, the idea that stem cells are a particular cell type, so that there are discrete entities that you could distinguish, has been questioned by the introduction of single cell RNA-seq. So single cell RNA-seq, it's a technology where you can see the gene expression in each single cell. And when you do that with, for example, your blood, what you will see is that no two cells are exactly the same. In fact, they slightly differ, but they differ in a really continuous way when we do combine each cell with the neighbor cells, suggesting that in fact, there is no step in the differentiation, and differentiation is really a continuous process. And that, of course, raised the question of if it is continuous when, then where is the boundary between the stem cells and the non-stem cells? So that's the first main issue, a quite recent one. A second one is related to the question of the definition of stem cells. On the philosophical aspect of the definition of stem cells, there are quite some work. So I can suggest, for example, the work of Melinda Fagin, who has done a lot of really nice work on this definition. Here I'm going to evoke the main issues that we need after. So the first issue is that these two properties, self-renewal and differentiation, those are quantitative properties. It's not that a cell cannot self-renew. Some can do it on an extensive time, and others on a much smaller scale. And it's the same for differentiation. Some cells, so I don't know if you are familiar with that, but the zygote, for example, is totipotent. It can give rise to a whole organism. Then during the oncology, you have only pre-potent cells, so they can give rise to each tissue, but they can't give rise to the entire organism. And then in the adult phase, in the mammoths, at least, cells are multipotent or unipotent, so they can give rise to only a few cell types. So the potential for differentiation is really a quantitative property. And the second problem is that none of these properties are specific to stem cells. So there are none stem cells that have a very high ability to self-renew. That's the case, for example, of the lymphocyte, and also we know that macrophages, we have macrophages that come from the embryology and that can self-renew during our whole life. There are also none stem cells that have a broad differentiation ability. It's the case in the blood of the monocyte that can really give rise to... So monocyte are innate immune cells, quite functional, but they can also differentiate into a broad range of cell type. So the easy answer to this is okay, but the stem cells, there are the cells that combine the two properties, the ability to self-renew and to differentiate, but the problem is that this definition comes with a number of counter-examples. So for example, you have stem cells in the adult organism that have a high self-renewal ability, but a very low potential for differentiation. It's the case of the muscle, for example, the muscle stem cells, they can only give rise to muscle cells, so they are unipotent, no more potential for differentiation. Then conversely, you have cells that have a broad differentiation potential, but a very low self-renewal potential. It's the case of the stem cells in the embryo. So the first 30-potent cells, it's for the first two divisions, and then the pre-potency stage is very short in the embryo. If you remove the cells from the embryo, you can keep them in culture, but in the embryo, the pre-potency is really very transitory. But you could say we could also consider that these cells are not really stem cells, and we should only call stem cells the cells that do have these two properties. That's a possibility for me. It's a scientific question. Scientific committee has to agree on what cells they want to call stem cells. But even if you do this choice, it's not that simple. Because in fact, if you look at each stem cell in a population, so I'll take the example of the hematopoietic system, so the blood. In the blood, the hematopoietic stem cells are conceived as a model for stem cells because they have a very broad potential for differentiation, and they can give rise to a high number of differentiated cells in your blood, and they can maintain through your life. So in that, broadly, they do meet the definitions. They are able to long-term self-renew and have a broad differentiation potential. But if you look at each hematopoietic stem cell individually, what seems to be the case is that in fact, they really vary each of the stem cells in their ability to self-renew and differentiate. So there has been a few recent technologies that allow to put a barcode in each of the hematopoietic stem cells. So you put the barcode in your cells, you look at what they can do, you look at the differentiation, and then once they have differentiated, you can see the barcode, so you know which cells have done what kind of differentiation. And what the data show is that some of the hematopoietic stem cells will give rise to all the blood cell type. So there are really high differentiation potential, and others will give rise to only megatario cells, for example, or only infocytes, so a much smaller potential for differentiation. So each individual stem cell actually show different ability for differentiation. And with regard to self-renew, self-renewals are also data indicating that in fact some stem cells might not divide or divide very few times during the life of an organism. There is a mice model in which they observe that cells, hematopoietic stem cells might in fact divide on me four times before their enter senescence. So I mean, so they are supposedly defined by this ability for long-term self-renewal when in fact that might be only four division. So the ways self-renewal and differentiation properties defines stem cells is really messy and complicated in practice. And this does have some important consequences. I'm not going to enter the detail, but it's important to know how many of the cells actually can self-renew on the long-term and give rise to the differentiated cells for topics such as plenalevolution or the evolution of somatic cells because if the number of stem cells is small, then you can have neutral drift in your population and so you will have expansion of some cells by merchants when this type of chronal expansion is usually perceived as a sign that there is a natural selection in your population. So understanding better the real number of stem cells is really an important issue. The last main characteristic is this idea that differentiation is a one-way street. This has a long history, so this concept of stem cells, it's not a new concept, has been there since the end of the 19th century and there is a high weight of this idea that differentiation can only go one way. But there has been data suggesting that in fact this differentiation might reverse. The first data that suggested that differentiation is reversible came from cloning and induced repotent stem cells. So both are technologies that consist in taking differentiated cells and reprogramming it into a pluripotent stem cell. John Gordon was the first scientist who was able to reprogram differentiated cells. It was in the 1960s, if I'm not wrong, and the induced repotent stem cell technologies much more recent, the first paper was in 2006. Both techniques, they show that the differentiated cells can return to a stem cell state. But both are in vitro technologies, so it shows that differentiation isn't irreversible, but it doesn't tell us if, in nature, it ever reverses. So one first question is, do we have clues about whether in an organism a non-stem cell can return to a stem cell state? So in plants, it has been acknowledged for a long time that, in fact, non-stem cells can return to a stem cell state and that's how you can, I don't know in English, butchery a new... Craft? Craft, yeah. So that's how growth is made possible. But you know, plants like a biology of animals don't care that much about the biology of plants, so they didn't see in that fact any lessons for the biology of the organisms. But studies of organisms that are able to regenerate, like this axolotl, so when you cut one of the limbs, what happens is that there is this little bloodstain that is produced, and there is this differentiation of the cells that are located there. So it produces a new pool of stem cells from which the limb is regenerated. And there are a number of organisms that can regenerate either numbers or tissues in which there is this first stage of differentiation and production of this blastema. But again, this is in organisms that are able to regrow a limb or tissue to regenerate a piece of the organism, which we, for example, can't do. So one question is, is it restricted, this de-differentiation to these organisms that have this very specific regeneration ability? Or is it something that can happen also in other organisms? And more recently, there has been a number of studies showing that even in mammals, we can have some instances of de-differentiation, in particular in epithelial tissues. So for example, the colon or the skin, when you lose your stem cells because of a particular injury, non-stem cells can recreate a pool of stem cells in those tissues. And what the literature is really the most abundant is in the case of cancer, where there are a lot of data suggesting that cells can move toward a non-stem cell state to a stem cell state and vice versa. So now we have data indicating that in fact, it's not true that de-differentiation is only one-way street. There are instances where a non-stem cell can return to a stem cell state. So the next question, of course, is how does that work? And here I show you an example that is really, I think, interesting and well described. So it's in the germline of the drosophila, but since it has been also shown in the mice. So it's a cut of the germline of the drosophila. Here you have the niche cells, here are the germline stem cells, and then they differentiate this way. What the experiment shows is that if you kill this germline stem cells, but leave the niche intact, what is happening is that the cells that are differentiating move back into the niche, and when they are in the niche, they re-acquire this stem cell property. So in this instance, it seems that the niche play a very important role on the fact that the cell is or isn't a stem cell. So on this topic, I need to make a distinction, a clarification of what exactly the stem cell niche is, and there are today, I think, two views that needs to be distinguished. So the most traditional view of the stem cell niche is simply the idea that stem cells are located in specific environments, and that matters. This environment where the stem cells are is actually sending a number of signals that change the behavior of the stem cells. So basically, the idea, so again, a traditional model of this way of working is the blood, so the hematobiotic stem cells are located in specific environments in your bone marrow. The bone marrow is sending some signal. Depending on the signal, the cell will self-remove or differentiate, divide or stay constant. So in this view, which is the dominant view, a cell is either a stem cell or not. If it is a stem cell, then what it does depends on the signal sent from the niche. Historically, the first time this notion of niche was introduced to stem cell biology, it was by Ray Scofield at the end of the 70s. The idea was slightly different. So Scofield idea was a stem cell is a stem cell as long as it is in the niche. As soon as the stem cell leaves the niche, it's not a stem cell anymore. That's the first idea, and the second one is any cells that would return to a niche, would re-acquire this stem-ness property. So in this view, stem-ness is really not just the property of a cell, but instead rather the property of a complex, the cell plus its micro-environment. So this is both a different view of what the stem cell is and also a different view of what the niche is. Because in this case, niche is not just able to regulate the property that is already there. The niche is able to induce stem-ness in the cells. So at the time, he had no data to support his view, so it didn't really work in the scientific community and we ended up with this view instead. But the germline, also the example that I showed you is data suggesting that this view can also apply because in this germline example, the non-stem cells, when they return to the niche, they do return to a stem cell state exactly as suggested in this niche model. So that shows that de-differentiation can occur through the role of this micro-environment or niche. But the question is, is it the case that for all the instances of de-differentiation, it's always the niche that induces this stem-ness property? There are data that suggests that it can also occur without any specific micro-environment. So this is a breast cancer germline experiment. What they did is that they took two breast cancer cell lines. In this breast cancer cell line, you have three types of cells. You have the stem cells and you have two differentiated types of cells which are called basal cell and luminal cells. They sorted out these three populations. They put them in culture. So it means that your stem cells are all in the same environment. The basal cells are together all in the same environment and some are the luminal cells. They let the cell grow and what they observe is a return to equilibrium. It's easier to see here. So each of the separated cell populations was able to return to the initial equilibrium. That was expected from the stem cells since they can self-renew and differentiate but it was much less expected for the basal cell and luminal cells which are differentiated cells. So this experiment what it suggests is that none stem cells here were able to return to a stem cell state independently of a specific micro-environment because here all the cells they are in the same micro-environment. So which one become a stem cell is not dictated by the fact that it is in a specific micro-environment. So really the question what is a stem cell as you can see is a question that is still open and debated in the scientific literature. There are data that really question the traditional view in which stem cell was perceived by the scientist. So from this scientific debate I want to try to provide an answer using philosophy and for that I'm going to change a little bit the question so in the scientific community the debate is about what stem cells are what I'm going to do is focus on what kind of property stemness is stemness being the property that define stem cells. The reason for that is that in philosophy we have this tradition of working on what properties are so I can use this tradition in order to better understand with the data that we have what seems to be this stemness property. So the idea is really to apply these tools to the scientific literature. First thing I need to say is that already in the scientific literature there is a debate that I will qualify as quite philosophical in nature so because of all the data that we have shown before some scientists started to question the way we perceive stem cells and this debate is always from the same way as a dichotomy so the idea is previously we conceive stem cells as a cell type or an entity of nature even more philosophical and instead we were wrong we should conceive stem cells as referring to a cell state a function or a nurture so I think that already this is showing that the scientific community is really asking a strong ontological question with regard to what are stem cells are really. Now the problem with these debates is really great that this debate is occurring but it are two issues I think with it the first one is that everything is crammed as if there was only one answer to the question so basically here we thought it was a cell type we were wrong in fact it's a cell state I'm going to argue that both might be possible in different stem cells that's the first issue and the second issue is that in these debates they tend to conflate that I think we need to be distinguished and I'm going to try to illustrate why so the first question is whether stemness can be acquired by non stem cells so in a more philosophical term whether stemness is a constitutive property of the stem cells or whether it can be acquired by non stem cells and the second question is whether the microenvironments play a determinant role in the fact that a cell act as a stem cell which provides two possibilities either stemness is a niche dependent or a niche independent properties so two simple biological questions that you can in theory at least address experimentally and two questions with two answers if you cross it gives you four answers and where it's really nice is that each of these four possibilities can be described quite precisely philosophical so I'm going to just explain that so the first possibility is that stemness is a categorical property so a property that is constitutive and independent of anything outside the entities themselves but classical example of a categorical property would be atomic structure of the elements with the idea that each of the elements of the same kind have the same atomic structure and each element that have the same atomic structure are of the same kind and in stem cell biology this is really the way stemness has been conceived traditionally so only the stem cells are stem cells so it's a constitutive property and in this framework there is no mention of the role of the environment in which the cells are so traditionally the stem cells has been conceived as a categorical property so the stemness has been conceived as a categorical property currently I have to say in the normal tissue I see no convincing example of tissue in which stemness is a categorical property but I'll show later in the talk that there are examples of this in the context of cancer for example the second possibility is stemness as a dispositional property so dispositional property are also constitutive property but one that depends on extrinsic environment so for example a typical example of dispositional property is fragility some stuff are fragile others are not the object but the fact that a fragile object will break that does not depend on the object itself it requires a shock so something from the outside and a good scientific example of stemness being a dispositional property is in the hematopoietic system so the blood because in the blood we have data indicating and we transplant that to an individual who will never give you the constitution of the hematopoietic system so it seems that there is no return possible in the hematopoietic system so stemness is really a constitutive property only the hematopoietic stem cells can act as stem cells but that property is highly regulated by the niche in which the stem cells are the third possibility is stemness as a relational property relational property this time is non constitutive so it's a property that can be acquired and acquisition really depends on the relationship so an example could be a brother being a brother or sister you can't have this property if you don't have a brother or sister in the case of stem cells a good biological example of stemness as being a relational property would be this germline example that I showed you because in this example stemness can be acquired in case they are lost non stem cells return to the niche and they acquire stemness and this acquisition really depends on the relationship between the stem cell and its niche and the third fourth possibility is stemness as a systemic property so what I call systemic property is a property that depends that is also acquirable but that depends that is regulated at the level of the whole system and for that the best example really is agent smithing matrix so I hope you have all seen matrix movies I'll give another example this is the best one so in matrix movies what matters is that agent smithing somewhere but it doesn't matter which human is taking the role of this agent and if you kill the agent you don't really kill the agent you kill the human that was the agent at that time but the agents can become any other human so really the function is maintained but the entity who is doing the job can be replaced so if you haven't seen matrix it's a little bit complicated to explain the movie but another example would be soccer or collective sport I know better about soccer so in soccer you have your system and that comes with each player having a specific function your team is not going to do well if the player is not doing what they are supposed to do so for example your goalkeeper has the function of avoiding from crossing the goal line now which is the goalkeeper gets hurt you can still change replacing by another player so the entity can be replaced what matters is that the function is maintained I like a little bit replace the soccer example because the function is associated with a specific location and that is not good in the analogy but otherwise the idea is that different entities in the system can do the function what matters is that someone is doing the job and a good biological example of stemness as a systemic property is this Brescon-Sarcell line that I have showed you because in this case it seems that any cells can act as a stem cells and that can be changed so in this paper there are hypotheses for what is going on here is the hypothesis that in fact there is stochastic gene expression so stochastically a certain amount of your cells are going to express these stem cell genes and act as a stem cells but there are other possible hypotheses it could be it's something like in the ant population where the different ants can be a worker or a soldier or I don't remember what it depends on the pheromone level which is produced by the entire colony so you have pherotypic properties that is really regulated at the level of the whole population it could be the way that all the cells are producing some kind of cytokines so at the level of the whole system this cytokine production will induce some of the cells being stem cells it's really difficult to survive the two hypothesis but in both instances I would say stemness is a system property in the sense that any cells can be stem cells and you can only understand what is going on and study it as a rule so the first conclusion for me is to see that stemness can be different type of properties that can be philosophically described and there is not one answer to what stem cells are because different type of stem cells can be of different ontology so now the question for me is whether this matters so again I really believe there is many ways of doing philosophy and it's up to even one to decide what they want so I like this joke on the internet about a guy who is dying so she asked for a doctor and he's saying he's a doctor but in philosophy and she said that he is dying and he asked but did he ever live and I found it quite funny really it's I do think that it does matter to ask whether we live before we die it's just it's really not going to be helpful in this instance and so for me it's really important to see that I'm really not doing that at the moment and that the philosophical analysis that I'm doing is actually helping the saints so I'm going to illustrate why I think this philosophical analysis really matters for scientists and I'm going to illustrate that with the case of the cancer so cancer is a now there are evidence that in cancer you have a similar organization than in your normal tissue so basically you would have some of your cancer cells that are cancer stem cells meaning they can self-renew so they maintain this pool of cancer stem cells and they can differentiate to produce all the other cells that constitute the tumor since we had the first experimental observation validation of this model in the late 1990 and after that there was data showing that this model would apply to a number of cancer so the idea is inside your cancer cells there are two types of cells the one that can self-renew and produce the other and everything else is just notable to maintain by themselves and this model really changed the way we thought about cancer treatment because currently what cancer treatment does is killing as much cancer cell as possible so that's even the way that the treatment are assessed for their efficiency the drug is efficient if it can remove as much cancer cell as possible but really what the cancer stem cell model suggests is we don't care about all these cancer cells if they aren't stem cells so really the issue here is that a minority of your cancer cells actually matter and this minority can be very good at escaping to the treatment cancer stem cells have several properties that can endose them with a higher ability to resist to treatment one is they have a drug effects pump so basically when they receive the drugs they can just push it out of the cell and they also can stay cohescent chemotherapy works a lot on dividing cells so if they don't divide they escape the treatment and only a few cancer stem cells that would be able to resist to your treatment will be sufficient to relapse today in oncology is that we have treatments that seems to be efficient and we have relapsed that can't be really anticipated because the number of resisting cells so low that you can't actually see if you have any in your patient and this is the cancer stem cell model so it first gave an explanation of what is going on with this late relapse and it also provides a suggestion on how to do better so the idea is really we don't care about the cancer cell in general what matters is really the cancer stem cells as they are at the roots of the disease so in theory you could be able to just target these cancer stem cells then everything else is just going to disappear with time because the other cancer cells don't have this self renewal ability and it's a big change so first it says we have to target specifically these cells but it also a bit change with regard to how we evaluate the efficiency of a drug because here you are going to have your drug doing nothing at first if the cancer stem cell population is small you won't see any impact of your treatment when they kill the cancer stem cell because you will have still the mass of cancer cells so that would need to revise the way we think about the treatment but also the evaluation of drug efficiencies so now this idea of targeting the cancer stem cells is strongly associated with a presupposition with regard to what stemness is goes here stemness has to be an inclusive constitutive property these are categorical dispositional if it is constitutive then you kill the cancer stem cell and it should be fine because nothing else here can act as a stem cell but now if stemness is for example a relational property then you kill your cancer stem cells fine but the niche is still there so if cancer stem cell return in those niches they might be able to return to a stem cell state which will lead to a relapse and actually recently we have data suggesting that this can happen so I'm going to try to explain that let me know if it's not clear so it's a mice model of colorital cancer so the mice develop colorital cancer then the colorital cancer metastasize everywhere in the mice but in this colorital cancer the cancer stem cells they express this gene called LGR5 so what they did is that they put a suicide gene in the LGR5 promoters so basically what you have is a system in which the LGR5 gene is associated with this little cassette it should give a drug to the mice all the LGR5 cells are going to die I hope to this so you have a system where you can induce at some point in time the death of all your cancer stem cells so what they do is that they let the cancer road and metastasize in the mice then they give the drug so all the cancer stem cells die in the primaritrum or endometastasis and then they look at what is going on and what they see is actually that the cancer non-stem cell return the cancer stem cell state but they do that only in the primaritrum or and not in metastasis suggesting that here the niche of the primaritrum is necessary for this stem cell acquisition so I think it's a very good experimental model because it both shows that stem cells can be a relational property if illustrated it and it also illustrates how this matters in the context of cancer treatment was that clear? now stemness is a systemic property in this case you kill your cancer stem cells and what you will expect is that actually your population will sense the absence of cancer stem cell in some way and this will lead to the prediction of your new pool of stem cell and relapse and actually this breast cancer cell line illustrates this possibility interestingly there is currently since the beginning of the century a lot of scientists are investing time and effort to try to target this cancer stem cell but it's very difficult and part of the community of the scientific community tries instead of targeting the cancer stem cell to target their niche and it's interesting because in the literature it kind of looks like you can either target the cancer stem cell or the niche in any way it will be efficient like it's the same but really targeting the niche rely on a quite different presupposition with regard to what stemness is and here the presupposition is that stemness is a niche dependent property if it is a niche dependent property so either dispositional or relational then if there is no more niche or no more signaling by the niche your cells are not going to be able to act as stem cells and so you should arrive to a culture and of course if stemness is not a niche dependent property then targeting the niche is really unlikely to be efficient so what you see with this example of the cancer stem cell model is that today we have a real question with regard to how we should treat cancer and really it's quite messy to understand what we should do and I think philosophy can help with regard to that so what I have shown is that depending on what type of property stemness will be is you will have different therapies that will vary and have different efficiency and what you can see so I told you there is already this quite philosophical debate about how to understand what stem cells are and I told you I think two is not sufficient what we need is four of you of what stemness is and here you can see why each of the different possibilities have its own consequences with regard to how to treat cancer what you can see here also is that we have a blank spot in the cancer stem cell model with nothing being done in the case where stemness is a system in properties so there is a question here that we may analyze by the scientific community so now the two next question I'm going to be short on this open question I think what this question are is more philosophical question with regard to the very nature of this philosophical analysis so the first question is ok so if stemness can be four different type of property what is the situation is it that each cells is part of one of these categories or is it that one cells can change from one category to another so in the lab in which I'm working it's an experimental lab in hematology so we work on leukemia and the question was in the context of the normal hematopoietic system as I showed you the stem cells is a dispositional property stemness is a dispositional property so in theory you could apply either cancer stem cell targeting or niche targeting and it should be efficient but really the question is can we consider that because stemness is a dispositional property in the normal blood it is also a dispositional property in a leukemia so in a malignant context and in fact so we dig into the literature with Eric Solari with the director of the lab and we find a few examples that are really questioning this influence so the first example is in myeloproliferative neoplasm it's a blood disease in this disease what happens is that the cancer cells really disrupt the bone marrow microenvironment they damage the nerve cells and the stromal cells and this damaging is really really bad for the hematopoietic stem cells because the hematopoietic stem cells rely on their microenvironment but apparently the malignant cells they don't care they live right fine in this disrupted microenvironment so this suggests that in cancer with one example there are other but several examples suggest that during the malignant transformation the cells that are mutated they lose their regulation by the microenvironment so if they lose this regulation it means they are no longer a dispositional property they become a categorical property they don't need any more stimuli from the microenvironment another example is in chronic lymphocytic leukemia it's also a blood cancer and in this blood cancer what has been observed is the expression of the genes really depends on the methylation of the DNA usually you have very pattern of methylation depending on which the gene will be expressed or not in this leukemia what we observe is a stochastic disorder in these methylation patterns and this allows a re-expression of genes that shouldn't be expressed and in particular it can allow the re-expression of stainless genes in this non-sense sense so it's unclear the data there is no functional data suggesting that this re-expression of the stainless genes come with re-expression of stainless function but if it does then stainless here would no longer be a dispositional property but a systemic one it's like the pre-sponsor cell experiment stochastically if the cells are demethylated for the stainless genes for example it's a weird one but I think a fun one so it's in the bovine so bovine have a very specific type of leukemia which is caused by an intracellular parasite so this parasite come into the blood cells in particular the monocyte and macrophages so there are mature cells the parasites come into the mature cells they differentiate these cells and they allow them to provide them the ability to self-renew on the long term so they become able to self-renew forever but as far as the parasite remain in that cells it's quite crazy so in this case stainless would become a relational property because which cell will act as a stem cell in your system will simply depend on whether the cell is infected by this intracellular parasite so here you see data suggest that stemness can change could change in a pathological context it might depend on the type of alteration you have shown genetic alteration or epigenetic alteration or intracellular parasite so depending on what is going on you might have different impact on what stemness really is and so it means it could also change during the progression of the disease indicating that we might have to change the treatment of that so I'm not going to enter the detail of that but those who are just first signal from the literature really questioning whether we can assume that stemness stays the same property in my Lignan context but really the data are not exactly sufficient to conclude so now I'm trying with colleagues to address that experimentally so now the last question it's a very simple question if stemness is for different type of property then the question the first question that occurs is then is there something like stem cells is stem cell a natural kind but is it an artificial hoping and if it is an artificial hoping then maybe we should stop calling all these stem cells and start calling them by different names so that we would better see to what biological entity we are confronted so this is a question that has been addressed in the context of phylogeny so for example we know that ice can be of very different biological nature so we know that for example our camera ice is not the same that the cup ice so ice is a biological entity they all have a lot to see in a way but they are biological entities that are of different nature because it occurs independently several times during evolution so I think one way to addressing the philosophical question of whether stem cells are a natural kind or an artificial hoping is through the phylogenetic analysis of the stem cells so the question is really simple the question is whether this different type of stem cells they have occurred independently during the evolution so the idea so we try to with colleagues so the idea is to reconstruct evolutionary story of stem cells and that could help us start out between different hypotheses so one hypothesis would be there is a common origin of stemness property and then either it evolve into separate entities or it's just the same but they appear differently because of the context the second possibility would be they each are of independent origin so the different categories that I have shown they actually relates to an independent phylogenetic origin and of course the third possibility would be a mix between these possibilities and then depending on what is the phylogeny of stem cells you have a better idea of the nature of these philosophical categories so I come to my conclusion I have shown that stemness can be for different type of property that's a question that can be scientifically addressed you have just to for that you have to see if stemness can be acquired or not in the system and if the niche play a determinant role and I've shown that this philosophical analysis does matter in a practical context I have illustrated that in the case of cancer where cancer stem cells are niche targeting strategies which will really be more or less efficient depending on what stemness is and I think a very important point for me was that stemness identity there is no one answer to the question it should be addressed in each stem cell type with the possibilities that it might change in a pathological context and the most important point for me is a question like what is a stem cell it is really a question if you don't bring together the philosophy, experimental biology and a genetic approach so I have many people to think this has been a collective effort I have worked on that with a lot of scientists and had really good feedback from philosophers and a lot of funding so I would like to send all these people if you want to read more this is my book Thank you very much for this wonderful talk I have a point which is stupid but almost stupid question because it's more it's a very basic understanding question about categorization which I find super interesting but I somewhat fail to really understand the philosophical force you can help me a little bit so of course what I do understand is the fundamental distinction between intrinsic and extrinsic what I'm present having some issues with is the relationship did the other choose some categories so the argument is positional and relational systemic for example the way I understand that relational and systemic are somewhat synonyms you have a whole system that sets the rules for what does what so I wanted to understand that the word of the main distinction but also the formal one I'm somewhat familiar with the distinction between categorical and distributional properties in metaphysics but especially with this positional approach but I wanted to understand a little bit more how you apply it specifically how you conceive of this specifically to your problem so that's actually it's a very very good question so the niche dependent niche independent classification is really not that simple so I guess so one first answer is this categorization is quite pragmatical so the idea for me is what makes the difference between these two and these two is whether there is a niche that you can target for example in the context of concert treatment or that if you want to understand your stem cells do you have to look at where they are or not so for example if you want to understand what is going on in the case where stemness is a relational property you need to have not just the cell for example in the germline example if you just look at the germline you will never understand what is going on you have to take into account the niche cells also whereas in the case of the systemic property there is no niche cells so what you have is really just your population and whatever they are secreting or stuff like that so there might be something like an environment so you could say the cell are secreting all kind of cytokines and that's the environment but it's not really like a physical place that you can target it's not a relationship between two exact cells that you can target so there is nothing like a relationship specific relationship that you can say this is what is going on here or this is what we can target so that's I guess so for example for the categorical disposition I do it's also like if you want for example to transplant a metabolic system you won't just need to put stem cells so you will need stem cells because it's intrinsic but you will need also to have a environment that is able to host your stem cells otherwise it's not going to work so for example in mice usually they first irradiate the mice to remove the blood cells from the microenvironment so that the new cells they transplant can actually find a space in this microenvironment if they don't do that it's very difficult to craft the hematopoietic stem cells whereas if it was a categorical property it wouldn't matter they would just find a spot anywhere and it would work what would be the definition that someone asked me what would be a general definition for a categorical property so categorical is just really intrinsic with no reference to anything outside of the entity and this position is a power inside the entity so in the metaphysics there is a lot of different view about what this position is here the view I take is so this position has categorical basis but the expression of the property will depend on extrinsic factor so this was really great thanks so much this is really cool I wanted to ask about another way you could make it more complicated because I'm sure you've thought about it I'm just interested to hear your thoughts so you've got one sort of diversity here which is varieties of stemness or ways that stemness might manifest itself there's another thing that I'm sure you've probably thought some about another kind of diversity that we're coming to appreciate in the cancer context which is just genetic heterogeneity between the different cells I wonder have you thought yet about sometimes when you kind of start to cross those two different kinds of diversity in these clinical contexts does everything just explode or are there some interesting and cool things that we can say about what happens so thanks for the question so that's a very interesting topic so that's one of my project is actually on that so there are these two models currently in the one is system cell model and another one is the clonal evolution model the clonal evolution model is really the heterogeneity inside the tumor is caused by the accumulation of mutation you have this accumulation will create a diversity, a genetic diversity in your cells and these two models kind of exist independently so one thing I try to do is cross them and see what it does so it has already been done in the scientific literature with regard to stem cells so the idea is that your stem cells they are going to evolve genetically speaking so mutation is occurring in these cells and this mutation will change the property of the stem cells so they can change them, for example by providing them the ability to metastasize but it's a possibility that they could also change what they are like the ontological identity but that's very difficult to analyze some specific mutation will occur through time and then for example stem has become switched from this position categorical so we have one clone where stem cells really depend on the niche and another that will become independent of that niche so that's one first scene, that's how clonal evolution impact stem cells and another is how stem cells impact clonal evolution and here it's I have an extra slide on that so the idea is how many stem cells you have in your population is really going to change the evolution and processes if you have only a few stem cells then the probability that you accumulate mutation in that compartment is really low so if you have the more mutation you might accumulate and those are the mutations that really matter because any mutations that you would have none stem cells they don't matter, they will just die so the clone will just fade away so what matters is really what is occurring on the stem cells so if stem cells are in fewer quantities then you will have less clonal evolution and if stemness is an acquirable property then it's much more flexible it's not just the number of actual stem cells it's also the number of potential stem cells and this will really change both the amount of clonal evolution and also the processes because if this is low then there can be neutral evolution where neutral evolution in this case is not going to change much what is happening I don't know if you can answer oh thanks, that's excellent it's really neat you mentioned stemness genes yeah if we don't agree on what stemness is, oh can you target stem in genes what do you think that stem is genes? so that's a very good question so the short answer is we don't know but so a lot of studies so one problem is stemness properties it's really functional so it means if you want to prove that the cell is a stem cell you have to have self-renew and differentiate so once you've done the experiment and you've shown that the first stem was a stem cell it's lost, right? you've lost the cell because it has divided so that's really problematic because it means any proof of stemness is always retrospective science can't work with that so they try to approximate what are these cells there is two ways to do that look at the cell surface markers but it's also an approximation and look at the gene expression so what has happened is that through time they have seen that they have stem cells for example hematopoietic stem cells tend to have these cell surface markers and when you sequence it they tend to have this and that gene that is over expressed there are also some functional data when you knock out a gene or over express a gene and you see that they can't self-renew anymore or stuff like that so there are a few so there are some genes which we know are involved in the function of the stem cells and some it's just when you look at this approximation of stem cell population you'll see that there are a bunch of genes that are probabilistic highly over expressed or down-regulated in these cells that's so it's an approximation but something like if you are a stem cell there is this cluster of genes that you will most probably express but part of this cluster will be expressed in your cells in terms of mechanisms so for only some of the genes we have data suggesting that they are actually playing a role so like in case where you inhibit all the genes you can take but that's for only a few genes yes thanks a lot Mary it's very cool so it's so comforting to see that we don't teach you to do that and actually contribute to saving lives by taking like this so I'm not sure from cancer so thanks for this but my question was about the prism that I mean the question of prism is the classification of stem cells so this is more like so the question I have is what is what is exactly this plurality so there are two ways I can conceive of it so one way to say we have four concepts of stem cell so there are four ways for something to be a stem cell and there's another way to look at it as a four hypothesis as stem is is because although the four things are exclusive and since that so if I follow correctly so there are data like showing that most of them maybe before them but it looks like all of them are exemplified which tends to see that it has to be sort of like so it pushes toward the classification view if you were looking for hypotheses about stem cells and of course you would have to choose one or the other and those are two different things and the way the classification is constructed it looks like trying to find the right hypothesis because it seems like being a new dependent or being a new dependent or being acquired or being because it seems like a very important hypothesis about stem cells it looks like a substantive question and if things are in different boxes they seem like two completely different things so I feel a tension between having concepts of stem cells and having hypotheses about stem cells so that's an excellent question too and I have no strong answer to make to it so at the moment I don't know so a few comments that I can make is first it looks like it's yes and no question but it really isn't probabilistic we should have a probabilistic understanding of this classification so for example it's not that a cell cannot be against stem cells it's that the question is more what's the probability of the event to occur so you could be in a system where the probability is really low and if it's low enough then you might be able to say I'm just going to ignore that it can happen and there can be situations where the probability is really high in a way that you just can't it doesn't make sense to ignore it so in this so if it is how it works if it's really continuum with a probability that can vary depending on the tissue then it gives you the idea that it's not that ontological the classification and a little bit more epistemic like it's a you would say in fact in this case considering stem cells as a systemic property is the best way to describe what is going on in that system so that's one comment and this question of what is the nature of this classification is also what have driven this phylogenetic approach that is in this phylogeny so for example if we are here then I'll consider that this philosophical analysis is much more ontological so in a way the systems that work differently they have a different biology because it has evolved in different ways so in this way I would say the philosophical characterization is really saying something about a different way for a system to work whether in this instance it can just be that tissues provide different context for stem cells so what we see as being a dispositional property it's just that in that tissue the context never is right for a cell to differentiate for example but maybe if the context was different it could have so that's really the driving notion so I don't know if it is epistemic or ontological for pragmatical perspective it doesn't matter but philosophically I would like to know more about that thank you very much I think the probabilistic way of thinking I think is a completely different outlook and I think it's very helpful to have this contrast instead of just like the dichotomies like the algorithm I have two questions one more related to your comment whether the classification that you propose in somehow can conform the idea of degenerative landscapes of coordinate value to you elaborate on that and the second thing is that the work on stem cells is much more done outside the animal so of the meta cellular organism so to what extent your classification I just contextualized this question then it's similar with your work for instance with immune cells or with immunology normally immunologists take the cells from the animal and they cultivate in the plate so you know that in immunology the theory of conal selection derived just because they were doing experiments in the plate and not in the animal so then you come with this theory that the immune system is kind of a wire not a defend something but then when other kinds of immunologies started to do experiments on the animal they come out with another theory which is the idiotic theory of the immune system which is basically a molecular coherence in the animal and it's not a defensive system so you came with two kind of theories about what is the immune system to how you do experiments so while one group of immunologists are doing experiments on the animal per se and are measuring the antipodes the dynamic of the antipodes autoantipodes and so on the other just isolate the cells and put in the plate and do experiments there and from there they arrive at the earth which is the conal selection theory which is a Darwinist theory to what extent your classification is taking into account the living of the life of the metasemular organism thanks for the question so first question is the epigenetic landscape I think so the epigenetic landscape also favours these views that differentiation is a continuum so with this comes two things first the difficulty in distinguishing stem cells from non-stem cells and the possibility that in fact the past might change and the landscape might change so if you change the landscape maybe the stem cell state will become down and so cells will return to this state so in this way I would say this new framework of the framework is not new the apply of this framework to stem cell biology really comes with this idea that we should conceive stemness as a cell state rather than as a cell entity so in my case I would say that's good but that doesn't really reflect some of the cases so yeah yes no for the second question most of the examples that I have shown they are in the organism so the germline it's really taking into account how the tissue is made what's the structure how it works in the animal so it's really not outside of the animal the experiment has been done in the animal there are many experiments done outside the animal stem cell biology but a lot of them are inside the organism the only exception is the case of the systemic property so for the possibilities of stemness the systemic properties are only experimental data that I have there are others but there are all others at the same time they are all out of the organism but I think it's just that per se you can't if you let them in the organism then how can you know that the location where they are doesn't matter so per se you can't see stemness as a systemic property unless you can extract the cells from their microenvironments but I'd like to have so I'm not sure how you could show it in vivo but it would be interesting and important even to validate that in vivo maybe mark these stem genes with some reporters yeah but so you can mark the genes you can mark the cells but for example you know in this in this experiment so here what they observe is that non-stem cells so they kill all the stem cells no more IGF life stem cells then they wait and they see new stem cells being there and they see that only the primaritumor so that allows me to say the niche is playing a role not suppose that the result was they show the appearance of stemness in both the primaritumor and the metastasis how can you tell whether the cell is a role or not you can't really so that's really the difficulty very good question you said something scientists are asking what stem states are and you as a philosopher you switch to view and do something that has what kind of property what kind of property stemness is is it true and why why scientists do not discuss stemness in a property is it true or is it not just a lot of facility of language that they use this idea of debating stem cells or maybe it's just a wealth they are just releasing it in the property is it that so you mean is it true that they ask a question what stem cells are instead of they don't ask the property so no it's not so it's a mix of all kind of questions related to what stem cells are so so it's just in my case I focus specifically on stemness as a property this is what I try to characterize but it's not true that scientists don't ask what is stemness it's just they ask all kind of stuff and what they want to know what stem cells are in general it's just for me it's like asking the question of the property itself that's what allowed me to use this philosophical tool try to address so that's for me it was the best way to clarify the debate focusing on the property instead of the stem but in a way so reconstruction for instance scientists are often aware that their concept are kind of fuzzy or that they can evolve so they are they are discussing about really entities are in the lab but it's not as a philosopher we have done in theory to to rave to substancelize things to discuss to conceptual issue but they don't care because they have very user management specific questions to solve and they don't go and so we don't have to do projects to much so that that depends really on the concept so for example the concept of cloning, clonal evolution and it's totally different because in this case the concept is very fuzzy and everybody seems to care to be okay with that like there is kind of a consensus of what the clone is in fact nobody use the term the same way but it doesn't seem to matter at all they don't care in the case of the stem cells it's really striking that it is one of the locations where the scientists actually matter so they really are interested in understanding what are stem cells they really feel they don't really understand what stem cells are and it's a problem like when you enter in the stem cell lab and you work in a project on stem cells problems are everywhere you don't know how to sort the cell you don't know what you are supposed to expect there are a lot of issues that are more escalated to the question of stem cells art really so they kind of can't escape the conceptual issue it's really and for that stem cell biology is quite special I think more philosophical than other there are plenty of cases where definition doesn't matter but in this case it does and they know it that's a more general question about the idea of being philosophically in science which are presented here and I think that the tomar project is also pushing and this is quite a so one question I have is how what you are doing is related to ontology because there is this whole field of biological ontology which is something that is done by people so it looks very philosophical in the sense that people would like to make very subtle distinctions among entities in a way as you can see of classification and I think I see some things that look like ontology and so I wanted to know how it is related to the work that people do in ontology and also I don't know I'm curious about whether you could say more about how to do philosophy in science as opposed to philosophy of science or maybe not so two very different questions so with regard to ontology there is no relationship as far as I can tell so maybe I'll see some relations at some point but for now so ontologies are a really hierarchical organization of the knowledge I don't really relate to what I do but maybe that's just because I'm too much of an ignorant with regard to these questions so I'm open to I just saw paper on stem cell ontologies where they make a lot of fine-grained distinctions which is obviously part of me where I'm very sophisticated classification with processes, entities so it seems to be related but from a very external point of view I should look at that if you can send me I'll be happy to look at that for now the only way I would like to ontology is when I do analysis otherwise as a philosopher I didn't find any grasp on this so with regard to your second question it's really difficult I mean it's so I think philosophy is kind of a landscape and you can find all kind of good question and all kind of good answer to the question so it really depends the way you are going to do philosophy it both depends on the landscape of the topic you have chosen in some instances and I would say stem cell is one of them you can't just do good philosophy if you don't know what a stem cell is I think it's I can't see how you can do something useful without knowing what a stem cell is there are other cases where you need to know less about the detail of the science and you can do very good philosophy so those are different landscape and then it also really depends on what you want to do as a philosopher so I'm crazy with this thing I want to be useful I want to be useful to the science and not just publish other philosophy papers that maybe one philosopher would read maybe not so that's personal that's personal goal I want to put one more brick in the science world or something like that and I have this conviction that philosophy can also bring something to the science so I want to do that and the fact that I want to do that is determining in many ways what I'm going to actually do and how I'm going to do it so it did push me to work in the lab because that's how you can follow how the science grows and develops and where are the questions it allows you to see what are the questions where you can be useful but then once you are in the lab there are these tools so you have a question and then you can address it so you start also doing some biology so it becomes very a mix so the last part of my talk where stuff that I want to address so it's a philosophical question I want to better understand my own philosophical work but then to understand that the tools are going to be phylogeny so it starts to be really a mix between these tools and for me to really I would say it doesn't matter that much how you call it and what are the boundaries of the disciplines it's just what is the question what is the driving question and with what you know how can you help but you can also learn what kind of ways so a ton of time people say but how is that philosophy and so when I do experimental biology or bioinformatic analysis how is that a philosophical job and I should leave that to the scientists but I think it's like when I speak English everybody knows I'm a French when I do experimental biology everybody knows I'm a philosopher it's like it's a way of addressing the issues the type of question you do the light you use it's just come from the fact that I learned philosophy instead of something else but it's difficult to really define that and I think it's really personal and everybody should feel free to find its own paths yes I have a question so maybe it's a bit naive I don't know but in the physics and the decision but this distinction that you made between between this position and the body it seems intuitively from outside that sometimes the distinction is more because we don't know the internal structures so it's more the internal structure of something is dispositional because we need something from outside to have an effect but in fact it's something internal that we still haven't discovered something that is there that it wouldn't be dispositional but categorical in that case and I was wondering whether whether this could be the case also in your talk if or whether there is a mean distinction between the two and there is no way in which one can be reduced to the other that's a good question so I would say again an important point with the classification I've made is that it's very pragmatic so I feel confident with my with my categorization because of the consequences in fact it should be better use that slide so I feel confident with that is this categorization because I know that if stemness according to my criteria appears as a categorical property I can anticipate that any targeting is not going to work and cancer stem cell targeting is going to work and that can be tested scientifically now whether it is how the word appear or how it is really is a question I can't answer but in a way it doesn't matter because I can still work with that level of approximation in some way okay so whether if I have a categorization with the physicians who say well in fact this positional is just categorical but with some ignorance it wouldn't affect what you want to say because I think the consequences exactly but then the science might progress and we might see that in fact there is I don't know what element that I didn't see so for example in the systemic possibility I said there is too possible interpretation of the data I have shown maybe at some point it will become crucial to distinguish the two possibilities for example if we are able so if you suppose it is some kind of cytokine production that plays the role of something like the pheromone suppose it is that and you can find which cytokines are involved then you can target that whether if it is stochastic gene expression you can't target this or not that the fact that that is stochastic so the approach will have to be different so for now I keep it as one category because we can't sort between the two hypotheses but the day we will become able to do it that might need some rewiring of the so yes knowledge of the science will possibly impact the classification just not currently but it could I have to ask I should have sort of thought of that but we have this project on algorithm that's why and I was organizing just very beginning how could we apply that knowledge your four categories to not to come to treatment not to differentiate to therapies but for instance to differentiate and to kind of organize could we do something like that so for instance if stem less is a categorical property then I can take a stem cell and turn it into an algorithm if stem less is a relational property I can take any cell which may not be a stem cell that's made in ego it's in somewhere and so on and put it in the right matrix and put it in signals and turn it into an algorithm could we use your framework to do something like you do for for cancer therapies could we do something like that and you think really like you and me every second of that before can we try to elaborate something for instance because it's a very different categorized for instance or to typology the first thing you see or to go back to discuss what kind of what kind of what kind of what kind of cells are in development so I think you actually answered your own question so in a way I can't move much better than anticipating what is what are the conditions in which an algorithm could go so if it is categorical or dispositional you won't be able to run an algorithm unless you put some stem cell in it if it is a relational system if you could it doesn't really matter if they are already stem cells if it is dispositional or relational it won't grow unless they have the proper factor in the environment so in this way you can see that the failure efficiency of producing organoids will depend on what stemness is and what you put in your experimental system now how this is useful and clear on that because we would have to look at what are the systems that are failing to do organoids and in this case is it because stemness is not taken into account the proper way but I don't know if this is how much of an issue this is like without a dish in which we can go organoids and does it relate to this I think it isn't sure because one of the very fast developing industries organoids technologies there are subgroups and for some organoids is very quickly you know that interesting is the most common types of organoids in which scientists are working on fronky effects maybe two-thirds of organoids in the world are interested in organoids but of course there are attempts to develop organoids of all types of organoids and so it is not the same of course not the same rate of success so would that be because we could but I don't know enough of the difficulties in generating organoids in other systems and in this scene where it looks to work quite efficiently and that might be because the cells that are put into that are used to generate organoids contain niche cells because on the other side they can also act as a niche for the stem cells how much it is because they found the right matrigel or don't remember what they used that is yeah I don't know enough to say something more implicit on that when part of the narrative of organoids technology they didn't know that it was very because at the end nobody tried to stem cells in the matrigel and once you put it in the matrigel it exploded and you just act as a good matrix and the matrix was existing 50 years before but we really did that and there was also the idea that there are organoids that self are organising this is one of the criteria to contrast organoids with organoids with organoids that are self-organising entities and in many cases you see these observing organoids as natural organoids it's not like in biotechnology that we are doing something that we can observe so if we have something that we can observe that we just see developing in front of us then we want to classify this and then we want to use something like that so one organoid scientist used this in a specific way I can't remember what organoids is working on and the claim was something like it's been a long time since I have not written this paper but the claim was something like stepnes seems to be a dispositional property if we can assume that it is the case then we should be able the best way to draw organoids is this way something of the kind so there is one example where scientists have used the framework to better understand how to make it efficient this is a good another way you don't have a question on the chat or something no I have three different thank yous come in over the chat for a wonderful and clear talk but nobody have any questions there is a part of the interview that I don't think I can answer the other part is the part where you were discussing how to make a vegetal image and all that you have published both of animal biology rather than the vegetal biology so no in any case I didn't want to do it so the idea is in vegetal biology the idea that the property can be acquired is an idea that is very well perceived and that doesn't cause any problems so we could just say with time, scientists maybe that can also happen in animal biology that's not true nobody said that what happened in plants could also happen in animal biology that's a fairly general phenomenon in animal biology so don't consider that something real in plants can be real in animal biology in this case it's a bit of a shame not to ask the question because we learned 50 years later on a phenomenon that was already well understood in plants but the idea is not on the classification that I made I made it on the reading of about 2,000 papers that was on all possible species all possible species without restrictions so the idea is that it really can be applied to all species in all species