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Intro: We are in a field that is booming now with a new discovery every week or month, with new knowledge, with new model system, with new technology, and so on. And that's super exciting because we have really the thing that we are the forefront of this new wave of discovery. And it's very exciting to see that we can really have an impact and all the projects we develop are part of this, this massive progress. AskDifferent, the podcast by the Einstein Foundation. 

Doris Hellpoldt: Hello, my name is Doris Hellpoldt. Welcome to this episode of AskDifferent. If you're into Greek mythology, you might know that Prometheus was punished in a pretty harsh way by the god Zeus for bringing fire to humankind. Tied to a mountain, he was supposedly being attacked every day by an eagle who fed on his liver, which then always grew back by the next day. A tiny part of that myth is, in fact, medical reality. The human liver can indeed grow back when a part of it has been removed. A lot of patients with acute or chronic liver failure rely on that very fact as they wait for or are lucky enough to receive a liver transplant because in some cases a diseased or damaged liver can actually be replaced by a portion of a healthy liver from another person. However, some people need whole liver transplants and generally, the number of people waiting for liver donations is far higher than the actual number of available transplant livers. The Central Institute for Public Health in Germany or Bundesinstitut fur Öffentliche Gesundheit, for example, regularly publishes statistics for organ donations. And according to their website in 2022, there were about 750 liver transplants in Germany. And at the same time, there were some 840 people on the waiting list for a liver donation. So clearly there is a need for solutions for patients who might otherwise not survive or at least be severely impacted in their quality of life. 

This is exactly where the research of today's guest on the podcast could potentially play a vital role in improving the situation for such patients. Ludovic Vallier and his team at the Berlin Institute of Health are working, among other things, on something called organoids grown from stem cells, which might hopefully lead to viable treatments and therapies in the near future. Thank you for being with us today and a very warm welcome to you, Ludovic Vallier.

Ludovic Vallier: Thank you. Thank you for this nice introduction and thank you also for giving me the opportunity to present the work of my group today on the podcast. And, hello to everybody. 

Hellpoldt: You started working in Berlin three years ago following an invitation by the Berlin Institute of Health at the Charité for an Einstein Strategic Professorship, specifically to research stem cell use in regenerative therapies. And most recently before that, you were based at the University of Cambridge doing similar research at the Cambridge Stem Cell Institute. So I think it's more than fair to call you an expert in that field. Also, excitingly, at the end of last year, you've been awarded an ERC Advanced Grant by the European Research Council, which comes with €2,5 Mio over a five-year period. Congratulations. As far as I understand, it's been the third time you got this award, which is, I guess, a rare privilege and shows how much interest and importance is placed in the kind of research work you do. What exactly are you going to use these funds for over the next few years?

Vallier: So, yes. As you mentioned, we're looking at the liver and how the liver can regenerate. Like the Prometheus legend, we know that the liver can repair itself very efficiently, especially in acute injury. Now if you cut the liver, you can cut two thirds of the liver and it will regrow in a few weeks in humans. That's actually the frontline treatment for liver cancer, that you should resect part of the liver that contain tumor and the liver of the patient recover. So we know it works in acute injury, but it's more complicated in chronic liver disease that represents by far the highest number of patients and especially diseases that are affecting the liver over a very long period of time. And in this case, we don't know exactly what are the mechanisms of regeneration and if the liver can really repair itself. And so the goal of this grant with ERC is to understand those mechanisms of regeneration in chronic disease and also to understand those mechanisms to promote those mechanisms of regeneration, so to promote the repair of the tissue and why avoiding any problem because we know also that this regeneration mechanism may be also associated with cancer. So we want to promote regeneration and block tumorigenesis at the center. And that's really trying to understand the mechanisms that are beyond this fine balance that we're going to use this funding for and then hopefully develop new treatment that will allow us to promote tissue repair and block liver cancer.

Hellpoldt: Can you give us some examples perhaps of chronic liver disease that you might possibly be addressing at some point in the future? 

Vallier: So the main chronic liver disease we're looking at is called nonalcoholic fatty liver disease or now also muscle leak. It's very clear a disease which is quite common. In fact, it's an accumulation of fat or lipids in the liver and it's often associated with overweight, obesity or diabetes. And in this case, as the liver is the main organ that processes lipids, when you have too much lipids, basically the liver starts to accumulate too much lipid. And 30, 40% of the population in Europe and in the US will have some fatty liver. So it's not a problem, but in some cases this accumulation of fat in the liver becomes toxic. Thus create an injury which takes a lot of time to develop but progressively, you know, go to cirrhosis which means basically liver failure. And we are focusing especially on this disease because there's a booming number of patients that's suffering from NASH or non-alcoholic fatty liver disease. And we're really interested to understand what are the mechanisms for regeneration in the context of the disease and how we can actually stop the progression of the disease and repair the tissue.

Hellpoldt: I find it amazing that liver cells or liver tissue has these properties of regeneration. Is it possible to explain how that works, or is that exactly the kind of research that you also do trying to find out how that happens? 

Vallier: So that's exactly the question we want to ask. Because, I mean, it's funny. As you said, it's known for a long time that the liver can regenerate. And, Prometheus is a legend, but it's known at least from the 1800s that the liver can regenerate. And so far, we don't really know in detail the mechanism that are involved in this regeneration, especially how the cells can reproliferate and regrow the organ, like how the organ regrow. That's really not fully understood, and also how the organ can regrow the same size and the same level of function. And that's really fascinating because in fact the liver is the only organ capable to do that. Of course, if you cut two thirds of your brain, your gut, your kidney, it will not regrow. It's only the liver that can do that. It's been almost two centuries now that we know the liver has this amazing property, but we still don't know the mechanism. And that may be an important message here to give to the audience: that the liver for a long time suffered from negative kind of publicity because one of the leading causes of liver disease is alcohol abuse. And as it's self-infected, for a long time the liver was seen as a bad organ, well not that interesting organ, which means that for a very long period of time the research on liver was underfunded. And that's really created a gap of knowledge, understanding of this mechanism of liver regeneration, and basic biology of the organ. Of course, as I mentioned, it's changing very quickly now because of the emergence of fatty and non-alcoholic fatty liver disease, which is now the predominant cause of hospitalization for liver disease. But for many years, in fact, research has been limited in the liver because of this dogma around alcohol abuse. That's a good example of, you know, where you can see that funding, I mean, public funding is really important to support research. And the gap of treatment we have now on liver disease is coming exactly because of this lack of funding for many years. 

Hellpoldt: That's very interesting, actually, how much the image of a disease can impact the level of funding. But that's not a question we want to address in detail today. As far as I understand, how you go about finding out more about the regenerative properties of liver tissue is that you use actual liver tissue but then try to grow it on in a lab dish to create, like, mini livers. Is that fair to say? 

Vallier: Yeah. So the philosophy in the lab is really to work on human patients. So we generate data from human patients. We access often a liver biopsy, which are basically piece of liver that are taken from patients for diagnostic purposes, and we use part of those biopsy to study cell behavior and to study the disease. And at the same time, we also derive from the same biopsy what we call organoids, which are basically small pieces of tissue that we can grow and expand in a dish in vitro. And that allows us to do molecular analysis that we can't do on patients or other models. And that's really this combination of patient data and organoids model in vitro that allows us to really study mechanisms of disease and to hopefully identify new treatment. 

Hellpoldt: The really interesting thing about the organoids is that, as I understand it, they have 3-D properties as opposed to, like, the kind of research and the kind of cell propagation that has been done in lab dishes maybe in even a few years back. What are the advantages of these organoids and the properties they bring? 

Vallier: The advantages of those system is that you really have a representation of the cell of the organ. Okay? So you take cells directly from the liver of a patient, put that in a dish, and grow it. And they conserve their characteristics in terms of identity, so if it's liver cells, it's the liver cells, but also in terms of disease. So, you know, if there are disease in the patient, they also disease in the dish. That really allows you to have a picture, an instantaneous picture of the tissue of the patient. And that's really unique because all the other systems we have are either based on cells that are transformed, so tumor cells that are not natural cell type at the end, or cells that are generated from human proven stem cells that are not fully functional or at least are not such a precise picture of the of the tissue of the patient. 

Hellpoldt: So you essentially retain the actual qualities of a liver cell or a diseased liver cell so they don't change or turn into a more general type of cell, they stay the same so you can actually repeat the experiments. 

Vallier: They're still very similar. That's the most similar model we can have from in vitro. Of course, they're not identical because they are not the tissue itself from the patient. There's nothing that will ever be a liver that is in a human being that we can grow in additional simply because of the complexity of the human body, the interconnection with all the other organs is impossible to fully reproduce in the dish. But they are the best model we currently have to really have access to the biology of the organ and the tissue. 

Hellpoldt: If I were to look through a microscope, what would I see if I look at one of your organoids? I probably have this very wrong concept of, like, a tiny lump of meat in a dish. What do they look like? Is it possible to describe it a little bit to us? 

Vallier: Yeah. Yeah. Of course. So they look like, they are sphere. They go as what we call spheroids. Of course, they are extremely small. You need a microscope to look at them. But they look like a football. And they are empty in the middle. They have a lumen, and they have a layer of cells, and they're very long. And or they grow with different size, but, basically, they all have all the same morphology. 

Hellpoldt: And what does it take to create an organoid like that? You use human cell material as a base. And what else does it take? What are the kind of conditions that you need in the lab or in in the dish? Do you need a particular type of source material? 

Vallier: So, of course, what we need is patient material, tissue from the patient, which started the start. And the way we do is to we then cut this piece of tissue in small pieces that we grow in a 3D in a what we call a hydrogel, which is basically a sort of gel. It's like a jelly, where we have the cells that can grow like that in 3D. We feed them with a medium that contain different growth factors, I mean nutrients and so on so that they are happy, they can grow and so on. And then to expand them, what we do is that we collect those organoids, those spheroids. We break them in small pieces, and every small pieces we're going to form a big spheroid. And that's all how we basically grow them. And we can grow them for 15, 20 months with a two-month period.

Hellpoldt: The goal, I imagine, is not necessarily just to grow them and grow them successfully, but also to be able to manipulate them and try things out with them. Because at the end, the goal is to be able to use this kind of research and the results of it for therapy. So do you actually manipulate the cells that you've created in a way to simulate diseases and or use drugs to try and see how they react?

Vallier: So, yeah, we do a lot of different things. We, for example, feed the cells with fat so that they become fat like in a fatty liver. And you can see that they have small lipid vesicles inside them, and so they become very full of this fat vesicle. We can, of course, put some drugs on them. We did a lot of work on COVID-19 at some stage also because those organoids can be very easily affected with the SARS CoV-2 virus from COVID-19, and we have no developed drug against SARS CoV-2 using those cells. We can do genome editing, so we can do genetic modification on those cells. And for example, what we're trying to do now is to induce mutation in LC cells, so cells from, don't know, that is LC. And we're inducing mutation to see if we can likely induce cancer in those cells by reproducing mutations that are supposedly known to induce liver cancer. That allows us to determine the function of all those mutations in the process of tumorigenesis. And so we're doing a genetic screen, we're doing a lot of different things on the on the cells. In fact, you can do almost so many things as long as you are in vitro. It's an amazing source of experimental manipulation for sure. 

Hellpoldt: What are the most, for you, the most exciting directions your research is taking or the most promising ones? Or is it all important as a groundwork for future research? 

Vallier: So, I mean, no. It's very difficult to say because all the projects that we do in the lab are exciting. Otherwise, we're not be doing them. So it's very difficult to give you a favorite one. I think what is very exciting for us, I think, is that as I told you, the liver field for a long time was a bit behind in terms of progress and especially in terms of knowledge and so on. That's changing very fast. So we are in a field that is booming now with a new discovery every week or month with new knowledge, with new model system, with new technology, and so on. And that's super exciting because we have really the thing that we are at the forefront of this new wave of discovery. And it's very exciting to see that we can really have an impact and all the projects we develop are part of this, this massive progress. And so, all the work we do on liver regeneration, developmental biology on cell based therapy. It's for us, it's super exciting because it's really topical right now, you know. I think we are really lucky because we're at the right time, right place to do this kind of work. 

Hellpoldt: It's not possible probably for many years to stick one of your organoids or, like, a bigger version of it into somebody, in a patient and expect it to fix their disease. What kind of timeframe are we talking about? Is it like, if you're a gardener, you won't be able to see a tree that you plant now in its finished state, like a hundred years later. How confident are you that you will see the results of your work being actually used in therapies to treat patients?

Vallier: We don't need to go for cell-based therapy to see an application. The model we have developed in the past are used now for drug screening in non-pharmaceutical companies and others and to validate drugs, to validate target for drug development and so on, and to validate the therapy. So we already can see some level of application of the work we have been doing. Of course now the direct impact on patients is a key objective and that's really something we'd like to achieve. So it's always difficult to give you a timeline because we don't control the timeline. I think we need to be very clear on that. We're not deciding, we're not the people that decide when those cells will go into patients. There's a lot of aspects that are not directly controlled by us. We already just know we need money, we need funding, we need all these kind of things to be able to do that, and that takes time, that's taking a lot of resources, and we're not the one that decide to invest in all that. That means that there's a whole process that need to be achieved. We have now several programs, and some of them are already progressing to other clinics. And the hope now is that, at least for some of those projects, we could know five, ten years of the first clinical trial. It's important to see that now there's a clear, the goal here is to have a clear balance between risk and benefit and that also will determine which disease, which patient, which type of therapy will be applying first. That's really a key goal, and we are working now very hard towards this objective. 

Hellpoldt: How patient do you need to be as a scientist to do that kind of work and know that it's probably gonna take a long time, or also more research possibly done by other people to actually come into effect at some point?

Vallier: I mean, that's a very important question. What drives basically scientists is, you know, of course, to see the work that we're doing into patient, but all day-to-day satisfaction is based on the data we generate in the lab and the knowledge we generate from our data. And all the new technology, the new understanding of basic mechanisms, and so on. Of course, we are super excited, but no, we're not hanging on only on the clinical development because otherwise it would be very frustrating and we'll become very desperate. So no. It's a key objective for us. That's really the final objective of our work. But all satisfaction in the lab now is the day-to-day work in the lab, the new discovery, the new technology, the data we generate, the new understanding is really our primary objective. 

Hellpoldt: Usually, the nonscientist public only hear about the successes, of course, the big leaps and innovations in a research field. But surely, there must be a lot of setbacks as well or failed attempts to even get to a stage where you can see research results being made use of in a practical way or in a way that furthers the research. How do you deal with that kind of discrepancy? 

Vallier: Well, first, it's true that, you know, the general public will hear only 0.001% of what is discovered in labs. Because a lot of things that are found in labs never reach the general public. Resilience is a key part of our job. No. It's, we are researchers. So that's been that we research. We don't find every day. That's clear. So that's really part of, you know, all training and, of course, one of our qualities that we need to be capable to accept that things won't work, that we won't find what we want, and that we need to spend a lot of time, energy in sometime just redoing things for them to be to work better. And that's really part of our job, and I think I don't know any researcher that will not be very good at managing this frustration. 

Hellpoldt: Apart from having to be patient and being able to manage frustrating situations, what would you say is the biggest challenge you face in your work? 

Vallier: I would say I would like really to have more time to focus on science. That's something that I know. That's for me personally, that's one of the limitations that I have a lot of administrative constraints and other that really block me to spend more time at, you know, reading papers, discussing with my team, doing research directly. And that's probably one of the major limitations when you become a bit more senior as I am, that you just have less time to think and to reflect on science. 

Hellpoldt: If you go into work, like, every day, do you have, like, a vision of what you want to end up achieving? Do you have a scientific result in mind? What keeps you going ultimately? 

Vallier: Oh, you know, it’s discovery. It's seeing new results in the lab. Even a tiny thing, you know, it's a new graph, a new study, a new mechanism. That's what really drives us. Well, I'm also really happy and excited when we can get to publish our data and that we can show to the field that we are making progress and share the knowledge and demonstrate that we have generated knowledge. Working with my team also, that's something that we are able to have the intellectual challenge and intellectual interaction, with my group is really something that I really enjoy. Promoting the new generation also, helping them to achieve their objective and their core objective. That's something that is also something that is a strong motivation for me. And, yeah, at the end, though, is doing research. Now that's the key and with all the different aspects that it entails. 

Hellpoldt: I'm sure you're not gonna run out of either ideas or material to do more research on. It's a very positive outlook there coming from Ludovic Vallier. He has been our guest on this episode of AskDifferent, the podcast by the Einstein Foundation. He and his team are, among other things, doing research on liver organoids, hoping to sometime in the future be able to derive treatments and possibly an alternative to organ transplantation as it is done now from this very work. Thank you so much for your time and for being with us today and giving us some insights into this very big and very exciting field of research. Thank you so much.

Vallier: Thank you for the opportunity. 

Hellpoldt: You've been listening to AskDifferent, the podcast by the Einstein Foundation, where we speak to scientists and researchers in inspiring and exciting fields about their work and their findings. And you'll find us wherever you get your podcasts from. Do subscribe if you haven't already. My name is Doris Hellpoldt. Once again, thank you for listening, and until next time. 

AskDifferent, the podcast by the Einstein Foundation.