E57: RV Short Medal with Dr. David Pepin

In this episode of the Future Conceived podcast, Dr. David Pepin, recipient of the Roger V. Short Medal, shares a candid and inspiring look at his non-linear path from a "failed" postdoc to a leader in reproductive biology. He details how a accidental discovery—finding that anti-Müllerian hormone (AMH) could "pause" ovarian activity—transformed into a decade-long mission to revolutionize contraception and oncofertility.

To learn more about Dr. Pepin's lab site, visit https://www.pepinlab.com/david-pepin

Learn more about the Society for the Study of Reproduction (SSR) at www.ssr.org.

Transcript

The following Future Conceived podcast is sponsored by the Virtual Education Committee of the society for the Study of Reproduction, with the mission to develop virtual programs that will aid in the education, highlighting the careers of society members, bringing technology updates, and the latest scientific advancements in reproductive biology. Thank you for listening. Hello, listeners, and welcome back to the future conceived and official podcast from the society of the Study of Reproduction. For today's episode, I'm your host, Andrew Kelleher from the University of Missouri. Today we continue our award series. I'm joined by Doctor David Pepin, an associate professor at Harvard Medical School and Massachusetts General Hospital. If you follow reproductive biology, as you do, if you're listening to this podcast, you know that David's work has fundamentally shifted our understanding of ovarian physiology taking molecules we thought we understood like anti-mullerian hormone and revealing new roles and potential therapeutic uses for them in female reproductive physiology. Doctor Pepin is the recipient of this year's Roger V Short Medal and Lecture. This award is special because it doesn't just honor the excellent science, David does. It honors the spirit of creativity and imagination that Roger short was known for. When you look at the David's approach to science and the way he runs his lab, which spans everything from structural biology to to onco fertility. He fits the description of this award to a t. It's an honor to have him here to discuss his journey. David, congratulations on the award and welcome to the podcast. Well, thank you and thank you for having me on the podcast. I'm excited to to talk with you today. Well, let's just kind of jump right into some of these things. Um, just to kick things off. What does it mean to you to be this year's recipient of the Roger V Short Medal and lecture? Well, you know, to get an award from, you know, my peers means a lot to me. Obviously, I, I've been, um, a member of the SSR since I was a grad student. And, and, you know, I, I've visited SRF and given lectures and talks there and I've yet to go into Australia, but I hope one day to, to visit the continent. Uh, but, you know, these are all my peers that study the same thing as I do that, you know, I, I look up to and interact with. And so it means so much more to me than, you know, any other possible way that I could get. So I'm very humbled, um, for having, you know, been chosen this year to, to receive this award. And I, and I'm humbled also from the past recipients that I know the award hasn't been, you know, there for very long. But, you know, I respect all the scientists that have received it before me and, and look up to them. So it's, it's really meaningful. I wanted to add that, of course, it goes without saying that none of the work that I've just described was done single handedly. It was the result of a team effort. And I'm very fortunate to have many talented trainees who have made the key observation and done all that work. And I'm also extremely grateful for all the generous collaborators that have made this possible. I'm thinking about people like Bill Swanson, who taught us about feline reproduction. Grumping about gene therapy. Tom Thompson about structural biology. And I'm fortunate to have so many generous collaborators. And really, that's how great science is made. It's a team effort. Yeah. It's I think it's a huge honor to receive the award. And it shows how well you've been doing in what is relatively early career as you need to receive this award within the first ten years of establishing your lab, which is, you know, taken off in the last several years for you. It's it's very interesting that your program in such a short period of time spans development, fertility, contraception, onco fertility. This is like a trainee based podcast and the society is very trainee focused. Can you give the listeners a little bit of a background about your scientific training or the journey that led you to the position you're in now? Yeah, I, you know, there's nothing I love more than talking to trainees about this. Um, when I was a trainee, I remembered, you know, you'd have people be invited from other prestigious institutions, give talks, and, you know, they would talk about their background and where they came from. It was always so intimidating. I felt like, you know, this, I didn't see myself in this. Like, I really, really wanted to, to pursue science. But it seems so unlikely to, to get a position like this because you hear about people that, you know, did their undergrad at Yale and were summa cum laude and, and captain of their football teams. I feel like, you know, it sounds so intimidating. And I feel like I'm just a normal guy and I just happen to love science and, and so, um, you know, I come from the University of Ottawa in Canada. Um, and I, through chance ended up working on ovarian biology and ovarian cancer thanks to a really good mentor. So Barbara Vanderhyden, who's actually a past president of the SSR, and she, you know, I didn't, I, I could have worked on anything. And it just happened that I fell in love with this particular subject. And I've been fascinated by all the problems that are left to be solved in there. And there's quite a few because, you know, for historical reasons, it's been underfunded area where there's probably has not been enough science. So I did my, my, my master's and PhD at University of Ottawa, and I studied basically the differentiation of granulosa cells in follicles and particularly chromatin modifying factors regulate granulosa cell differentiation. So it's really very, you know, a small corner of ovarian biology. And I was using mouse models and, and, you know, identifying basically ovarian phenotypes to looking at two factors the Snf2 agents Snf2, L, Smarcb1 and Smarca5 is there the names and. At the same time I was also working on ovarian cancer, so I've basically. Since the beginning I've done both, and what I thought I was going to do for my postdoc is maybe, you know, learn something different. So initially I wanted to learn a different model organism, maybe work on something like C.elegans. I always liked development, and I thought maybe I could go deeper into the development goal. And I thought, maybe I'll go more onto the chromatin remodeling side and, you know, do something a little bit different than cancer and reproduction. And I think this is where, you know, I reached a critical point in my career, um, where I was just not the right lab for me and things didn't work out. And I had a very difficult choice. Basically I to whether I should continue doing this or or maybe choose a different career path because I was very unhappy and it was very difficult. And, and this is why I like to talk to, to trainees about this, because it's not always obvious what you need to do. Sometimes, you know, the, the hard, the hard path. And you know, it seems it doesn't seem that obvious. So I ended up quitting and, and looking at other options, like maybe going to medical school or law school or something like that, and nobody would have me. I tried to go teach, you know, a part time position maybe. And they're like, well, maybe I just need to give it another go and try another postdoc. And I ended up in a lab that I didn't really had planned to go into in the first place. Uh, Patricia Donoho at MDH to do my postdoc. And since there was no plan, you know, for me to have me there. I ended up with the project that nobody wanted to do, which was basically to just make reagent, make recombinant protein. Everybody needed it for their experiments. Nobody could make it at scale. So that was sort of impeding progress there. So you know, I didn't. This was in the past. That was well groomed or I knew where I was going. I just stumbled upon this, um, uh, and I had never quit on anything in my life before. And it seemed weird to go from Canada all the way to Harvard, and then six months later to quit at it. And yet that turned out to be the right decision. Huh. So I think it's really important. Some of the things you said along along your journey, uh, it's not every path is not a straight line. And a lot of maybe, um, early success can be serendipitous. And your ability to find what is working and follow the, the data and passion is what's kind of led you to be in the position you're in now and receive some of these very notable awards. I think that's important for a lot of the trainees within the society to hear. Yeah. And, and then basically everything kind of worked in a weird way. I could have never expected that I would have worked on all these different things, but like just to take you through it. Uh, so my first task was basically making recombinant protein, which basically I'd never done before. And I had no idea how to do so. So I, you know, I studied this and there's a couple of different approaches and small modifications I could make to the peptide. I looked at how it was being purified. What could we improve there? It's more like a technical work that was not really trained to do. Um, and then, you know, I saw one little problem after another. I didn't even think I didn't even think we should publish it. I, I, you know, it's my supervisor, you know, she's like, no, no, you need to publish this. You need to publish this and you need to patent this. But honestly, I thought I was just making your agent then. Like it didn't seem, you know, it didn't seem that important at the time. But what I didn't anticipate is actually, uh, it gave me a really, really unique chance because all of a sudden I had something that nobody had their hands on before. So nobody it was very, very difficult to produce recombinant proteins for a couple of reasons for this. I don't need to get into a lot of details, but it's a very large protein and it it is produced as a proprotein, so it needs to be cleaved to be activated. It's held as a complex. It's a very large one hundred and forty Kilodalton complex. Some of it is covalently bound, some is non-covalently bound. And then you get any of these things wrong and the protein doesn't work. So once I had the protein and I could produce a lot of it. Um, I started working on a project that was also ill fated, which was basically trying to use it to treat ovarian cancer And, um, you know, it sometimes works, sometimes didn't work. I was really puzzled as to why that was. Um, and it took me another ten years to figure that out. But the, the other tool that I developed at the time is that, um, because we were treating mice with, uh, xenografts of patient tumors, so we're implanting a patient tumor in there. Sometimes it takes a really long time to, to grow. And these tumors are very slow growing. And so you would need to, if you want to treat that mouse, you would need to give it injections for like weeks or months on end. And it's very difficult to produce that much protein. So another technology that was emerging, uh, was gene therapy. And then, you know, I thought this would make my life a lot easier if instead of giving an injection a day for two months or three months, I could just give it one injection and then use the animal itself as the bioreactor. Essentially it produced the protein, so I didn't have to. And then it's a creative, it's a creative way to make less work for yourself. Exactly. Because I was lazy, I had my background as a reproductive biologist. I spent a lot of time during my PhD looking at ovaries, doing follicle counts. And, and my thesis, I, you know, I had in the introduction, I had written a chapter, um, you know, detailing all the, the different mouse models that had ovarian phenotypes. And I put it by follicle stage. And the primordial follicle chapter was, was really, really short because we, there's so few mouse models or transgenic mice where primordial follicles were affected. And so I still remember the AMH being, you know, a potential break. It's like the, a break to that system in terms of primordial follicle activation. Um, the evidence is mostly from a mouse knockout. There was not that much more work around it. A little bit of work, uh, in vitro with a little bit of recombinant protein, but nothing in vivo, essentially. So, um, when I was doing these long term experiments now with my new tools and trying to treat these tumors, I thought, well, why don't I just look at the ovaries while I'm at it? And I'm doing all the work and I'm kind of curious what's going to happen in the ovaries. And then, you know, the, the first mouse where I did this, it's been about about a month. So it took a really long time for that tumor to grow. Uh, when I looked at the endpoint and I found the ovaries when I opened, the first mouse was really tiny. They're about the size of a newborn mouse ovaries. Well, that's that's kind of weird. And then I opened, I opened the second mouse, and it's the exact same thing. The ovaries were shrunk. Like what? Well, like, one mouse is maybe, you know, just a weird coincidence. Sometimes you see weird things, but two mice in a row. And of course, all the mice were like this, and I sort of immediately knew what was happening because I was always I was already predicting it would be a, you know, a mild break to follicle activation and development. Clearly it was underestimated because what clearly was happening is that all follicle development was stopped or it was just massively reduced at the very least. And, and so I was really, really excited about this. In fact, I, you know, I basically couldn't sleep all night that night, and I just couldn't wait to figure out what was going on. Um, and basically that's been what I've been working on since. So, so I think that kind of leads into the next thing I wanted to ask you, um, you know, this is kind of speaking to like in undergraduate, when people learn about AMH, we just know that it's involved in the regression of malaria in ducks. Um, all of this work that you're describing is really like redefining this like a whole chapter that people should learn about in basic reproductive physiology classes. You described this like moment when you saw these small ovaries in these in these mice, and that you immediately knew what happened. And this kept you up that night because you were so excited about it. Was that the moment that you knew that, like, this is kind of what you wanted to build your program around? Or was there other coalescing moments that you can recall that were as exciting as this for you? No, I it was there. And then it's like, you know, the life flashes by you. Like I could just see it like, this is what I'm going to do. I just knew it. And, and in fact, I sort of worked on this project secretly for, you know, a couple of months because I wanted to, I wanted to like discover it all. I just wanted to know before I told anybody about it. And then when I presented it at that meeting, I had a slide up there and I and I said, basically, I think this is, you know, a fundamentally important. And I think this might also be useful. And I listed some potential applications. And I said, I think this might be useful in contraception because obviously if you have follicles are not growing, then you're not going to be ovulating. I think you might be interested in fertility because if follicles are not growing, they'll be less susceptible to chemotherapy. And I even thought, well, maybe this might be useful in, in, uh, invasive animal and pet population control. Because particularly because we have gene therapy, this basically means, you know, sterilization. Uh, and so I, I, I had basically my entire program set up for the next decade and my first lab meeting after I presented it. I think that's really cool. Like the story that how things coalesce is, uh, I think all of us hope to have some time like that, where you can see the next decade of work in front of you. Um, so like, one of the things that I'm curious about is, you know, this breadth of work that you do in your lab that, you know, you, you've mentioned gene therapy, structural biology, purification, onco fertility, contraception. Now, this is like a huge amount of work for one lab and it's very multidisciplinary. So you seem to have thought you were going to do all of these things from day one of starting your lab. How did you approach that? Did you hire for each individual project, or did you allow your lab to kind of grow organically as the as the data presented itself? No, it was very organic. So I had the sort of long term vision of what I wanted to do. But I think day to day, it's just solving a lot of little problems and, and sometimes taking a big detour. Right. So the, you know, I first wanted to map out exactly how this was working on follicles and and, you know, I had shown that, you know, I could basically cause contraception in adult mice and it took about a month for follicles basically to, for the ovaries basically to be completely void of growing follicles. So I thought, well, if I want to study this in primordial follicles, maybe I should do it in, in newborn mice because that's the first wave. So you get a lot of primordial follicles. And it'd be a lot easier to time things and to see how this was working. And then so I, you know, I treated a young newborn mice. And then I noticed that their uterus weren't growing. Also like the, the adults, the uterus were fine. There was no effect, um, just an effect on the ovary. But if you give it a newborn, then the basically the uteri just did not develop at all. They remained the way they are when they're newborns. I was like, well, this is also interesting. Maybe I'll pause there for a second and like, figure this out because that's a really cool problem. I remember your paper when it came out like, I'm a uterine biologist, and I remember it was in eLife that it came out, um, this one really like you were kind of on the beginning of a lot of the single cell now that had erupted in like uterine and reproductive biology. And I remember that paper when it came out because it made a really big splash because again, it was showing a brand new role of a in postnatal development in a mouse that we would have no idea would occur if we were just studying the textbook. So this, I mean, that's, that's what intrigued me about this is that, um, I had, you know, I had, I thought I knew from developmental biology that image, you know, it gets its name from anti-müllerian hormone. It causes a regression of the Mullerian ducts. So it's produced by the testis, the developing testis of the male. And it causes the the Another inductee regrets that males don't grow your fallopian tubes and uteri and those structures. And I thought that, well, it was supposed to be only active during that short period of development, you know, in a rat basically around day fourteen fifteen. Embryonic development, I think in mice is like day twelve thirteen, something like that. And, and that essentially after that, it didn't really matter play a role. And so I was surprised that if you treated a mouse that's born now, it's having an effect on the, you know, the early development of the uterus. So so that means that must be wrong, right? So one of the assumptions that we had must be wrong. And, and then I, and I looked and found that, yeah, AMH receptor was expressed right there under the lumen, just like it is really early in development. And basically what that would mean is that, you know, we think that we think about them as basically male cells that respond to the male signal and cause the Mullerian duct to go away, but the early fetus is bipotential. So these are not male cells. They're also female cells. And what is their role in the female? Exactly. So it turns out that, you know, they stick around. And if they're not triggered by the male hormone, they have a different role in development in the female after there appeared to be, you know, endometrial stroma. So they have a dual purpose. I think, again, some of these things you're saying is, is really speaks to follow, follow your data and just follow observations that you see. And don't be afraid to challenge what might already be known. Um, that kind of again leads me to ask the question, do you have. So for people, trainees that are either, you know, moving from PhD to postdoc or postdoc into faculty positions, do you have any advice for them that are looking to bridge basic biology and translational science? Do you start at the basic biology and find a question that you can answer with it? Or is your approach to start with the question, the question in the translational side, and then use basic science to address that question. Yeah, I wish I was smart enough that I could see a problem like in translation side and see like, this is cancer and I'm going to cure it. Unfortunately, like this doesn't really work for me. Uh, so I do, I work it the other way around, um, which has worked out pretty well so far, which is find a problem that I find interesting and then look for the solution. Um, and so this is purely curiosity driven and you have the basis, but at the same time that, you know, that's um, um. Uh, how do you say this in English again? Um. Selfish. So to, to work on the on the on the problem purely out of curiosity is selfish because it's just to satisfy your own curiosity. So I, I try to remind myself that, you know, I have an incredible privilege to be able to work on things that interest me, but I have to make sure that they're useful and not just out of my own curiosity. So when I work on something, I, and I find what I think might be something useful about it that I have an obligation to, to develop this. Right. And so that's allowed me to do both at the same time. And sometimes I'll start with just an interesting problem that I'd like to solve or, or just a question that I'd like an answer. It doesn't really matter if I have to solve it. I'm equally happy if somebody else solves it. I just want to know what the answer is. And then if I do find new answers, you know, unexpected findings to try to think of, well, what is this useful for? Is there. Is the information itself useful for other people on their own project? Um, or even, you know, could, is there a context, a human disease or a place for this to fit where it could be useful? Um, so that, you know, I didn't put all this effort and time and money into, into a vacuum. I think that's a really good way to look at things. Um, so maybe, you know, speaking of this selfishness that you kind of bring up maybe this kind of question that is ill timed, but I think thinking about the award itself, um, and Roger Schwartz legacy of creativity. So your work using gene therapy to deliver AMH, I mean, I would argue is, was, was a risk when you, when you were first starting to do this. I'm curious if you can kind of like remember or take us back to the conversations you either had with yourself or with the lab, or with the people that were around you. When you're proposing using viral vectors not to like cure a disease, but to control fertility. Yeah. So, you know, I basically stumbled upon it, right? I in that I was using gene therapy and then I found out that it was contraceptive, but then it immediately dawned on me that actually this is a really good way to do contraception, right? Not just because I'm lazy and I just want injection, but, you know, you can get permanent contraception out of one injection here. And, and, um, the problem with it at the time is that it was extremely expensive. So, um, gene therapy was making a bit of a comeback. You know, there's a whole history about this basically with there's inherent risk with certain viral vectors. And, and unfortunately, there had been, you know, basically accidents in the past in treatment of human disease. Um, but this was a new up and coming vector, so it didn't know associated vectors. It's quite different from previously used vectors in that they don't integrate. So there's less of a chance of it going into an oncogene and turning it on and, and causing cancer or something like that. And it's also they're not, you know, low immunogenicity. So they appear to be have a lot of positive attributes that make it an ideal vector. But there's still the problem of cost, right? So gene therapies in humans basically cost millions of dollars. And then producing the virus at the time was very, very expensive. And, you know, although I knew that it could likely solve the problem. So it probably would work as a contraceptive in most mammalian species. Um, you know, would it be a cost effective way to produce contraception? And I made a little bit of a calculated bet, right, that I thought that with time, particularly if, you know, if this becomes Um, approved medicine in humans that are capacity to build it, to produce it. Uh, um, uh, you know, at a larger scale would bring the cost down. And then eventually this, you know, this might be cost competitive with other contraceptive methods. And, um, you know, the first study I did in cats where you need quite a bit more virus than you do for a mouse, uh, I think it costs around twenty thousand dollars per cat. So clearly it's not, not an expensive contraceptive. Uh, but then to get to the, you know, to the proof of concept and basically I worked on it for a decade. Um, and then now the, the costs that, you know, were the back of the envelope calculation that we do when we think about the scale at which this would be produced, how much virus we need, we're getting better and better and, you know, making better virus, better transgene. Um, now it's basically cost competitive with surgery. We're in the same ballpark. So, um, so I think there is a world in which this would work. So I'm like from a personal side of things, I remember as an undergraduate living, you know, we're all there's trash, there's feral cats everywhere. And you know, this was I don't it was a while ago, fifteen years or so ago. Um, it would have been great for them to be able to control the feral cat population. And I think the programs going on then locally were as capture and surgery. Um, but this seems like a more humane way to be able to control the population. So I think like in a timely, you were really on like par with what needed to be done, especially to control these like massive feral cat populations that are causing widespread issues, even with like songbird populations. Um, so were you looking for a model to test this in or ended feral cats come up, or you've indicated in your first lab meeting when you discovered these things, you thought contraception. Uh, is this something you again, just had the foresight to see that it could be useful for. Well, yes and no. So I had the foresight to think that gene therapy with AMH would be useful in controlling invasive species populations. And then there's also I again, like most of my career, was basically strokes of luck, you know, except the beginning part, the, the, that there was um, a new foundation called the Michelson Found animal Foundation and they were um, giving grants and they had announced surprise, um, to develop contraceptives for cats and dogs. And what they were looking for is something that would work in cat and dog, male and female, that would be low cost and be an alternative to surgical sterilization. And, um, I, I knew I didn't fit all the criteria because, you know, my method worked on the ovary and it is somewhat species specific because if you use, um, um, a gene therapy vector, you have to match the, the, the gene with the species. Otherwise you get antibody production. But um, thankfully they were supportive of, of this project. Um, and, uh, it became the first project to, to go all the way to, to proof of concept in cats. So that was very exciting. And I wouldn't have been able to do, um, this work in cats without them. And it's been extremely useful for me even beyond cats because, um, I think other mammalian systems in which to study the ovary, uh, is really useful in many respects. Cats are much closer to humans than mice are. And, you know, just the number of things that we've, we're following up on in terms of understanding ovarian biology that and that are applicable to humans is just so exciting. Wow. I'm really appreciative of your time. And I, we won't keep you a lot longer. I do have like a couple more questions that I think our listeners would enjoy hearing your perspective on, or at least your thoughts. Um, so you've talked to us a lot about your history and all the work that has led to the award that you're receiving. Can you talk to us maybe briefly about what's the current focus of your lab or what? You know, you don't have to tell us specifically what you're doing, but just what direction you're going in right now. Um, that's not my problem is that I tried to go in many directions at once because there's all these great problems that I like to work on and all these questions that I wish I could get answers to. So I think the the one that I've been working on basically since the beginning that I think we're starting to make a little bit of progress and that I'm dying to know is basically how do follicles, primordial follicles, especially how do primordial follicle follicles stay quiet, stay quiescent. You know what drives their activation? How is that um, uh, basically controlled as a unit because, you know, it's not a cell here. It's not one cell. It's a it's multiple cell types. You know, you've got your oocyte and your granulosa cells. And how do they come to a consensus on what to do and what's the push and pull and what controls it. You know, I don't take this purely stochastic. I think there are inputs and I'd love to understand exactly what's the the push and pull that that puts a follicle further towards quiescence or further towards activation. And what controls that? I think that's just fascinating. And the image is a small part of this, but, you know, I'd really like to understand how that process is regulated. So AMH is controlling everything and the world view. But yeah, those cell fate decisions that are happening in the ovary are fascinating. Um, which again leads me into one of these last questions that I want to ask. So it's you always have to kind of structure your work again on what is relevant to either humans or of large question in general. But if you had, if you didn't have to worry about getting funded and you could be a selfish scientist that you don't want to be, what question would you go after if you had just infinite funding? That could be, that would really speak to like the essence of the creativity and the award from or the Roger V short award. Um, do you have anything in mind that is just like a moonshot experiment you would be interested in doing? I have like thousands of those. But the there's a there's a couple of things, you know, I've always considered myself more of a reproductive developmental biologist, but I've been sort of tugged over time to look at aging as well. And it's become an increasingly big part of my lab. And, you know, new focus is to understand the other side of it. So, you know, what happens to the ovary as it ages. And I'm just as like, I'm fascinated by what happens at the beginning in terms of activation, like why, why does it accelerate as you go towards menopause? Why does the ovarian reserve depletion accelerate? What drives that process? Why in humans and, and, and why do humans age differently than other mammals? And do they, you know, and what is happening to their hormones at this time? And what's the interplay between the hormones? And can we do something about it? And should we do something about it, I am very curious about that whole part of the development. The end part as well. I'd love to learn a lot more about this. What would happen if you. What would happen if you. We know if you remove one ovary, for example, you. You don't you know, you don't get menopause halfway earlier. You know, it's basically what one or two years difference. So what if you had extra ovaries? What if you had four ovaries? What would what would happen? Is it is it a variant intrinsic like? Or what if you use those ovaries then into one ovary. Would that change things? Like I, I would really like to understand all of that. Yeah. I think another example of that is I think in PCOS, you only really see PCOS on one ovary. And usually if they remove one, you can get it in the other one, but they don't happen simultaneously. So I think what you're talking about is very interesting concept of what is the intrinsic versus cross communication in these, in these systems that we don't think about. the PCOS is another one I'd really like to get into. I really would like to understand PCOS because it's always pointed out to me when I present that there's elevated AMH in PCOS. Yet when I treat animals with AMH. I do not cause PCOS. If anything, I got the opposite of PCOS is that there's basically no more antral follicle, I reduce androgens. Like everything about PCOS goes down, so I'll come in PCOS, AMH is elevated. And so I would love to understand this better as well. It's going to bring you back to your structural biology days, and you're going to find a new isoform or how I mean, you laugh, but that's maybe part of it. Yeah. It's I mean, this is why like the multidisciplinary approach of your, your group, I think, you know, yields so many dividends and is, is seen as very creative in the field and solving these very challenging questions. Well, David, I don't want to keep you any longer than we have to. And it's been like a real pleasure to talk to you. And if anybody else is interested in how David's perspective has changed over the years, there's, uh, he was interviewed when he won the twenty twenty two New Investigator Award. And that is episode, uh, either I think eleven. So it's great to go check this out. Um, but thank you so much for joining us. And again, congratulations on the award. Um, I'm sure more and more great things will come from your lab in the future. And thank you to the listeners for tuning in to the episode of the Future Conceived. We hope to see you next time. Thank you. Thank you for having me.