Cells aren't just the building blocks of our bodies – they could also become medicines. In this episode, Soyoung Oh, Senior Director and Senior Principal Scientist, Synthetic Immunity, joins Danielle Mandikian to explain how scientists are engineering T cells to better recognize disease and respond to signals in their environment, while also keeping the fight going when conditions get tough. They discuss the differences between autologous and allogeneic treatments across indications, the challenges of tracking and scaling these therapies, and where this rapidly changing field is heading next.

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Transcript of Two Scientists Walk Into A Bar: “The Secret Life of T Cells” with Soyoung Oh

Maria: I’m Maria Wilson.

Danielle: And I’m Danielle Mandikian.

Maria: And we are scientists. We. Love. Science.

Danielle: Yeah, we do. So, when we aren’t doing it, the next best thing is to talk about science! And what’s really awesome is that we’re surrounded by some of the most brilliant minds in research!

Maria: We are going to step away from the labs today to talk to other scientists about the cool stuff they are thinking about, working on and imagining . . .

Danielle: . . . as well as how some of these discoveries just might lead to new medicines. So, grab your favorite drink, get ready to unlock your science brain and join us for Two Scientists Walk into a Bar…

Maria: The show for scientists, science geeks, and the people who love them!

Danielle: What's the difference between allogeneic and autologous cell therapies?

Employee responses:

No, I don't know those words. [Laughs]

No, I don't know the difference.

At one point I did, but I don't remember it.

Almost allergic allogeneic and autologous. The height, one's a little “tall-ogous.” [Laughs]

Autologous is when cells come from yourself and allogeneic is when they come from another person.

Autologous is when you use the patient's own cells, T cells, to make, say, CAR T cells and treat their disease. Allogeneic is when you use a donor cell.

Danielle: Welcome back! So it wasn't that long ago that the idea that we can engineer someone's own cells to fight disease sounded like science fiction – to everyone, including scientists. But recently, we're seeing patients with cancer, autoimmune disease, neurological degeneration and even rare diseases entering into clinical trials where that's exactly how we're fighting the disease. So, we're following up on a great cell therapy episode from last season, and we really want to continue that exploration about what is so fundamentally different about this moment in cell therapy. Why is this actually starting to work? With us today is Soyoung Oh, who specializes in cell therapy, synthetic immunity and cancer immunology. Welcome to the bar, Soyoung.

Soyoung: Yeah, thank you! Excited to be here.

Danielle: For those listeners joining us for the first time and don't know what cell therapies are, could you take us through a condensed cell therapy 101? And also to kind of help us get in this head space, what makes using a living cell so attractive as a therapeutic?

Soyoung: I think that the beauty of a living cell as a drug is that it has the ability to sort of evolve along with a particular illness in a way that a traditional molecule doesn't, so thinking about living cells sensing their environment, what signals do they receive? How can we use that to maybe develop an even better drug? I think there are some really unique opportunities with a living cell as a drug as opposed to more traditional approaches.

Danielle: We always hear about autologous versus allogeneic when we hear about cell therapies. Could you refresh our memories of what these definitions are?

Soyoung: Yeah. So when people say autologous cell therapy, it's taking cells from a patient, modifying them and then putting them back into the patient. When we say allogeneic, the cells are coming from a different source. And it could be multiple sources, but it's not coming from the patient themselves.

Danielle: What about the types of cells that are used?

Soyoung: Yeah so I'm really focused on the T cell therapy side. And so, that would be taking T cells, which are a part of your immune system and really critical for mounting responses against, you know, infections, and taking those T cells and engineering them. From the autologous perspective, it's a patient's own T cells and modifying them, and then, from the allogeneic, it's taking someone else's – a healthy donor’s – T cells, modifying them and basically treating a patient. There are also approaches where people are trying to take stem cells and then differentiate them into T cells as another allogeneic cell therapy. Now, there are other types of cell therapies that people are exploring. Stem cell derived therapies to generate other cells, for example, you know, there has been work trying to generate pancreatic islet cells to treat diabetes. There are other approaches to try to generate cell types, maybe to treat vision. So there are cell therapy approaches that extend beyond immune cells for sure.

Danielle: Okay, last kind of definition. Often when we talk about therapies, we talk about mechanisms of action. When it comes to the cell therapy space, what types of mechanism of action would you classify are approachable as cell therapies?

Soyoung: Yeah. Again, going back to what I've really been thinking about, which is T cell therapies, we're really using them as soldiers to directly, for example, recognize and kill tumor cells in cancer. In autoimmune disease, there's been a lot of excitement to use these T cells to also kill the B cells that are critical for autoimmune disease. But then, for some of the other approaches I mentioned that are not immune cells, it's more, can you restore a cell type that has been damaged in a particular disease?

Danielle: What makes cell therapies so fundamentally different from other types of medications?

Soyoung: So I do think the fundamental difference is that it's a living drug. I think it challenges so many of the aspects of more traditional drug development because it's a living cell, and understanding the biology of that cell is so critical. I think I'm really coming from a research perspective. One of the things cell therapy has taught me, as you interact with, you know, other groups who are instrumental for developing this, for example, is that thinking about consistency and quality of something that's alive and changes based on its environment is so different from like making an antibody –

Danielle: Yeah.

Soyoung: – or a small molecule. So I think that is just fundamentally different.

Danielle: Can you expand a little bit more on that? Normally, when we think about therapies, they're something that are acting on cells. But now, our therapy is a cell. So like how does this change how we view the development or medicine in itself?

Soyoung: I think . . . hmm. I think it changes, you know – what do we define as the properties that you want going into the cell therapy, like before you even treat a patient? You made the cell therapy. What do you want it to look like? I think there are so many questions there still that it doesn't feel like there are these very clear guidelines in the way that some other modalities where there's a lot more experience in the field might have. And then, on the flip side, it's – you can put a certain number of cells into the patient and say, okay, this is my dose. But because they sense the environment differently, they proliferate differently, they’re going to kill differently. Like what that actually looks like and understanding, you know, how long are they around, like how do we define exposure? How do we understand that to say what success looks like? I do think it's just very different.

Danielle: That's one of the things I think makes you so cool as a scientist is that you're not just dealing with the biology, but there's so much engineering that goes into it that you don't really get to kind of get involved in, in other types of, like, disease indications or strategies.

Karen: Hi, Danielle.

Danielle: Hey, Karen.

Wellington: Hi, Danielle.

Danielle: Hey, Wellington.

Karen: Danielle, how do cell therapies affect the way we look at PKPD in the lab?

Danielle: Yeah, so PKPD is actually my area of jargon. And PK is pharmacokinetics – like where is the therapy going in the body? And PD is pharmacodynamics – what is the therapy actually doing? And so when it comes to cell therapies, we're kind of figuring that out together in the field as we go. So where you have the most examples of this is for hematologic malignancies, and so people are looking to see how long are the T cells staying in circulation, right? Because hematologic malignancies are liquid blood tumors that are also in circulation or in hotspots. And so we look to see, are our cell therapies actually going there? And a lot of times we do this by taking out blood and characterizing it with different kinds of equipment like FACS. But here's the challenge. Now as we start to develop these kinds of cell therapies where we're looking at solid tumors, it becomes more of a nuclear imaging strategy, right? Because I can't just, like, pop out a chunk of the solid tumor and be like, hey, where are the T cell therapies in there? Because if I could remove it, that's what I would do. So now people are trying to come up with really clever ways to image them, but it's actually challenging, because we do such a good job of making the cell therapies look exactly like a person's natural immune system, so being able to pick it out and have some way to label it can sometimes be a real struggle in development.

Wellington: Danielle, why do we see so much data about these blood cancers versus solid tumors?

Danielle: You know, that's a topic of hot debate. My two cents, take it or leave it, is basically that one of the things that makes it kind of easier to study and track is that I can take out blood, sample it and see what's going on with the cell populations. When it comes to solid tumors, those are challenging to treat across all types of therapies because they're hard to get whatever type of therapy you've developed into the solid tumor space. Now, we're developing these imaging tracking, cell stalking strategies so that we can figure out where our cell therapies go. But again, doesn't matter whether it's a cell therapy or a small molecule, you still have to figure out how to get it actually into the tumor parenchyma, like into the “meaty meaty” of the tumor.

Danielle: Do you think that whatever promise we're seeing is gonna translate into other indications?

Soyoung: Yeah. I think that is – it's definitely a multilayered answer, and I think that it gets a little bit also at sort of the future and where we want to go. So T cell therapies have shown that they can be transformational in hematological cancers, and I think that's for a couple reasons. One is definitely that, in this case, you have a very clean target on the tumor cell.

Danielle: Accessible?

Soyoung: Yes, accessible and also specific. Because one of the things you're worried about is, if your T cell is targeting a protein on a cell surface and it's expressed all over the body, then you really worry about only killing the cells that you care about. And where we initially have seen this kind of success with cell therapy, you do have that specificity, which gives you the safety. And so I think that has really presented a unique opportunity and then the accessibility of a blood cancer itself is also a big piece. As to why the cell therapies don't work well in some patients I do think it gets to questions about, well, how are the T cells functioning? Like what is their state?

Danielle: What do you mean by state?

Soyoung: How – sort of, if you were to characterize how active they can be or how responsive they can be, sort of what's their identity at the moment that you're trying to use them for the cell therapy? And there's work in the field suggesting that understanding that differentiation state as that T cell therapy product is being given to a patient may correlate with activity. And so if you think about T cells along a spectrum, you can think of a – what we could call a naive T cell, which hasn't really experienced anything. But then, the T cell gets that activating signal, and then it starts to differentiate to be able to produce cytokines or produce cytotoxic molecules, which would then kill the tumor cell. There can be a point where there's too much signal and the cells are in a less functional state. And so one of the questions has been can we pinpoint what a desired state is? And I think also that's a potential differentiation between those autologous patient-derived cell therapies we were talking about versus an allogeneic cell therapy coming from a healthy donor.

Danielle: What are the things that happen, or what are the pathways in the T cells that as they're kind of like being differentiated, starts to make them less active?

Soyoung: Yeah, a lot of the work in the field has been focused on trying to understand what defines T cell dysfunction. And in some cases, there seems to be a change in really the transcriptional state. So you have a transcription factor that regulates gene expression and you have a specific transcription factor that can really be important for establishing less functional T cells. But then, there are other signals that the T cell can receive, for example, a suppressive cytokine in the tumor microenvironment. So there's multiple ways to shut down the T cell response and I think teasing apart which one of those is – I don't even want to say most important because they can all contribute but maybe really thinking about how do we counter each one of these challenges for the T cells?

Danielle: Is there, like, engineering strategies that you often keep in mind when you're thinking about this kind of puttering out or exhaustion of the T cells?

Soyoung: Yeah. Absolutely, and there's work in the field where people have started to try to engineer the cells either by knocking out a gene that they think is important for the T cells being less functional or trying to overexpress genes that they think are important for retaining T cell function. And so an example is there have been therapies that knock out the gene PD-1, and PD-1 is really associated with T cell exhaustion. And you know, there are immune checkpoint inhibitors to block that pathway to reinvigorate your immune response. There are other cytokines, for example, TGF-beta is an example that is known to have many different functions but also to be suppressive, and so people have also tried to engineer cells to be less sensitive to TGF-beta signaling. And that's just scratching the surface. When you look at all of the things people are trying, there are so many different approaches – knocking out other genes, overexpressing other cytokines, actually, in some cases, designing what are called switch receptors where the T cell expresses a receptor that would sense what is normally a suppressive signal but then turn that into an activating signal.

Danielle: Oh, so like the downstream mechanism is altered?

Soyoung: Yeah.

Danielle: That's cool.

Soyoung: So I think, you know, that's probably the beauty of going back to sort of T cells sensing their environment and what is unique about a living drug because, now, you can try to take advantage of that.

Danielle: When you were talking earlier about all of the different things that can come into play, and that there's reasons why we want to have like different sources of T cells and things like that, do you think like, in the future, when people are really kind of getting at the best acting, you know, cell therapy, it kind of sounds like it's not just the cell itself but something that's either going to modify the environment or just reimagine what it's seeing in the environment?

Soyoung: Yeah. I think those are the really exciting opportunities. It's how do we change what the cell is sensing to stay functional, but then also thinking about the T cells maybe as a delivery sort of agent as well is really interesting, because you can think about having a T cell that is going to recognize a tumor and then, once it receives this activating signal through the receptor, now produces something else that might reprogram the tumor environment.

Danielle: Oh!

Soyoung: So I think that really that sense of, you know, generating circuits, like having something that can respond in real time and alter the response, I think that is sort of what I see as a really exciting, like, future opportunity, particularly to tackle some of the more challenging cancers. You know, thinking about trying to get into solid tumors where we know that so much of the environment, whether it's suppressive signals from the tumor directly or changes in the immune cells in the tumor – like, those are all things that we know the T cell is going to have to fight against in order to be successful.

Danielle: One thing I also wanted to ask you is like, when you think about different disease indications – you know, like you had mentioned that the hematological malignancies are going to be like the best suited because of like what we know – or what we can currently access, what targets and the actual therapy can access in terms of like biodistribution. What other types of disease indications do you think are going to be like faster adopters for cell therapies versus the ones that are going to be like we've got to do a call to arms to get everyone sorted out?

Soyoung: Yeah. I think we're seeing it right now and that's partially because the targets are the same. And the question about, is like a very rapid response that is very deep – and by that I mean really getting rid of, for example, the autoimmune-disease-driving B cells – is that sort of rapid short response enough? When we think about autologous T cell therapies, you know, they have been so successful. But this is a patient-by-patient product. And so when you think about scaling it up, making it accessible to a broader population, you inherently can't do that with an autologous approach. But with an allogeneic approach, having something that's off the shelf is a real possibility. One of the things – like one of the fundamental challenges with an allogeneic approach is that you're taking something that's foreign to the patient and giving it to them. So the patient's immune system is really good at recognizing, hey, this isn't me. And so the T cells themselves will be eventually rejected, like the patient immune system will kill them. And so one of the fundamental challenges that the field has to address for these allogeneic T cell therapies is understanding how long do they need to stick around, how else can you engineer them maybe to protect them from being killed by the patient immune cells, and what does that need to look like to have a successful response in hematological malignancies versus autoimmune disease? In the allogeneic cell therapy space, it might be that in autoimmune disease, if you don't need the cells to stick around as long, that maybe this like quick, deep response is sufficient even if the T cells don't last.

Danielle: Yeah.

Soyoung: Whereas in cancer, typically the thought is that you need to have a sustained response. But I think this is something that we also still need to understand on a disease-specific basis because, even across the cancers, you know, some cancers might require the T cells to be around longer than others. And we won't know that until we start to see what the field achieves.

Wellington: Danielle, I'm sorry, but I got a dad joke here. Naive T cells, I mean, can we help them? Can we send them to school, maybe get some life experience, maybe an internship?

Danielle: Well, you know what, that's a really good lead into cell therapies and what we're doing with them. They're naive. They do know some stuff. You know, they may have already gone through enough maturation process to know what they might target or we could have engineered it in. But really what we are doing is we're taking these T cells and doing everything we need to do to get them in a more active state so that they'll actually, once they get back into the body that we reintroduce them as a therapy, they'll be able to not only know what they’re going after, but be in a state where they can do something about it. And kill those cancer cells.

Karen: And tell us a little bit more about T-cell exhaustion. How does that happen and what can we do about it?

Danielle: Well, as a mom, you know that you've only got so much water in your cup during the day, right? It's the same thing with T cells. They – it's a really – and I'm probably not the best person to talk about this – but like when we use the T cells as a therapy, we're kind of signaling them to be in an active state and then it's gonna have them do cellular processes that lead to cell death with how they interact with their target cell. And that's gonna go on a few times, and there's these kind of like natural mechanisms within the T cells so that they just don't go rampant and kill everything without, you know, stopping. So there's natural breaks that happen in place. And so T cell exhaustion is like hitting that breaking point where they're like, okay, I need to chill out for a little bit.

Danielle: So I'm a bit of a cell stalker, so I always wanna ask people, how are you thinking forward about once we're in a clinic, we're dealing with people, how are we tracking what's happening with the T cells in that person? Are they exhausted? What's up with that?

Soyoung: I don't think the field knows yet what it should be looking for, right? There are some signals that maybe having cells that we call a more memory state or very naive is better. There has also been a lot of work looking at, for example, whether T cells come in two flavors, CD4s and CD8s, whether the specific mix of that is important or whether T cells that have acquired a specific functional state might also be better. But I think that there aren't clear answers and this is something where the field will need to really gather the information. How do we characterize the product before it goes into a patient. And then how do we connect that with the responses that we see in patients? And then, importantly, can we get enough of the T cells after they've gone into the patient to understand how they differentiate? Because I think that's a real gap is that you don't get enough T cells back to really be able to ask these important questions. And so maybe that's where some of the technologies that people are using now, like single-cell sequencing, thinking about how you can get more information maybe from lower numbers of cells would be valuable. But I do think it's just a fundamental challenge for the field.

Danielle: Or even from like compartments, right? Like you know, it's, like, accessible to do a blood draw.

Soyoung: Yes.

Danielle: But like, if the microenvironment has such a big impact on the T cell, how are you going to figure out what's up from like an inaccessible tumor?

Soyoung: Exactly. Yes.

Danielle: Right?

Soyoung: And that's a big challenge, and I think something that you see when people have used T cell therapies for the blood cancers – you can at least sample from the blood. But then when you try to see what can people acquire after you've used T cell therapies to treat solid tumors, like getting a biopsy, for example, is really challenging.

Danielle: Yeah.

Soyoung: So absolutely, to your point of, can we even get the right material to ask those questions or to understand the T cells more deeply? Like that, itself, is a challenge.

Danielle: One of the things Maria Wilson was really curious about was, from your perspective, when you start talking about scaling up cell therapies realistically for production and access to patients and all of this, how do you think the field is rising to meet that challenge?

Soyoung: Yeah. I think for the scaling up, I guess that's where a lot of it, I think, centers on manufacturing. And so something I've seen, you know, in the autologous T cell therapy field where you're really relying on the patient's own material, is a lot of times the cells may be generated like at the hospital where the trial is being run. It's an academic trial and the lab makes the cells, and you treat the patients. And so then, the question becomes how do you expand sort of the network of sites that can actually make this product to be able to treat in a patient-specific way? And so that's where, for me, the allogeneic approach does offer this opportunity if you really can have something that is off the shelf. Then, you can imagine manufacturing maybe in a specific site but then being able to distribute that anywhere. I think, in terms of scaling up, then it becomes, you know – it can be purely a numbers question, you know, how many T cells can you make from one healthy donor? Like what's the dose that you need to treat a given patient? But then, maybe where there are some other exciting opportunities is, you know, talking about the synthetic immunity angle and engineering the cells, we can also think, how do we make a better cell so that you can use fewer cells but still get the desired outcome that you want? And so I think like both of those are things to consider. Maybe going back as well to your question about, well, what makes a T cell good versus bad, the deeper our understanding about what we desire in a T cell might also help us pick better donors and really more clearly define better product. And this last part is a little bit outside of what I've been thinking about on a regular basis, but I think it's hard to talk about T cell therapy right now without touching on the fact that there's a whole wave of in vivo CAR T cell therapies and really like directly editing in the patient, and I think that's something that is clearly exciting and nascent. But on a scalability question, you know, it's likely easier in many, many ways than generating cells from somebody and freezing those down and thinking about how to ship them.

Danielle: Can you define synthetic immunology for us?

Soyoung: Yeah, I think when I think about synthetic immunity in the T cell therapy field, I think a bit about what we were talking about earlier about, you know, how do you actually modify the cell? And so it can be: how do you modify the cell to sense its environment, how do you modify the cell to take a negative signal and convert it into a positive signal? And so to me, it's the engineering itself. You know, what tools do you choose to edit your T cells? How do you design a construct, for example, to express in the T cell to actually express the receptor that recognizes the tumor, maybe to design another receptor that senses the microenvironment to overexpress a cytokine that might help the T cell retain its functionality? And so then there's the design elements of the receptor itself, you know? And this is where I think you have the experts in what do I know about how these receptors work, what do I know about protein design? And it's really all coming together to make something new really, I think, fundamentally.

Danielle: We talked a little bit about T cell exhaustion. Could you expand on this more from like a therapy side – like why does this matter? And kind of, maybe, what are like the most common ways that we're dealing with this potential problem now or in the future?

Soyoung: Yeah so I think T-cell exhaustion really came to the forefront with the success of the checkpoint inhibitors, like anti-PD-1, anti-PD-L1. In this case, you're really just – you're administering this drug to patients and allowing those T cells to become – their own T cells to become more functional to really kill the tumor cells. And so that's really the foundation for understanding that what that T cell state is can really impact how effective they can be. And so then I think it made sense in the context of T cell therapies, especially when you're starting with taking a patient's own cells and you know that they've experienced the tumor, you know, do we think that they're exhausted? Do you already start out with exhausted material so that, when you engineer that T cell to express, you know, in this case let's say, a CAR to recognize the tumor, you're already at a disadvantage. I guess that's what I'm trying to say.

Danielle: Yeah. [Laughs]

Soyoung: And so that's where some of those other engineering approaches have come in, for example, people trying to knock out PD-1. But in some sense, I guess, I wonder about the challenge of really reprogramming a cell to become more functional as opposed to going down the route of trying to have – trying to select for the most functional cells to begin with. And that's where I think there are opportunities in making T cell therapies from someone who's healthy – being able to really characterize the cells before you even start the engineering process to try to give them the best chance.

Danielle: Yeah, set them off on the right foot.

Soyoung: Yes, exactly.

Danielle: How much of the future of cell therapy depends on better cells versus better ways of measuring what those cells are doing inside of patients?

Soyoung: Yeah. I think they're interconnected and I think we can still learn by doing more upfront to really deeply characterize the product that we have. You know, maybe going to the point earlier that, because it's a living cell, there's a lot more variability, and it's not like having this list of criteria that we know, like, this is what an antibody should look like. While that presents a challenge, I think we can really think about what are the important ways we characterize the cells whether it's understanding, you know, their gene expression profile, making sure we have the best experiments to ask how functional did they look before they go into a patient? And I think that tied with some of the initial information that you could get from a clinical trial. You know, tracking how much do the T cells actually proliferate? How long do they stick around? How does that correlate with the response that you see in the patients? I think that can be a good starting point. But as we're doing that, and maybe as you're getting better T cells where you get more of them out of the patient, having that deeper profiling in the patient after they've been exposed to the cancer, to other signals in the environment, I do think that becomes critical – especially for thinking about next engineering, like next-generation engineering.

Danielle: Yeah. Soyoung, it was so great to have you here. Thank you so much for sitting down with us.

Soyoung: Thank you so much, Danielle. It was really great to talk with you.

Wellington: Danielle, that was a really interesting episode. I think it feels like we're at the edges of science when we're talking about cell therapy, and I enjoy that. And as a science fiction person, any time you bring up science fiction, I'm all in. But I'm wondering about this concept of cells that sense things, and I started thinking about how cells are things that sense their environment. Do we even know anything about this, other than platitudes of “They talk to each other?” Is this like cell-splaining?

Danielle: [Laughs] I do not know. But you know, like, this is probably like – everything with cell therapies is probably one of my favorite areas to learn about and to be witnessing in real time just because there's so many complex layers to cell-to-cell communication. And what makes it really wild is some of it is so, like, concentration dependent. You know it's kind of like people – like if I whisper to you versus I scream at you, like you're hearing my message with different ways and different tones, right? But think about from, like, an analytical standpoint – how do you tease that out? If you have like local concentrations versus like what's realistic in a clinic – and just to bring you into my world, we always think about like, oh, if I wanna know what's happening with a patient, I have to go to, you know, something where it's like clinically accessible, meaning like I can actually take blood and it's realistic, right? So whenever you're talking about these cell-to-cell communications, like, how do we get down there? Do we have, you know, like, to that kind of nitty gritty different locations in the body? I think it's a very interesting field because we kind of rely on these downstream kind of biomarkers to let us know what were those conversations? But hearing those conversations in real time is very hard to do. I mean, there's like cytokine assays and stuff where we can like look for the words that they're spitting out, but having them in concentration and like region specific is I think like the next area when we start thinking about tracking cell therapies, where are they in certain locations and what are they doing in those locations versus like globally in the body? It's a very weird, interesting place to kind of analyze.

Karen: Is there an area of cell therapy that you're particularly excited about that maybe we didn't get into as much on this episode?

Danielle: I feel like we touched – like, okay, so the thing I think is the most exciting, of course, is tracking the cells and understand, like really kind of understanding what are they doing in those little nooks and crannies in the body? I think it's from a technical standpoint, wildly interesting. Biological standpoint, what the heck is happening? I mean, there's just so much that I think over the next five years we're gonna learn that has been such like critical parts of biology. But until we've been forced into a functional space where we have to find the answer, it's going to put us in a very different position to understand the biology.

And that's our show. Thanks so much for listening. If you haven't already, rate our podcast, wherever you listen – it will help new people to find us. And make sure to subscribe. If you have any questions about the show, you can contact us at podcasts@gene.com. And now for me, it's back to stalking cells!

The name Two Scientists Walk Into A Bar is under license and used with permission from the Fleet Science Center

For decades, KRAS was considered one of cancer research’s toughest targets. Discover the fresh thinking behind a new chapter in KRAS research.

In a conference room buzzing with ambitious ideas, a colleague leaned back and whispered loudly a phrase that made the whole research team laugh: "This entire project is science fiction."  They laughed because everyone in that room knew the daunting reality: for decades, KRAS had been considered one of the toughest targets in cancer research.

In certain lung cancers, specific mutations like KRAS G12C prolong the protein’s
active state¹ - acting like a jammed accelerator pedal that keeps growth signals permanently switched on to drive uncontrolled cell growth. For Genentech Research and Early Development (gRED) senior director, Hans Purkey, who has spent his career bridging computational chemistry and drug discovery, the work also carried a personal connection through his own family’s experience of cancer.

Yet in the early stages, progress felt agonisingly slow. The team spent six long months "wandering in the wilderness," where nearly 99 percent of their chemical tweaks did not make compounds better than where they had started.

“We knew other teams were making progress, which made it an incredibly exciting time to be working on KRAS. But it also made us ask, what could we do differently?”

Targeting the "back pocket"

The answer lay in a landmark 2013 discovery by academic researchers at the University of California, San Francisco. They revealed that the inactive KRAS G12C protein features a hidden, transient pocket - known as the Switch-II pocket - that occasionally opens allowing a small molecule to slip inside and lock the mutant protein in an inactive state.¹ With this discovery in mind, Purkey’s team saw an opportunity to engineer a candidate tailored to fit as snugly and selectively as possible into this pocket and shut down the continuous signals driving cancer cell growth.

Combining computational design and other methods of modern medicinal chemistry, Purkey and his team spent several years designing molecules to bind the Switch-II pocket with high affinity, by optimizing the interactions deep inside the pocket. By ensuring the molecule fits as snugly as possible inside the pocket before irreversibly locking in place, the team aimed to develop a compound with high biochemical potency in their early research.

By engineering a novel structural piece to slip into a region of Switch-II, nicknamed the "back pocket," they created a candidate that altered the trajectory of their research. In the summer of 2018, the first activity test results arrived for this new molecule. In preclinical laboratory assays, this candidate demonstrated ten times the potency of any molecule the team had previously synthesized. Worried that this could be an experimental mistake, Purkey ordered a repeat measurement the following week, just to rule out a testing error. When the results came back confirmed, the team knew they had found a new direction to pursue and accelerated its advancement.

An elegant two-step lock

The secret behind this change in laboratory potency was the molecules architecture. At the molecular level, the team’s design centred on a two-step mechanism. First, the molecule fits tightly into the binding pocket through highly optimized interactions. Second, it is designed to rapidly form a permanent bond with the mutated G12C protein, locking the protein in its inactive state.² Because cancer cells can continuously produce new KRAS G12C proteins,¹ the team designed the molecule to bind tightly and react rapidly and selectively.

Science in the service of patients

For Purkey, engineering a molecule designed to target cancer signaling was never just a biophysical puzzle - it was a personal mission. Earlier in his career, while visiting a family member in hospital, a physician told Purkey that while doctors may treat thousands of patients in a lifetime, a scientist who discovers a medicine has the opportunity to touch many more lives. Today, as science continues to move forward, his project stands as a testament to human persistence. It serves as a powerful reminder of how curiosity, collaboration, and courage can transform decades of scientific doubt into new avenues of clinical research for patients facing cancers.

For Jorg Blumel, the appeal of biology always lay in translation. Growing up in Germany, his parents encouraged him to explore a wide variety of interests, but Jorg became fascinated by science early on because of how applicable it was to his environment. He loved figuring out how concepts from his biology classes applied directly to the world around him. And as he explained his learnings to non-scientists like his parents, he found it very meaningful to translate scientific complexity into clarity for the people around him, too.

“For me, science is not only a matter of creating knowledge. It's about how knowledge impacts us as individuals, as a society, and our environment,” Jorg reflects. “That’s what really drove me from my earliest days in biology.”

This early inspiration led Jorg to study biology in his undergraduate years at the University of Göttingen in Germany. However, it was an internship in the pharmaceutical industry that truly narrowed his scope and cemented his interest in drug development. Jorg didn’t know much about the process at first, but when his supervisors suggested that he focus on toxicology to experience a wide variety of projects, he thought, “Yeah, why not?”

Toxicologists evaluate the safety of therapeutic candidates and help translate that data into critical patient-centered decisions to support the overall risk-benefit assessment. The field immediately captured Jorg’s interest – translational insight, after all, was at the core of his passion for science. Furthermore, safety considerations are relevant from the very inception of discovery research, through clinical trials, and even after drug approval. This meant Jorg wasn’t limited to either research or development; he could be involved in the entire life cycle of a medicine.

TAKING THE ROAD LESS TRAVELED

When it came to his graduate studies, Jorg chose a non-traditional academic path. “I wanted to apply science and not just accumulate scientific knowledge,” he says. He obtained an industrial Ph.D. through the University of Düsseldorf in Germany, which allowed him to conduct his research at a pharmaceutical company. There, he studied immunotoxicology to better understand how drugs interact with, and disrupt, the immune system.

Following his Ph.D., Jorg wholeheartedly pursued a career in industry. In his very first role he supported a global filing that paved the way for a commercial drug launch. Watching this internal project transform into a physical medicine for patients – even reaching his own friends and family – was not only memorable, but constituted a significant source of motivation for him. “A lot of people work for a lifetime and barely see one of their drugs come to market,” Jorg explains. “You can get easily kind of lost a little bit in science and portfolio. But I had a very early understanding of what it feels like to actually get it over the finish line.”

Another pivotal moment came when Jorg left Germany, his home country, to take a position at a biotech company on the east coast of the United States. He was now translating concepts not only within science, but across cultures. He credits this shift with broadening his perspective beyond the European way of thinking to a more global perspective.

Then, Jorg visited California with his wife for the first time. He recalls how she jokingly asked if he would get a job there so they could come back, and that got him thinking. He had long admired Genentech’s commitment to innovation. “It has a tremendous legacy,” he says, “where really excellent science, drug development, impact – impact on patients, on society – coalesce.”

PUTTING THE “&” IN “R&D”

Twelve years on, as the Senior Vice President and Global Head of Development Sciences (DevSci) at Genentech, Jorg leads multiple teams that support the end-to-end drug development process. “My team is, in its entirety, responsible for doing that translation from research into development, from preclinical development to clinical development,” Jorg explains. But the translation doesn’t only go one way: “We learn a lot in clinical development both from our successes, but also from failures that can inform how we think about future projects.”

The Translational Safety team within Development Sciences, for example, is involved from the earliest stages of discovery research. The team conducts studies to understand the safety implications of engaging different therapeutic targets or modalities, guiding the strategic selection of lead candidates and preparing a well-characterized safety profile for the molecule so it can move into clinical development. Although unfavorable safety data can prevent molecules from progressing past the preclinical stage, Jorg’s philosophy is one of enablement. “It's relatively easy to kill a project; it's much more difficult to enable it,” he says. “You have to ask the bigger question: ‘How can we make it work in a safe way for patients?’”

Once in development, Jorg’s teams help turn the therapeutic molecule into a medicine that can be safely administered to humans and tested in clinical trials. Groups like the Translational Pharmacokinetics and Pharmacodynamics (PK/PD) team predict how the drug will affect and move through the body, helping determine a starting dose, route of administration, and dosing regimen that balance therapeutic efficacy with patient safety. Other teams play a more prominent role as the molecule enters clinical development. One goal of the Bioanalytical Sciences group is developing methods to measure therapeutic drug concentrations and quickly test for unwanted immune responses in patients. Meanwhile, a key role of the Clinical Pharmacology team is to ensure that individual patients are appropriately dosed in clinical trials to maximize clinical benefit while ensuring patient safety.

Jorg also makes sure that his teams adhere to global regulatory requirements while innovating new technologies, and facilitates cross-functional collaboration to support drug filing for regulatory approvals. The teams continue to gather and analyze data about the molecules even after commercialization. “DevSci is really about connecting across the entire R&D value chain,” Jorg emphasizes. “It's not an individual entity who delivers a work package and then walks away.”

Looking to the horizon, what truly drives Jorg is the incredible speed at which science and technology are evolving – and, more importantly, how we can harness that momentum. His core passion lies in partnering with his teams to turn these cutting-edge tools into practical, innovative approaches that give us clearer answers earlier in the drug development journey. “Bringing tools like complex in vitro systems, machine learning, and predictive modeling into our scientific toolbox isn't only a technical upgrade, but rather a foundational piece of our DevSci strategy and a critical enabler for where we're headed,” Jorg shares. Yet, he is quick to keep the patient impact at the forefront: “Innovation for the sake of innovation isn't the goal. The real magic happens when these novel approaches don't just exist in a vacuum, but are seamlessly woven into how we make decisions for our portfolio and patients every single day.”

SEIZING MOMENTS OF SERENDIPITY

Beyond leading Development Sciences at Genentech, Jorg takes time to mentor the next generation of scientists. He values forming bidirectional relationships in which he is learning something new, too.

As a mentor, Jorg stresses that a career rarely follows a straight line. “You cannot plan the availability of an opportunity. But what you can work toward is the readiness to take it on,” he advises. “In my career, most of the successful roles I took on came by surprise.” He also underscores the importance of taking risks in order to grow and ultimately flourish. “You have to be willing to get out of your comfort zone, which means a lot of opportunities might feel a little bit challenging, maybe a little bit too far off. And I tell people, if you don't have that uneasy feeling when you take on something, the opportunity is probably not the right one.”

Jorg admits his brain is often firing on overdrive; when the workday ends, he needs a way to decompress. Nature offers the perfect respite. He finds particular joy walking along the beach with his Australian cattle dogs: “At home with my dogs – walking with them, enjoying nature, enjoying quietness – it is something that gives me the reset I need to get up and begin again the next day.”

MASH (metabolic dysfunction-associated steatohepatitis) is a serious and progressive liver disease driven by cardiometabolic risk factors such as obesity and type 2 diabetes.^1-3 Yet symptoms can be vague or absent, making the disease difficult to recognize, and liver damage may progress for years without being detected.^2,3,5 As MASH progresses, inflammation and fat accumulation can cause fibrosis, or liver scarring, which can eventually progress to cirrhosis and other serious liver complications. Because symptoms can be vague or difficult to recognize, some people may not be diagnosed until the disease has already advanced.^2-4

For Lori Merz, that reality became clear in the most unexpected way. Like many people living with MASH, Lori's health journey involved multiple interconnected metabolic conditions long before she knew her liver was at risk. Following treatment for Graves' disease, an autoimmune condition affecting the thyroid, she experienced ongoing thyroid dysfunction that dramatically slowed her metabolism. Over time, she gained nearly 100 pounds and developed type 2 diabetes and gastroparesis, a condition in which the stomach empties more slowly than usual.

Managing these conditions became the focus of her healthcare journey. The possibility of serious liver disease never crossed her mind.

"I thought I understood the health issues I was dealing with," Lori recalls. "Liver disease wasn't something I was worried about."

That lack of awareness is common. MASH is strongly associated with obesity, type 2 diabetes and other metabolic conditions.^1-3 Because the liver plays a central role in the body’s metabolic processes, metabolic dysfunction can directly affect liver health. Yet many people, and even some healthcare providers, may not recognize the relationship between metabolic dysfunction and liver disease. As a result, MASH can progress silently for years before being diagnosed.^2,3

In 2017, Lori was preparing to undergo gastric bypass surgery to help improve her health. But shortly after the procedure began, surgeons discovered something alarming.

"They stopped the surgery because they found cirrhosis," she says.

Cirrhosis can be the result of progressive liver scarring caused by MASH, and Lori’s diagnosis revealed just how far her liver disease had progressed without her knowing it. What was even more shocking was that none of her routine blood work had ever pointed to a liver problem and even today, still doesn’t. If surgeons hadn’t discovered the cirrhosis during her 2017 surgery, she may not have known how advanced her liver disease had become.

The diagnosis was a complete shock.

"I don't drink," Lori explains. "I didn't know someone could develop cirrhosis if they didn't drink alcohol."

Historically, public understanding of cirrhosis has often been associated with alcohol-related liver disease. However, MASH has emerged as a leading cause of advanced liver disease and liver transplantation, driven by the growing prevalence of obesity and type 2 diabetes.^1-3,5 Progressive fibrosis, or liver scarring, can eventually lead to cirrhosis, liver failure, liver cancer and the need for transplantation.^2-4

Following the discovery, Lori underwent a liver biopsy and further evaluation at the University of Pennsylvania. Physicians confirmed that her liver disease was advanced and explained that she could eventually require a liver transplant.

The news transformed her understanding of her health.

"It was terrifying," she says. "One minute you're preparing to take a step toward improving your health and the next you're hearing about the possibility of a transplant."

Lori's experience highlights one of the greatest challenges in MASH: the disease often produces few warning signs until substantial liver damage has occurred.^2-4

Looking back, Lori cannot identify symptoms that clearly pointed to liver disease. Instead, most of her attention was focused on managing diabetes, gastroparesis and other immediate health concerns. Between the constant medication changes, insulin management and day-to-day symptoms, there was little reason to suspect that her liver disease had progressed so significantly. Since her diagnosis, however, monitoring her liver has become a permanent part of her life. Regular bloodwork, endoscopies, ultrasounds and cancer surveillance appointments help her healthcare team watch for signs of disease progression.

Last year, doctors identified lesions on her liver that required additional investigation. Fortunately, follow-up magnetic resonance imaging (MRI) scans confirmed they were not cancerous. Even so, the experience underscored the uncertainty that many people with advanced liver disease live with every day.

MASH does not exist in isolation. The disease is deeply connected to broader metabolic health, and many people experience multiple serious conditions simultaneously.^1-3

For Lori, diabetes management has been one of the most difficult aspects of her health journey. At one point, her HbA1C climbed to approximately 13%, requiring intensive treatment with multiple forms of insulin. Although an insulin pump initially helped, a malfunction later contributed to a serious medical event that resulted in a tonic-clonic seizure. The seizure was so severe that she bit chunks from the side of her tongue during the episode.

She has also faced additional health complications including sepsis, diabetic ketoacidosis and kidney stones.

Fatigue remains one of Lori's most persistent symptoms.

"I wake up feeling sick most mornings," she says. Some days are better than others, but fatigue, nausea, bloating, and the challenges of managing multiple conditions continue to affect her life daily. She has also dealt with hip issues and what she describes as diabetic shoulder, adding to the physical burden of her health journey.

For many people living with MASH-related cirrhosis, fatigue, nausea and uncertainty can have a profound impact on daily life.^2-4 Yet because these symptoms are often invisible to others, the true burden of disease may be overlooked.

Despite these challenges, Lori is committed to raising awareness.

"If I had known I was at risk because of my diabetes and other health issues, I would have wanted someone to check my liver sooner," she says.

Her story reflects a larger need within the MASH community. Significant gaps remain in identifying, diagnosing and managing people living with MASH, particularly those with advanced fibrosis and cirrhosis.^1-3

Increasing recognition of these connections may help more people receive appropriate evaluation and care before they develop advanced chronic liver disease.^1-3

Lori’s experience also highlights the liver’s important role in the body’s metabolic processes. MASH is a complex and progressive disease that can advance without obvious warning signs and have life-changing consequences if left undetected.^1-5

"People need to know this can happen," she says. "I never imagined I would be diagnosed with cirrhosis. If sharing my story helps someone catch it earlier than I did, then that's something positive."

Stories like Lori’s reinforce the need to increase understanding of the connection between metabolic and liver health. At Genentech, we are committed to advancing science that addresses the complex biology of MASH, including liver fibrosis and the underlying metabolic dysfunction associated with disease progression.^1-3

Through greater awareness, earlier identification and continued innovation, our goal is help improve the future of care for people affected by this serious and often overlooked disease.^1-3,5

When Julie began experiencing watery eyes and increased sensitivity to sunlight, she didn't think much of it. The longtime educator spent her days traveling throughout the county, training teachers, supporting schools, and managing programs, and she chalked the irritation up to long hours and screen time. Over time, though, the symptoms got harder to ignore.

The swelling around her eyes worsened. Her vision blurred. Eventually, she started seeing double, which made it difficult to read, drive, and keep pace with the job she loved. “Things weren't the same,” Julie recalls. “It became harder to keep up each day.”

It took years of searching for answers, and nearly three more after a Graves’ disease diagnosis and a total thyroidectomy, before Julie was finally diagnosed with thyroid eye disease (TED).

TED is an autoimmune disease that causes inflammation and swelling of the tissues around the eyes, including the eyelids, eye muscles, and tear glands. People with Graves' disease, like Julie, are at an increased risk of developing TED, which can cause symptoms including: eye pain, redness and swelling, light sensitivity, blurred or double vision, difficulty moving the eyes, and visible changes such as bulging eyes, eyelid retraction, or a staring appearance. Other risk factors include family history, other autoimmune diseases, gender, stress, or smoking. While some cases are mild, it can potentially lead to lasting vision changes, serious eye complications, and permanent damage to the tissues around the eyes.

“Receiving the initial diagnosis was a shock that left me fearful and searching for answers,” Julie says.

As a longtime educator and patient advocate, Julie knew how to research a condition and ask her doctors the right questions. But she soon learned that some of TED's heaviest effects don't show up in any exam room.

“Patients with thyroid eye disease may not look ‘sick,’” she says. “What you don't see are the symptoms that are difficult to put into words and less visible to others.” Those symptoms, she found, were often harder to explain to others than the visible ones.

That gap, between what she felt and what she could explain, followed her for a long time. Until she found a new avenue to express herself through art therapy.

Julie has always considered herself an expressive person, so when the emotional weight of her diagnosis became too heavy to carry alone, she looked for a creative outlet. “I was anxious for the first class,” Julie remembers. But once she was there, surrounded by others facing their own health challenges, something clicked. “I saw others who are also going through the same thing,” she says.

Through guided prompts and creative exercises, Julie found a way to put her experience with TED into a form words hadn't quite reached. “Art allowed me to express myself in a different way.”

Over time, art therapy became more than an outlet. It became a practice. “It was the best thing I could have ever done,” she says. She began looking forward to each session and the community she found there.

Art gave her a way to slow down, reflect, and communicate what she was going through, not just to her doctors, but to herself. That experience reinforced something she now says she believes deeply: care for a chronic condition has to include care for the mind, not just the body.

Because TED symptoms often develop slowly and are easy to dismiss at first, many people spend months or years searching for a diagnosis. “For anyone noticing changes in their eyes or vision, speak up!” says Julie. “Ask questions, and find providers who take the time to explain things clearly.”

She also encourages something less expected: finding your own way to express what a diagnosis feels like, whether that's through conversation, advocacy, or, as she discovered, art.

“Through my experience, I've learned that better communication is a team sport,” she says. “The lines must be open on both ends, both to alleviate fear and smooth the path to better outcomes.”

Julie hopes that sharing her story, including the unexpected role art has played in her journey, helps others feel less alone in navigating TED, and more confident asking for what they need. For her, a clear diagnosis, an engaged care team, and a creative outlet that fits her own way of processing hard things, has made all the difference.

To learn more about TED, click here.

The Impossible Bet explores Genentech’s journey from a bold scientific vision — first sketched across a series of napkins at a local bar — to 50 years of innovation and patient impact. Through firsthand patient experiences, archival storytelling, and employee perspectives, The Impossible Bet examines how a bold idea advanced care for patients around the world and launched the biotech industry.

More than a retrospective, The Impossible Bet uses Genentech’s first 50 years to show why scientific progress matters: because of what it can make possible for patients, families and the communities around them.

The Impossible Bet was produced by T Brand, the content studio within New York Times Advertising, with support from Brother Films and SJB Productions.

Explore Genentech’s 50th anniversary story to learn how 50 years of science, bold breakthroughs and the people behind them have helped change lives and continue to shape what comes next.

^{Please see the HERCEPTIN full Prescribing Information for additional Important Safety Information.}

Is the human heart an evolutionary miracle or a single point of failure? In this episode, host Maria Wilson is joined by Saptarsi Haldar, Senior Vice President, Head of Research Biology, to dive into the central engine of the human body. Together they explore how the heart functions, what happens when it fails, and the evolution of treatment, up to the latest breakthroughs. From the future of cardiac repair and precision medicine to the game-changing role of AI, this episode is a front-row seat to the next frontier of cardiovascular science. Join us to learn about the muscle that powers billions of lives.

If you would prefer to read a transcript of this episode, please click here.

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If you want to learn more about the groundbreaking science happening in our labs, click here. To learn more about the jobs in our research and early development group, click here.

Transcript of Two Scientists Walk Into A Bar: “State of the Heart” with Saptarsi Haldar

Maria: I’m Maria Wilson.

Danielle: And I’m Danielle Mandikian.

Maria: And we are scientists. We. Love. Science.

Danielle: Yeah, we do. So, when we aren’t doing it, the next best thing is to talk about science! And what’s really awesome is that we’re surrounded by some of the most brilliant minds in research!

Maria: We are going to step away from the labs today to talk to other scientists about the cool stuff they are thinking about, working on and imagining . . .

Danielle: . . . as well as how some of these discoveries just might lead to new medicines. So, grab your favorite drink, get ready to unlock your science brain and join us for Two Scientists Walk into a Bar…

Maria: The show for scientists, science geeks, and the people who love them!

Maria: Our question this month is how many times does the human heart beat in an average lifetime?

Employee responses:

In an average lifetime? Oh wow.

I don't even know how many times it beats in a day.

In an average lifetime? 60 to 80 beats per minute.

I'm at 80 – I am at 86, maybe 80 on average.

It's at 60 per minute. 65, maybe.

60 per minute? Mine's like 80, dude.

Okay, yeah. I'm stressed. 80 per minute.

What's our average, 64?

64? 78. Give us a little more faith here.

Oh, wow. That's 2 billion.

Oh, that's 2 billion. Whoops.

2.4 billion.

2.4 billion.

Each one of them goes by so fast, you know?

2 billion, yeah?

Unless you are giving interviews, it beats even faster. [Laughs]

Maria: Welcome back! So we're gonna talk today about the heart, which is not a topic we've talked about before on the podcast. And when I was preparing for this, I was reminded of a scientific talk I saw back in the '90s and this has stuck with me. The investigators showed a picture of a zebrafish – developing zebrafish embryo at the moment the heart starts beating, and in the video, the embryo goes from being completely colorless to being pink. And it's just this really awe-inspiring moment of seeing that there is a moment in time for an organism when its heart starts beating, and that heart just keeps on beating! Our heart beats apparently 35 million beats per year, hopefully for 70 or 80 years, and it's incredible how much work the heart does, and we just take it for granted. So today, I have with me a fantastic guest, Dr. Saptarsi Haldar, who is a cardiologist and a scientist, and the perfect person to tell us all about the heart, how it works and what happens when it fails. Saptarsi, welcome.

Saptarsi: Thank you for having me, and excited to talk about one of my favorite areas of medicine, drug discovery and science.

Maria: So, the human body has redundancy – this is from Wellington, we were talking about this. We've got two lungs, two kidneys, two eyes. Octopuses do have three hearts, I reminded Wellington, but most organisms only have one. The question is, why do we only have one heart? Is that poor design by evolution, or just because it's so amazing we only need one of them?

Saptarsi: Somewhere along the road, evolution made a choice, so to speak, or a trade-off that, you know, we're gonna have humans with only one heart, as opposed to kidneys, where you have two. Maybe there's some cost to having two hearts. You can't have two hearts pumping blood at once, and you've got to kinda maintain each organ. Probably, it was better evolutionarily to just have one heart and actually preserve it and take care of it.

Maria: Tell us a little bit more about the heart, and how it works, and what its challenges are in staying, keeping going for 70, 80 years.

Saptarsi: So, let's kinda take a step back. You know, the heart is a muscle, and it's kind of like a cousin to the muscles we're all used to like the skeletal muscles in your biceps or in your legs, except it's evolved to be a little different. And one thing that it's evolved to do, you know, is actually keep going and going and going without getting fatigued and tired. If you think about it, when you exercise a lot, even if you go for a light jog, eventually your muscles in your legs get tired, right? But it doesn't happen that way for your heart, right? Your heart keeps beating all night when you sleep, and it doesn't get tired.

Maria: So the heart doesn't get tired, but in some people it does slowly or rapidly fail. What do we know about this common disease we call heart failure?

Saptarsi: Yeah, it's probably one of the most common diseases out there. And in the United States, and increasing worldwide, it is the number one cause for hospitalization. I told you the heart's job, it's a muscle, and its job is to seamlessly and reliably pump blood to all the organs in your body, and the blood contains oxygen and nutrients. So if your heart isn't pumping blood, the rest of the organs in your body are not gonna function, and most importantly your brain. If you think of your heart as kind of an engine in a car, because all of the cells – the muscle cells in your heart are kind of like the cylinders of an engine. The problem with the heart, at least the mammalian human heart, is that if at any point along your long life you damage or lose a cylinder or two or three, the heart has not evolved the ability to regenerate or replace those cylinders of the engine. And if the heart sustains enough wear and tear and damage, it's not going to be able to pump blood to the rest of the body in a manner that supports your daily activities. And so this is the way I think about heart failure – heart failure is really a syndrome. It's not any one disease where I can take a blood test and say you have heart failure, or I can do a scan and say you have heart failure. It's actually a constellation of symptoms and clinical findings that boils down to your heart cannot pump enough blood to the organs in your body to meet the needs of your activities of daily living. What's interesting is you can have that syndrome of heart failure. You can have it obviously if you start with six cylinders, if you get down to two cylinders or one cylinders, you can have heart failure, but you can actually have heart failure with five or six cylinders as well. That's kinda the analogy, but how do you get heart failure, right? What damages those cylinders, right? Many many many things can damage those cylinders.

Maria: I suppose simplistically, I tend to think of it – in the people I know who've had heart failure, it's been subsequent to a heart attack or MI, and many years later, that damage to the muscle leads to heart failure. But that's not the only way to develop heart failure.

Saptarsi: No, it's one of the most common ways to develop heart failure. So, for those in the audience, a heart attack or myocardial infarction is basically when you lose blood supply to a portion of the heart because of lack of blood flow from one of the arteries that supplies the heart. And the heart being highly, highly energetically demanding doesn't tolerate that well. So, if, you know, 30 minutes, an hour goes by, you actually lose the muscle. You can very quickly lose a cylinder or two or three depending on the size of the heart attack, and if you don't restore that blood flow, the heart muscle's gonna die, you're gonna lose those cylinders permanently. But there's lots of other things that can damage the heart. Common things. So, having high blood pressure, for too high for too long. You can get it from, you know, problems with the kidneys can put you into heart failure because the kidneys aren't getting fluid out of the body, the fluid can overload the heart. You can get problems with your heart rhythm. You can have problems with the heart valves leaking. You can be born with heart abnormalities that happen in kids, and they can lead to heart failure. There's actually genetics that cause heart failure, often due to some sort of mutation that you're born with that causes the heart muscle cell to malfunction over time. There's things that can infiltrate the heart from outside the heart. People might have heard of amyloid in Alzheimer's disease in the brain, there's actually types of amyloid that can infiltrate the heart as well.

Maria: So, many many causes.

Saptarsi: Many many many causes.

Maria: But the person usually shows up at the hospital with the same type of symptoms for an initial diagnosis.

Saptarsi: Yeah, and what people may not understand is that when you actually present with symptomatic heart failure, particularly symptomatic heart failure that requires you to come to the hospital, unfortunately even with today's standard of medical care, it's not a great outlook. And presenting with advanced heart failure carries a prognosis that's as bad as advanced forms of some of the common cancers.

Maria: And people really don’t appreciate that.

Saptarsi: Yeah.

Karen: Hi Maria.

Maria: Hi Karen!

Wellington: Hi Maria.

Maria: Hi Wellington!

Wellington: I'm a little disappointed that evolution didn't give us more than one heart, not gonna lie. But my question for you is when I grew up being a little older, heart failure was seen like dementia as something that just happens to you. But you guys didn't talk about aging as a cause of heart failure – is it?

Maria: Yeah, incidence of heart failure goes up with age, for sure. And by treating heart failure and preventing it, we will extend lifespan and health span. I also, on the evolution point, you've got to remember that all evolution wants to do is to get you to reproduction. So it's very, we don't evolve to really live past passing on our genes.

Wellington: Boo!

Maria: [Laughs]

Karen: Maria, what is one of the best ways to prevent someone from getting heart failure?

Maria: So there's lots of things that we could do to take care of our hearts. But the one thing I'd like to call out is just to make sure that you know what your blood pressure is. You can be leading a healthy life with exercise and diet and yet have hypertension. And if you don't get your blood pressure measured once a year at the doctor, or even get yourself a blood pressure cuff to measure it at home, you're missing out on an opportunity to intervene and really prevent heart failure and cardiac issues.

Maria: So, I did want to get into a little bit about the different types of heart failure. This idea of preserved ejection fraction and reduced ejection fraction in heart failure.

Saptarsi: I would say the more straightforward way to understand heart failure is kind of the cylinder analogy that I made before. Classically, we thought of heart failure as losing some of those cylinders in the engine, and then, you can understand, I started with six cylinders, and progressively wear and tear, damage, I went down to two cylinders, and now that heart basically can't generate as much force and can't meet the needs of the body. So that's basically the form of heart failure we've all come to know and it's called heart failure with reduced ejection fraction. I'm not gonna get into the semantics, but ejection fraction is just some metric of how much the heart can squeeze with one pump, and it's reduced because you've lost some cylinders. And what happened starting in the '70s and '80s, it was recognized that there were patients coming into the hospital with something that looked like heart failure. You know, shortness of breath, fluid in their lungs, fluid in their legs, inability to walk and exercise – and even got better with removing the fluid. But what was interesting is, the reason why this got really noticed in the '70s and the '80s was because in the '70s and the '80s was really when the technology of noninvasive ultrasound came into clinical practice. So it's called echocardiography, but it's basically an ultrasound of the heart where you can put some jelly on and you can take pictures of the heart, these black-and-white pictures, and you can get really detailed images of the heart to see all the structures, and you can see it moving in real-time, and contracting. You can see how the blood's flowing. And so what people noticed when people came in with these symptoms of heart failure, they're thinking, oh, the heart must not be squeezing as well. But lo and behold, when they did these ultrasounds, they found, oh, the heart's squeezing actually normally with each pump, and the heart's not all dilated like a round basketball, and so they just called it heart failure with preserved ejection fraction.

Maria: It's kind of a diagnosis of exclusion type of thing.

Saptarsi: Yeah, but the problem was, and the problem kinda still is, we're not sure exactly what causes it. I think we've learned a lot in the last 40, 45 years, but we're still trying to unravel what causes it. And it turns out it's as common as the original form of heart failure with the reduced ejection fraction. So the preserved ejection fraction is kinda the analogy where you can have heart failure, but now five or six of the cylinders are actually firing, so there's something else wrong with the mechanics of the engine. If you thought heart failure with reduced ejection fraction was heterogeneous and so many different things could cause it, this newer form, the preserved ejection fraction, is even more heterogeneous. But the one thing I'll say we've learned is that the demographics are starting to change. I think we're starting to see over the last 40 years that this preserved ejection fraction form of heart failure is becoming more and more prevalent. And I think there's a very, very strong link in many cases to obesity and diabetes. But what's interesting is, if you get this second kind of heart failure, heart failure with preserved ejection fraction, and you get hospitalized, it turns out that it's just as bad as the first kind of heart failure as far as your prognosis and mortality. And we still don't exactly know why these patients are doing so poorly, and so we have a lot to learn.

Maria: I wanted to chat a little bit about what have been the breakthroughs in the treatment of heart failure. And when I was thinking this through, because I've lived some of this stuff as well, I was realizing that heart failure is quite a good analogy for drug discovery and development in general, because you have, sort of, nice scientifically driven hypotheses like the neprilysin inhibitors, then you have beautiful science like the myosin activators which is just such cool drug discovery. And then you have SGLT2 inhibitors, which I guess really were a bit of a wild card, and does anybody even understand how they work? So please, what do you think are the biggest breakthroughs in heart failure that we've seen, and tell me a little bit about what you think about the standard of care, the landscape of care?

Saptarsi: I think what we've learned for heart failure, the best thing we can do for patients is to try to prevent it in the first place. And I think we've learned that all these things that can damage the heart over time, many of them are preventable. So, you know, if you're at risk for having cholesterol clog your arteries, let's prevent you from ever having that heart attack in the first place, right? So let's treat that cholesterol, let's treat the blood pressure. If you have a leaky valve, let's see if we can get that fixed before it becomes a problem. And so I think these things are really important. Now we're actually learning if you are living with obesity, maybe treating that can prevent future heart failure.

Maria: That's a huge recent learning.

Saptarsi: And I think we're gonna learn a lot more about this. So I think prevention, prevention, prevention is gonna be the most impactful. But despite our best efforts to prevent, the heart's still gonna get into trouble in a lot of patients, right? So it's interesting to see, let's take the original form, the heart failure with reduced ejection fraction. If you actually think about it, you can say all right, my engine's damaged. I'm living off three cylinders instead of six. So, why don't I give a little bit of like juice to juice up those three cylinders? That's what people thought would be the right idea in the late '70s and the early '80s, and they gave medicines that were kinda equivalent to the hormones epinephrine, these fight or flight responses to flog the heart into pumping more. And what's interesting is, if you did that to a heart failure patient, they would feel better. Actually, many of them would feel a lot better really quickly, and actually some of their organ function will improve. And we actually ran trials on this in the '90s – like large randomized placebo-controlled trials, the gold standard in this field. And it turns out when you do that, and you follow patients over years, you're actually adding fuel to a fire. They actually make the heart muscle worse over the long-term, and they put patients at risk for electrical disturbances in the heart and sudden cardiac death, which is actually something that heart failure patients are at risk for substantially. So this is an important lesson in pharmacology, because it turns out that we learned through basic science that doing just the opposite may actually be better. It's counterintuitive. If we give a medicine that kind of blocks that epinephrine-like fight or flight response – and this class of medicines was an old class of medicines called beta blockers, which many people know about. When you think about it, beta blockers actually, if you give them acutely, will make the heart squeeze less powerfully.

Maria: Yes.

Saptarsi: That's what they do. But it turns out over long periods of time, that protected the heart, and protected the heart dramatically in randomized controlled trials. So we had this whole era of neural hormonal blockade, and it actually revolutionized heart failure therapy.

Maria: It did, yeah.

Saptarsi: The other thing I should mention is actually devices. Heart failure is one of these fields where human device therapy also co-evolved with the drug therapy, and so pacemakers and defibrillators, the implantable cardiac defibrillator was also revolutionary, because you can implant them, and because heart failure patients are at risk for unexpected sudden death, right? The heart will just stop beating due to a malignant electrical disturbance. These defibrillators – it's fully self-sufficient. It's got a battery, and it'll shock you from the inside.

Maria: And it detects when it needs to do it.

Saptarsi: Yep, it can detect when it needs to do it. And those have turned out to be life-saving in the high-risk patients. So, this has really evolved. And so there's been a couple other interesting things you mentioned here – SGLT2 inhibitors. This is a really interesting story. I know you know it, you're smiling right now.

Maria: It's fascinating. I love when things turn out how we don't expect them, and serendipity helps drug discovery.

Saptarsi: Yeah. And you know, a lot of science and a lot of innovation happens through accident and serendipity. And so this is an interesting story. So, for those that don't know, this class of medicines, SGLT2 inhibitors, they target a channel in the kidney that transports sugar or glucose. And they were initially developed as a diabetes medicine to basically block this channel and make you spill out glucose in your urine so you're losing glucose, and they worked. They actually lowered your blood glucose over time. And they're good anti-diabetic medicines. So it turns out when you run an outcome study, a randomized control study with these SGLT2 inhibitors in diabetic patients, the investigators did not see a striking effect on reducing heart attacks. But, what they did see, unexpectedly, was a whopping unmistakable signal for preventing heart failure and its complications. And that was really a surprise to the field, but the effect was so big that drug companies and academic investigators said we're gonna run a separate trial for heart failure. And several companies did this and the rest is history.

Maria: And they have labeled indications now for heart failure for these drugs.

Saptarsi: Labeled indications with big effect sizes with add-on to established standards of care. So that's been great.

Karen: Wellington and I were really curious about this SGLT2 story. It's fascinating that that medicine was discovered to treat diabetes, but then later found to impact and help people with heart failure. Do we have other examples of other medicines that started out helping in one disease and then turning out to be useful in heart failure?

Maria: Yeah, the incretin medicines, the GLP-1s, have also shown benefits in heart failure. And I think especially in cardiometabolic diseases, which are intersected with each other, medicines that treat one disorder, such as diabetes or weight, can often have benefits in other aspects of cardiometabolic disease. Sometimes signals emerge in clinical trials showing some potential benefit in another indication, and it's always interesting to sometimes follow those signals with dedicated trials for other indications to seek to make sure that these medicines give their maximum benefit to patients.

Maria: Can we reverse the damage? You were talking about how somebody presents with advanced heart failure, and at the moment there's not really all that much we can do. What do you think about the ability to reverse damage or regenerate cardiomyocytes? Is that completely out of scope? Will we ever be able to do that?

Saptarsi: You know, it's the holy grail still. There's a lot of organs and tissues in the human body that can regenerate naturally, even into old age.

Maria: Like your liver, it's only about three years old, right, your average liver? It's regenerated itself over time, yeah.

Saptarsi: Yeah, and familiar to most people is your skin. You get a cut in your skin, as long as it doesn't get infected, it grows back, reliably. It turns out for reasons in evolution, evolution went along a path that when it created the modern human heart, the heart muscle lost its ability to regenerate soon after birth to the point where the adult heart, or even well into your late childhood and teens, there's not a huge capacity for the heart to regenerate.

Maria: So every cardiomyocyte you have, you've had since you were a child.

Saptarsi: Yeah, and I think evolution made a trade-off there. And a lot of people are interested in why that trade-off was made, and there's been a lot of speculation in science in that direction. But we're left with, you know, a critical organ, and you only have one of them.

Maria: So you need to take care of it.

Saptarsi: It's a single point of failure! And it can't regenerate. So prevention, prevention, prevention – but regeneration is gonna be key. So there's been a lot of research in this over the last, say three decades, in the heart. Maria, you were around in the heyday of cell therapy and stem cell therapy.

Maria: I remember some excitement and then some disappointments in that field.

Saptarsi: Yeah so, you know, there was a lot of research in the early days of stem cells. Can we inject cells of all different flavors – people had their own flavor they thought was scientifically the most likely to be able to regenerate the heart – and inject them into the heart and make new muscle and make the heart function better. It turns out that people tried and tried and tried in pre-clinical experiments, there are clinical trials of this, and, you know, there was modest if any improvement in the heart. And none of those cell types actually really made new muscle cells out of the heart. They may be doing other things we don't fully understand – right? – that may have had some modest improvements in heart function, but not that real needle-moving I've regenerated the heart the same way your skin regenerates. And so, I think that's fallen by the wayside a little bit. And I think people are looking for ways to actually make your existing heart muscle cells, somehow coax them into dividing once again. And there's a lot of active research going on in that space. So that's one angle, rather than injecting other cells.

Maria: Yeah, yeah. Exogenous cells. This is another question about where do you think breakthroughs will come from, because you can imagine – well there are some known targets and pathways in the heart around the calcium handling and stuff that have just been very difficult and intractable from a sort of drug ability perspective, and with AI and machine learning and making better, more selective molecules, maybe there's a path forward there. Also, we're learning so much more about biology, and you talked about patient heterogeneity, but potentially we will learn enough about, from single-cell genomics, from AI understanding of genetic genomic pathobiology interactions, that we can find actually new biology that we don't understand yet that could be targetable. What would you put your money on at the moment for next-generation therapies?

Saptarsi: That's a great question. So first of all, I'm gonna tell you what I'm gonna put my money on in a second, but I fully agree with you that this is a really exciting time in discovery biology and drug discovery. It is because there's biology technologies meeting AI and computational technologies, and that intersection is catalytic. And what it allows us to do is to actually start with human beings and patients, and do discovery in humans first.

Maria: Not zebrafish.

Saptarsi: And look, like you, I grew up making discoveries in cells in a dish and those are pretty powerful too, because they teach you how living things work, and how things can go wrong potentially in a disease. But the best place to understand human disease has been in humans, and we just didn't have the technologies to do that when I was a postdoc in the same way we do now. And now it's accelerating in a very exponential way. And so, one of the ways that's evolved over the last 15-20 years to do human discovery is large-scale genetics, human genetics at a very large scale across a population. So you can make discoveries in humans that point to a gene or a location in your genes that say I am important in this disease, put your magnifying glass on me and figure me out. And I think in drug discovery, we put a lot of emphasis on that. Now add to that all these emerging technologies – so human genetics is kind of your foundation, now you add the ability to look at individual cells in the context of a human organ and tissue, and all the flavors of cells within that tissue, you can ask, how are they behaving, what are they doing, what makes them tick?

Maria: It still kinda blows my mind that we can do that, actually, like you, having grown up with much more crude technologies in the lab. [Laughs]

Saptarsi: Yeah, we can not only observe the genomes and the activities of cells in the context of a human tissue, but now we're developing the technology to perturb genes one at a time, or more than one at a time.

Maria: On a massive scale.

Saptarsi: On a massive scale, and ask, well, if I tweak this gene in this cell type, what happens? And I can do it in a completely unbiased manner across all the genes in the body, and start developing relationships between, if I tweak this, this happens. If I tweak gene Y, this happens. Now imagine trying to put all that data – the human genetics and this single-cell profiling and all these perturbational experiments – I would say the human mind is not built to recognize patterns there. Some brilliant people can do it better than others, but we're just not built to do that. But we have computers that can be trained with massive amounts of training data, and using algorithms that are built into what we call AI today can actually recognize patterns there. And the hope is one day, we're gonna be able to predict human biology. That's what we're all after. Can we predict human biology, and can we predict causal human biology that's involved in diseases such that we can develop drugs against those mechanisms that we discover?

Maria: Yeah, absolutely. I completely agree with you there. I'm going to put you on the spot and ask, what about the sort of current medicines and therapies that are being explored in the early clinical trials? Where do you think those are going to go?

Saptarsi: If you ask me where I think some of the big needle-movers in heart failure therapies are, I'm gonna list a couple. I'm not gonna rank them, it's too early to do that, but looking into the future, I think metabolism. There's, can we treat obesity and improve heart failure? I think we're starting to see big signs of that, and there's even more to go there. There's also, can I improve the actual metabolism within the heart? Like I told you, it's a highly energy-consuming organ, and when things go wrong, the way it actually makes energy from nutrients starts to go awry. And I think there's some clues in the biology that we may be able to fix some of that. I mentioned regeneration. I think a lot of research needs to be done, but I think we need to keep pushing, and maybe one day we'll be able to trick nature into unlocking the ability of these heart muscle cells to divide. I think there's gonna be ways to treat these genetic heart failure syndromes. So you're unlucky to be born with a gene you inherited or just came at birth, and since we know how to genotype people relatively easily now, we can identify those and actually create precision therapeutics that correct some of those – either directly correct or just address the mechanism that's gone awry. I think, thinking about the heart, not just an organ in isolation but how it's interconnected to the other organs, I think there's gonna be a future of therapies where we treat blood vessels, and it's gonna improve the heart. I think there's gonna be therapies where we treat the kidney, and it's gonna improve the heart. The brain, and it's gonna improve the heart. The skeletal muscles.

Maria: I like this idea of the blood vessels. We don't really think about that as a pathology as much as perhaps we should, especially the small blood vessels which are often driving the disease.

Saptarsi: We think a lot about the big blood vessels that people think they get –

Maria: Yeah, the big atherosclerosis, and plaque and things like that. But then you've got all sorts of tiny little vessels that are really important.

Saptarsi: – the little sprouts that are going in, the kinda small roots. I think there's a lot of biology there that goes awry. So I think there's lots to discover, but what I'll say is that we need to start human first, and start to work our way backwards in understanding these mechanisms. The other thing I'll say is what I'm excited about is actually drug delivery. That's the other thing, is I think we're at the precipice of being able to deliver drugs not just to the whole body and going to every organ and tissue in the body. But imagine I could give you a drug as a pill or as an injection under your skin or in your vein, and it goes into the bloodstream, but there's a zip code targeted to the drug, and it takes it just to the right address, to a heart muscle cell or maybe a kidney cell. We can already do this for the liver, there's approved drugs on the market that go right to the liver. So what you're having is tissue-specific drugs. What it allows you to do is not worry about effects you don't want on all these other organs, and you can go straight to where, you know, the action is. And then things we can deliver, the cargo, we're generating things that can basically interdict biology in ways that we hadn't imagined before. So, CRISPR, for example.

Maria: Yeah, turn genes on, turn genes off, change things.

Saptarsi: Turn genes on and off, and there's ways to leverage CRISPR where you don't even have to cut the DNA. You can just turn genes up and down. We can deliver actual RNA to make genes go up and down. We can deliver molecules inside the cell that create new biology that didn't exist before, like bringing two proteins together, or disrupting their ability to come together, or relocalizing them. So I think it's really our imagination, and understanding human biology, and then just unleashing our imaginations.

Maria: So my co-host, Danielle, had this question for you, which is how do you see wearables and AI driving changes in early detection? And do you think this could also change some of our fundamental understanding about heart failure by just having more data from people wearing their devices all of the time, and then that being so accessible to everybody?

Saptarsi: Yes, yes and yes. I would say that the more data, the better. And this is human data – right? – from real humans in the real world, living their lives. And it's amazing what kinda data you can collect from these sophisticated devices that people buy and wear and enjoy and find useful. The best way to get at heart failure is to prevent it in the first place. So these devices are giving unparalleled data into human biology and human behavior that we didn't have before, so we can understand people's activities, what they're eating, how they're sleeping, what their heart rate is, what their heart rhythm is. And we can couple that to their risk of a disease. And we can start to understand which patients have which risk factors. There's even devices that can noninvasively, without a blood stick, look at your blood glucose, all of this. And then you merge all that data with all the molecular data we were talking about before, and you have this tremendous data set we can deploy AI to actually understand patients. And that's gonna give us new mechanisms and potentially new drugs, and then even understanding which patient is going to benefit from which drugs. So, I think the future is really bright.

Maria: It's kind of mind-boggling and very exciting, and there's so much going on in this space. What, for you, are the key takeaways?

Saptarsi: I would say that from the standpoint of societal unmet need and what we have to do in science, whether it's in academia or the pharmaceutical industry, that heart failure is one of the biggest unmet needs in society, if not the biggest unmet need in society. Because it's the final common pathway for the cardiovascular system to go awry. And the problem is that we've done well in society about preventing heart attacks.

Maria: Preventing them, and treating them.

Saptarsi: We could do better, we can do better.

Maria: There's more people who have survived a heart attack than there used to be.

Saptarsi: Yeah, people are surviving those initial insults. If your heart valve has a problem, we can fix it with surgery, or now noninvasively more and more. And so what it means is that we are now – and human longevity is increasing – these are all good things. But now we're getting into an aging society where you're dealing with more area under the curve for wear and tear under that single heart you have that can't regenerate. And so, this is really an urgent, urgent need for us to innovate. If we leverage the science and all the technologies available to us and all the human capital, and we put our heads together, we can solve this problem and have a huge impact for society.

Maria: That was such a fantastic and fascinating conversation, Saptarsi, thank you so much for your time.

Saptarsi: I should thank you, because this was a really really provocative discussion. And I actually want to thank everyone who's listening. I hope by sharing some of my excitement and insights, I've gotten the audience really thinking about how we can do better for patients with heart failure.

Karen: Maria, you get to talk to so many interesting and talented scientific minds on this show. Was there anything that Saptarsi and you discussed today that was completely surprising to you or made you look at heart failure in a totally new way?

Maria: What I think I'm most excited about from the conversation is the idea that with our high throughput genomic and proteomic types of techniques and the deep, deep human genetics we have now, that we can potentially, using patient samples, tissue, biobanks, really have a much, much deeper understanding of what's going on in the pathobiology of a failing heart, and I think that's where we'll see really exciting future medicines coming from. And I think that applies across all of our disease areas, honestly, but I think it's particularly exciting because the heart failure has stalled a little bit, and the therapies got a lot better and then now we're sort of waiting for the next step change in therapy to really extend healthspan, and that's where I can see that this magic might come from in the future.

Wellington: You guys touched on this in a couple of places, but I know one of your passions is obesity, and there seems to be a strong correlation between heart failure and obesity. Can you tell us more about that and how the GLP-1s might have an effect on the future of heart failure?

Maria: Yeah, I think it's a really good question. And I think in lots of ways, like very specifically, and I think we talked about this in the podcast, there's a subtype of heart failure called HFpEF, heart failure with preserved ejection fraction, which is very associated with obesity and most likely with some of the inflammatory environment of having excess adiposity. So that's a sort of very specific type of heart failure that seems to be tightly linked to obesity and modifiable with GLP-1s. But then in general, we often think of – we've talked about obesity as adiposity-based chronic diseases, and a lot of the negative outcomes of adiposity do end up on the heart, whether that is atherosclerosis, which leads to myocardial infarction or heart attack, which ultimately leads to weak heart muscle and then heart failure. It's all of the, the obesity is at the beginning of that cardiometabolic sort of cascade and decline. And so by, hopefully by preventing and reducing obesity, we will prevent people ever getting to the point where they might develop heart failure, and equally for people who have obesity and already on the path toward heart failure, that you could potentially halt or maybe even ultimately reverse some of the damage that's been done. But that close intersection between metabolic and cardiovascular diseases is, I think going to be something that becomes more and more recognized going forward and maybe even treated in a more holistic way.

And that's our show. Thanks so much for listening. If you haven't already, rate our podcast, wherever you listen – it will help new people to find us. And be sure to subscribe. If you have a question about the show, you can contact us at podcasts@gene.com. That's G-E-N-E dot com. And now for me, it's back to wrestling with data!

The name Two Scientists Walk Into A Bar is under license and used with permission from the Fleet Science Center

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