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.

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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

Across five decades, Genentech scientists have turned bold ideas into historic firsts — breakthroughs that launched and advanced the biotechnology industry and redefined patient care. From the initial success of recombinant DNA technology to introducing the first therapies in our therapeutic focus areas, each “first” reflects a moment when our research opened new doors for science and medicine.

Together, these milestones illuminate a single, enduring mission: transforming deep biological insight into therapies that change lives.

Foundational First: The Birth of Biotechnology

• Genentech was the first company to commercialize recombinant DNA technology, creating the global biotechnology industry.
• Genentech secured the industry's first foundational patent and first key publication in Science on engineering bacteria to produce the human protein somatostatin, proving that human medicines could be mass-produced.

Oncology: Pioneering Targeted Cancer Therapy

• In 1998, Genentech received FDA approval for the first HER2-targeted therapy for metastatic breast cancer, and the first therapeutic antibody launched with a required companion diagnostic to realize the potential of precision medicine.
• Genentech co-developed and commercialized the first anti-CD20 monoclonal antibody approved in the U.S. for cancer (non-Hodgkin's lymphoma) and the first anti-CD20 monoclonal antibody approved for treating an autoimmune condition (rheumatoid arthritis).
• Originating from a 1983 collaboration between Genentech and City of Hope Medical Center, the Cabilly patents established fundamental recombinant DNA methods for producing therapeutic antibodies, which were instrumental in oncology as well as immunology. The patents transformed the biotechnology industry, yielding many new medicines.

Immunology: Redefining Autoimmune Treatment

• Genentech developed the first anti-IgE biologic therapy for moderate-to-severe persistent allergic asthma and food allergy, in collaboration with Novartis.

Ophthalmology: Innovation in Eye Health

• In 2006, Genentech achieved the first FDA approval for an anti-VEGF therapy for wet age-related macular degeneration (AMD): Lucentis (ranibizumab)
• In 2022, the first and only dual-pathway inhibitor for wet AMD and diabetic macular edema was approved: Vabysmo (faricimab) 

Neuroscience: Breaking Barriers in Brain Disease

• In 2017, Genentech launched the first B-cell depleter approved for relapsing and primary progressive forms of multiple sclerosis (MS): Ocrevus (ocrelizumab) 
• In 2020 Genentech achieved approval for the first medicine for spinal muscular atrophy that can be taken at home, shifting drug treatment from the clinic to the patient’s home: Evrysdi (risdiplam)

Cardiovascular, Renal & Metabolic Disease: Addressing High Unmet Need

• In 1987, Genentech pioneered the first medicine approved to treat both acute myocardial infarction and acute ischemic stroke, and the first recombinant tissue plasminogen activator (rt-PA) approved for acute myocardial infarction: Activase (alteplase) 
• Genentech developed the first new stroke treatment in nearly 30 years, approved by the FDA in 2000 to treat acute ischemic stroke as well as acute myocardial infarction: TNKase (tenecteplase)  

Placing a Priority on Publishing

From the beginning, Herb Boyer and Bob Swanson made a deliberate choice: scientists would publish their research in journals, with proprietary information protected by patents.

As Herb explained, "I felt it was extremely important for attracting the outstanding young scientists in the community that were interested in doing work in an industrial setting."

Herb’s goal was to bring together the best from industry and the best from the academic community.

In December 1977, that philosophy delivered. Genentech's first paper appeared in Science: "Expression in Escherichia coli of a chemically synthesized gene for the hormone somatostatin" - and as dry as the headline was, it was game-changing news for the scientific world.

Creating a Postdoctoral Program

As a fledgling company, Genentech welcomed a few postdocs in an ad hoc capacity in the 1970s and 1980s.

But to truly bring the "best of academia to industry" as Herb and Bob had always intended, Genentech established its formal postdoctoral program in 1990.

This program, the first of its kind in the industry, provided a structured path for PhD graduates to pursue basic discovery research within a corporate setting. It has a proud history of training scientists at the forefront of innovation and discovery.

Collaborating at Afternoon “Ho-Hos”

In the late 1970s, employees first established regular, Friday afternoon social gatherings called “Ho-Hos.”

As Bob recalled, “There wasn't management on the one hand and science on the other. We were all in it together. Ho-Hos were a way that people could get together in their shirt sleeves and relax at the end of the week, but wind up talking about how to do things better.”

Bob wanted people to be brave enough to follow the science wherever it led and feel comfortable speaking up with their ideas.

Five decades later, Ho-Hos are alive and well at Genentech. Learn more about the intentional approach to creating culture here.

Advancing Scientific Thinking at Asilomar

In February 1975, the Asilomar Conference on Recombinant DNA in Pacific Grove, California, gathered geneticists, ethicists, and journalists to establish standards and safeguards for genetic engineering.

Genentech was founded shortly thereafter. In fact, one story says that Bob called the list of attendees alphabetically until he reached the "B's," finding a willing partner in Herb Boyer.

Genentech began using the historic Asilomar Conference Grounds in January 1985 for internal scientific conferences. These events included talks, posters, evening dances, poker, and long nights, shaped by a commitment to sharing ideas, fostering collaboration, and driving innovation to yield scientific breakthroughs. This tradition continues today across many Genentech groups.

Doubling Down on Science

When Art Levinson became Genentech’s CEO in 1995, he made a bold decision: drive the company’s growth through best-in-class internal research and development.

In one of his first actions as CEO, Art convinced the board to invest 50 percent of revenues back into research. He focused on significant unmet needs in oncology, immunology, and tissue growth and repair- and on still-unproven technologies like monoclonal antibodies.

"If we took the long-term perspective - if we funded a lot more of the projects coming out of research than a typical company would fund - we could ultimately help patients best," Art explained.

He believed great science would yield great medicines, and he was willing to take the risks, both in business and science, to make it happen.

And today… Roche and Genentech invest nearly $15 billion globally in R&D each year, representing one of the largest R&D budgets in the industry.

Our Culture: Taking Our Work Seriously, Not Ourselves

From the beginning, our founders believed that Genentech’s success was tied directly to creating an environment that enabled employees to do their best work.

That principle still guides us today.

We're deeply proud that for fifty years, we’ve nurtured a compassionate, caring and playful culture where the persistence and hard work required to improve the lives of patients is balanced with celebrating our successes, building community, contributing together beyond our doors…and having plenty of fun.

Recombinant DNA technology is a foundational breakthrough that changed biology forever. It gave scientists the ability to cut, insert, and join genetic material—essentially rewriting genomes by merging natural code with new instructions to alter how cells behave.

This innovation laid the groundwork for modern biotechnology and fundamentally transformed how medicines are discovered, developed, and manufactured.

The “Cut and Paste” of Life: Recombinant DNA

Genentech was founded on the revolutionary idea of using recombinant DNA to create life-saving medicines. This "cut and paste" technique uses molecular scissors to insert human genes into bacterial DNA, essentially turning microbes into microscopic protein factories. This foundational tool was the key that Genentech used to unlock the future of medicine.

Pioneering Biotechnology: From Proof to Product

Genentech quickly validated its pioneering recombinant DNA technology by successfully cloning the human hormone somatostatin in 1977. A year later, our scientists cloned human insulin, proving the commercial feasibility of biotechnology. They licensed the technology to Eli Lilly, leading to the development of the world's first genetically engineered pharmaceutical drug.

Humanized Antibodies: Redefining Treatment

One breakthrough led to another as the team next tackled one of the immune system's most powerful tools: antibodies.

Antibodies are brilliant at finding and neutralizing targets, but early mouse-derived versions were often rejected by the human body. Genentech's scientists pioneered a revolutionary solution: "humanized" antibodies that cleverly fused the targeting part of a mouse antibody onto a human antibody "scaffold."

This new class of targeted treatments became a cornerstone of modern medicine. Today, roughly 10% of all FDA-approved antibody therapeutics were developed by Genentech and the Roche Group.

Roche and Genentech have always shared the same passion, the same integrity, and the same desire to transform the lives of patients. The connection between Roche and Genentech reaches back to a 1979 partnership agreement focusing on the development of interferons. Roche recognized early on that Genentech's pioneering research held immense potential.

In the years following, Roche closely watched Genentech’s progress, through the successes of early products and the challenges that many young companies face. In 1990, Roche purchased 60% of Genentech, an investment that solidified Genentech’s financial picture and helped drive the next generation of innovative treatments. Leveraging Roche’s global reach allowed Genentech to bring life-changing treatments to patients worldwide. Over the following two decades, Genentech medicines grew to represent more than 50% of Roche’s global pharmaceutical sales.

Thirty years after our first collaboration, Genentech joined the Roche Group in 2009. The successful transition was founded on a shared set of values that focus on patients, innovation, science and people.

Explore Roche's 125-year history.

For five decades, Genentech has made news as a leader in scientific innovation, a highly regarded employer, a dedicated community partner, and a pioneer in developing life-changing medicines. Our breakthroughs, impact, progress and people have been chronicled in the media.

While this is a moment to reflect on how far we've come, it doesn't stop here. Learn how we're still pushing the boundaries of what is possible. We can't wait to see the headlines in our future.

Imagine What Comes Next

The Right Tool for the Job

As pioneers in biotechnology, Genentech's goal is to understand the precise, molecular drivers of disease. This deep knowledge allows us to build a sophisticated scientific toolkit—a range of advanced modalities and technologies, each designed to attack disease in a different way.

This toolkit gives us the power to match the right tool to the right target, pioneering the next generation of personalized medicines.

Antibody Engineering

Genentech scientists can re-engineer antibodies into antibody-drug conjugates (ADCs) that link a potent drug to an antibody "guided missile" designed to deliver treatment directly to tumors while sparing healthy cells. We also create bispecific antibodies with two different arms that pull cancer cells and immune T-cells together to ignite a focused attack.

Cell Therapy

Cell therapy can turn human cells into a powerful “living drug.” Immune cells are taken from a donor and reprogrammed with new genetic instructions to recognize that patient's specific cancer. Millions of these cells are grown and infused into a patient, creating a therapy that can in some cases destroy tumor cells and in others restore function to specific tissues and organs.

Computation and AI

Genentech harnesses the power of computation and AI to find the "signal in the noise." Our algorithms sift through mountains of complex biological data—from genetic sequences to patient records—to uncover hidden patterns in disease. This computational power helps us design and predict the effectiveness of new medicines on a computer before they are created in a lab.

Omics

"Omics" is the study of the entire biological picture. Our scientists can analyze the unique pattern of active genes and proteins in every individual cell inside a tumor. This high-resolution map helps us spot the "bad actor" cells and genes and discover highly specific new targets for our next generation of medicines.

Delivering new medicines demands innovation in medical discovery, and how those medicines are made. We are continually evolving the processes that move life-changing therapies from the lab bench to the patient.

From synthesizing human insulin and our early biologics in the 1980s to today's novel and complex molecular formats, our manufacturing journey is focused on innovation, quality and scalability.

We are building the capabilities needed to reliably and sustainably supply groundbreaking treatments to patients around the world.