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This podcast series features Mass General Brigham researchers whose work is redefining what's possible and how we care for patients. Our goal is to spotlight transformative discoveries, the people leading these transformations, and how they can improve patient outcomes, highlighting how today's research is shaping the future of medicine, including training the next generation of clinicians and scientists.
This podcast series is not accredited for CME/CE at this time.
SEASON 1: Crossing Medical Frontiers: Research Innovations Transforming Care hosted by Dr. John Co
SEASON 2: Learn, Discern & Return: An MGB Physician's Journey hosted by Dr. Erik Alexander
Hello. Welcome to the new podcast series, Crossing Medical Frontiers, Research Innovations Transforming Care. My name is doctor John Co, and I'm the Vice President for education at Mass General Brigham. This podcast series features Mass General Brigham researchers whose work is redefining what's possible in how we care for patients. Our goal is to spotlight transformative discoveries, the people leading these transformations, and how they can improve patient outcomes, highlighting how today's research is shaping the future of medicine, including training the next generation of clinicians and scientists.
John Co:But today, I'm delighted to be talking with doctor Pradeep Natarajan, a preventive cardiology physician doing personalized medicine and translational genomics. He's an expert and researcher at Mass General Brigham. So, doctor Natarajan, thank you for being here today. I'm super excited to be here.
Pradeep Natarajan:Yeah. Thanks for the invitation.
John Co:Well, I'm sure our audience is gonna love getting to know you and your work. So along those lines, I'd love to start by them just learning about you as a person. Like, how did you start getting interested in medicine? And maybe even more specifically, how did you get interested in the areas of research that you're doing now?
Pradeep Natarajan:Yeah. So I have had a long standing interest in cardiovascular disease. And I always wonder why anybody any physician chooses something else because cardiovascular disease is so common. Coronary artery disease is the leading killer in the world. It's the number one killer in the US.
Pradeep Natarajan:And so I, at a very early age, recognized that this was a common issue. I would see it in my community. I didn't know it at that time, but it's well recognized now that individuals of South Asian ancestry have higher rates of diabetes and coronary artery disease. So seeing it around me was very interesting, felt like an important thing to potentially study and understand better. Now nobody in my family actually went to medical school.
Pradeep Natarajan:I do have a lot of researchers and scientists in my family, and all of them said, don't be a researcher. Go on and be a clinician. You know, work directly with patients. So I had the core foundation of being interested in cardiovascular disease. But in college, I started to understand how the two could go together.
Pradeep Natarajan:In my community, we actually didn't have physician scientists. So it's not a common thing to see somebody who is interested in clinical medicine also advancing the field through research. So I was really excited that I would hear about these concepts in my chemistry class, in my biology class. And in the lab, I was working I was working in a very small lab, and we were interested in these families that had really interesting lipid patterns, higher HDL cholesterol values, but the families, the folks in the families didn't seem to get cardiovascular disease, and there was a recurrently observed mutation in the family. And so I was really excited to bring many of the fundamental concepts that I saw in chemistry to this, you know, interesting observation to try to understand what that mechanism might be.
Pradeep Natarajan:Fast forward many years later, I continued to retain that interest in coronary artery disease and really addressing that important problem. And it was clear, especially through training as a resident at Brigham and Women's Hospital, as a cardiology fellow at Mass General Hospital. There was you know, there were the guidelines, but there was a lot of nuance, and practice was not exactly the same for every patient. And where there was clinical equipoise, it was clear to me that there were so many important questions. They were interesting to me as well.
Pradeep Natarajan:And in parallel, actually, in Boston, there was a substantial evolution in genetics and how to profile the human genome. That now, as I was wrapping up my clinical training, many of the questions and things I was interested, you know, in college and looking at these exceptional families, we can now start to do it population scale. And it's really made sense for me as a physician scientist to really bring in mechanisms of disease that are directly applicable and relevant to humans and modeling it with these new data types.
John Co:Wow. So you you've had this interest for a long time, like starting in college, you're saying. And you translated that into your, sounds like your medical school interest, your residency, and your fellowship interest. Tell me more about how you got involved as a a trainee in doing some of this stuff. Because I know a lot in our audience are probably aspiring physicians, cardiologists, and they wonder if you train at
John Co:place like this, how can can you get involved
John Co:in this kind of stuff that you're doing?
Pradeep Natarajan:Yeah. I think it's important to recognize that the tools that we use today, the data types, the data sets, none of this was really well conceived, certainly when I was in college, and only starting to come together when I was a resident, and increasingly so as a cardiology fellow. I think what was important for me is earlier on just understanding experimental design, how do you understand problems, how do you identify problems, how you might ask a question. But then working now with physician scientists actually was not something, as I said, exposed to earlier on in my training. I was it felt like just kind of two separate things.
Pradeep Natarajan:A lot of people were kind of doing and it was exciting and it was a lot of fun. And then when I saw that there were exceptional folks here driving the field in many different areas, they were, like, the best clinicians in the world, but they were also driving the field forward. And I found that to be a really important part of being a really good doctor, is really advancing the entire field to address many of the questions that we see today. I mean, even today, the questions that come up when I'm rounding in the hospital, when I'm seeing patients in the office, many of those are the key questions that we're using to drive the research that we're doing today. So, you know, the coronary artery disease thread was consistent throughout.
Pradeep Natarajan:I'll say, like, how I chose to ultimately practice evolved. When I was in college and medical school, the folks that were focusing on coronary artery disease were the interventional cardiologists. That field has evolved substantially. Much of the excitement and enthusiasm and training was focused on valvular heart disease, heart failure, and increasingly, there were more and more medicines that folks could use to prevent cardiovascular disease. And coming back to the, you know, to the earlier motivations, you know, much of the coronary artery disease manifestation that I was seeing were fatal heart attacks.
Pradeep Natarajan:And, you know, there is limited opportunity in that scenario to to diagnose and then prevent the complications. If the first inciting manifestation is death and something quite devastating, really, we should start thinking about this earlier. And as I got with amazing mentors who are doing really innovative things with technology, datasets across large populations across the world, and also, you know, bringing the insights that they got from the clinic, working with deep technical expertise that was available in Boston, all of that seemed possible. None of that was, like, clear to me that all that could actually happen. So seeing it here, being a part of it here has has been amazing and has kept me here as I continue to advance these threads both in clinical medicine and technology development.
John Co:Yeah. And that's you know, I think you've been here for different stages of your training, and now as an attending physician, I think we take it for granted how the research and the clinical care is so intertwined. Right? Yeah. Because as you said, we take care of some of the sickest patients in the world, frankly, and that informs the research questions and the transformation the transformative innovations that we seek.
John Co:So you've talked a lot about your career and your initial interests and how they've been building over time. So tell us about some of the, you know, the work that you're doing now, which is fascinating and and again, I think can transform how we think about cardiovascular care.
Pradeep Natarajan:Yeah. Yeah. I mean, I think I guess even just taking a step back, why even use human genetics to understand disease, especially cardiovascular disease? Now the typical approach to identify something that has an important mechanism for a disease, including cardiovascular disease, are you know, there's many different approaches, but the typical approach would be to take a biomarker, some exposure, could be cholesterol, smoking, could be gray hair. See what's associated or correlated with cardiovascular disease, and oftentimes, you know, maybe develop a model in a model system, an experimental system.
Pradeep Natarajan:That latter part was many of the many of the assays and things that I was working on before. But as you can imagine, things like cholesterol, smoking, gray hair, not all of those, even though they're correlated with cardiovascular disease, they may not all represent causal mechanisms. And the reason why we care about causal mechanisms is that can inform what the therapeutics might be. Now human genetics, our exposures naturally occurring human genetic variation in you, me, and the whole world, our exposures are things that are present at conception and are static from birth from conception and onward. Alright?
Pradeep Natarajan:So if you find a naturally occurring genetic signal that's correlated with cardiovascular disease, nothing else is influencing the allocation of that genetic variant that happened, you know, preconception. And so that can form the basis for causal inference. And there have been great examples of this. Probably the the poster child for taking that insight to a medicine, this class of medicines called PCSK9 inhibitors, where it was found that about one in a hundred individuals of African ancestry just happened to have a loss of function mutation in PCSK nine. Right?
Pradeep Natarajan:Everybody has two copies of a gene, one from mom, one from dad. And about one in a hundred just happened to have a dysfunctional copy of one PCSK9 gene. Nobody even knew what that was. Part of that genesis was from a a broad genomic scan that was enabled from newer technologies. Those individuals have lower cholesterol, and they also have lower risk for cardiovascular disease.
Pradeep Natarajan:Now that foundational insight was about twenty years ago now. And ten years afterwards, there were medicines that were developed and shown in large groups of individuals, not just in these one in a hundred, that if when you inhibit PCSK9 , that leads to lower LDL cholesterol, lower cardiovascular disease. As the technologies have advanced that we can sample all of the coding genes at larger scale, about ten years ago, we made an observation that about one in three hundred individuals has a naturally occurring loss of function mutation in a gene called APO C-III . Now those folks have lower triglycerides, higher HDL cholesterol, and they also seem to have lower risk for cardiovascular disease. Today, in 2025, there are actually now approved medicines that inhibit APO C-III that have been shown in clinical trials in large groups of folks that when you give an inhibitor for APO C-III , that similarly leads to lower triglycerides.
Pradeep Natarajan:Very high triglycerides, a major complication is pancreatitis. Now interestingly, there have been a few different classes of triglyceride lowering medicines that have been evaluated for cardiovascular disease benefit. That's what I care about as a cardiologist. And none of them actually have been shown to be beneficial for lowering cardiovascular disease risk. However, based on what we see with the human genetics that seems to parallel PCSK9, we're excited about the prospect of piece of APO C-III inhibition lowering cardiovascular disease, and those clinical trials are ongoing.
Pradeep Natarajan:Wow. It's it's amazing what you just said, the history of this.
John Co:It's obvious that it takes a long time sometimes to to bring sort of the research from, like, here's an interesting question to translating it into, like, therapeutics and care delivery. So it's so important to be at a place where people have been looking at these questions for so long. Right?
Pradeep Natarajan:Totally. Yeah. We build on the legacy of our our mentors Yeah. The many folks that are advancing the field. And I'll say, you know, that that timeline is not so long in the scope of drug development.
Pradeep Natarajan:Yeah. At least it spans, you know, my career so far, but we've been really excited. You know, as the director of preventive cardiology, I'm seeing a lot of patients who are at high risk cardiovascular disease that have abnormal lipids, often elevated triglycerides. And in the clinic, we're a site for these clinical trials where we're giving APO c three inhibitors and participating in the research to see the outcome. And actual I mean, kind of as an aside, there are many patients that would come to our program in preventive cardiology, many of them would hear about it because we were doing a lot of research, and they wanted to partner in the research.
Pradeep Natarajan:And most of our studies are in large population based data sets that I can't necessarily enroll all of my patients in, you know, the various different multinational biobanks. But we can start looking at the evidence and the data that seems to be closer to translating directly to patients, and the clinical trials are the way that we've been we've been doing that.
John Co:Yeah. So you you touched upon probably my next question, and, you know, is sometimes we hear about these research, you know, discoveries, and people wonder, well, that's in the lab, you know, but how close is it to actually impacting patients we take care of? And, you know, here at MGB, like, these discoveries that you're talking about impacting what we're doing now for patients?
Pradeep Natarajan:Yeah. You know, that that is the, you know, number one, two, three motivation is trying to think, you know, as we're designing the research and as we're starting to make discoveries, what are the multiple steps that one needs to surmount to ultimately get it directly back to patients? And there are many different stages where I would say we have deep expertise in, but, like, you know, my lab can't develop medicines. It's not necessarily in a position to design the clinical trials. So we definitely collaborate with colleagues locally.
Pradeep Natarajan:Actually, those clinical trials are being done by are being led by colleagues at Brigham and Women's Hospital in cardiology. And the medicines are being made by partners in the pharmaceutical industry. So we have many different folks that can engage on multiple lines of investigation to get it directly back to the patients. But I'll give you another example where, you know, another output of doing this broad based genomic profiling is that we can take all of these features together to also predict risk. And the and this is a core concept in preventive cardiology because, you know, most of our time as specialists, cardiologists, oncologists, often is to diagnose disease and then basically manage the manifestations and prevent the progression and and adverse prognosis.
Pradeep Natarajan:As I said, a lot of my motivation is to try to go upstream. And so much of how we identify individuals at risk is based on risk prediction, and that's an evolving concept as the, you know, distributions of risk factors evolve, as new risk factors emerge, and the importance of risk factors change. Now but the main issue is that in all of these, for clinical risk scores, age is the most important predictor because most of the events are still happening later in life. But that actually prevents us from identifying folks who are gonna be at risk for premature events. And what we do today, and the the field has been doing for almost half a century, is screening lipids to identify in about one in three hundred individuals that has severe hypercholesterolemia.
Pradeep Natarajan:But, obviously, many more folks get premature events. And if you can identify folks early on in the disease process, you're much more likely to be effective in your preventive therapy. As I said, the genetic factors there are being established at conception. So not necessarily that we have to look there for adult onset disease, but early in life, if we can take the totality of that information, if we have an accurate genetic predictor, that actually might really help in identifying those at risk. And a and and a major reason why I chose to focus on this is that a major reason that folks come to me if they don't know they're at risk, that they're younger, is it's it's the family history that really sets them up.
Pradeep Natarajan:Dad had an event maybe in the forties or a brother got a CAT scan that had a lot of coronary artery calcium, and they're wondering, you know, why is that does is that relevant to them? And the cool thing is that, you know, these genotypes, they're static for you and me and in the population, but our ability to interpret is continually evolving. And the datasets have gotten large and diverse enough that it turns out they're actually pretty good predictors for predicting disease. Just so happens today, we actually announced that we successfully translated these into a clinically validated test that is being run by Mass General Brigham, where it's a set of these so called polygenic risk scores that includes coronary artery disease because you only really need to sequence somebody one time, and then you can calculate these scores for many different things. And, you know, we've been able to surmount this because we have deep expertise in the, you know, in the discovery of genetic factors related to coronary artery disease, in risk prediction, in the development of clinical assays, and even the logistics of putting together a clinical assay and what all that, requires.
Pradeep Natarajan:So couldn't happen anywhere else, and it's not really just the people. It's really the multiple different components of people who are really interested in working together for something new, innovative, and important.
John Co:Yeah. It's if I'm understanding correctly, I think what you're a lot of your work is trying to take, like, primary prevention to, like, a new level. Yeah. I mean, just I think screening in a you know, just even way before we could even think that might be a problem. Right?
John Co:That's fantastic.
Pradeep Natarajan:Yeah. I mean, it requires, I think, a lot of thought in just how to communicate this information Yeah. Because, you know, the clinical risk factors, they're you know, except for age and sex, they're modifiable. You know, clinicians can prescribe medicines. They can recommend lifestyle interventions.
Pradeep Natarajan:These polygenic risk scores, they're not gonna change. However, even though they're like a baseline trajectory, the disease itself is still highly modifiable. Lifestyle modification, exercise, diet, and in some cases, preventive therapies like statins can still substantially alter the risk trajectory. That's that's the reason to look. And, looking earlier for those high risk individuals, you're more likely to see benefit from those changes.
John Co:Are there other I mean, you alluded to this. Like, it takes a team, a village to, you know, bring these innovations to the bedside. Right? Are there other investigators at MGB that you'd like to, like, just make people aware of that are impacting the work you're doing, but just this field in general?
Pradeep Natarajan:Yeah. I guess before I call out specific folks, a major reason why we expand to many different areas in cardiovascular disease is actually the trainees. The trainees as the, you know, cardiology fellows, vascular surgery fellows have had the pleasure working with internal medicine residents Yeah. They're going through the wards, and they're getting excited about lots of different things. They're hearing about and seeing the things that we are doing, and they're excited about the disease area of interest for them.
Pradeep Natarajan:And we have the operation to look at lots of different diseases and advance the field for many different areas. You know, we've had, you know, recent junior faculty member, actually now at Brigham and Women's Hospital, Aeron Small, who've been really interested in valvular heart disease. Aortic stenosis, aortic valvular stenosis, the only therapy for that is surgery or catheter based therapies, but it's only procedural. No medicine has been shown to be demonstrably effective. Aaron has effectively come in and leveraged all the datasets that we have, the extensive collaborations, and done the the largest genetic discovery for aortic valve stenosis aortic valve stenosis and has nominated many new potential medicines for aortic aortic valve stenosis.
Pradeep Natarajan:So I am excited about the continued expansion that has been, like, the genesis of our in initial infrastructure into many different disease areas. You know, close colleague and collaborator Patrick Ellinor, who's the executive director of our Heart and Vascular Institute, has been a world leader in this for, arrhythmias, in particular particularly atrial fibrillation. And his lab has continually expanded in new data types and new data elements that we take inspiration from, has brought in, MRIs, MRIs of the heart, MRIs of of the body to look at many different features that all are important and relevant in the ultimate manifestation for cardiovascular disease. And his focus has been on arrhythmia and cardiomyopathy and heart failure, but we take those insights and learn and collaborate into areas of interest for us, like vascular disease and coronary artery disease.
John Co:Yeah. It's great to see and hear that trainees are involved, you know, significantly in a lot of these discoveries. And I think some of them, like yourself, stay continue the work, which is great.
Pradeep Natarajan:Yeah. I mean, they're like, the the main thing that I give advice to trainees, because they've all done so much work to get to basically the best residency programs, the best fellowship programs, that I really encourage them at this stage really focus and continue to focus on being the absolute best clinician, cultivate the clinical interest, cultivate the passion, because ultimately, that is what's gonna lead to impactful science. You know, I had various different experiences in research and basic research, but I don't have a PhD. I didn't take any time off. And all of these new data types were new to me, And so I actually was in a great infrastructure to really learn, cultivate, and develop those skills.
Pradeep Natarajan:Now I'm not at the terminal day to day coding, but I have developed that deep appreciation, deep knowledge base of the foundation, the fundamental concepts, that it makes me capable of overseeing and spearheading this kind of lab and going into new data types and new data methodologies. So as as as the clinical trainees are trying to figure out what they're interested in, you know, I have been really motivated in trying to cultivate and continually expand this kind of infrastructure that they can learn, you know, and some elements go along the same lines of scientific investigation that I'm learning in, but most of the times, really continually expanding and rich enriching the overall operation.
John Co:Great. Well, you know, you've covered a lot of the research that you're doing and others are doing. Is there anything else you'd like the audience to know about this field? Things they should be watching for exciting developments.
Pradeep Natarajan:Yeah. You know, like, I would say genomics 2.0 is the acquisition of mutations. And you might say, okay. That's that's well known because that relates to cancer. But it turns out that actually may have implications for other non oncologic disease.
Pradeep Natarajan:We'll still have core insights and importance to cancer, but that seems to have relevance to cardiovascular disease, liver disease, diabetes. You know, with collaborations both within MGH pathology and with Dana Farber, Ben Ebert, who's now the president of Dana Farber, we made this observation with Ben and others that when you do the regular genomic profiling in the blood, exome sequencing looking at each of the genes, In the blood, it turns out that a lot of people in the population who are healthy, about one in ten who are above the age 70, have already cancer causing mutations that have expanded. We know that they've expanded because they have to expand to get it at the resolution of this kind of coarse screen across the blood, this phenomenon of clonal hematopoiesis. And, you know, many of us were kind of working on a variety of different genomic datasets, but that culture of working together and, you know, making new innovative observations because it really did require new methods to detect this kind of, these kinds of mutations. But having, the data sets to be able to look at both cancer prognosis and cardiovascular prognosis allowed us to work together and really understand both that there were cancer relevance, but actually there seemed to be more important car cardiovascular, relevance.
Pradeep Natarajan:And so we brought in other collaborators, Peter Libby, who was the former chief of cardiology at Brigham and Women's Hospital, world leader in an inflammation in these circulating blood cells and their role in cardiovascular disease. And that observation was in 2017, and that's kind of been the genesis of a new field, a new highly innovative interdisciplinary field that really requires pathology, hematology, oncology, cardiology. And then in parallel with the development of, again, more genomic technologies because, you know, you and I have a germline genome, but each of the cells often have slightly different genomes. And now those technologies are increasingly scalable. We're using those to actually uncover new acquired mutation patterns across the different tissues and their relevance both with cancer and noncancerous disease.
Pradeep Natarajan:So, I mean, the arc of my career has been, you know, since going on this path of genetics has been in parallel with the the rich deep, technological advancements that have been happening locally, but also really been enabled with generous collaborators, often already world class collaborators willing to work with folks who are earlier in their training to really go out into new exciting areas.
John Co:Yeah. It's amazing how technology and informatics is impacting all areas of medicine. Right? The areas that we wouldn't have thought of in the past.
Pradeep Natarajan:Yeah. I mean, the the silos across the world are certainly breaking down a bit with things like Zoom and others. Obviously, there's email. But it's so much easier to go, you know, down the hall, across town, people that you're seeing all the time, trainees that you see on the wards. It's so much easier, and that's how things kinda catalyze together.
John Co:Great. Well, I learned a lot from this and I'm sure our audience did too. I wanna thank you for stopping by our podcast and I look forward to hearing of all your successes and discoveries and having you back at some point. For the next episode, we will be speaking with doctor Chi Fu Yang whose expertise is in lung cancer research. We hope you will subscribe and join us.