Pradeep Natarajan studies genetics to uncover the secrets of the heart

Broad associate member Pradeep Natarajan shares what he’s learned as head of an academic research lab, and talks about his work at the intersection of genetics and cardiology, in a #WhyIScience Q&A

Photo by Miriam Joy Michelson, courtesy of Massachusetts General Hospital's Center for Genomic Medicine.
Credit: Photo by Miriam Joy Michelson, courtesy of Massachusetts General Hospital's Center for Genomic Medicine.

Cardiovascular diseases are the leading causes of premature death worldwide, and South Asian Americans carry at least double the risk of heart disease than the general population. Having witnessed many in his South Asian community contend with cardiovascular ailments—including both of his seemingly healthy grandfathers, who succumbed to fatal heart attacks at a young age—Pradeep Natarajan committed to studying atherosclerotic cardiovascular disease while still in high school.

Now, as director of preventive cardiology at Massachusetts General Hospital, assistant professor of medicine at Harvard Medical School, and associate member of the Broad Institute of MIT and Harvard, Natarajan fights cardiovascular disease on several fronts. As a physician-scientist, he both cares for patients in the clinic and works in the lab, identifying and characterizing the root causes of heart disease to promote prevention. Specifically, he analyzes naturally-occurring genetic variation in humans to identify genes that influence cardiovascular diseases and traits. This information can help Natarajan and other researchers predict who might be at risk of developing cardiovascular disease, and whether targeting specific biomarkers with therapeutics might benefit certain patients.

In a #WhyIScience Q&A, Natarajan talks about his research and his work in the clinic, how they’re connected, and how he balances the two:

Q: You’re a physician-scientist. Could you describe what you do day to day?
My responsibilities are quite varied but the majority of my time is focused on research. Much of that involves doing computational analyses and writing papers. But like many at the Broad, a lot of what I do is highly collaborative—with my lab, local collaborators, and colleagues across the globe—so a large portion of my time is spent in meetings (in-person or virtually) to drive research projects, help with analyses, and troubleshoot issues.

At the same time, I direct Preventive Cardiology at Massachusetts General Hospital. That encompasses primary cardiovascular disease prevention, advanced lipid management, metabolic syndrome programs, atherosclerosis genetics, and cardiac rehabilitation. I see patients, and I am involved in various efforts to support and grow our section, such as starting new clinical programs.

Additionally, I am one of the core faculty of the Massachusetts General Hospital cardiology fellowship training program, where I oversee preventive and genetics training for cardiology fellows and supervise them while they work in the clinic. And I teach genetics to first-year Harvard Medical School students.

Q: That’s a lot to balance. What tricks have you learned to manage it all?
Balancing research, meetings, clinical work, teaching, administrative duties, family, and sleep can be challenging—and can easily become overwhelming if not appropriately managed. It’s a common challenge that even senior colleagues face. As Sekar (Sek) Kathiresan, one of my mentors, told me: work on the most meaningful thing you can now. Stephen Covey says something similar in his book The 7 Habits of Highly Effective People. He says to define and prioritize tasks in the following order: 1) important and urgent, 2) important and not urgent, 3) not important and urgent, and 4) not important and not urgent. I strategize each day by identifying and prioritizing tasks accordingly.

Q: What, in your opinion, has been your biggest scientific accomplishment to date?
One particular study that I enjoyed working on as a postdoc in Sek’s lab was the description of a “human knockout” project—a systematic effort to understand how the complete disruption of a human gene affects associated traits, or phenotypes (Nature, 2017). A longstanding goal of biomedicine has been to understand the function of all the genes in the human genome, and one highly fruitful approach has been to experimentally disrupt genes in model organisms to yield these insights. We were interested in doing this directly in humans by leveraging naturally-occurring human genetic variation.

We collaborated with colleagues in Pakistan, where there is a higher rate of consanguinity, increasing the likelihood that mates harbor genes that carry identical copies of the same alleles from both parents. We recruited healthy individuals and looked for examples of “knocked out” genes in this cohort—instances where inheriting two identical alleles kept a gene from functioning. One such gene was APOC3, which is involved in regulating the breakdown of fats. Sek’s team previously showed that loss-of-function in APOC3 seemed to protect against heart attack and we were able to show in the 2017 study that triglyceride levels in individuals who had this gene “knocked-out” remained low even when fat was added to their diet. This may help explain how APOC3 disruption protects against heart attack.

But, in addition to the science I’ve had the opportunity to work on, I’d also say one of my biggest accomplishments has been finding exceptional mentors along the way during my training! Working as a postdoctoral fellow with Sek was particularly formative and serves as a model for how I’d like to be as a physician-scientist, mentor, and collaborator.

Pradeep Natarajan at work at Massachusetts General Hospital. Photo by Miriam Joy Michelson, courtesy of the Center for Genomic Medicine.

Q: What other trends in cardiovascular disease research are particularly intriguing to you?
There are quite a few. Our field has largely focused on treating symptomatic conditions. However, with tools such as polygenic risk prediction and, potentially, the improved quantification of health-related behaviors made available through mobile health technology, there is an opportunity to identify individuals who are at high lifetime risk while they’re still very young. These tools are almost certainly coming to clinical medicine well before an adequately powered clinical trial will be completed to definitively assess efficacy. I’m excited to see how preventive medicine will evolve and how clinical medicine broadly will react to data points that have not previously been available.

Q: You have only been running your own lab for a year at this point. What has been the most rewarding thing about being the principal investigator of a lab so far?
I’m sure everyone says this, but I really enjoy working with motivated trainees. I enjoy building their confidence to challenge current approaches and develop new ideas. It benefits me as well, since we succeed together.

Q: What has been the most surprising thing to you about starting and leading an academic research lab?
I’m most surprised about how creative I can be. During the first year of my lab, I have had immense joy collaborating with local colleagues studying diverse cardiovascular conditions by applying various integrative genomics methods to test biological hypotheses. These varied collaborations have exposed me to new methods and approaches to tackling scientific questions.

Q: What is the best advice you have for mentees or others who are starting up their own labs?
Your environment and the people you surround yourself with are key determinants of success, particularly during the early, vulnerable stage of starting a new lab. Some of this is in your control when you choose the place you will start your lab. However, you can enrich this by being a contributor to your local community through collaboration, attending local seminars, and seeking out mentorship. In addition to seeking the advice of prior mentors, seek out new mentors who can help take your research program in new and exciting directions.