Physician Scientists Take Collaboration to Heart

Q: How do your skill sets come together?

PL: My work is in atherosclerosis, or the hardening of the arteries, which is a common interest of ours. But my research is based in basic science, conducted in a wet lab using cells and preclinical experiments. Our search in the lab meshes incredibly well with the informatics skills, population science, and genetic expertise of Dr. Natarajan.

We have shared trainees who learn from both of our groups. One of those trainees is Michael Honigberg, who is now getting national and worldwide recognition for his work in cardiovascular research. Other exceptional mentees we’re both working with are Tetsushi Nakao and Aeron Small. Dr. Natarajan was a soaring comet in his peer group — now others we have jointly mentored are following a similar trajectory and making important contributions to the field. Another one of my former trainees is Dr. Elena Aikawa — she’s now a full professor and provides mentorship to many of the trainees we work with.

PN: One of the unique strengths of the Mass General Brigham healthcare system is the robust depth of physician scientists working on atherosclerosis. We have investigators approaching it from different angles and using distinct tools to investigate it, many of which were not commonplace when I was a resident. We’re exploring new avenues for potential treatment and prevention as new kinds of studies become feasible. These new approaches can complement the experimental methods used in the lab to unpack disease mechanisms.

Q: Can you give us an example of a disease area where your combined efforts are helping the field progress?

PN: One project that brought us together was the observation that clonal hematopoiesis may be a risk factor for atherosclerosis and cardiovascular conditions such as stroke, heart failure and cardiac arrhythmia. Clonal hematopoiesis refers to a situation in which a single bone marrow stem cell undergoes a mutation that gives rise to many progeny that bear the same unusual genetic pattern. The causal mutations accumulate in blood cell precursors with aging. These clones of white blood cells carrying one mutation are a step on the way to blood cancers. But surprisingly, they also increase the risk of cardiovascular problems.

That observation led us to work together on an experimental design to explore and understand the mechanism behind this connection.

It’s much more powerful to have multiple lines of investigation to understand these mechanisms, but, from the beginning, it requires working together on a coherent scientific project. This work also involved human genetics — often, these exercises are done in isolation and identify genetic associations, but when you have a cohesive enterprise working through multiple lines of investigation, linking the genetic findings to biological functions and disease can start to come together.

PL: From the world of population science, you can get strong associations when you use large population datasets, but associations don’t prove causality; when you test in the lab, you can nail that causality. For our work on clonal hematopoiesis, observational science and the lab-based studies joined to show causality.

Q: What is it like to be a physician scientist and why is it important to train the next generation?

PL: Part of our mission at Mass General Brigham is to train and educate physician investigators. Physician scientists have been considered an ‘endangered species’ for the last 40 years or so, and there is a lot of pressure on academic medical centers, such that few are able to foster the development of physician scientists. But we’re fortunate here to be able to provide an environment that connects investigators to the clinic and to patients. That keeps us focused on asking the important questions in medicine. The physician investigator trained and working in that kind of environment is equipped to answer questions that matter to patients in a way that someone working in a pure research environment or commercial enterprise may not.

PN: That’s what differentiates our physician scientists: the questions we’re passionate about are the questions our patients are coming in with. In my field of human genetics, there aren’t that many physician scientists.

Q: What happens after training ends for physician scientists?

PL: Part of our job is to help the next generation establish independence — it’s the right thing to do. At the Brigham, we try to retain our most talented and productive trainees, but we’re also very proud of the diaspora and seeing them go on to become independent investigators, chairs or chiefs, and flourish in their careers.

PN: Mentors and mentees grow to become colleagues at our institutions. One of the most fortuitous things about my career is that I get to collaborate with someone like Dr. Libby. We’re not only collaborators; we’re friends.