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When the Breakthrough is Only the Beginning

Five Questions with physician-scientist Aswin Sekar on the long arc of translational science.

Aswin Sekar, MD, PhD, hit the science jackpot early. As a grad student in geneticist Steven McCarroll’s lab at Harvard Medical School, he helped unlock a key genetic mystery in schizophrenia. The finding was hailed as a breakthrough with the potential to inform development of new drugs for schizophrenia based on an understanding of its biology.

For Sekar, a physician-scientist whose goal is to turn scientific discoveries into treatments that help people, the experience drove home an important lesson: The finding is just the beginning, and the arc connecting bench to bedside can be a long one.

Sekar now studies precancerous stages of leukemias and lymphomas in Benjamin Ebert’s lab at Dana-Farber Cancer Institute and sees patients as an attending physician in the lymphoma division, a career track driven in part by his mother’s diagnosis with leukemia when he was in high school.

Sekar likens the long slog of MD/PhD training to a game of Chutes and Ladders. Among its many ups and downs, the transition from clinical training to postdoctoral research at the bench stood out as particularly challenging. We caught up with him recently to talk about his experience taking our Models of Disease course (aka MoD boot camp) in 2020, a time during which he was immersed in that transition.

As a grad student in 2013, you were part of a team that discovered a major finding in schizophrenia genomics. Looking back 10 years later, what have you learned from that experience?

One thing I’ve learned is that the arc of drug discovery and development is quite long. It also gave me a better appreciation for what is involved in translating a basic science finding into a drug. In academia, to arrive at a finding like we did can feel like a milestone, but in reality it’s just the beginning of a lot more work to see if that finding can be clinically actionable.

It definitely felt rewarding to be able to arrive at a finding that we think could help us understand the biology of the disease, and to be part of a multidisciplinary collaboration across many labs. None of us could have achieved it individually. But it’s not the end point. It’s the starting point.

You started your MD/PhD training in 2008. That’s 15 years of post-college training so far, with a year or two of research fellowship remaining. What drove you to embark on this journey?

Part of it was personal motivation. I can trace the roots of my interest in medicine back to high school, when my mother was diagnosed with leukemia. I realized I wanted to be a doctor earlier than when I realized I also wanted to be a scientist.

The scientist part came from exposure to lab research in college, where I worked in a lab part-time starting the summer after my freshman year. That was enough to get a sense of what laboratory research is like. But it wasn’t until I took a year off between college and medical school to work in a lab full-time that I became convinced that this was something I could see myself doing and enjoying as a primary part of my career. Having that immersive experience was key.

“In some ways, physician-scientist training can be like a game of Chutes and Ladders. You go through one aspect of training and just when you’ve reached a certain level of maturity in that, you switch.”

You took another year off from academic studies 10 years later, between residency and fellowship, this time to work at Vertex Pharmaceuticals. What was your motivation for wanting exposure to industry?

During my PhD training I studied the genetics of schizophrenia as well as lupus. It was exciting and rewarding to be able to see firsthand what we can learn about disease biology from genetic insights and large-scale analyses of genetic data. At the same time, what was less clear to me was how a basic discovery in biology or disease pathogenesis gets translated into something that benefits patients. What is the process from point A, the finding, to point B, having a drug that meaningfully improves a patient’s life? How does one prioritize which discoveries should be translated?

I realized that spending time in industry was the best way to understand what happens after the research finding. I knew I would return to academia to pursue my clinical and postdoctoral fellowship, and I wanted to approach the rest of my training and career with that perspective in mind.

Around that time, Vertex developed a fellowship program. Its intention was to enable individuals to get precisely the kind of exposure I sought. I’m grateful for having had that exposure relatively early on because it helped me understand the ways in which the academia and industry settings can be similar, different, and complementary.

You then returned to academia to start your fellowship training in hematology/oncology and attended Models of Disease Boot Camp a year later, in 2020. What attracted you to the course at that time?

In some ways, physician-scientist training can be like a game of Chutes and Ladders. You go through one aspect of training and just when you’ve reached a certain level of maturity in that, you switch. You go from the first two years of medical school to entering grad school and then back to medical school for the last two years. Then there is a transition from medical school to internship and residency. All these different points can feel like chutes or ladders.

Ultimately, I think the transition that felt the most challenging was finishing clinical fellowship and going back to the lab. Up until then, the next step in your training is clear. Then the number of options becomes vast, and you have to choose an area in which to focus. That choice can impact your research life for at least the immediate future and possibly the rest of your career.

In that sense, I felt like this transition was more than just the “next transition.” It was about the potential impact it was going to have for the next five, ten years or more.

What stands out for you from your boot camp memories?

It was not just about learning new hot topics or techniques, although that was certainly a part of it. It was being able to hear from scientists and speakers who could rekindle that interest and excitement about going back into the lab by showing what’s possible. For example, we heard from scientists who have successfully navigated the bench-to-bedside arc, such as Stu Orkin, whose basic science discoveries contributed to the first CRISPR-based treatment for sickle cell disease, and [Harvard Medical School] Dean George Q. Daley, or people who had moved from academia to industry like Jay Bradner [chief scientific officer of Amgen].

“Techniques can become obsolete very quickly; the process of how to do science well does not.”

We also heard from physician-scientists only a few years ahead of us in training, which was really motivating and enjoyable. Multiple sessions included people who had just gotten their first K grant or had just secured an assistant professor position. To meet individuals who have recently navigated this transition successfully and see what’s possible afterward was encouraging. In the midst of a daunting transition, that gave us optimism.

In my case, my graduate work was in a different field than what I’m now doing during my postdoc, which is studying pre-cancer states that precede leukemias and lymphoma. So my transition to postdoctoral research involved switching fields and learning about approaches and experiments that were new to me.

Even so, for me the boot camp–and really, scientific training in general–was less about specific techniques or analytical approaches and more about learning to do science well: thinking critically and creatively, choosing the right questions, and figuring out what experiments or analyses will address those questions in the most rigorous and definitive way. Techniques can become obsolete very quickly; the process of how to do science well does not.

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