Sixteen years ago, Michael Segel was a rising senior at Brookline High School in Massachusetts when, acting on a friend’s suggestion, he signed on for a summer stint at a Harvard stem cell lab.
“I was somewhat interested in science, in particular biology, but never thought that it was for me,” Segel says.
But working with renowned biologist Douglas A. Melton, now a distinguished research fellow at Vertex Pharmaceuticals and the Catalyst Professor in the Department of Stem Cell and Regenerative Biology at Harvard Medical School and the Harvard Faculty of Arts and Sciences, and with then-postdoctoral researcher Richard Sherwood, now HMS assistant professor of medicine at Brigham and Women’s Hospital, brought an epiphany.
Segel said his curiosity and passion were stirred by the stakes involved in the researchers’ quest — a cure for type 1 diabetes, and with it, the promise of doing research that could one day improve and save lives.
“Almost right away,” Segel recalls, “I realized that research is what I wanted to do with my life.”
Inspired by his summer in the lab, Segel went on to receive an A.B. degree in human developmental and regenerative biology from Harvard College and completed his PhD in clinical neurosciences at the University of Cambridge and MIT. In his doctoral work, Segel investigated how aging affects glial stem cells — the cells that provide nourishment, protection, and support to neurons in the central nervous system — with a primary focus on understanding how the growing brain restricts these cells’ ability to regenerate.
In July 2024, Segel joined the ranks of faculty in the Blavatnik Institute at HMS and the Harvard Faculty of Arts and Sciences as an assistant professor of stem cell and regenerative biology. He has come full circle, working back on the ground floor of the same building where, as a high school summer intern, he once washed test tubes and moved liquids from bench to bench.
“It feels like coming home to a building and an institution that really shaped my life,” Segel said. “I am excited to contribute to this community that gave me so much.”
Today, Segel melds together his training in the biology of aging, in genome engineering, and in developing new gene-delivery vehicles toward one goal: therapeutically modifying the cells of the aging brain. His ultimate quest is to design new treatments for age-related diseases of the brain.
Harvard Medicine News spoke with Segel.
Harvard Medicine News: You study the lifespans of mammals and the molecular events that regulate their development. Why?
Michael Segel: Aging is the root of so many diseases and affects virtually every cell type in the body, yet we do not understand the very mechanisms that drive the pacing of adult life. The natural variation of mammalian lifespan provides us with a powerful lens through which to answer this question. A fundamental question for me since graduate school has been: Do cells age individually or, collectively, as an organism? In other words, does each cell have a ticking clock of its own, or are there cellular command centers that dictate the age-state for the entire organism? We are pretty excited about the prospect of studying lifespan changes across mammals.
HMNews: You have done research into the mechanisms that underpin the aging of glial cells, which nourish, shield, and support the all-precious neurons of the brain and spinal cord. What makes glial cells and their aging an object of scientific fascination?
Segel: Historically, glial cells have been relegated to the status of mere support cells of neurons. However, in recent years, there’s been newfound interest in non-neuronal cells in the brain and their role in brain function. The cells we have been interested in are called oligodendrocyte progenitor cells. They are the most widespread stem cell population of the brain, making up somewhere between 5 and 10 percent of all brain cells. The reason they are so interesting is that throughout adulthood, they give rise to new glial cells. However, around middle age, they begin to lose their generative capacity and cannot produce more glial cells.
Almost right away, I realized that research is what I wanted to do with my life.
Michael Segel
If we look agnostically at all the cells of the aging brain, this cell population includes some of the most pronounced age-related changes in terms of behavior and gene expression patterns. As scientists interested in untangling the processes involved in brain aging, we are setting our sights on these cells. We believe that the consequences for this loss of regenerative capacity in these cells are profound for brain health and may in part explain the onset of a whole range of age-associated neurodegenerative diseases.
HMNews: What is on your to-do list for the next year?
Segel: I am looking forward to recruiting fantastic trainees to the lab who are creative and want to work on these really difficult problems.
HMNews: What recent advances in the field are you most excited about?
Segel: I am most excited about the ability to evolve potent new classes of gene-delivery systems that bring genome editing technologies to specific cell types and tissues. We can now deliver these technologies to most of the cells in the mouse brain to specifically manipulate DNA and gene expression. The question that animates me is, “What can we do with these technologies to study and cure aging and age-associated disease?” This remains an open question — one that I am very interested in.
HMNews: Artificial intelligence is reshaping biomedicine and has had an enabling and amplifying effect in basic science research. How do you foresee the role of AI in your field?
Segel: Generative AI is truly revolutionary for education. As an educator, students in my lab can now explore areas of biomedicine and computational biology outside my expertise. In the past, I would ask trainees to trawl methods sections, GitHub, or ResearchGate to find solutions to computational problems. Now generative AI can efficiently teach us new computational methods, design mini-courses to teach us new computational techniques, and tailor these solutions for problems our lab is trying to address. Of course, AI is helping to trawl large datasets, design new proteins, and so on, but its power to teach trainees is what makes me so optimistic about these tools as an educator.
HMNews: Who is Michael Segel outside of the research lab and the lecture hall?
Segel: We have two girls, 3 years old and 6 months, so virtually all of my time outside of the lab is spent at home with my wife and daughters.
This conversation was edited for length and clarity.
