[…] the thing worth doing well done has a shape that satisfies, clean and evident.
Marge Piercy — "To Be of Use"
“I’m just so grateful that I’ve had the opportunity to do science as a career,” reflects Sean J. Morrison, PhD, founding director of Children’s Medical Center Research Institute at UT Southwestern in Dallas, Texas.
Dr. Morrison’s journey into the field began during his graduate studies at Stanford University in the lab of Irving L. Weissman, MD. It was a pivotal time, as the lab had just identified a set of cell surface markers that could purify hematopoietic stem cells (HSCs). “Suddenly, we could separate the needle from the haystack and study HSCs directly,” he recalls. “It opened the door to an explosion in our understanding of these cells and their properties.”
At the time, the field was just beginning to suspect that stem cells existed across various tissues, though little was known about how they were regulated. “I felt the most pressing question was understanding self-renewal,” Dr. Morrison explains. “Self-renewal is the key distinguishing feature of stem cells, the ability to go in and out of cycle throughout life to maintain themselves and regenerate tissues.” This question set the course for his research as he established his own lab, focusing on uncovering self-renewal mechanisms conserved across stem cells in different tissues. “I wasn’t sure that we knew how to do it, or that we would succeed,” he says. “But I thought it was a really good story, and it persuaded people to give me a job.”. The Morrison lab went on to identify a series of gene products that were necessary for the self-renewal of stem cells in multiple tissues, without being generically required for cell division.
The Morrison lab also studied cell extrinsic mechanisms that regulate HSC maintenance. One of Dr. Morrison's most influential contributions was his proposal in 2005 that HSCs reside within perivascular niches (PVNs). His team observed that HSCs were consistently found near sinusoidal blood vessels in the bone marrow and spleen, suggesting a specialized environment for their maintenance. “We proposed that HSCs are maintained in a PVN, but at the time, the idea was widely dismissed,” he recalls. “Most of the field favored a different model, and for a while, I felt very unpopular at conferences.”
Undeterred, Dr. Morrison continued with a series of rigorous experiments to test his hypothesis, facing years of skepticism before the data began to convince his peers. By 2012, his lab had shown that leptin receptor-positive (LepR+) perivascular stromal cells and endothelial cells were critical sources of multiple growth factors necessary for HSC maintenance, providing definitive evidence that HSCs depend on PVN for their maintenance. “Once we showed that LepR+ cells were the main source of known factors needed for HSC maintenance, the field shifted,” he says. “That experience taught me the importance of always trusting the data. Even if an idea doesn’t resonate initially, careful science can ultimately shift the paradigm.”
In his lecture yesterday as this year’s recipient of the E. Donnall Thomas Lecture and Prize, Dr. Morrison focused on new insights generated by his laboratory into the mechanisms that regulate HSC maintenance and the implications for clinical HSC transplantation. His lab continues to probe how HSCs adapt to different physiological contexts. A study this October focused on how HSCs respond to the challenge of mammalian pregnancy to produce more red cells than at steady state1 — identifying a novel role for retrotransposon activation in HSCs, driving innate immune responses that activate HSCs and erythropoiesis. Unpublished work examines the role of beta-adrenergic receptor signaling in LepR+ cells during bone marrow regeneration following stem cell transplantation, with direct implications for clinical practice.
Hematopoiesis is a neat analogy for mentorship in science, and Dr. Morrison acknowledges how mentorship from Dr. Weissman and David J. Anderson, PhD, has been critical to his career. Over the past 25 years, Dr. Morrison has in turn trained dozens of scientists, with more than half of his former trainees now leading their own labs. “One of the things that excites me most is seeing them approach science the right way — taking on tough experiments, telling the whole story, and being rigorous,” he says. “It’s incredibly rewarding to see them advance the field in their own ways.”
His advice for young scientists? Nothing is more important than the quality of the work. “If you’re going to spend years on solving a problem, make sure it’s an important one, and approach it with rigor,” he advises. “The best scientists constantly update their ideas based on the data and are unafraid to try to disprove their own hypotheses. High-quality work stands the test of time.”
Dr. Morrison said he feels fortunate to have the opportunity to do meaningful work and to make discoveries with the potential to impact patient care. “When you’re immersed in it, it’s easy to lose sight of how lucky we are to have this job,” he reflects. “Discoveries that change clinical practice are rare, but that one breakthrough can make all the challenges worth it.”
REFERENCE
- Phan J, Chen B, Zhao Z, et al. Retrotransposons are co-opted to activate hematopoietic stem cells and erythropoiesis. Science. 2024;386(6722):eado6836.
