Stuart H. Orkin, MD, Investigator at Dana-Farber/Boston Children's Cancer and Blood Disorders Center, David G. Nathan Distinguished Professor, Harvard Medical School and Investigator, Howard Hughes Medical Institute, has been honored with The Breakthrough Prize in Life Sciences for discovering how the body turns off fetal hemoglobin after birth, a finding that led to a new treatment strategy for sickle cell disease. Dr. Orkin shares the prize with SweeLay Thein, Investigator at the National Institutes of Health (NIH).
The Breakthrough Prize, widely known as the "Oscars® of Science," recognizes major advances in the life sciences, fundamental physics, and mathematics. This year's laureates were recognized Saturday at the Breakthrough Prize gala in Los Angeles, where leaders from science, technology, and business joined actors, filmmakers, writers, musicians, athletes, and past laureates to celebrate scientific discovery and achievement. This year, six Breakthrough Prizes of $3 million each were awarded.
"This year's laureates show what great science can do - deepen our understanding of the world and lead to discoveries that improve millions of lives," said Mark Zuckerberg and Dr. Priscilla Chan, founders of Biohub. "We're proud to recognize their work."
In landmark research, Orkin and colleagues identified BCL11A as a key regulator that shuts off fetal hemoglobin after birth. That discovery helped solve one of the most important long-standing questions in hematology and provided a powerful new idea for treating sickle cell disease: if fetal hemoglobin could be switched back on, it could compensate for the defective adult hemoglobin that drives the disease. Today, that concept forms the basis of an FDA-approved gene-editing therapy for sickle cell disease.
"For us, the long arc of discovery has really come full circle. I started at a time when we could not clone genes, and now we can treat patients through gene modification and see them well," said Orkin. "The Breakthrough Prize is special because it recognizes a singular discovery rather than a whole career."
Sickle cell disease is caused by a mutation in the adult form of hemoglobin, the protein in red blood cells that carries oxygen throughout the body. Before birth, however, babies rely on fetal hemoglobin, not adult hemoglobin, and therefore do not experience the damaging sickling of red blood cells that defines the disease. Symptoms emerge after birth, when fetal hemoglobin is naturally turned off and adult hemoglobin takes over.
For decades, scientists and clinicians recognized that patients with higher levels of fetal hemoglobin tended to have milder disease. But the molecular mechanism controlling that switch remained elusive.
Orkin's work changed that. In a seminal paper published in the journal Science in 2008, his team identified BCL11A as a major repressor, or "off switch," for fetal hemoglobin. That discovery offered a new therapeutic target: reduce BCL11A activity in blood-forming cells and restore fetal hemoglobin production.
Subsequent studies from Orkin's lab helped show just how powerful that strategy could be. In a mouse model of sickle cell disease, turning off BCL11A in developing red blood cells reactivated fetal hemoglobin and corrected the disease phenotype. Those findings laid the groundwork for gene-editing approaches that target BCL11A regulation in a patient's own blood stem cells.
"All of us who are physician-scientists want to see our work translated," Orkin said. "The most gratifying part of what we do is seeing the science actually reach patients and benefit patients."
That translation is now a reality. Clinical studies of gene-edited therapies based on reactivating fetal hemoglobin have shown striking results in people living with sickle cell disease, dramatically reducing or eliminating the painful vaso-occlusive crises that define the condition for many patients.
"For the sickle cell patients, they no longer have crises, pain crises," Orkin said. "After therapy, they're now having a totally new future. And so, it really is transformative."
Orkin has authored more than 500 peer-reviewed publications, spanning the fields of hematology, human genetics and stem cell biology. He has also edited several books and holds a number of patents.
His many awards and honors include the Warren Alpert Foundation Prize in 1993; Jessie Stevenson Kovalenko Medal from the National Academy of Sciences in 2013; Mechthild Esser Nemmers Prize in Medical Science, Northwestern University in 2018; King Faisal International Prize for Medicine in 2020; Harrington Prize for Innovation in Medicine from the American Society for Clinical Investigation and Harrington Discovery Institute in 2020; Gruber Foundation Prize in Genetics in 2021; the Canada Gairdner International Award in 2022; the Elaine Redding Brinster Prize in Science or Medicine in 2023; The Shaw Prize in Life Science & Medicine in 2024; and the Ernest Beutler Lecture and Prize in 2024.
Orkin is a member of the National Academy of Sciences, the National Academy of Medicine, the American Academy of Arts and Sciences, and the American Philosophical Society. He is a fellow of the American Association for the Advancement of Science, an investigator with the Howard Hughes Medical Institute, and the David G. Nathan Professor of Pediatrics at Harvard Medical School. Previously, Orkin served as chairman of the Department of Pediatric Oncology at the Dana-Farber Cancer Institute and associate chief of the Division of Hematology/Oncology at Boston Children's Hospital.
Orkin received his medical degree from Harvard Medical School in 1972, after earning a Bachelor of Science at Massachusetts Institute of Technology. He completed clinical training in pediatrics and hematology/oncology at Boston Children's Hospital and the Dana-Farber Cancer Institute, as well as postdoctoral research at the National Institutes of Health.
