2024 Prize Winner

Stuart H. Orkin, MD (Harvard Medical School)

Recognized for landmark discoveries of the molecular basis of blood disorders and using the basic science findings for therapeutic approaches, the Institute for Regenerative Medicine at the University of Pennsylvania has awarded Stuart H. Orkin, MD the third Elaine Redding Brinster Prize in Science or Medicine. He elucidated the mechanism controlling the switch from fetal to adult hemoglobin, and reduced to practice reactivation of fetal hemoglobin as a therapeutic strategy for sickle cell disease and other blood cell disorders.

When Orkin initiated his research over 40 years ago, little was understood about how the development of the different kinds of blood cells is programmed. His work laid the foundation for the molecular study of blood cell formation (hematopoiesis). Central to these studies has been pursuit of the hemoglobin-producing red blood cell as a model, leading to discoveries with a broad impact on understanding cell differentiation and on medicine, more broadly.

In 1980s, Orkin applied newly developed methods of gene cloning to determine the genetic basis of thalassemias, blood diseases in which hemoglobin production is impaired. This work provided the first molecular description of a human disease, and a database for prenatal diagnosis of thalassemias by DNA. He established a paradigm for genetic dissection of inherited disorders.

The genetics of thalassemia illustrated how different mutations cause the disease, but failed to answer how genes, such as hemoglobin, are specifically expressed in red cells. Coincident with another investigator (Gary Felsenfeld at the U.S. National Institutes of Health), Orkin and colleagues discovered GATA1, the first master hematopoietic cell specific regulator. Orkin’s laboratory identified other related factors, including GATA2, the first hematopoietic stem cell regulator. Members of the GATA family have provided critical insights into development of numerous tissues and organs (including the heart, brain, nervous system, and the gut), and oncogenesis. Studies of GATA1 have served as a paradigm of molecular developmental biology.

A major clinically relevant question remained: How is the switch from fetal hemoglobin to adult hemoglobin, which occurs normally in development, controlled, and how can the knowledge be used to reactivate fetal hemoglobin expression in adults with thalassemia or sickle cell disease as a potential therapy?  Orkin and his colleagues elucidated the mechanism of the fetal to adult hemoglobin switch and, in so doing, created opportunities for curative genetic therapy.  His group discovered that the protein BCL11A silences fetal hemoglobin production by acting directly on the fetal globin gene, to shut off expression. Using gene knockouts and engineered sickle cell-diseased mice, the Orkin laboratory showed that BCL11A loss in erythroid cells prevents sickle cell disease due to consequent high-level expression of fetal hemoglobin, a finding that provided the rationale for therapeutic targeting in hemoglobinopathies. In further mechanistic studies, Orkin and associates discovered that common genetic variation within an erythroid-specific regulatory sequence within the BCL11A gene controls its own expression. They identified a GATA1 binding site in the gene regulatory sequence whose disruption impairs BCL11A gene expression, thereby permitting fetal hemoglobin reactivation. This “Achilles heel” represented a favorable target for CRISPR/Cas9 editing, which was leveraged for first-in-man gene editing therapy in a collaboration of two companies, CRISPR Therapeutics and Vertex, for both sickle cell disease and thalassemia. The success of the clinical trials validates Orkin’s fundamental contributions and establishes fetal hemoglobin reactivation as therapy for the hemoglobin disorders.  Dr. Orkin’s foundational work in this area is the basis for the Elaine Redding Brinster Prize.

Orkin will accept the prize March 13, 2024, as part of the day-long Ralph L. Brinster Symposium. The symposium will feature several eminent speakers from across the biomedical sciences, including Titia de Lange, PhD, Leon Hess Professor, Laboratory of Cell Biology and Genetics from the Rockefeller University; Carla Shatz, PhD, Sapp Family Provostial Professor, the Catherine Holman Johnson Director of Stanford Bio-X, and Professor of Biology and Neurobiology at Stanford University; Alejandro Sànchez Alvarado, PhD, President and Chief Scientific Officer, the Sánchez Laboratory, Stowers Institute for Medical Research; and Marianne Bronner, PhD, Edward B. Lewis Professor of Biology, Director of the Beckman Institute, Division of Biology and Biological Engineering at the California Institute of Technology.

Photos from the Elaine Redding Brinster Prize in Science or Medicine ceremony and lecture held on March 13, 2024. Credit: Dan Burke

Past Winners

2023- Huda Zoghbi, M.D. (Baylor College of Medicine)

For her work pinpointing the underlying, genetic causes of a pair of devastating neurological diseases, the Institute for Regenerative Medicine at the University of Pennsylvania awarded Huda Zoghbi, MD, the second Elaine Redding Brinster Prize in Science or Medicine. Zoghbi’s research advanced the field’s conceptual understanding of how gene expression can influence neurological health, even in non-inherited disorders.

Zoghbi began her career as a clinician before diving into research to understand the causes of some of the conditions she saw affecting her patients. Through a longstanding collaboration with Harry Orr, PhD, at the University of Minnesota, Zoghbi discovered that a lengthening of the ATXN1 gene causes spinocerebellar ataxia 1, a progressive disorder characterized by issues with balance and movement.

In a different line of work, Zoghbi was pursuing the genetic basis of Rett syndrome, a rare and sporadic neurological and developmental disorder that affects the way the brain functions after birth, causing a progressive loss of motor skills and language, primarily in female patients. In 1999, her research team identified mutations in methyl-CpG-binding protein 2 gene, known as MECP2, as the root cause for Rett syndrome. Further work showed that the brain is sensitive to changes in the levels of MECP2 expression and that duplication of the gene can cause other neurological issues.

Zoghbi accepted the prize on March 15, 2023, as part of the day-long Ralph L. Brinster Symposium. The symposium featured several eminent speakers from across the biomedical sciences, including Janet Rossant, PhD, of the University of Toronto, Lynne Maquat, PhD, of the University of Rochester, Karl Deisseroth, MD, PhD, of Stanford University, and Lorenz Studer, MD, of Memorial-Sloan Kettering.

Photos from the Elaine Redding Brinster Prize in Science or Medicine ceremony and lecture held on March 15, 2023. Credit: Dan Burke