Image: Gairdner Foundation
Stuart Orkin, David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School and Dana-Farber Cancer Institute, has been awarded a 2022 Canada Gairdner International Award. The award is being presented for his work toward the discovery of the molecular mechanism responsible for the switch from fetal to adult hemoglobin gene expression and translating this discovery into a novel treatment for sickle cell disease and beta-thalassemia.
The award, which recognizes significant biomedical and global health research and discoveries, was announced April 5 in Toronto.
Much of what is known about the control of gene expression during blood cell development can be traced directly to Orkin’s pioneering studies. His most recent studies led to the discovery of the molecular mechanism responsible for the switch from fetal (HbF) to adult (HbA) hemoglobin gene expression during human development.
Capitalizing on genetic clues from human population studies, Orkin and colleagues established that the protein BCL11A acts as the critical silencer of HbF expression in adults.
Recognizing that turning HbF expression back on could lessen disease severity in sickle cell disease and beta-thalassemia—genetic disorders affecting HbA production—he proposed downregulation of BCL11A as a therapeutic approach.
Dialing down the amount of BCL11A would reactivate HbF expression and effectively substitute for mutant or deficient HbA in these disorders.
Orkin’s group first demonstrated that downregulation of BCL11A expression corrects sickle cell disease in engineered mice, an important proof-of-principle for therapeutic translation.
He and colleagues identified a site within the BCL11A gene that, if deleted by CRISPR gene editing in blood stem cells, would impair BCL11A expression within developing red blood cells and safely reactivate HbF expression.
This work laid the groundwork for promising, ongoing clinical trials in patients with sickle cell disease and beta-thalassemia, diseases that affect more than 5 million people worldwide.
The outcomes of these trials will have significant impact for patients with hemoglobin disorders around the world and will encourage future development of cheaper and more readily accessible therapies for global application.
The Gairdner Foundation awards annual prizes to scientists whose discoveries have had major impact on scientific progress and on human health.
Since 1959, 402 scientists have received a Canada Gairdner Award and 96 to date have gone on to receive the Nobel Prize.
