The rockefeller university

Event Details

Type

Friday Lecture Series

Speaker(s)

Stuart Orkin, M.D., David G. Nathan Distinguished Professor of Pediatrics, Dana-Farber Cancer Institute, Boston Children's Hospital, Harvard Medical School; investigator, Howard Hughes Medical Institute

Speaker bio(s)

The strongest genetic modifier of severity of the hemoglobin disorders, β-thalassemia and sickle cell disease, is the level of fetal hemoglobin (HbF, α2γ2). Although the principal transcriptional regulators determining erythroid cell gene expression and differentiation have been known for many years, the basis for the switch from fetal (γ)- to adult (β)-globin in ontogeny has been obscure until recently. Genome-wide association studies (GWAS) provided potential candidate loci for control of HbF. Dr. Orkin’s studies establish BCL11A as a major repressor of HbF and also demonstrate that the target of common genetic variation detected in GWAS is an extended cell-specific regulatory element within BCL11A. High resolution, unbiased CRISPR/Cas9 mutagenesis revealed a remarkably small region accounting for the majority of enhancer activity that is amenable to genetic disruption as a therapeutic approach to directed HbF reactivation in hemoglobin-disease patients. Parallel, collaborative work has identified a second HbF repressor and a co-repressor complex that functions with both repressors. These factors likely account for the near entirety of the major components required for HbF silencing. Although gene therapy and editing approaches are rapidly progressing toward clinical application, lessening the global impact of the hemoglobin disorders will require development of small molecules that interfere with the critical factors of the HbF repression pathway. Multidisciplinary approaches will be required to meet this challenge. 

 

Dr. Orkin's work focuses on the intersections of transcriptional control with stem cell biology, hematopoiesis, and cancer. His research achievements include comprehensive dissection of the molecular basis of the thalassemia syndromes, positional cloning of the first human disease gene, cloning of the first master regulator of blood cell development, and identification of a major silencer of fetal hemoglobin expression.

 

Dr. Orkin received his B.S. from MIT and his M.D. from Harvard Medical School. Before joining the faculty of Harvard Medical School, where he is currently the David G. Nathan Distinguished Professor of Pediatrics, he was a research associate in the Laboratory of Molecular Genetics at the National Institutes of Health with Dr. Philip Leder. From 2000 to 2016, he served as chairman of the department of pediatric oncology at the Dana-Farber Cancer Institute. He has also served on the National Research Council Committee on Mapping the Human Genome and as co-chair with Dr. Arno Motulsky of the Panel to Assess the NIH Investment in Gene Therapy. He was the inaugural chair of the Grants Reviews Committee of the California Institute of Regenerative Medicine.

 

Dr. Orkin is the recipient of numerous honors for his work, including the William Dameshek Prize, the E. Donnall Thomas Prize, and the Basic Science Mentor Award, all from the American Society of Hematology; the E. Mead Johnson Award from the American Academy of Pediatrics; the Warren Alpert Foundation Prize; the Helmut Horten Foundation Prize; the Distinguished Research Award from the Association of American Medical Colleges; and the Donald Metcalf Award from the International Society of Experimental Hematology. In 2013, he received the Jessie Stevenson Kovalenko Medal from the National Academy of Sciences for important contributions to the medical sciences. In 2014, he was honored with the William A. Allan Award from the American Society of Human Genetics. Dr. Orkin is an investigator of the Howard Hughes Medical Institute, a fellow of the American Academy of Arts and Sciences, and a member of both the National Academy of Sciences and the National Academy of Medicine.

Open to

Public

Host

Alexander Tarakhovsky, M.D., Ph.D.

Reception

Refreshments, 3:15 p.m. - 3:45 p.m., Abby Lounge

Contact

Justin Sloboda

Phone

(212) 327-7785

Sponsor

Justin Sloboda
(212) 327-7785
jsloboda@rockefeller.edu

Readings

http://librarynews.rockefeller.edu/?p=4227