Orkin joined the faculty of Harvard Medical School in 1978, becoming Assistant Professor of Pediatrics, and rose to the rank of full professor in 1986.[6] He was named an HHMI Investigator in 1986, a position he continues to hold.[7] From 2000 to 2016, he served as Chair of Pediatric Oncology at the Dana–Farber Cancer Institute.[8] In 2017, he was appointed the David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School.[9]
Research
Orkin reading DNA sequencing gel of b-thalassemia mutations (early 1980s)
In the 1970s and 1980s, Orkin identified genetic mutations associated with the thalassemia syndromes, providing the first comprehensive molecular description of an inherited disorder.[10][11] In 1986, he and collaborators cloned a gene responsible for chronic granulomatous disease, the first example of positional cloning of a human disease gene without prior knowledge of its protein product.[12][13] His laboratory subsequently cloned the first hematopoietic transcription factor, GATA1,[14] and later defined the roles of the GATA family in blood cell development and cancer.[15]
In 1985, David Ginsburg, then a fellow in Orkin’s laboratory, cloned cDNA encoding von Willebrand factor (vWF), which later enabled the development of recombinant vWF therapies.[16]
Beginning in 2008, Orkin and colleagues identified BCL11A as a key repressor of fetal hemoglobin (HbF).[17][18][19] His group later showed that silencing BCL11A could reverse sickle cell pathology in mice.[20] In 2013 and 2015, Orkin published findings in Science and Nature, respectively, that described DNA regulatory elements as potential therapeutic targets for gene therapy in sickle cell disease.[21][22] His foundational research on BCL11A paved the way for the first approved CRISPR/Cas9-based gene-editing therapy, Casgevy, for sickle cell disease and β-thalassemia.[23][24] His group continues to define the molecular biology of BCL11A, including showing that it functions as a tetramer in hemoglobin regulation.[25]
Service to science
Orkin has served on several national committees addressing genetics and biomedical research policy. In 1987, he was a member of the National Research Council committee on the Mapping and Sequencing of the Human Genome, which provided a blueprint for the Human Genome Project.[26]
In 1995, at the request of Harold Varmus, then director of the National Institutes of Health,[27] Orkin co-chaired (with Arno Motulsky) the Panel to Assess the NIH Investment in Research on Gene Therapy. The panel issued a report that highlighted the limited rigor of existing gene therapy studies and emphasized the need to strengthen fundamental science in the field, a redirection later credited with enabling future advances.[28][29]
From 2005 to 2008, Orkin served as the inaugural chair of the California Institute for Regenerative Medicine's Grants Working Group, which reviewed research funding applications. He was later recognized by the Institute for his leadership and contributions.[30]
Orkin has been married to Rosyln W. Orkin, a developmental biologist, for more than 50 years and has one daughter.[4][59]
Selected publications
Orkin, SH; Alter, BP; Altay, C; Mahoney, MJ; Lazarus, H; Hobbins, JC; Nathan, DG (July 27, 1978). "Application of endonuclease mapping to the analysis and prenatal diagnosis of thalassemias caused by globin-gene deletion". N Engl J Med. 299 (4): 166–172. doi:10.1056/NEJM197807272990403. PMID661890.
Treisman, R; Orkin, SH; Maniatis, T (April 14, 1983). "Specific transcription and RNA splicing defects in five cloned beta-thalassaemia genes". Nature. 302 (5909): 591–596. doi:10.1038/302591a0. PMID6188062.
Ginsburg, D; Handin, RI; Bonthron, DT; Donlon, TA; Bruns, GA; Latt, SA; Orkin, SH (June 21, 1985). "Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization". Science. 228 (4706): 1401–1406. doi:10.1126/science.3874428. PMID3874428.
Tsai, SF; Martin, DI; Zon, LI; D'Andrea, AD; Wong, GG; Orkin, SH (June 8, 1989). "Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells". Nature. 339 (6224): 446–451. doi:10.1038/339446a0. PMID2725678.
Royer-Pokora, B; Kunkel, LM; Monaco, AP; Goff, SC; Newburger, PE; Baehner, RL; Cole, FS; Curnutte, JT; Orkin, SH (July 3–9, 1986). "Cloning the gene for an inherited human disorder—chronic granulomatous disease—on the basis of its chromosomal location". Nature. 322 (6074): 32–38. doi:10.1038/322032a0. hdl:2027.42/62926. PMID2425263.
↑ Orkin, Stuart H.; Kazazian, Haig H.; Antonarakis, Stylianos E.; Goff, Sabra C.; Boehm, Corinne D.; Sexton, Julianne P.; Waber, Pamela G.; Giardina, Patricia J. V. (April 1982). "Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphisms in human β-globin gene cluster". Nature. 296 (5858): 627–631. doi:10.1038/296627a0.
↑ Antonarakis, Stylianos E.; Kazazian, Haig H.; Orkin, Stuart H. (January 1985). "DNA polymorphism and molecular pathology of the human globin gene clusters". Human Genetics. 69 (1): 1–14. doi:10.1007/BF00295521.
↑ Tsai, SF; Martin, DI; Zon, LI; D'Andrea, AD; Wong, GG; Orkin, SH (1989). "Cloning of cDNA for the major DNA-binding protein of the erythroid lineage through expression in mammalian cells". Nature. 339 (6224): 446–451. doi:10.1038/339446a0. PMID2725678.
↑ Orkin, SH; Motulsky, AG (January 1996). "Report and recommendations of the Panel to Assess the NIH Investment in Research on Gene Therapy". Nat Med. 2 (1): 7–8. doi:10.1038/nm0196-7. PMID8564825.
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