Orkin joined the faculty ofHarvard Medical School in 1978, becoming Assistant Professor of Pediatrics, and rose to the rank of full professor in 1986.[6] He was named anHHMI Investigator in 1986, a position he continues to hold.[7] From 2000 to 2016, he served as Chair of Pediatric Oncology at theDana–Farber Cancer Institute.[8] In 2017, he was appointed the David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School.[9]
Orkin reading DNA sequencing gel of b-thalassemia mutations (early 1980s)
In the 1970s and 1980s, Orkin identified genetic mutations associated with thethalassemia syndromes, providing the first comprehensive molecular description of an inherited disorder.[10][11] In 1986, he and collaborators cloned a gene responsible forchronic granulomatous disease, the first example ofpositional 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 theGATA family in blood cell development and cancer.[15]
In 1985, David Ginsburg, then a fellow in Orkin’s laboratory, cloned cDNA encodingvon Willebrand factor (vWF), which later enabled the development of recombinant vWF therapies.[16]
Beginning in 2008, Orkin and colleagues identifiedBCL11A as a key repressor offetal 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 inScience andNature, respectively, that described DNA regulatory elements as potential therapeutic targets forgene therapy in sickle cell disease.[21][22] His foundational research on BCL11A paved the way for the first approvedCRISPR/Cas9-basedgene-editing therapy,Casgevy, for sickle cell disease andβ-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]
Orkin has served on several national committees addressing genetics and biomedical research policy. In 1987, he was a member of theNational Research Council committee on theMapping and Sequencing of the Human Genome, which provided a blueprint for theHuman Genome Project.[26]
In 1995, at the request ofHarold Varmus, then director of theNational Institutes of Health,[27] Orkin co-chaired (withArno Motulsky) thePanel 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 theCalifornia 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, 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.
Zheng, G; Yin, M; Mehta, S; Chu, IT; Wang, S; AlShaye, A; Drainville, K; Buyanbat, A; Bienfait, F; Tenglin, K; Zhu, Q; Orkin, SH (November 29, 2024). "A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing".Science.386 (6725):1010–1018.doi:10.1126/science.adp3025.PMID39607926.
^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.
^Zheng, G; Yin, M; Mehta, S; Chu, IT; Wang, S; AlShaye, A; Drainville, K; Buyanbat, A; Bienfait, F; Tenglin, K; Zhu, Q; Orkin, SH (2024). "A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing".Science.386 (6725):1010–1018.doi:10.1126/science.adp3025.PMID39607926.
^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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