In the 1970s and 1980s, Orkin identified genetic mutations associated with the
thalassemia syndromes, providing the first comprehensive molecular description of an inherited disorder. 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. His laboratory subsequently cloned the first hematopoietic transcription factor,
GATA1, and later defined the roles of the
GATA family in blood cell development and cancer. 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. Beginning in 2008, Orkin and colleagues identified
BCL11A as a key repressor of
fetal hemoglobin (HbF). His group later showed that silencing BCL11A could reverse sickle cell pathology in mice. 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. 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. His group continues to define the molecular biology of BCL11A, including showing that it functions as a tetramer in hemoglobin regulation. ==Service to science==