Stuart Orkin Receives Breakthrough Prize in Life Sciences

Stuart H. Orkin and Swee Lay Thein share the Breakthrough Prize in Life Sciences. Their research transformed the devastating blood disorders sickle cell disease and beta-thalassemia from incurable to treatable conditions through gene editing therapy.

In beta-thalassemia the body fails to produce enough healthy hemoglobin; while in sickle cell disease, defective hemoglobin causes red blood cells to become stiff, sticky and sickle-shaped. But people who produce elevated levels of fetal form of hemoglobin as adults, rather than switching entirely to adult hemoglobin, have much milder forms of the diseases. This presented a tantalizing possibility for translational medicine: genetically switching fetal hemoglobin production back on, and so mitigating disease symptoms. Thein mapped the trait of persistent fetal hemoglobin production to chromosome 2, and subsequently identified the gene BCL11A as the key genetic player. Orkin demonstrated that BCL11A functions as the master repressor of fetal hemoglobin, shutting down its production after birth, and that inactivating it restored fetal hemoglobin production in mice and eliminated sickle cell disease symptoms. His laboratory identified a specific DNA enhancer region that controls BCL11A expression itself, but crucially only in red blood cells, providing a precise and safe target for therapeutic intervention without affecting other cells.

The translation of these discoveries into a CRISPR-based gene therapy (Casgevy) that edits this enhancer region in patients’ own blood stem cells resulted in the first CRISPR-based medicine approved for any disease. This work has revolutionized treatment for sickle cell disease and beta-thalassemia, providing a potentially curative one-time therapy for conditions affecting millions worldwide.