Sickle cell disease and β thalassemia are blood disorders that affect more than 20 million people worldwide. 5% of the world’s population carries the trait genes for hemoglobin disorders and 300,000 babies are born each year with severe hemoglobin disorders. Most people who have sickle cell disease are of African ancestry or self-identify as Black. The sickle cell trait protects against malaria, explaining the prevalence of the sickle gene in populations in particular regions of the world.

The first sickle cell case was documented in 1846 and the disease was named sickle cell anemia in 1922. In people with the disease, red blood cells become abnormally sickle-shaped due to low oxygen levels which are caused by a hemoglobin defect. Hemoglobin is the protein in red blood cells that transports oxygen throughout our tissues. Our blood cells are usually doughnut shaped and flexible whereas sickle cells are rigid and adhesive, impeding blood flow in the body. Sickled red blood cells also die prematurely, further decreasing oxygen throughout the body, resulting in anemia and severe fatigue. Pain crises are also a major symptom of sickle cell disease, due to sickle cells blocking blood flow to the chest, abdomen, and joints. People with sickle cell disease are prone to infections and have shortened lifespans.

Importantly for the work of this year’s Shaw Awardees in Life Science and Medicine, it has long been known that shortly after birth, a switch occurs, from a fetal form of hemoglobin to an adult form. Moreover, sickle cell disease severity varies. Indeed, patients with a hereditary condition that results in continued production of fetal hemoglobin makes sickle cell disease milder. This condition is called hereditary persistence of fetal hemoglobin.

Over the course of their distinguished careers, Swee Lay Thein and Stuart Orkin each made wide-ranging, independent contributions to the analysis of blood cell disorders. Their work intersected when they made complementary and reinforcing discoveries that led to the development of a therapy to treat sickle cell disease and β thalassemia.

Swee Lay Thein made a transformative discovery when she performed a genome wide association study of individuals displaying extreme differences in sickle cell and β thalassemia traits. Her goal was to identify genes associated with severity of the disease. She transformed our understanding of how sickle cell disease can vary in severity when she discovered that most variation in hemoglobin production was due to changes in genes encoding components other than hemoglobin. Using a technique called linkage analysis, Thein identified the genetic regions that influenced variation of the sickle trait. She mapped the changes to a gene called BCL11A, making the first connection between the BCL11A protein and red blood cell disorders. She reported that BCL11A encodes a so-called zinc finger DNA binding regulatory protein on chromosome 2. She concluded that the BCL11A protein is the major regulator of fetal hemoglobin production. Thein’s discovery presaged curative therapies in which manipulation of BCL11A could counteract the sickle cell and β thalassemia disorders by increasing the amount of fetal hemoglobin present in patients with sickle disease and β thalassemia.

In elegant work, Stuart Orkin established that the BCL11A protein is a repressor of the fetal hemoglobin “promoter”. A promoter is a region of DNA that drives production of a particular protein, in this case, fetal hemoglobin. Moreover, it is this promoter that is mutated in humans with hereditary persistence of fetal hemoglobin. Orkin demonstrated that decreased BCL11A expression corrects sickle cell disease in engineered mice, an experiment that was crucial for advancing the exciting notion that altering BCL11A production could indeed be a strategy for the treatment of sickle cell disease and β thalassemia. Orkin next identified a particular site in the BCL11A gene that, when deleted using CRISPR gene editing in blood stem cells, dampened BCL11A expression. This genome alteration reactivated fetal hemoglobin production. Orkin’s mouse work provided the foundation for clinical trials using CRISPR genome editing in patients with sickle cell disease and β thalassemia. The trials yielded transformative results: freedom from sickle crises and anemia in sickle cell disease and transfusion-independence in β thalassemia.

The FDA approved two sickle cell stem cell therapies in December 2023. One is called CASGEVY made by Vertex, and is based on Thein and Orkin’s findings. CASGEVY is the first approved therapy that uses CRISPR genome editing.

Thein and Orkin’s work exemplifies how basic discovery, disease research, and translational medicine can lay the foundation for development of transformative therapies that save lives.

12 November 2024 Hong Kong