The Shaw Prize in Life Science and Medicine 2024 is awarded in equal shares to Swee Lay Thein, Senior Investigator and Chief of the Sickle Cell Branch, National Heart, Lung, and Blood Institute at the National Institutes of Health, USA and Stuart Orkin, David G Nathan Distinguished Professor of Pediatrics at Harvard Medical School, USA, for their discovery of the genetic and molecular mechanisms underlying the fetal-to-adult hemoglobin switch, making possible a revolutionary and highly effective genome-editing therapy for sickle cell anemia and β thalassemia, devastating blood diseases that affect millions of people worldwide.

Sickle cell disease and β thalassemia are blood disorders that affect more than 20 million people worldwide. Five percent of the world’s population carry 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. Blood cell sickling occurs due to low oxygen levels which is caused by an abnormal hemoglobin protein. Hemoglobin is the protein in red blood cells that transports oxygen throughout our tissues. Shortly after birth, a switch occurs, from the fetal form of hemoglobin to the adult form.

It has long been known that although sickle cell anemia is a disorder that is a consequence of changes in a single gene, disease severity varies. Indeed, studies conducted in the 1970s–1990s showed that patients with a hereditary condition that resulted in continued production of fetal hemoglobin made the 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 examination of individuals displaying extreme differences in sickle cell and β thalassemia traits. Her goal was to identify genes associated with severity of disease. She transformed understanding of how phenotypes due to sickle cell traits can vary when she discovered that most genetic variance in fetal 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 BCL11A 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 BCL11A 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.

In elegant work, Stuart Orkin established that the BCL11A protein is a repressor of the fetal hemoglobin promoter, and it is this promoter that is mutated in humans with hereditary persistence of fetal hemoglobin. Orkin demonstrated that downregulation of BCL11A expression corrects sickle cell disease in engineered mice, an experiment that was crucial for advancing the exciting notion that altering BCL11A production could be pursued for therapeutic translation for both sickle cell and β thalassemia. Orkin next identified a particular site in a BCL11A enhancer element 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. Indeed, 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 of them, called CASGEVY and made by Vertex, is based on Thein and Orkin’s findings, and 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.

Life Science and Medicine Selection Committee
The Shaw Prize

21 May 2024, Hong Kong