Sickle Cell Branch

Swee Lay Thein, M.B., B.S., F.R.C.P., F.R.C.Path., D.Sc.

Senior Investigator and Chief

The Sickle Cell Branch conducts research to understand sickle cell disease and identify markers of disease severity. Specific projects aim to better predict long-term outcomes and to develop therapies through genetics and genomics. Researchers in this Branch also study how genes influence disease symptoms such as pain and vascular complications; and new approaches for better outcome in bone marrow transplant and gene therapy. The Branch is a leader in the Department of Health and Human Services (HHS) sickle cell program, which fosters government-wide collaboration to rapidly move basic discoveries to treatments for patients. This basic research helps fuel scientific discovery that may one day help advance research related to heart, lung, blood, and sleep conditions or other fields.

Our Labs

Cellular and Molecular Therapeutics

Sickle cell disease has its roots in genetic mutations that cause a single amino acid change in the β-globin chain of hemoglobin A; this change provides protection against malaria. Whereas one mutated copy of the hemoglobin A gene is an asset in areas where malaria is endemic, two copies of the mutated hemoglobin A gene causes hemoglobin to clump and deform red blood cells, leading to anemia, increased hemolysis, and vascular occlusions that affect multiple organs. The Cellular and Molecular Therapeutics Laboratory, led by Dr. John F. Tisdale, is working on multiple strategies both in the laboratory and in the clinic to cure sickle cell disease by repairing or replacing the precursor bone marrow cells that give rise to sickled red blood cells. In addition, strategies to correct the underlying mutation which causes sickle cell disease are being pursued utilizing newly developed gene editing tools, and work in the laboratory to develop methods for efficient editing of hematopoietic stem cells is underway.


Early Sickle Mortality Prevention

The Laboratory of Early Sickle Mortality Prevention, led by Dr. Courtney Fitzhugh, is exploring new avenues of hematopoietic stem cell (HSC) transplantation for sickle cell disease. Currently, HSC transplantation offers the only real cure for patients with sickle cell disease, though the transplantation procedure can only be applied to select people, and it carries its own set of health risks. One risk is that traditional stem cell transplants involve near total destruction of existing bone marrow, thus severely immunocompromising the transplant recipient. Dr. Fitzhugh and her team have been developing an alternative approach in which the donor and recipient stem cells coexist, potentially reducing the risk for serious infections or other immune complications. Dr. Fitzhugh has demonstrated the efficacy of this nonmyeloablative procedure in both mice and human volunteers, and is now working to develop a widely available approach which uses parents, children, or half-matched siblings as donors. Dr. Fitzhugh is also examining why sickle cell disease patients develop heart disease, and what can be done to prevent or possibly even reverse heart-related complications in this population.


Sickle Cell Genetics and Pathophysiology

Research in the Laboratory of Sickle Cell Genetics and Pathophysiology, led by Dr. Swee Lay Thein, examines the genetic factors underlying the phenotypic variability of sickle cell disease and beta thalassemia disorders. Both conditions are caused by mutations affecting the beta globin gene. A crucial difference between these conditions is that beta thalassemia results from a reduced number of red blood cells, while sickle cell disease results from abnormal sickle hemoglobin, or HbS, that makes red blood cells rigid and sickle-shaped, causing acute intermittent pain due to blockages of blood vessels and interruption of oxygen supply to vital organs. The rigid red blood cells are also very fragile and easily destroyed, causing a life-long anemia.


Vascular Physiology

Red blood cells use hemoglobin protein to carry oxygen throughout the body. Hemoglobin is made up of alpha and beta globin subunits. Sickle cell disease is a group of inherited disorders in which people make abnormal sickle hemoglobin that causes red blood cells to be sickle shaped. As a result, sickle shaped red blood cells stick to blood vessel walls and slow or stop blood flow. When this happens, oxygen cannot reach nearby tissue, and patients may experience pain or organ damage. Sickle cell disease is a major cause of death and disability worldwide and carries an exceedingly high risk of vascular complications such as stroke, kidney damage, cardiovascular changes, and skin ulcers. Research in the Laboratory of Vascular Physiology, led by Dr. Hans Ackerman, focuses on understanding and treating the vascular complications of sickle cell disease. His group addresses these questions with basic and clinical research. He is studying a genetic factor that changes the severity of sickle cell disease. Some people inherit genetic deletions of alpha globin that cause a milder form of anemia called alpha thalassemia. When an individual is born with sickle cell disease and alpha thalassemia, they are partially protected against major sickle cell disease vascular complications such as stroke and kidney disease. However, the mechanisms of protection are debated.