Sickle Cell Genetics and Pathophysiology

Research in the Laboratory of Sickle Cell Genetics and Pathophysiology, led by Dr. Swee Lay Thein, examines the genetic and biological factors underlying the phenotypic variability of sickle cell disease to accelerate translation of basic discovery to therapeutics.

Swee Lay Thein

Senior Investigator Research Interests

Research Interests

The Thein group conducts research on the pathophysiology of sickle cell disease (SCD) applying insights from genotype-phenotype observations to accelerate translation of basic discovery to therapeutic applications. By combining clinical, laboratory, imaging and new diagnostic techniques, we hope to improve phenotypic definition of SCD at all levels and to introduce more targeted pharmaceutical therapies for SCD. The Thein laboratory is also involved in pre-clinical and clinical testing of drugs and innovative compounds that reduce sickle hemoglobin (HbS) polymerization, improve red cell rheology, or induce fetal hemoglobin.

SCD is an inherited hemoglobin disorder prevalent in regions where malaria was historically endemic, including sub-Saharan Africa, India, the Middle East, and the Mediterranean. Currently, an estimated 300,000 affected babies are born each year, more than 80% of whom are in Africa. In the United States, SCD is considered “rare”, but nonetheless affects and estimated 100,000 Americans (the majority being of African descent) and 1 in 365 African-American births.

The single nucleotide change underpinning SCD belies the extreme variability and severity of SCD complications, that will become more apparent with aging, and presents major challenges in clinical management. Both acquired and inherited factors contribute to this clinical complexity of SCD. Numerous genetic association studies (candidate gene, genome-wide association (GWA), whole exome and whole genome sequencing) have attempted to identify genetic variants with particular disease complications. In a GWA study in 2007, the Thein group identified BCL11A as a key repressor of gamma-globin gene, a finding that resuscitated the field in fetal hemoglobin regulation and therapeutic re-activation of gamma-globin genes for the beta-hemoglobinopathies. The finding has led to genetic strategies targeting BCL11A regulation for therapeutic reactivation in SCD and beta thalassemia under clinical development with promising results.

Prediction of disease severity and clinical course of SCD has been the topic of many reviews and, to date there is no clear algorithm using genetic and/or imaging, and/or laboratory markers that can reliably predict mortality risk in SCD. The clinical implications of delineating the genetic modifiers of SCD are significant; it will provide us the ability to predict disease severity based on a genetic SCD “panel”, and dissecting the role of new genetic modifiers might suggest new therapeutic targets for investigation. A primary approach for disease risk prediction has been polygenic risk scoring but the results remain moderately successful; they may not be so applicable in a complex disorder such as SCD that has numerous potential predictor variables. Towards the advancement of personalized medicine, the Thein group is exploring new machine learning methods incorporating predictive biomarkers (laboratory, imaging, and physiological) with genetic (germline and somatic) risk variants into risk assessment algorithms to improve risk stratification before end organ damage sets in.

While we apply insights from the basic research to identify new therapeutic targets, the Thein lab is also involved in a project with Dr Bill Eaton (Laboratory of Chemical Physics, NIDDK/NIH) to discover newer anti-sickling agents using high throughput screening of drug libraries. Not only will the compounds provide further insight on the sickling mechanisms, but those that show therapeutically significant effects at concentrations known to be non-toxic can be very rapidly approved for clinical trials as these agents are either already FDA-approved or under clinical development for other diseases. It could well be that this small molecule game changer for SCD already exists among the drugs that are being used for other disorders. Furthermore, unravelling the mechanisms of the anti-sickling effects of these agents could well reveal fresh insights on the HbS fiber formation.

Team Photo

Thein Lab Group


Optimism for new drugs for treating sickle cell disease


Sickle cell red blood cells retain mitochondria.
Click the image to expand

Sickle cell red blood cells retain mitochondria.

Confocal imaging of blood cells from a sickle cell disease patient stained with mitochondrial (MTG; green), and nuclear (Hoechst; blue) markers.


Electron microscopy analysis of sickle cell disease red blood cells (RBCs).
Click the image to expand

Electron microscopy analysis of sickle cell disease red blood cells (RBCs).

Ultrastructural analysis of RBCs using electron microscopy. RBCs from sickle cell disease patient were processed using focused ion beam-scanning electron microscopy (FIB-SEM).

Clinical Trials and Studies

Todas las edades
No Se Aceptan Voluntaries Saludables
Crisis de dolor y complicaciones pulmonares en la anemia de células falciformes El interés de este estudio es comprender las crisis de dolor y las complicaciones pulmonares que se producen en pacientes con enfermedad de células falciformes y en los pacientes con otros trastornos que afectan los glóbulos rojos. Para participar en este estudio, debe tener al menos 2 años, con enfermedad de células falciformes presunta o conocida, rasgo falciforme u otros trastornos que afectan los glóbulos rojos. A los participantes se les realizará un examen físico y recibirán atención médica estándar para la enfermedad de células falciformes, incluidas pruebas y procedimientos de seguimiento de rutina. Este estudio se lleva a cabo en Washington (D.C.) y Bethesda (Maryland).
Adult, Older Adult
All Genders
Accepting Healthy Volunteers
Are you an adult of African descent who hasn’t had a recent transfusion and doesn’t have a known pyruvate kinase deficiency? This study investigates how the PKLR gene affects the function of red blood cells and contributes to sickle cell disease. The PKLR gene helps make a protein called pyruvate kinase that is necessary for red blood cells to function properly. To participate in this study, you must be between 18 and 80 years old, with or without sickle cell disease. This study takes place in Bethesda, Maryland.
Adult, Older Adult
All Genders
Not Accepting Healthy Volunteers
Are you at least 18 years old and have sickle cell disease and taking the medication Hydroxyurea? For this study, researchers testing are tool for measuring oxygen levels, blood flow, and the makeup of skin and muscle in patients with sickle cell disease. To participate in this study, you must be at least 18 years old and have sickle cell disease and also be taking the medication Hydroxyurea. This study is taking place at the National Institutes of Health Clinical Center in Bethesda, Maryland.

Meet the Team

Swee Lay Thein

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

Senior Investigator

Swee Lay Thein was educated in both Malaysia and the United Kingdom. She completed her specialist training in hematology at the U.K. Royal Postgraduate Medical School, Hammersmith, and the Royal Free Hospital, London. In 1982, she joined the U.K. Medical Research Council Molecular Hematology Unit in Oxford where she held various positions, including clinical training fellow, Wellcome Senior Fellow in Clinical Science, senior clinical scientist, and honorary consultant hematologist.

Dr. Thein was appointed in 2000 to the position of professor of molecular hematology and consultant hematologist at King’s College London, and served as clinical director of the Red Cell Centre in King’s College Hospital. At the hospital, she treated adult patients with sickle cell disease and also provided consultation to clinicians and researchers throughout the world on patients with unusual forms of thalassemias, inherited blood disorders that disrupt the normal production of hemoglobin, resulting in anemia.

Dr. Thein joined the NHLBI in spring 2015 as Senior Investigator and Chief of the institute’s newly formed Sickle Cell Branch.

Dr. Thein is author or co-author of more than 400 peer-reviewed research publications, invited review articles, and book chapters. She has been honored for her research with a fellowship from the U.K. Academy of Medical Sciences in the U.K. Dr. Thein also was awarded a visiting professorship from Kuwait University and an honorary professorship in pathology from the University of Hong Kong. She has served/serves on the editorial boards of the research journals Blood, Pathology, Annals of Haematology, Hemoglobin, and the American Journal of Hematology and was feature editor of the journal Blood’s Sickle Cell Disease hub, a micro-website that complements research published in the journal with links to articles, images and slideshows, and other multimedia.

Dr. Thein was chair of the European Hematology Association’s scientific working group for red blood cells and iron disorders from 2011–2014 and has organized annual international conferences on sickle cell disease (Sickle Cell in Focus, SCiF) since 2006. She also has been instrumental in organizing scientific and educational conferences on red blood cell disorders for the European Hematology Association and European School of Hematology.