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.

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Swee Lay Thein

Video

Optimism for new drugs for treating sickle cell disease

Images

Sickle cell red blood cells retain mitochondria.
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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).
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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

Natural History of Sickle Cell Disease

Recruiting
All Ages
All Genders
Not Accepting Healthy Volunteers
Do you or your child have sickle cell disease or sickle cell trait? This study is interested in understanding pain crises and lung complications that occur in sickle cell disease patients and patients who have other red blood cell disorders. To participate in this study, you must be at least 2 years old with known or suspected sickle cell disease, sickle cell trait, or other red blood cell disorders. Participants will have a physical exam and receive standard medical care for sickle cell disease, including routine follow-up tests and procedures. This study is located in Washington, D.C., and Bethesda, Maryland.

Genotype -Phenotype Correlation of PKLR Variants With Pyruvate Kinase, 2,3-Diphosphglycerate and Adenosine Triphosphate Activities in Red Blood Cells of People With Sickle Cell Disease

Recruiting
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.

Featured Publications

Phenotypic screening of the ReFRAME drug repurposing library to discover new drugs for treating sickle cell disease.

Authors: Belhu Metaferia, Troy Cellmer, Emily B. Dunkelberger, Quan Li, Eric R. Henry, James Hofrichter, Dwayne Staton, Matthew M. Hsieh, Anna K. Conrey, John F. Tisdale, Arnab K. Chatterjee, Swee Lay Thein, and William A. Eaton.
Proc Natl Acad Sci U S A 2022 Sep 26;119(40):
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A Phase 1 Dose Escalation Study of the Pyruvate Kinase Activator Mitapivat (AG-348) in Sickle Cell Disease.

Authors: Xu JZ, Conrey A, Frey I, Gwaabe E, Menapace LA, Tumburu L, Lundt M, Lequang T, Li Q, Glass K, Dunkelberger E, Iyer V, Mangus H, Kung C, Dang L, Kosinski PA, Hawkins P, Jefferies N, Eaton WA, Thein SL
Blood 2022 May 16:
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Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin.

Authors: Henry ER, Metaferia B, Li Q, Harper J, Best RB, Glass KE, Cellmer T, Dunkelberger EB, Conrey A, Thein SL, Bunn HF, Eaton WA.
Blood. 2021 Sep 30;138(13):1172-1181
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Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease.

Authors: Tumburu L, Ghosh-Choudhary S, Seifuddin FT, Barbu EA, Yang S, Ahmad MM, Wilkins LHW, Tunc I, Sivakumar I, Nichols JS, Dagur PK, Yang S, Almeida LEF, Quezado ZMN, Combs CA, Lindberg E, Bleck CKE, Zhu J, Shet AS, Chung JH, Pirooznia M, Thein SL.
Blood. 2021 Jun 03;137(22):3116-3126
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Genetic variants of PKLR are associated with acute pain in sickle cell disease

Authors: Wang X, Gardner K, Tegegn MB, Dalgard CL, Alba C, Menzel S, Patel H, Pirooznia M, Fu YP, Seifuddin FT, Thein SL.
Blood Adv 2022 Jun 14;6(11):3535-3540
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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.

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