Swee Lay Thein, M.B., B.S., F.R.C.P., F.R.C.Path., D.Sc.
Sickle Cell Branch
Dr. Thein’s research examines the genetic factors underlying the phenotypic variability of sickle cell disease and beta thalassemia disorders. Both of these 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.
HbF is the blood component primarily responsible for fetal oxygen transport and is present in infants until they are about 6 months old. The persistence of HbF beyond infancy is highly variable. High levels of HbF minimize many complications of sickle cell disease and can increase life expectancy. Drug therapy can reactivate HbF production in both children and adults, reducing the severity of sickle cell and beta thalassemia symptoms.
By studying identical twins, who share very similar DNA, Dr. Thein’s lab has demonstrated that HbF levels are predominantly genetically controlled, and that almost 90 percent of the difference in HbF levels from person to person can be accounted for by differences in genetic background, both outside and within the environment of the beta globin gene. Through genetic studies, she has identified segments of DNA, called quantitative trait loci, on chromosome 11p (where the beta globin gene is located), chromosome 6q, and the BCL11A gene on chromosome 2p that are involved in stimulating HbF production in adults. These have now been associated with increased HbF in diverse populations, both with and without sickle cell disease or beta thalassemia and have a beneficial clinical effect. Although the quantitative trait loci account for up to 50% of the HbF difference, a substantial proportion of HbF variation remains unexplained. Further, individual differences in HbF and alpha thalassemia trait loci do not account for all the variation in clinical severity.
Dr. Thein and her research team now hope to identify and validate genetic and biomarkers that will allow early detection and monitoring of severe sickle cell complications, using new genome technologies and deep phenotyping. They plan to contribute to discovery and development of drugs designed for treatment of sickle cell disease, including those that promote HbF synthesis and inhibit HbS polymerisation. They specifically would like to explore targeting the 6q HBS1L-MYB intergenic enhancers as a genetic therapeutic approach for reactivating fetal hemoglobin. By gaining a deeper understanding of the pathophysiology of acute sickle pain, they hope to develop treatments to reduce severity and length of acute vaso-occlusive crises.
Identification of the HbF loci has invigorated interest in re-activating the production of fetal hemoglobin in the treatment of sickle cell disease and beta thalassemia. Through her research, Dr. Thein hopes to eventually delineate the genetic architecture of fetal hemoglobin control in adults and identify the loci and sequence variants that account for disease variance among individual adults. This work will have implications for novel therapeutic options, more accurately informed genetic counseling, and improved predictive diagnosis of disease severity in sickle cell and beta thalassemias.
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 300 peer-reviewed research publications, invited review articles, and book chapters. She has been honored for her research with awards from the U.K. Academy of Medical Sciences and the Academy of Life Sciences for Chinese 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 serves on the editorial boards of the research journals Blood, Pathology, Annals of Haematology, Hemoglobin, and the American Journal of Hematology and is 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 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.
- Xu JZ, Conrey AK, Frey IC, Gwaabe E, Menapace LA, Tumburu L, Lundt M, Lequang T, Li Q, Glass KE, Dunkelberger EB, Iyer V, Mangus H, Kung C, Dang L, Kosinski PA, Hawkins P, Jeffries N, Eaton WA, Thein SL. A Phase 1 Dose Escalation Study of the Pyruvate Kinase Activator Mitapivat (AG-348) in Sickle Cell Disease. Blood. 2022.
- Wang X, Gardner K, Tegegn MB, Dalgard CL, Alba C, Menzel S, Patel H, Pirooznia M, Fu YP, Seifuddin FT, Thein SL. Genetic variants of PKLR are associated with acute pain in sickle cell disease. Blood Adv. 2022;6(11):3535-3540.
- 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. Circulating mitochondrial DNA is a proinflammatory DAMP in sickle cell disease. Blood. 2021;137(22):3116-3126.
- Henry ER, Metaferia B, Li Q, Harper J, Best RB, Glass KE, Cellmer T, Dunkelberger EB, Conrey A, Thein SL, Bunn HF, Eaton WA. Treatment of sickle cell disease by increasing oxygen affinity of hemoglobin. Blood. 2021;138(13):1172-1181.
- Sachdev V, Tian X, Gu Y, Nichols J, Sidenko S, Li W, Beri A, Layne WA, Allen D, Wu CO, Thein SL. A phenotypic risk score for predicting mortality in sickle cell disease. Br J Haematol. 2021;192(5):932-941.
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This page was last updated on Thursday, September 1, 2022