Swee Lay Thein | |
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| Born | |
| Alma mater | University of Malaya |
| Known for | Sickle cell disease |
| Scientific career | |
| Institutions | National Institutes of Health King's College London |
Swee Lay Thein FRCP FMedSci is a Malaysian haematologist and physician-scientist who is Senior Investigator at the National Institutes of Health. She works on the pathophysiology of haemoglobin disorders including sickle cell disease and thalassemia.
Thein was born in Kuala Lumpur, Malaysia. [1] She studied medicine in both Malaysia and the United Kingdom. [2] She graduated from the University of Malaya in 1976. [3] She specialised in hematology at the Royal Postgraduate Medical School and the Royal Free Hospital. She moved to Oxford, where she worked at the Medical Research Council (MRC) Molecular Hematology Unit in the Weatherall Institute of Molecular Medicine and the John Radcliffe Hospital. She held various positions at Oxford, including a MRC Clinical Training position, a Wellcome Trust senior fellowship and an honorary consultancy. [1]
In 2000 Thein joined King's College London as a Professor of Molecular Haematology. She was made Clinical Director of the Red Blood Cell clinic at King's College Hospital. Her work considers the pathophysiology of haemoglobin disorders; which include sickle cell disease and thalassemia. The only cures for sickle cell disease and thalassemia are bone marrow transplants, but these are not always available. Whilst both conditions can present with a variety of clinical severities, a remediating factor is the ability to produce foetal haemoglobin (HbF). Foetal haemoglobin is the haemoglobin that transports oxygen during foetal life and in infants until they are six months old. [4] She has studied the mechanisms responsible for the formation of foetal haemoglobin.
Thein demonstrated that HbF levels are mainly controlled by genetics, and that majority of the genetic variance is accounted for by factors outside the globin locus. [1] Thein used linkage analysis to identify two of the quantitative trait loci (QTL) for this HbF variability. These loci are involved with the control haematopoiesis and the production of HbF. The loci are located on the chromosomes 6q and 2p which are located within the BCL11A gene. Whilst it was known that BCL11A was involved with cancer, Thein was the first to show that BCL11A was associated with red blood cell disorders. [5] The 6q QTL contains single-nucleotide polymorphisms distributed across three linkage disequilibrium blocks, in an intergenic region between MYB and HBS1L. [1] Thain showed that this interval contains regulatory sequences. She has investigated how QTL regulates the expression of MYB and HBS1L. [1] These two QTLs (6q and 2p), and a single-nucleotide polymorphism on the HBB cluster account for around half of the variability in HbF levels. [1] She established that these two variants had spread from Africa into almost all human populations. [6]
By delineating the genetics of foetal haemoglobin control in adults, she hopes to explain the trait variance in adults as well as identifying the loci and sequences of variants. She believes that by identifying the HbF QTLs she will be able to improve patient management through the development of novel therapies, more sophisticated genetic counselling and better predictions of disease severity. These therapies may include approaches to activate the BCL11A gene. [5] By trying to find the relationships between genotypes and phenotypes, Thein has helped with DNA diagnostics in the haemoglobinopathies. [1]
Sickle cell disease occurs because rigid strands form inside red blood cells, destroying their structure and resulting in the formation of sickled cell shapes. Thein is working on therapeutic agents that can work against this polymerisation, stopping the cells changing shape. [5] Thein has served as Chair of the European Hematology Association working group on red blood cells. [7] She has been involved with the teaching of their programs on haematology. [7]
She moved to the National Institutes of Health as Senior Investigator and Chief of the new NIH Sickle Cell Branch in 2015. [8]
Thein is an editor for Blood , Annals of Haematology, Hemoglobin, and the American Journal of Hematology . [5] She is feature editor of the Sickle Blood Hub, an online space for the journal Blood. [14]
Hemoglobinopathy is the medical term for a group of inherited blood disorders involving the hemoglobin, the protein of red blood cells. They are single-gene disorders and, in most cases, they are inherited as autosomal co-dominant traits.
Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time. Older terms included Cooley's anemia and Mediterranean anemia for beta-thalassemia. These have been superseded by the terms Transfusion-Dependent Thalassemia (TDT) and non-Transfusion-Dependent Thalassemia (NTDT). Patients with TDT require regular transfusions, typically every two to five weeks. TDTs include Beta-thalassemia major, nondeletional HbH disease, survived Hb Bart's disease, and severe HbE/beta-thalassemia.
Fetal hemoglobin, or foetal haemoglobin is the main oxygen carrier protein in the human fetus. Hemoglobin F is found in fetal red blood cells, and is involved in transporting oxygen from the mother's bloodstream to organs and tissues in the fetus. It is produced at around 6 weeks of pregnancy and the levels remain high after birth until the baby is roughly 2–4 months old. Hemoglobin F has a different composition than adult forms of hemoglobin, allowing it to bind oxygen more strongly; this in turn enables the developing fetus to retrieve oxygen from the mother's bloodstream, which occurs through the placenta found in the mother's uterus.
Hemoglobin A (HbA), also known as adult hemoglobin, hemoglobin A1 or α2β2, is the most common human hemoglobin tetramer, accounting for over 97% of the total red blood cell hemoglobin. Hemoglobin is an oxygen-binding protein, found in erythrocytes, which transports oxygen from the lungs to the tissues. Hemoglobin A is the most common adult form of hemoglobin and exists as a tetramer containing two alpha subunits and two beta subunits (α2β2). Hemoglobin A2 (HbA2) is a less common adult form of hemoglobin and is composed of two alpha and two delta-globin subunits. This hemoglobin makes up 1-3% of hemoglobin in adults.
Hemoglobin C is an abnormal hemoglobin in which glutamic acid residue at the 6th position of the β-globin chain is replaced with a lysine residue due to a point mutation in the HBB gene. People with one copy of the gene for hemoglobin C do not experience symptoms, but can pass the abnormal gene on to their children. Those with two copies of the gene are said to have hemoglobin C disease and can experience mild anemia. It is possible for a person to have both the gene for hemoglobin S and the gene for hemoglobin C; this state is called hemoglobin SC disease, and is generally more severe than hemoglobin C disease, but milder than sickle cell anemia.
Alpha-thalassemia is a form of thalassemia involving the genes HBA1 and HBA2. Thalassemias are a group of inherited blood conditions which result in the impaired production of hemoglobin, the molecule that carries oxygen in the blood. Normal hemoglobin consists of two alpha chains and two beta chains; in alpha-thalassemia, there is a quantitative decrease in the amount of alpha chains, resulting in fewer normal hemoglobin molecules. Furthermore, alpha-thalassemia leads to the production of unstable beta globin molecules which cause increased red blood cell destruction. The degree of impairment is based on which clinical phenotype is present.
Beta thalassemias are a group of inherited blood disorders. They are forms of thalassemia caused by reduced or absent synthesis of the beta chains of hemoglobin that result in variable outcomes ranging from severe anemia to clinically asymptomatic individuals. Global annual incidence is estimated at one in 100,000. Beta thalassemias occur due to malfunctions in the hemoglobin subunit beta or HBB. The severity of the disease depends on the nature of the mutation.
Hemoglobin subunit beta is a globin protein, coded for by the HBB gene, which along with alpha globin (HBA), makes up the most common form of haemoglobin in adult humans, hemoglobin A (HbA). It is 147 amino acids long and has a molecular weight of 15,867 Da. Normal adult human HbA is a heterotetramer consisting of two alpha chains and two beta chains.
Hereditary persistence of fetal hemoglobin (HPFH) is a benign condition in which increased fetal hemoglobin production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin should be produced.
Sickle cell disease (SCD), also simply called sickle cell, is a group of hemoglobin-related blood disorders that are typically inherited. The most common type is known as sickle cell anemia. Sickle cell anemia results in an abnormality in the oxygen-carrying protein haemoglobin found in red blood cells. This leads to the red blood cells adopting an abnormal sickle-like shape under certain circumstances; with this shape, they are unable to deform as they pass through capillaries, causing blockages. Problems in sickle cell disease typically begin around 5 to 6 months of age. A number of health problems may develop, such as attacks of pain in joints, anemia, swelling in the hands and feet, bacterial infections, dizziness and stroke. The probability of severe symptoms, including long-term pain, increases with age. Without treatment, people with SCD rarely reach adulthood but with good healthcare, median life expectancy is between 58 and 66 years. All the major organs are affected by sickle cell disease. The liver, heart, kidneys, gallbladder, eyes, bones, and joints also can suffer damage from the abnormal functions of the sickle cells, and their inability to flow through the small blood vessels correctly.
Hemoglobin Lepore syndrome is typically an asymptomatic hemoglobinopathy, which is caused by an autosomal recessive genetic mutation. The Hb Lepore variant, consisting of two normal alpha globin chains (HBA) and two delta-beta globin fusion chains which occurs due to a "crossover" between the delta (HBD) and beta globin (HBB) gene loci during meiosis and was first identified in the Lepore family, an Italian-American family, in 1958. There are three varieties of Hb Lepore, Washington, Baltimore and Hollandia. All three varieties show similar electrophoretic and chromatographic properties and hematological findings bear close resemblance to those of the beta-thalassemia trait; a blood disorder that reduces the production of the iron-containing protein hemoglobin which carries oxygen to cells and which may cause anemia.
Julie Makani is a Tanzanian medical researcher. From 2014 she is Wellcome Trust Research Fellow and Associate Professor in the Department of Haematology and Blood Transfusion at the Muhimbili University of Health and Allied Sciences (MUHAS). Also a visiting fellow and consultant to the Nuffield Department of Medicine, University of Oxford, she is based in Dar es Salaam, Tanzania. In 2011, she received the Royal Society Pfizer Award for her work with sickle cell disease.
Stuart Holland Orkin is an American physician, stem cell biologist and researcher in pediatric hematology-oncology. He is the David G. Nathan Distinguished Professor of Pediatrics at Harvard Medical School. Orkin's research has focused on the genetic basis of blood disorders. He is a member of the National Academy of Sciences and the Institute of Medicine, and an Investigator of the Howard Hughes Medical Institute.
Hemoglobin Hopkins-2 is a mutation of the protein hemoglobin, which is responsible for the transportation of oxygen through the blood from the lungs to the musculature of the body in vertebrates. The specific mutation in Hemoglobin Hopkins-2 results in two abnormal α chains. The mutation is the result of histidine 112 being replaced with aspartic acid in the protein's polypeptide sequence. Additionally, within one of the mutated alpha chains, there are substitutes at 114 and 118, two points on the amino acid chain. This mutation can cause sickle cell anemia.
HBS1 like translational GTPase is a protein that in humans is encoded by the HBS1L gene.
Phaedon Fessas (1922-2015) was a Greek Professor of Medicine at the Medical School of Athens University. He was Director of the 1st Department of Internal Medicine at the Laikon Hospital in Athens (1969-1989), where he established a very strong Hematology Division, his particular subspecialty. Professor Fessas was a clinician, teacher and researcher. His main research interest was thalassemia.
Hemoglobin O (HbO) is a rare type of hemoglobin in which there is a substitution of glutamic acid by lysine as in hemoglobin C, but at different positions. Since the amino acid substitution can occur at different positions of the β-globin chain of the protein, there are several variants. In hemoglobin O-Arab (HbO-Arab) substitution occurs at position 121, while in hemoglobin O-Padova (HbO-Padova) it is at 11 position, and in hemoglobin O Indonesia (HbOIna) it is at 116.
The MRC Weatherall Institute of Molecular Medicine at the University of Oxford is a research institute located at the John Radcliffe Hospital in Oxford. Founded in 1989 by Sir David Weatherall, the institute focuses on furthering our understanding of clinical medicine at a molecular level. It was one of the first institutes of its kind in the world to be dedicated to research in this area.
Hemoglobin D (HbD) is a variant of hemoglobin, a protein complex that makes up red blood cells. Based on the locations of the original identification, it has been known by several names such as hemoglobin D-Los Angeles, hemoglobin D-Punjab, D-North Carolina, D-Portugal, D-Oak Ridge, and D-Chicago. Hemoglobin D-Los Angeles was the first type identified by Harvey Itano in 1951, and was subsequently discovered that hemoglobin D-Punjab is the most abundant type that is common in the Sikhs of Punjab and of Gujarat.
Irene Roberts is a British physician-scientist specializing in pediatric hematology. She is an emeritus professor of paediatric haematology at the MRC Weatherall Institute of Molecular Medicine at the University of Oxford.
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