Ashar Farrukh, Hillsborough High School, Tampa, Florida, USA
Beta-Thalassemia at a Molecular Level:
Thalassemia is a blood disorder characterized by defects in hemoglobin chain synthesis. There are two classifications of thalassemia: alpha-thalassemia and beta-thalassemia. Beta-thalassemia results from point mutations that occur in the promoter and splicing sites of DNA (Resnick, 2019). Point mutations (including insertion, deletion, and substitution of nucleotides in a genetic sequence) cause a defect in the beta-globin gene of the eleventh chromosome. This defect reduces or stops hemoglobin synthesis. Hemoglobin is vital as it is a protein in red blood cells and hence carries essential compounds such as oxygen to tissues and organs.
Beta-thalassemia results in physical impairment. Patients experience expanded bone marrow as the body attempts to produce more red blood cells. This may result in fragile bones, deformities, poor growth, fatigue, and enlargement of the liver and spleen (Johns Hopkins Medicine, 2020).
Beta-Thalassemia’s Frequency and Global Measures:
Beta-thalassemia affects nearly 2% of the global population – largely in the Mediterranean, Middle East, and South Asia – with nearly 80 to 90 million Beta-Thalassemic patients worldwide (Galanello & Origa, 2010). Beta-thalassemia is an autosomal recessive disease; children with the disease inherit a mutated copy of a gene from each parent (Medline Plus, 2015). As the number of beta-thalassemia carriers spread across the world, reproduction with healthy patients increases, resulting in growing numbers of silent carriers that possess the HBB gene mutation.
Thalassemia can be detected by conducting hemoglobin electrophoresis and blood count examinations. Due to the defective beta-globin chains, the body produces excess alpha-globin chains, which in turn lead to high levels of hemoglobin A2 (delta chains) and fetal hemoglobin (gamma chains). A low quantity of hemoglobin may also indicate beta-thalassemia (Resnick, 2019).
Figure 1: Global prevalence percentage of beta-thalassemia (IthaMaps, 2022)
Genetic mutations generally occur from a mutagen, usually radiation or chemical substances, which cause defects. In the case of beta-thalassemia, these defects are present in the beta-globin gene. Figure 1 shows how environmental pressures may contribute to HBB genetic mutation and result in variation in the prevalence of beta-thalassemia across the world. In 2022, the IthaMap database reveals the highest frequency of beta-thalassemia occurred in the Maldives, with 18% of its constituents affected, followed by Papa New Guinea with 13%, and Cyprus with 14%. The high frequency of beta-thalassemia in Cyprus, Sardinia, and South Asian countries was due to selective pressures from malaria in previous years (Galanello & Origa, 2010).
Additionally, the changing epidemiology of beta-thalassemia is influenced by migration and prevention programs. Refugees from Afghanistan, Syria, and Myanmar seek refuge in neighboring countries (known as host countries), often with a better standard of living, including Germany, Greece, Italy, Turkey, Lebanon, Iran, and Pakistan. Luckily, prevention programs are being instituted in these countries such as prenatal diagnostics, population screening, and public education. However, the efficacy of prevention programs depends on awareness and stigmatization of beta-thalassemia. For example, increased understanding of the disease will yield successful innovations and treatment, and reduced stigmatization will make discussions easier (Forni et al., 2020).
A Modern Approach for Treatment:
Blood transfusion is a common treatment for beta-thalassemia. Blood or blood components from a donor are intravenously inserted into a patient. However, blood transfusion can result in iron overload, a condition in which excess iron is deposited in, and damages organs. This can manifest as cardiac disease, liver fibrosis, and endocrine dysfunction such as diabetes mellitus (Galanello and Origa, 2010). Therefore, regular blood transfusions necessitate iron chelation, a procedure that removes iron from the body through iron chelator drugs. Patients receiving blood transfusions may also develop alloimmunity, an immune response to foreign blood group antigens from members of the same species. White blood cells target these newly introduced red blood cells, hindering the effectiveness of transfusion with time (CDC, 2022).
Fortunately, recent discoveries in gene therapy have signaled new methods for addressing beta-thalassemia. An increasingly sustainable alternative to blood transfusion is bone marrow transplantation. Allogenic bone marrow transplantation is a curative method in which healthy somatic cells (specifically from the bone marrow of a healthy donor) are inserted into the bone marrow of a beta-thalassemic patient (Rattananon et al., 2021).
Bone marrow gene therapy is another option. Blood stem cells are taken from bone marrow and treated with a retrovirus to insert a working copy of the beta-globin gene (Morgan et al., 2017). These modified stem cells are placed back into the patient’s body. Gene therapy does not require a donor and uses the patient’s own stem cells.
Figure 2: Genetic modifications in bone marrow transplantation (Morgan et al., 2017).
Figure 2 illustrates how scientists extract blood from the patient’s bone marrow or peripheral blood to obtain hematopoietic stem cells (immature cells that can develop into a white blood cell, red blood cell, or platelet). CRISPR/cas9 is a notable genome editing tool that replaces defective alleles with healthy variants by using guided RNA. Genome editing tools are used to remove the disease-causing beta-globin gene, producing modified hematopoietic stem cells to be placed into the patient’s body (Rattananon et al., 2021).
As thalassemia increases in prevalence, advanced technology such as CRISPR/cas9 and other instruments of gene therapy suggest a long-term, promising treatment. Bone marrow transplantation and modification of the hematopoietic stem cells are a modern approach characterized by their sustainability. Since it does not require a donor and does not have complications such as iron overload, gene therapy is more favorable than transfusion therapy. These recent advances in genetic modification indicate a favorable chance for curing beta-thalassemia.
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