Thalassemia historical perspective

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shyam Patel [2]

Overview

Our knowledge about the origins of thalassemia date back to more than 6000 years ago. At that time, persons of Mediterranean descent began their migrations to other regions of the world, carrying gene variants that eventually gave rise to thalassemias. The expansion of empires led to further propagation of the defective globin genes throughout the world. It was soon noted that persons with thalassemia were relatively resistant to malaria, and further molecular studies were done to identify the underlying pathophysiology of thalassemias. The initial treatment approach to thalassemia was supportive care, especially red blood cell transfusions. In the recent years, bone marrow transplant and gene therapy have been exploited as possible treatments to treat thalassemias. These treatment strategies are still being explored.

Historical Perspective

  • In 4000 B.C., persons of eastern Mediterranean descent migrated to Sicily, carrying thalassemia gene variants with them.[1]
  • In the 800s-900s, there was mass migration of Arabs, who harbored globin gene mutations.
  • In the 1400s-1500s, there was further influx of beta-thalassemia mutations with the expansion of the Ottoman Empire.[1] The Ottoman Expire expanded to Eastern Europe, Central Asia, and Northern Africa, leading to additional globin mutations to develop in the population.
  • In 1948, the biologist J.B.S. Haldane hypothesized that a heterozygote advantage existed for patients with beta-thalassemia in the context of malaria infection. This theory was similar to that of the heterozygote advantage conferred by sickle cell trait for malaria resistance. It was thought that thalassemia mutations would be selected for and would propagate in areas of high prevalence of malaria. Microcytic erythrocytes are less susceptible to malaria infection.
  • In 1952, Silvestroni and colleagues noted that beta-thalassemia trait was highly prevalent in the Po River's delta region.[1]
  • In the 1970s, the predilection of beta-thalassemia to affect Mediterranean populations was recognized, and pilot prevention programs were established to raise awareness and provide education about thalassemia. During this time, red blood cell transfusions were a mainstay for therapy. Transfusions were complicated by the risk for infections with hepatitis B, hepatitis C, and HIV.
  • In the 1970s-1980s, scientists began to understand the mutational landscape of thalassemias.[2] Further insight into the molecular basis for thalassemia was made as biotechnology developed over the coming years.
  • In 1978, the concept of the hematopoietic niche in the bone marrow was introduced by Dr. Schofield.[3] This was important because hematopoietic stem cells in the bone marrow give rise to mature red blood cells via the megakaryocyte-erythrocyte progenitor.
  • In the 1980s, the concept of allogeneic bone marrow transplant was introduced with the goal of correcting the nonfunctional globin chain. The donor cells in from a bone marrow transplant contain the normal globin gene product, and this could reconstitute normal erythropoiesis, or red blood cell production.
  • In 1989, Higgs and colleagues reported on the molecular basis of thalassemias.[2]
  • In the 2000s, gene therapy was conceptualized for thalassemias. Efforts were made to introduce exogenous wild-type globin genes into patients to restore normal globin function.[4] The goal was to achieve highly efficient transduction of hematopoietic stem and progenitor cells (HSPCs) such that a normal functional globin could be produced.[4]

References

  1. 1.0 1.1 1.2 De Sanctis V, Kattamis C, Canatan D, Soliman AT, Elsedfy H, Karimi M; et al. (2017). "β-Thalassemia Distribution in the Old World: an Ancient Disease Seen from a Historical Standpoint.". Mediterr J Hematol Infect Dis. 9 (1): e2017018. PMC 5333734Freely accessible. PMID 28293406. doi:10.4084/MJHID.2017.018. 
  2. 2.0 2.1 Higgs DR (2013). "The molecular basis of α-thalassemia.". Cold Spring Harb Perspect Med. 3 (1): a011718. PMC 3530043Freely accessible. PMID 23284078. doi:10.1101/cshperspect.a011718. 
  3. Lane SW, Williams DA, Watt FM (2014). "Modulating the stem cell niche for tissue regeneration.". Nat Biotechnol. 32 (8): 795–803. PMC 4422171Freely accessible. PMID 25093887. doi:10.1038/nbt.2978. 
  4. 4.0 4.1 Finotti A, Breda L, Lederer CW, Bianchi N, Zuccato C, Kleanthous M; et al. (2015). "Recent trends in the gene therapy of β-thalassemia.". J Blood Med. 6: 69–85. PMC 4342371Freely accessible. PMID 25737641. doi:10.2147/JBM.S46256. 



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