Molecular Medicine

, Volume 20, Issue 1, pp 478–485 | Cite as

A Journey in Science: Early Lessons from the Hemoglobin Field

  • David J. Weatherall
Anthony Cerami Award in Translational Medicine


Real innovations in medicine and science are historic and singular; the stories behind each occurrence are precious. At Molecular Medicine we have established the Anthony Cerami Award in Translational Medicine to document and preserve these histories. The monographs recount the seminal events as told in the voice of the original investigators who provided the crucial early insight. These essays capture the essence of discovery, chronicling the birth of ideas that created new fields of research; and launched trajectories that persisted and ultimately influenced how disease is prevented, diagnosed, and treated. In this volume, the Cerami Award Monograph is by David J Weatherall, Founder, Weatherall Institute of Molecular Medicine, Oxford University, John Radcliffe Hospital. A visionary in the field of hemoglobin, this is the story of Professor Weatherall’s scientific journey.



This work was supported by the Medical Research Council (MRC), Wellcome Trust, and the Anthony Cerami and Ann Dunne Foundation for World Health. The author thanks John Clegg and many other research colleagues for help and Liz Rose for help in preparing this review.


  1. 1.
    Weatherall D. (2002) Sir Cyril Astley Clark, C.B.E., 22 August 1907–21 November 2000. Biogr. Mem. Fellows R. Soc. 48 71–85.CrossRefPubMedGoogle Scholar
  2. 2.
    Weatherall DJ. (2012) Cyril Clarke and the prevention of rhesus haemolytic disease of the newborn. Br. J. Haematol. 157:41–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Weatherall DJ. (2010) Thalassaemia: The Biography. Oxford: Oxford University Press.CrossRefGoogle Scholar
  4. 4.
    Kunkel HG, Ceppellini R, Müller-Eberhard U, Wolf J. (1957) Observations on the minor basic hemoglobin component in blood of normal individuals and patients with thalassemia. J. Clin. Invest. 36:1615–25.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Weatherall DJ, Vella F. (1960) Thalassaemia in a Gurkha family. BMJ. i:1711–13.CrossRefGoogle Scholar
  6. 6.
    Weatherall DJ, Boyer SH. (1961) The genetic control of the a chains of human hemoglobins. Trans. Assoc. Am. Physicians. 74:89–99.PubMedGoogle Scholar
  7. 7.
    Weatherall DJ. (1963) Abnormal haemoglobins in the neonatal period and their relationship to thalassaemia. Br. J. Haematol. 9:265–77.CrossRefPubMedGoogle Scholar
  8. 8.
    Conley CL, Weatherall DJ, Richardson SN, Shepard MK, Charache S. (1963) Hereditary persistence of fetal hemoglobin: a study of 79 affected persons in 15 Negro families in Baltimore. Blood. 21:261.PubMedGoogle Scholar
  9. 9.
    Dintzis HM. (1961) Assembly of the peptide chains of hemoglobin. Proc. Natl. Acad. Sci. U. S. A. 47:247–50.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Clegg JB, Weatherall DJ. (1967) Haemoglobin synthesis in alpha-thalassaemia (haemoglobin H disease). Nature. 215:1241–3.CrossRefPubMedGoogle Scholar
  11. 11.
    Weatherall DJ, Clegg JB, Naughton MA. (1965) Globin synthesis in thalassemia: an in vitro study. Nature. 208:1061–5.CrossRefPubMedGoogle Scholar
  12. 12.
    Weatherall DJ, Clegg JB. (2001) The Thalassaemia Syndromes. 4th Ed. Oxford: Blackwell Science.CrossRefGoogle Scholar
  13. 13.
    Alter BP. (1990) Antenatal diagnosis. Summary of results. Ann. N. Y. Acad. Sci. 612:237–50.CrossRefPubMedGoogle Scholar
  14. 14.
    Clegg JB, Weatherall DJ, Eunson CE. (1971) The distribution of nascent globin chains on human reticulocyte polysomes. Biochim. Biophys. Acta. 247:109.CrossRefPubMedGoogle Scholar
  15. 15.
    Clegg JB, Weatherall DJ, Milner PF. (1971) Haemoglobin Constant Spring: a chain termination mutant? Nature. 234:337–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Fessas P, et al. (1972) Identification of slow-moving haemoglobins in haemoglobin H disease from different racial groups. Lancet. i:1308.CrossRefGoogle Scholar
  17. 17.
    Weatherall DJ, Clegg JB, Boon WH. (1970) The haemoglobin constitution of infants with the haemoglobin Bart’s hydrops foetalis syndrome. Br. J. Haemat. 18:357–67.CrossRefGoogle Scholar
  18. 18.
    Ottolenghi S, et al. (1974) The severe form of a thalassaemia is caused by a haemoglobin gene deletion. Nature. 251:389–92.CrossRefPubMedGoogle Scholar
  19. 19.
    Taylor JM, et al. (1974) Genetic lesion in homozygous α-thalassaemia (hydrops foetalis). Nature. 251:392–93.CrossRefPubMedGoogle Scholar
  20. 20.
    Embury SH, Lebo RV, Dozy AM, Kan YW. (1979) Organization of the α-globin genes in the Chinese α-thalassemia syndromes. J. Clin. Invest. 63:1307–10.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Embury SH, et al. (1980) Two different molecular organizations account for the single α-globin gene of the α-thalassemia-2 genotype. J. Clin. Invest. 66:1319–25.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Orkin SH, et al. (1979) The molecular basis of α-thalassemias: frequent occurrence of dysfunctional a loci among non-Asians with Hb H disease. Cell. 17:33–43.CrossRefPubMedGoogle Scholar
  23. 23.
    Higgs DR. (2012) The alpha thalassemias. Cold Spring Harb. Perspect. Med. 2:a011718.Google Scholar
  24. 24.
    Orkin SH, Old JM, Weatherall DJ, Nathan DG. (1979) Partial deletion of β-globin gene DNA in certain patients with β0-thalassemia. Proc. Natl. Acad. Sci. U. S. A. 76:2400–4.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Spritz RA, et al. (1981) Base substitution in an intervening sequence of a β+ thalassemic human globin gene. Proc. Natl. Acad. Sci. U. S. A. 78:2455–9.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Westaway D, Williamson R. (1981) An intron nucleotide sequence variant in a cloned β+ thalassaemia globin gene. Nucl. Acids Res. 9:1777–88.CrossRefPubMedGoogle Scholar
  27. 27.
    Orkin SH, et al. (1982) Linkage of β-thalassaemia mutations and β-globin gene polymorphisms with DNA polymorphisms in human β-globin gene cluster. Nature. 296:627–31.CrossRefPubMedGoogle Scholar
  28. 28.
    Thein SL, Wood WG. (2009) The Molecular Basis of β Thalassemia, δβ Thalassemia, and Hereditary Persistence of Fetal Hemoglobin. In: Disorders of Hemoglobin: Genetics, Pathophysiology, and Clinical Management. 2nd ed. Steinberg MH, Forget BG, Higgs DR, Weatherall DJ (eds.). Cambridge: Cambridge University Press; pp. 323–56.CrossRefGoogle Scholar
  29. 29.
    Haldane JBS. (1949) The rate of mutation of human genes. Hereditas. 35:267–73.CrossRefGoogle Scholar
  30. 30.
    Allison AC. (1954) Protection afforded by sickle-cell trait against subtertian malarial infection. BMJ. i:290–4.CrossRefGoogle Scholar
  31. 31.
    Flint J, et al. (1986) High frequencies of a thalassaemia are the result of natural selection by malaria. Nature. 321:744–9.CrossRefPubMedGoogle Scholar
  32. 32.
    Allen SJ, et al. (1997) α+-Thalassemia protects children against disease due to malaria and other infections. Proc. Natl. Acad. Sci. U. S. A. 94:14736–41.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Williams TN, et al. (1996) High incidence of malaria in α-thalassaemic children. Nature. 383:522–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Modiano D, et al. (2001) Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature. 414:305–8.CrossRefPubMedGoogle Scholar
  35. 35.
    Williams TN, Weatherall DJ. (2012) World distribution, population genetics, and health burden of the hemoglobinopathies. Cold Spring Harb. Perspect. Med. 2:a011692.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Williams TN, et al. (2005) An immune basis for malaria protection by the sickle cell trait. PLoS Med. 2:e128.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Williams TN, et al. (2005) Both heterozygous and homozygous alpha+ thalassemias protect against severe and fatal Plasmodium falciparum malaria on the coast of Kenya. Blood. 106:368–71.CrossRefPubMedGoogle Scholar
  38. 38.
    Williams TN, et al. (2005) Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait. Nat. Genet. 37:1253–7.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Penman BS, Pybus OG, Weatherall DJ, Gupta S. (2009) Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean. Proc. Natl. Acad. Sci. U. S. A. 106:21242–6.CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Weatherall DJ. (2010) The importance of micromapping the gene frequencies for the common inherited disorders of haemoglobin. Br. J. Haematol. 149:635–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Fucharoen S, Weatherall DJ. (2012) The hemoglobin E thalassemias. Cold Spring Harb. Perspect. Med. 2:a011734.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Olivieri NF, et al. (2008) Studies in haemoglobin E beta-thalassaemia. Br. J. Haematol. 141:388–97.CrossRefPubMedGoogle Scholar
  43. 43.
    Weatherall DJ. (2001) Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nat. Rev. Genet. 2:245–55.CrossRefPubMedGoogle Scholar
  44. 44.
    Fisher CA, et al. (2003) The molecular basis for the thalassaemias in Sri Lanka. Br. J. Haematol. 121:662–71.CrossRefPubMedGoogle Scholar
  45. 45.
    Thein SL, Menzel S. (2009) Discovering the genetics underlying foetal haemoglobin production in adults. Br. J. Haematol. 145:455–67.CrossRefPubMedGoogle Scholar
  46. 46.
    Premawardhena A, et al. (2001) Genetic determinants of jaundice and gallstones in haemoglobin E beta thalassaemia. Lancet. 357:1945–6.CrossRefPubMedGoogle Scholar
  47. 47.
    Allen A, et al. (2010) Adaptation to anemia in hemoglobin E-beta thalassemia. Blood. 116:5368–70.CrossRefPubMedGoogle Scholar
  48. 48.
    Piel FB, Hay SI, Gupta S, Weatherall DJ, Williams TN. (2013) Global burden of sickle cell anaemia in children under five, 2010–2050: modelling based on demographics, excess mortality, and interventions. PLoS Med. 10:e1001484.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Piel FB, et al. (2010) Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nat. Commun. 1:104.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s) 2014

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (

Authors and Affiliations

  1. 1.Weatherall Institute of Molecular MedicineOxford University, John Radcliffe HospitalOxfordUK

Personalised recommendations