Page 10 - Haematologica Vol. 107 - September 2022

LANDMARK PAPER IN HEMATOLOGY
David C. Rees
The beginnings of molecular medicine
David C. Rees
Department of Haematological Medicine, King’s College Hospital and King’s College London, UK E-mail: david.rees@kcl.ac.uk
https://doi.org/10.3324/haematol.2022.281711
TITLE
Globin synthesis in thalassaemia: an in vitro study.
AUTHORS
Weatherall DJ, Clegg JB, Naughton MA.
JOURNAL
Nature. 1965;208(5015):1061-1065. DOI: 10.1038/2081061a0 PMID: 5870556
Thalassemia was first described in the 1920s by Thomas Cooley and Pearl Lee in Detroit. They described four chil- dren with massive hepatosplenomegaly, anemia, jaundice and marked bony abnormalities, including enlargement of cranial and facial bones.1 It initially seemed more likely that this was a disease of bones than blood, as more cli- nical descriptions gradually emerged from the Mediter- ranean and Asia, where this seemed to be a common problem. In parallel with advances in genetics, red cell biology, and hemoglobin analysis, it became apparent that thalassemia was inherited in an autosomal recessive manner, with mild red cell abnormalities typically present in both parents. Protein sequencing had shown that some hemoglobinopathies, most notably sickle cell disease, were caused by structural abnormalities of the globin
chains, whereas others had no detectable globin abnor- malities, and were referred to as thalassemia syndromes. It was suspected that thalassemia was caused by quan- titative defects of globin chain synthesis, but there was no direct evidence of this until Weatherall et al. published their landmark paper.2 The authors were able to assess the relative rates of globin chain synthesis by incubating reticulocytes with radiolabeled leucine, and measuring the rate of leucine incorporation over different time pe- riods. In this way, they showed that the rates of b and a globin synthesis were matched in normal reticulocytes, whereas there were quantitative deficits of b and a globin in the respective types of thalassemia. This discovery was the beginning of the molecular understanding of thalas- semia, and led to an exponential increase in the under-
Figure 1. Rates of globin synthesis in reticulocytes from a patient with b-thalassemia major. Incorporation of radioactivity into globin chains after reticulocytes from a patient with b-thalassemia major had been incubated for 60 minutes with 14C-leucine. The solid line shows the amount of total protein, which is approximately the same for both b and a globin chains. The dotted line shows the rate of synthesis of new globin chains over the 60 minutes of the incubation, with significantly less synthesis of b globin compared to a globin.
Haematologica | 107 September 2022
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