The beginnings of molecular medicine

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 children 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 clinical descriptions gradually emerged from the Mediterranean 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 abnormalities, and were referred to as thalassemia syndromes. It was suspected that thalassemia was caused by quantitative 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 periods. 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 thalassemia, and led to an exponential increase in the understanding of its pathophysiology, including an appreciation of ineffective erythropoiesis, and that the cellular pathology resulted from an excess of the unaffected globin chain rather than a deficiency of the protein from the mutated gene. This technique of globin chain synthesis was refined slightly over the years, but remained essentially the same. It was central to many of the discoveries concerning transcriptional and translational control of the globin genes, which in turn acted as paradigms for molecular biology in general. In particular, globin chain synthesis was used to identify the significance of many variants identified in the globin genes, and was only really replaced when quantitation of messenger RNA became routine in the 1990s. Similarly, it was used in the routine diagnosis of hemoglobinopathies until the 1980s, and in particular was used in the early prenatal diagnosis of hemoglobinopathies from fetal blood samples.³

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.

This landmark paper arose primarily from the interaction between a very astute hematologist, David Weatherall, who had identified an important question, and a very skilled protein chemist, John Clegg, who knew how to answer it. Together they went on to write 200 papers together, including more than 20 published in Nature. This interaction was one of the driving forces behind the development of molecular medicine, with the establishment of the Institute of Molecular Medicine (later the Weather -all Institute of Molecular Medicine) in Oxford, and the spawning of numerous clinical and laboratory scientists across the world.

Footnotes

Correspondence

david.rees@kcl.ac.uk

Disclosures

No conflicts of interest to disclose.