By the late 1950s, scientists were grappling with information that they had amassed about thalassemia, an inherited anemia that arises from unusually fragile red blood cells. They knew that the ailment takes many clinical forms and that it stems from misbehaving hemoglobin, the body’s oxygen-carrying molecule. However, unlike another familial blood disease — sickle cell anemia — thalassemia was not associated with structural abnormalities of hemoglobin. Instead, the condition seemed to result from insufficient fabrication of the protein’s component α- or β-globin chains. That idea was impossible to test, as no methods existed to gauge globin production, in part because existing techniques did not adequately separate the α and β chains from each other. With no reliable means to take this first step in unraveling the disease’s molecular underpinnings, the field stalled.
In 1965, Weatherall cracked the problem. First, he, John Clegg, and Michael Naughton figured out how to pull the α and β chains apart from each other. Next, Weatherall and Clegg developed a way to accurately measure rates of α- and β-globin synthesis. Applying their scheme to blood from thalassemic patients generated the first clear evidence that thalassemias spring from imbalanced globin-chain production. Many groups subsequently adapted the method to define defects that underlie different forms of thalassemias.
Weatherall soon got a hint of the tremendous heterogeneity that scientists would unearth as they defined the molecular bases of thalassemias. In one family, he found an α chain that extends 31 amino acids longer than usual. In a 1971 report, he suggested that the messenger RNA blueprint for this α chain encodes an amino acid at the spot where it normally would instruct the protein-making machinery to stop. Consequently, the cell continues adding amino acids until it fortuitously hits another “stop” signal. This genetic glitch somehow results in diminished amounts of α hemoglobin.
Weatherall exposed other types of novel anomalies as well. In 1970, he showed that babies who were stillborn because of a particularly severe form of α thalassemia did not make any α chains. Four years later, he and John Paul (Beatson Institute for Cancer Research, Glasgow) reported that infants with this disorder lack α globin genes. Independently Yuet Wai Kan (University of California, San Francisco) made similar observations. This work provided the first description of a gene deletion that instigates a human disease.
In the meantime, Weatherall was moving these advances toward the clinic. For years, prenatal diagnosis of β thalassemias seemed impractical, as the fetal form of hemoglobin does not contain a β chain. However, in 1973, Weatherall and others demonstrated that fetal blood cells start manufacturing small amounts of β chains at eight weeks’ gestation. Prenatal tests followed and several Mediterranean countries with high rates of β thalassemia deployed programs based on these techniques, which markedly reduced births of babies with the illness.
However, results could not be obtained before the second trimester, and women had to decide whether to terminate pregnancies at about 20 weeks gestation. As DNA analysis emerged, Weatherall adapted this strategy for use earlier in pregnancy. In 1982, his team published the first series of first-trimester diagnoses, an approach that is now employed worldwide.
Weatherall has also improved therapies for thalassemic children. Repeated transfusions can control symptoms, but iron builds up and harms multiple organs, including the heart, liver, and lungs. If adequately transfused, children grow normally, but they die of cardiac failure in their late teens. Weatherall significantly advanced “chelation” therapy, which removes iron from the body. In particular, he modified a constant-infusion procedure devised by David Nathan (Children’s Hospital Medical Center, Boston). Weatherall discovered that he could administer the appropriate dose while a patient sleeps, and thus alleviate the need to wear a pump during daytime activities. This method is much more practical and people all over the world now exploit it.
International reach. Weatherall established a partnership with workers at the District General Hospital in Kurunegala, Sri Lanka. He subsequently raised money to build a National Thalassemia Center for the country.
During his career, Weatherall has uncovered numerous links between thalassemias and other clinical problems. In 1981, for example, he identified forms of the blood disorder that associate with mental retardation. This work opened up new avenues into the causes of this condition and led to novel screening tests. He also confirmed the notion that the α thalassemia trait protects people against the severe form of malaria, an observation that explains the high prevalence of α thalassemia in the gene pool.
An estimated 300,000 children are born annually with sickle cell anemia, one of its variants, or thalassemia; low- and middle-income countries bear the vast burden of cases. Starting in the 1970s, Weatherall began establishing clinical and research relationships with workers in developing countries. Rather than arriving, snapping up blood to study, and returning home to write papers, Weatherall engages in true partnerships: Personnel travel back and forth, share information, and build one-on-one relationships. These enterprises have cultivated local expertise, spawned long-term research projects, and allowed significant capacity building. For instance, a partnership in Sri Lanka is now 15 years old, and Weatherall raised money to build new treatment and diagnostic centers there. He also helped create a national program for managing and studying the disease.
Weatherall has educated people around the globe through hundreds of original research papers and 14 books. In particular, the text he wrote on thalassemias with his long-time collaborator John Clegg is in its 4th edition and is commonly considered the bible on this family of diseases. In 1983, he created and edited the Oxford Textbook of Medicine, whose 5th edition was just published.
In 1989, Weatherall established Oxford University’s Institute of Molecular Medicine. He has built it into a world-renowned biomedical research establishment that focuses on human disease. When he retired in 2000, it was renamed the Weatherall Institute of Molecular Medicine.
In the last five decades, Weatherall has demonstrated extraordinary talents as a relentless investigator, stimulating teacher, compassionate physician, and devoted public servant. The concept of molecular medicine has grown out of his work, and researchers now look deep inside cells as they attempt to understand illness. In his quest to fuel clinical progress with modern science, Weatherall has improved the healthcare of children with thalassemia everywhere, including some of the world’s poorest nations.
by Evelyn Strauss
Key publications of David Weatherall
Weatherall, D.J., Clegg, J.B., and Naughton, M.A. (1965). Globin synthesis in thalassaemia: an in vitro study. Nature. 208, 1061-1065.
Wood, W.G. and Weatherall, D.J. (1973). Haemoglobin synthesis during human foetal development. Nature. 244, 162-165.
Ottolenghi, S., Lanyon, W.G., Paul, J., Williamson, R., Weatherall, D.J., Clegg, J.B., Pritchard, J., Pootrakul, S., and Boon, W.H. (1974). Gene deletion as the cause of α thalassaemia. Nature. 251, 389-392.
Weatherall, D. (1994). Science and the Quiet Art: The Role of Medical Research in Health Care. W.W. Norton, New York, 337 pp.
Weatherall, D.J. (2003). Genomics and global health: Time for a reappraisal. Science. 302, 597-599.
Weatherall, D.J. (2004). Thalassaemia: The long road from bedside to genome. Nat. Rev. Genet. 5, 625-631.