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Weatherall, David

David J. Weatherall

Oxford University

For 50 years of international statesmanship in biomedical science — exemplified by discoveries concerning genetic diseases of the blood and for leadership in improving clinical care for thousands of children with thalassemia throughout the developing world.

The 2010 Lasker~Koshland Award for Special Achievement in Medical Science honors a physician-scientist who has melded astute bedside observations with rigorous experiments to generate countless insights about inherited blood disorders, especially thalassemia. In the last half century, David J. Weatherall (Oxford University) has deployed diverse investigational approaches that have catalyzed advances in our understanding of the biochemical, genetic, and clinical aspects of thalassemia and has delivered fruits of this wisdom to patients worldwide. Weatherall made global health a priority before doing so was fashionable, and he has inspired scores of young physicians and researchers to apply the power of molecular medicine.

At the beginning of his career, Weatherall pursued his interest in thalassemia despite lack of support. He almost got court-martialed for his first paper, on a Nepalese patient he had studied during a late 1950s stint in the British Army, because he had not gotten permission from military commanders to publish. Furthermore, a senior officer disapproved of broadcasting the fact that one of its regiments had “bad genes.” Later, a medical thesis examiner suggested that he switch to psychiatry rather than study an obscure disease. Fortunately, Weatherall persevered.

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.

Applying insights

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.

David Weatherall and workers at the District General Hospital in Kurunegala, Sri Lanka

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.

Global activities

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.

Award presentation by Lucy Shapiro

Sir David Weatherall is the most respected clinical scientist of his generation. He has been knighted, his portrait hangs in the UK National Portrait Gallery, and there is an institute at Oxford that carries his name. Behind these accolades is a gentle, wry man with a deep passion for understanding the molecular basis of disease and its application to the health of his patients. Along the way, he has changed the training of physician-scientists and medical practice in the developing world.

David was raised and educated in Liverpool. Upon completing his medical degree in the late 1950s, he was asked where he’d like to do his obligatory National Service. Being petrified of flying, fighting, and snakes, he opted for service in London. The British Army promptly sent him to Singapore, where he first did a six-month stint in surgery, after which his surgical boss told him that on no account should he be let loose as a surgeon. When he next moved on to spend six months on a medical service, he carefully explained to the powers that be that his only experience was in adult medicine. He was promptly put in charge of a children’s ward. This turned out to be a seminal event not only in David’s life and career, but an event that ultimately has had a significant impact on world health.

A critically ill young daughter of a Ghurka soldier appeared in David’s ward with an undiagnosed illness that required regular blood transfusions. David diagnosed the illness as a specific genetic error in the child’s hemoglobin, no mean feat at the time. He published the data that led to this diagnosis of this genetic defect and was nearly court- martialed for revealing that someone in the Gurkha regiment might have ‘bad genes’. Upon being ordered not to do that again, David knew that his career was launched. David’s lifelong passion has been to understand (and, yes, publish), diagnose, treat, and manage thalassemias, diseases caused by aberrant hemoglobin.

David’s quest to understand inherited blood diseases led him to Johns Hopkins University, where he began his remarkable work, along with John Clegg, to separate and identify the different forms of hemoglobin chains in patients suffering from thalassemias. This led to the surprising discovery, in those early days of research into the molecular basis of genetically inherited diseases, that some thalassemias result from unbalanced globin chain production. His continued work on patients with this disease at the University of Liverpool led to an important breakthrough — the correlation of a given genetic mutation with a disease. In 1971, David was contacted by a physician from Kingston, Jamaica, whose patients were a family affected by α-thalassemias. David made the surprising discovery that the α-globin chain in this family was extended beyond the normal stop codon — the first report of a chain termination mutant. David also found that in some thalassemias, no α-chains chains are made — these still-born babies had a complete deletion of the gene encoding the α-chain: this was the first demonstration of a gene deletion in a human disease.

In 1974 he moved to Oxford as the Nuffield Professor of Clinical Medicine. The offer of the Chair was made and accepted by telephone ,and then he didn’t hear a word for several weeks. Afraid that he had perhaps been hallucinating, he got his secretary to phone the appropriate dignitary at Oxford and was told “It was announced in the Times! What more does he want?”

Although a founding father of molecular hematology, David was never far removed from patients, and he transferred his fundamental laboratory discoveries to practical clinical applications that are now in worldwide use. These included the first DNA-based tests for prenatal and postnatal diagnosis of globin abnormalities, the design of a technique to control iron overload in thalassemic patients, and a novel mode of treatment for children with thalassemias using transient transfusions through periods of maximum bone marrow expansion.

Throughout his career, David has been committed to the development of international health, working to develop partnerships between Oxford and Sri Lanka, Singapore, Vietnam, China, Thailand, Malaysia, and Kenya. With funding from the Wellcome Trust, he trained people to deal with their local health problems, and not simply having scientists from developed nations swoop in, do some research, and go home to write glossy papers in high-profile journals. Rather, David envisioned and successfully implemented an economically feasible way of helping developing countries deal with endemic diseases. Notably, when he designed prenatal tests for the thalassemias, he established programs in third-world nations to easily and effectively use this simple DNA technology, while always being mindful of the cultures of each country. When David retired as governor of the Wellcome Trust in 2000, instead of a grand farewell event, he chose to use the money towards equipping a new hospital in Sri Lanka.

In addition to being a compassionate clinician, a scholar, a scientist, and a devoted public servant, there is a completely different side to David — he is a committed and effective academic leader. As senior editor of the Oxford Textbook of Medicine, he helped set the standard for good clinical medicine. Then, during the 1980s, David began the work of putting together an institute at Oxford for early translational research — the first of its kind. This vision, of course, stemmed directly from his own lifetime of successful service as both a basic research scientist and clinician. During the necessary fund-raising efforts, he came up against Syndey Brenner, who came to Oxford to review David’s plans. Brenner is alleged to have opined that he was “skeptical of doctors mucking about in the laboratory.” (Sydney has since come around on the issue.) Nevertheless, in 1989, the Oxford University’s Institute of Molecular Medicine was established to “foster basic research in molecular and cell biology with direct application to the study of human disease.” This Institute, renamed the Weatherall Institute of Molecular Medicine, focusing on areas of medicine from AIDS to malaria to cancer, has had, and continues to have, a major impact on the application of the molecular analysis of disease syndromes to the practice of medicine.

In 1992, David Weatherall was appointed Regius Professor of Medicine at Oxford University, the most prestigious honor in UK medicine. David has managed to lead an oversized life with humility and kindness, and to provide a unique form of leadership that has inspired and empowered scientists, physicians, and healthcare providers around the globe.

Acceptance remarks by David J. Weatherall

David J. Weatherall Acceptance remarks

Nature Medicine Essay

Acceptance remarks, 2010 Lasker Awards Ceremony

In thanking the Lasker Foundation for this wonderful honor, my current mood is one of enormous pleasure tinged with total disbelief. The latter is engendered by the fact that my first effort at research into common inherited anemias was an embarrassing disaster. After qualifying in medicine in Liverpool in 1956 and an internship, I received my call-up papers from the British army to serve what was then a compulsory two years of National Service. Terrified of violence, flying, or snakes, I volunteered to serve in the UK; three weeks later I found myself on a troop ship bound for Singapore, where I was put in charge of the Childrens Ward at the British Military Hospital. There I encountered a Nepalese baby whose father was serving with a Ghurka regiment and who was profoundly anemic and being kept alive on blood transfusion. I discovered that this child had thalassemia, which at that time was thought to be a disease of Mediterranean populations. I thought the world should hear about this and published a case report of this child as my first paper. Shortly afterwards I was told to come and see the head of the Armed Forces for the Far East, who asked me whether I had had permission from the British government to publish this work. I said I hadn’t, and he told me that to publish details about British military personnel without permission was an offense for which I could be court-martialed. “Never do it again,” he said, “and anyway it is extremely bad form to tell the world that our best regiments have bad genes.” Fortunately, I ignored this first piece of career advice.

The second chance event which molded my career came in 1967 when I received a request from the World Health Organization to go on a two-month tour of Asia and report back to them on the clinical importance of thalassemia. The Organization always required an en-route briefing by a local expert. Because of the war between India and Pakistan, the ‘expert’ for the Indian subcontinent had been moved to Egypt,where I met him to be briefed. He did not speak a word of English, and an interpreter told me that he was an expert on building drains and had never heard of thalassemia. Hence the briefing was extremely brief, and I set off for my trip not knowing what to expect. In the event I met many groups with whom I later developed long-term collaborations and evolved the whole concept of North/South partnerships, which have lasted to this day. They have led to the development of exciting research programs but also allowed us to carry out a considerable amount of capacity building in the poorer countries in Asia.

Given this bizarre background, I accept this award with considerable surprise tinged with enormous personal pleasure and also on behalf of the extraordinarily talented colleagues in the hemoglobin field whose work led it to becoming one of the foundations of molecular medicine. But particularly, I thank the Lasker Foundation for telling the world that its extremely distinguished jury is aware of the importance of the inherited blood diseases as a global health problem. If this message can be learned by the major international health agencies and governments, there is some hope for the future of the thousands of children with inherited blood diseases in the poorer countries of the world.

Interview with David J. Weatherall

Video Credit: Susan Hadary