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Prof Sir David Weatherall with HRH the Princess Royal at the official opening of the (then) Institute of Molecular Medicine
Prof Sir David Weatherall (second from right) with HRH the Princess Royal at the official opening of the (then) Institute of Molecular Medicine

The Clinician

Written by Professor John Ledingham, Dr Jim Holt and Professor David Warrell

Appointment as Nuffield Professor

Some sixty years ago, most of Oxford’s undergraduate medical students chose to complete their clinical studies in London or elsewhere, rather than staying in the small local clinical school. Since then, Oxford’s Medical School has grown in size and reputation to become the world’s top rated institution. How did this happen? It was due largely to the efforts of three professors of medicine: George Pickering, Paul Beeson and, in particular, David Weatherall.

David was unknown in Oxford until 1971. At the Association of Physicians meeting in Sheffield that year, the third paper on the agenda was by DJ Weatherall, JB Clegg and PF Milner on “‘New’ molecular mechanism as the basis for a genetically determined haemolytic anaemia”. In a presentation that struck the Oxford physicians in the audience as being scintillating, David described a new abnormal haemoglobin (Constant Spring) found in members of a large Jamaican family with severe haemoglobin H disease.

In early 1973, Paul Beeson, the Nuffield Professor of Medicine, confided in Jim Holt that he intended to retire back to the United States. He remarked that it would be rather nice if his chair went back to blood disease which was his predecessor LJ Witt’s interest. “How about that young chap Weatherall from Liverpool who gave the splendid paper on haemoglobinopathies at the Association of Physicians meeting?” Jim was due to lecture in David’s department in Liverpool in early April and was authorised to mention the impending retirement. He invited David down to Oxford for a weekend in May and hosted a dinner with Renwick Vickers, John Badenoch and John Ledingham, at which the conversation focussed more on Mozart’s operas than medicine. Next day, John arranged meetings with the Regius, Richard Doll, and with Beeson. David was encouraged to apply by the eminent professor of Medicine in Liverpool, Sir Cyril Clarke. Unfortunately, the Regius’s preferred candidate was a senior figure from a London teaching hospital, whose appointment had been promised as virtually a fait accompli. However, the other electors; who included Ledingham, Badenoch, and Hugh Sinclair, chaired by Alan Bullock; were swayed by the argument that it would be more stimulating to bring in a promising younger man whose name and reputation were not yet made, but might be established in Oxford. David was duly appointed in early 1974, but, as the October start of the academic year approached, he had received no letter of confirmation from the University. He wondered whether it was safe to send in his letter of resignation. His secretary, Mrs Coggley, rang the VC’s secretary but was told haughtily: “It was announced in the Times, what more does he want?”

Incoming priorities

In the meantime, John Ledingham had been made May Reader and became acting head of the Nuffield Department of Medicine. In a letter to John, David delineated his priorities as incoming Nuffield Professor: to make the department outstanding clinically, in teaching and, only in third place, in research! He had gone into medicine primarily to heal the sick, regarded himself as “basically a humble haematologist”, and hoped that they would work together as equals. Despite their contrasting backgrounds, education and styles, David and John proved, in the years to come, a highly effective diarchy, in which David was never domineering.

The clinician in action

David’s junior staff recall that, at the bedside, his approach to the patient was homely and unaffected. Like his predecessor Paul Beeson, he showed great concern for their feelings and anxieties. His attitude was always thorough, methodical, and thoughtful, and he never gave the impression of being rushed. He discouraged excessive investigations, but was rigorous in pursuing with the house staff the results of tests that he had recommended. David would probe the history and check physical signs when necessary. He was adept at analysing complex clinical findings to arrive at a diagnosis but, despite his encyclopaedic knowledge, was always willing to seek outside advice from specialist colleagues, and to admit rare errors in diagnosis. As a senior registrar in Liverpool, he remembered writing up investigations and treatments only to have them contested or cancelled by Cyril Clarke his consultant. He was responsible for David’s tendency to therapeutic nihilism, and his  rejection of claims for treatment that went beyond the evidence. David wrote that “Cyril believed in minimal intervention. His advice to his new house staff on the use of drugs came, he claimed, straight from the mouth of one of his teachers at Guy’s, who, as he got older, restricted his personal pharmacopoeia to morphia  and sodium bicarbonate, and was not too liberal  with the bicarbonate”.

David virtually never missed a take round, routine ward round or Thursday NDM clinical meeting, and would insist on flying back from the United States to chair a Wednesday grand round. He developed excellent relationships with the medical and nursing staff and with his secretaries, creating a warm atmosphere on the firm.

The Oxford Textbook of Medicine

In the late 1970s, John was approached by Richard Charkin of Oxford University Press to edit a new “Oxford Textbook of Medicine”, to succeed “Price’s Textbook of the Practice of Medicine”. He was disinclined to do this due to other commitments, but David felt that the medical school deserved a locally produced textbook and that the Oxford brand should not be surrendered into other hands. As a result, Weatherall, Ledingham and Warrell became editors of this magnum opus. They used to meet on Saturday mornings in David’s office to select authors for a book that had to be authoritative and comprehensive, with memorable descriptions of the clinical phenotype as well as discussion of pathophysiology and treatment. Inevitably, amusing and destructive anecdotes were exchanged about  some of the proposed authors, and many a fine reputation hit the dust.

David Weatherall was the very model of that endangered species, the clinician scientist. He never relinquished the ideal, expressed when he was appointed here, of making the Oxford Medical School a world leader in clinical practice, teaching, and research.

 

The scientist

Written by Professor John Clegg

David Weatherall’s first encounter with thalassaemia – while serving in the RAMC in Singapore on National Service – was the stimulus for a life-long fascination with genetic blood diseases. In 1962, when he began a training fellowship at the Department of Medicine at the Johns Hopkins Hospital in Baltimore, thalassaemia was already known to be a genetic disorder affecting haemoglobin, with two broad classes, depending on which globin subunit, alpha or beta, was involved. But, despite much theorising, there was no direct experimental evidence for any of the proposed mechanisms.

During most of his three years at Hopkins, David (and many others) had struggled unsuccessfully to get the established methods used for haemoglobin synthesis in rabbits to work with human blood samples. In fact, a simple technical problem was responsible and, early in 1965, he learnt to his surprise that it had just been solved by a protein chemistry group in a different Hopkins department across the road from the hospital! A mutual friend put the two in contact. In the few months left before he had to return to Liverpool, they carried out the definitive experiments showing that the basic defect in thalassaemia was imbalanced synthesis of the alpha and beta globin proteins. The methods that the Weatherall group developed at this time subsequently became the basis for the prenatal detection of haemoglobin disorders: this was, until the later DNA era, the major reason for the remarkable decline in new cases of thalassaemia in some Mediterranean countries.

Ironically, the key paper that described the 1965 experiments was published too late to make the first edition of David’s authoritative book ‘The Thalassaemia Syndromes’. Nevertheless, its impact may be gauged from the comment of a speaker at a New York Academy of Sciences meeting on the biochemistry of thalassaemia a few years later. It was, he said, ‘the fountain-head of all this’. Almost fifty years on, it had lost none of its significance: the citation for the American Society of Haematology’s 2013 Coulter Award to David described it as ‘a truly ground-breaking and transformative report’.

In the ensuing years, the Weatherall group published over 200 research papers on various aspects of the genetics, molecular biology and pathophysiology of thalassaemia. Many of these arose from collaborations and contacts David had made during fact-finding trips he had undertaken for the World Health Organisation. Occasionally, some of this work crossed over into other areas of medicine and biology. In one, a chance conversation with a doctor from the New Hebrides (now Vanuatu) led to large-sale surveys of thalassaemia and malaria in the S. W. Pacific. This, and subsequent clinical case-control studies in Vanuatu and Papua New Guinea, provided convincing proof of the ‘malaria hypothesis’ –first mooted in 1949 by the geneticist J.B.S. Haldane – that carrier states of thalassaemia offer some protection against malaria.

David Weatherall was always patient-driven and he helped to set up a number of treatment and diagnostic centres in developing countries. Most notable, perhaps, was the National Thalassaemia Centre in Kurunegala, Sri Lanka. David was a regular visitor: it was ideally placed and suited his research on one of his longstanding interests, HbE /beta-thalassaemia. This, the commonest form of the disease in S. E. Asia, affects hundreds of thousands of individuals and has a remarkable clinical heterogeneity despite having precisely defined (to the single base pair) genotypes. David had received long-term funding for this project sometime before his ‘retirement’ in 2000. As anyone who knew him well could have predicted, he was still at work on it at the time of his death.

 

To read further articles in the Oxford Medicine newsletter, please click here.