David Grahame-Smith, MB, BS, PhD

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Br J Clin Pharmacol. 2012 May; 73(5): 830–832.

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David Grahame Grahame-Smith (DGS) was one of the UK's leading clinical pharmacologists. His work on the pharmacology of the neurotransmitter serotonin (5-hydroxytryptamine) began with the identification of a key enzyme in its synthesis and continued over the next 35 years through a series of innovative and elegant experiments on its functions and its roles in depression and the tumours that cause the carcinoid syndrome, on the clinical management of which he was an expert.

Born David Grahame Smith in Leicester on 10 May 1933, he studied medicine at St Mary's Hospital in London from 1951. As a House Officer in Paddington General Hospital, he found himself in the company of four other David Smiths. In order to reduce the hospital switchboard's constant confusion he changed his surname to Grahame-Smith. Some years later, criticizing the Lancet's overuse of hyphens, he cited the Fowler brothers' manual, The King's English (1906): ‘Hyphens are regrettable necessities and to be done without when they reasonably may’[1]. His ability to laugh at himself in this way was a major asset when he had to tackle the many problems that Oxford clinical professors face.

After house jobs and service in the Royal Army Medical Corps (1957–60), he returned to St Mary's to work with Albert Neuberger, the founder of glycoprotein research [2]. For his PhD degree he identified tryptophan hydroxylase, the enzyme that catalyses the rate-limiting step in the synthesis of serotonin [3], [4]. He won the H. A. M. Thomson Research Scholarship of the Royal College of Physicians (RCP; 1961–2), the Saltwell Research Scholarship of the RCP (1962–5), and a Wellcome Trust Research Fellowship (1965–6) and was Honorary Medical Registrar under the tutelage of Professor Stanley Peart. Peart's attention was first drawn to Grahame-Smith by the epidemiologist Geoffrey Rose, and his interest was aroused by a contribution to the Physiological Society on a peculiar difficulty that a sergeant instructor in the gym had had with rotation in a somersault manoeuvre. Grahame-Smith had studied the problem and come up with an original suggestion relating to the semicircular canals and balance. The hypothesis was received kindly by the always critical members of the Society and alternative suggestions were made. The fact that he had seen the possibilities when most would not, said Peart, made him take Grahame-Smith on as a research fellow. It was Peart who suggested that Grahame-Smith should study the carcinoid syndrome, which started him on the 5-HT pathway. His monograph on the subject was for many years the standard reference in the field [5].

In 1966 a Medical Research Council Travelling Fellowship took him to Vanderbilt University in Nashville, Tennessee, where he worked with Grant Liddle (of Liddle's syndrome), Bill Butcher, and Earl Sutherland (Nobel prize, 1971). Now well trained in clinical medicine and biochemical pharmacology, he returned to St Mary's as Senior Lecturer in Clinical Pharmacology and Therapeutics (1967–71). When the Medical Research Council decided, in 1971, to establish a Unit of Clinical Pharmacology in Oxford, he was the obvious choice as its Director, and he took up the post in 1972 (Figure 1). That the new University Chair of Clinical Pharmacology was funded by the Rhodes Trust was due to the fact that the Professor of Pharmacology in Oxford at the time, William Paton, was also Chairman of the Rhodes Trust.

Learning the sometimes Byzantine ways of the University of Oxford, the Medical Research Council, and Corpus Christi College, of which he was a Fellow and later Vice-President (1998–2000), was no mean task. But the new MRC Unit and University Department of Clinical Pharmacology, situated in a prime site on the first floor of the north wing of the old Radcliffe Infirmary, flourished under his direction, and attracted a wide range of both highly skilled pharmacologists and clinicians. The concerns of the Unit were published in the Medical Research Council's Handbook as follows:

the study of the biochemistry and pharmacology of brain monoamine and other neurotransmitter substances, particularly as they relate to the action of psychotropic drugs and electroconvulsive therapy;
to develop further biochemical and pharmacological techniques as an index of drug action in man and to link thereby pharmacokinetic and pharmacodynamic processes with therapeutic effects;
to apply the techniques of biochemical pharmacology to the study of disease.
The Unit's large output of scientific papers dealt not only with serotonin and psychopharmacology [6], but a wide range of other topics, including the pharmacology and clinical pharmacology of drugs used in diverse medical disciplines, particularly cardiology [7] and cancer [8], and the physiology and pharmacology of transmembrane ion transport [9]. DGS's publications, as listed in Pubmed, numbered 235. His most highly cited paper (613 citations), for those who like that sort of thing, dealt with many of his psychopharmacological preoccupations [10] and his h-index was 53.

DGS also mentored many young scientists, who delighted in his skilled direction and later achieved eminence elsewhere: two Presidents of the British Pharmacological Society and two Presidents of the British Association of Psychopharmacology spent significant parts of their careers in his department, and he trained several professors, both basic and clinical.

He was a highly accomplished physician and his consultant master classes were a popular feature of Oxford medicine during the 1990s. To sit next to him during a case presentation was often a revelation; before the presentation was halfway through he would have pushed across a piece of paper on which he would have written, not the diagnosis, but the key features that led to it; he was almost always right. In 1975 he instituted what became known as ‘Prescription of the Week’, a 5-minute demonstration at the start of the weekly grand round, in which a horrific prescription, usually involving gross and inappropriate polypharmacy, would be analysed. When, the message successfully transmitted, the supply of such prescriptions dried up, the presentations became vignettes about individual medications, always with a single simple message. These ‘prescriptions’ were highly educative, not only for the members of the audience but for the succession of clinical pharmacologists who presented them.

When in 1993 DGS reached the MRC's age of retirement, the MRC Unit closed, but the University Department continued until his retirement in 2000, part funded by the pharmaceutical company SmithKline Beecham in the Oxford University SmithKline Beecham Centre for Applied Neuropsychobiology (1989–99).

During his time in Oxford, David Grahame-Smith's influence was felt widely. He was a loyal supporter of the British Pharmacological Society, and skilfully steered the British Journal of Clinical Pharmacology as Chairman of its Editorial Board (i.e. Editor in Chief, 1988–95). He served on the Committee on Safety of Medicines (now the Commission on Human Medicines) from 1975 to 1986, and chaired its Safety, Efficacy and Adverse Reactions (SEAR) subcommittee and two influential working parties, on guidelines for preclinical toxicity testing (1980) and on post-marketing surveillance (1983–5). The latter resulted in what came to be known as the Grahame-Smith report [11]. He chaired the subgroup on hepatitis B immunization for the Joint Commission on Immunization and Vaccination (1988–9) and was the founding Chairman of the Government's Advisory Council on the Misuse of Drugs (1988–98), a post in which he was succeeded by Mike Rawlins. His visiting professorships included a trip to Beijing in 1985, during which he was delighted that the ballet dancing talents of his wife were as much in demand as his own clinical and scientific ones, perhaps even more so.

His awards included an Anna Monika Stiftung Prize for Studies in Depression (with A. R. Green, 1977) [12], the 1980 Paul Martini prize in Clinical Pharmacology (with J. K. Aronson and A. R. Ford) [13], the Lilly Prize of the British Pharmacological Society in 1995 [14] and the British Association of Psychopharmacology's Lifetime Achievement award in 2002. He was appointed CBE in 1993.

If you wanted to find DGS in a crowd, you only had to follow the sound of laughter. His extracurricular interests were wide and often surprising. He was a strong swimmer and a vigorous player of water polo, a game in which there is fair play above the surface and dirty work below – the perfect training for an Oxford professor. He rode to hounds. He tap-danced with verve. He contributed many gently quirky cartoons to the medical magazine World Medicine, under the title ‘Meanwhile’ (Figure 2). And he was an accomplished pianist, whose jazz-playing friends saw him off at his funeral with ‘When the Saints Go Marching In’ and organized a memorial concert held at Corpus Christi College, Oxford, on 19 November 2011, featuring the Dark Blues Sextet and The George Haslam Big Band.

David Grahame-Smith died of liver cancer, perhaps a cholangiocarcinoma, on 17 June 2011, aged 78 years. He leaves his wife, Kathryn Frances (née Beetham) and two sons, Harvey and Henry. His deep scientific insights, his clinical judgement and acumen, his administrative skill and clear-headed perceptive advice, and above all his sense of fun and the companionship that many of his colleagues enjoyed will be greatly missed.
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