Exceptional Matters: Clinical Research from Bedside to Bench
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I COLLEGE LECTURES Exceptional Matters: clinical research from bedside to bench Keith Peters Introduction ...a word of counsel to beginners, it is: ‘Treasure your exceptions! When there are none, work gets so dull that no In his Harveian Oration of exactly 80 years ago, one cares to carry it further. Keep them always uncovered Archibald Garrod, one of the greatest clinical and in sight. Exceptions are like the rough brick-work of a researchers of the last century, quoted from a letter growing building which tells that there is more to come written by Harvey (only six weeks before his death) and shews where the next construction is to be’. to a Dutch physician who had sent him an unusual specimen:1 Garrod’s Oration in 1924 was titled The debt of sci- ence to medicine. Today’s catch-phrase is ‘from bench The Harveian It is even so – Nature is nowhere accustomed more openly to bedside’ and university medical centres are strug- Oration is given to display her secret mysteries than in cases where she gling with the promotion of translational research. annually at the shows traces of her workings apart from the beaten path; But in the relatively recent past, the debt of science to Royal College of nor is there any better way to advance the proper practice medicine has in fact grown more than even Garrod Physicians of London under an of medicine than to give our minds to the discovery of the might have envisaged – often in the most surprising indenture of usual law of Nature, by careful investigation of cases of ways. rarer forms of disease. For it has been found, in almost all William Harvey in I shall describe examples which reflect a largely 1656. This article things, that what they contain of useful or applicable is personal experience, where astute observations of is based on the hardly perceived unless we are deprived of them, or they single cases or small groups of patients have been the 2004 Oration become deranged in some way. starting point of voyages of scientific discovery – given on 19 Garrod then went on : from, as it were, the bedside to the bench – but in October 2004 by doing so I shall illustrate the synergy between clinical Sir Keith Peters These words, as true to-day as when they were written, are and basic biomedical research that now provides FRCP FRS PMedSci, full of encouragement for those of us for whom the study of medical scientists with investigative tools of hitherto Regius Professor of Physic, Head of the Nature’s experiments and mistakes has a special attrac- unimagined power. Indeed, I hope to persuade you tion. The structural malformation, or the hereditary and School of Clinical that the golden age of clinical science does not belong inborn departure from the normal of metabolism, Medicine, to a long-gone era but that it is about to begin. although unimportant from the practical standpoint, may University of My professional life has been divided into two Cambridge throw a ray of light into some dark place of embryology or overlapping phases: the first as a practising physi- biochemistry; and not a few of the rare maladies, such as cian/clinical scientist, and the second with strategic chloroma, polycythaemia vera, sulphaemoglobinaemia, Clin Med JRCPL responsibilities for teaching and research at the Royal 2004;4:551–66 and the disease of which Bence-Jones albuminuria is a Postgraduate Medical School (RPMS) and at the sign, offer fascinating and still unsolved problems of Clinical School in Cambridge. I hope to show some- physiology and pathology. thing of the power of blending the values and cul- The force of these much-quoted observations remains tures of the two institutions: the RPMS, the crucible undiminished today. of clinical science, pioneering medical technology Garrod, stimulated by the black urine of a patient and providing the breeding ground for leaders in with alcaptonuria, introduced the concept of the clinical academic medicine, and Cambridge with its inborn error of metabolism. Influenced by William tradition of basic medical science, especially molec- Bateson, he suggested that inborn errors are caused ular and cell biology. by (genetic) defects in enzymes: his 1908 inference I was an undergraduate in Cardiff where I was that genes encode enzymes antedated by 35 years the taught by Harold Scarborough, the Professor of Nobel Prize winning rediscovery by Beadle and Medicine. He was then well known to medical stu- Tatum.2 dents as the co-author of ‘BDS’: Bell, Davidson and I believe I can be confident that my title would Scarborough, Textbook of physiology and biochem- have found approval with Garrod, and Harvey and istry. He was an exceptional teacher who sought to Bateson. Bateson declared:3 explain disease in physiological and biochemical Clinical Medicine Vol 4 No 6 November/December 2004 551 Keith Peters terms. I also saw a great deal of Archie Cochrane, for he invited nisms of disease in nephritis, then the principal cause of end- our small band of medical students to his elegant home and stage renal failure, and application of Dixon’s ideas was a natural tried passionately to convert us to epidemiology by proselytising starting point. Antibodies to GBM were usually associated with the virtues of the randomised clinical trial. He had few total a devastating disease (Goodpasture’s syndrome) in which the converts but his influence was enduring. lung basement membranes were also damaged causing life- In 1965, I moved to Birmingham to join John Squire in the threatening pulmonary haemorrhage, and where kidney func- Department of Experimental Pathology; this was my first expo- tion was rapidly lost due to a severe proliferative nephritis sure to experimental models of disease in animals. Squire was in (rapidly progressive glomerulonephritis (RPGN)). We reasoned every way exceptional and was planning, as Director Designate, that if circulating autoantibodies were indeed the cause of dis- the MRC Clinical Research Centre at Northwick Park, but sadly ease, then interventions aimed at reducing their generation – died five months later. Memorably, I met Emil Unanue who had immunosuppression, combined with plasma exchange to gone to work with John Humphrey at Mill Hill but had earlier, remove antibody – should alleviate the disease.6 with Frank Dixon, conducted comprehensive and definitive The surprising finding was not that disease was alleviated but studies of experimental models of nephritis.4,5 Unanue, Frank that antibody production was permanently arrested in some Austen and Hugh McDevitt, who also worked with John patients in less than a few weeks (Fig 1). It has taken many years Humphrey, have become leading immunologists in the USA: of research into immunoregulatory mechanisms to begin to they acknowledge the scientific inspiration that John unselfishly throw light on how this might have been brought about. Only in provided. John Humphrey was later to become Professor of the last decade has there been a convincing characterisation of Immunology at the RPMS in succession to Peter Lachmann. regulatory T cells whose engagement (shifting the balance Frank Dixon had established the paradigm for pathogenetic between activatory and regulatory T cells) could explain the ter- mechanisms in glomerulonephritis – namely that there were mination of an autoimmune response. The subject of regulatory two underlying immunological mechanisms, the first mediated T cells is now a major area of immunological research – and by autoantibodies (especially to glomerular basement mem- devising immunological interventions specifically to promote brane (GBM)) and the second due to accumulation in the the generation of immunological control systems to suppress glomerulus of circulating antigen–antibody complexes – unwanted immune responses, including immune responses to immune complex disease; and that these two processes were transplanted organs, is a major goal of modern immunology.7 readily distinguishable by immunofluorescent examination of (It should be added that despite thousands of publications on renal biopsies. the subject of regulatory T cells in mice there is as yet no test which identifies their specific functional presence in regulating From experimental models to the clinic: autoimmune disorders in man.) autoimmunity and plasma exchange Success in the anti-GBM syndromes led to a consideration of other diseases where patients were not critically ill and were I was appointed to a lectureship in renal medicine at the RPMS therefore easier to evaluate. The first of these was myasthenia in 1969 with the intention of developing research into mecha- gravis (MG), then suspected though not proven to be due to Prednisone Cyclophosphamide Dialysis Plasmapheresis 16 700 14 600 12 Creatinine ( 500 10 Creatinine 400 8 µ 300 mol/l) 6 Anti–GBM antibody 200 4 Anti–GBM antibody 100 (% binding by radioimmunoassy) (% binding by 2 NORMAL Fig 1. Effect of plasma exchange and RANGE 0 0 immunosuppression on anti-GBM antibody 22 31 7 14 21 28 7 15 5 and renal function. Autoantibody production Aug Sept Oct Dec ceased and never recurred (from Ref 6). 552 Clinical Medicine Vol 4 No 6 November/December 2004 Exceptional Matters autoantibodies to the acetylcholine receptor (AChR). Tony was flimsy; nevertheless, cytotoxic drugs such as cyclophos- Pinching, who had worked with John Newsom-Davis as a junior phamide seemed beneficial. Since it could be argued that certain doctor at Queen Square, suggested that we invite John to collab- plasma protein constituents, such as complement and fibrin- orate. To our delight, there