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Obituary J Med Genet: first published as 10.1136/jmg.38.5.281 on 1 May 2001. Downloaded from

Cyril Astley Clarke

last half century. This work typified his unwill- ingness to be deterred by the gloomy prognisti- cations of experts in their fields, who often told him that his thinking was way oV the mark, and his instinctive gift for what Peter Medawar called “the art of the possible”, reflected in his ability for sensing the quality of his younger colleagues and the science that they were pur- suing. Cyril Astley Clarke was born in 1907. His father, Astley Vavasour Clarke, was a physician at the Royal Infirmary and one of the first to use x rays in this country; his grandfather was senior surgeon to the same hospital. He was educated at Oundle, Caius College, Cambridge, and Guy’s Hospital Medical School. After three years in life insur- ance practice, which allowed him time to indulge in his passion for sailing and oVered him the opportunity to examine Winston Churchill, he enrolled as a medical oYcer in the RNVSR and served throughout the war in the navy, ending his service by writing one of his first papers, on the neurological complica- tions of malnutrition that he observed in Brit- ish prisoners of war in Hong Kong. After the war Cyril moved to Liverpool http://jmg.bmj.com/ where he became Consultant Physician at the The passing of marks the end of David Lewis Northern Hospital. Despite busy the era of great medical all rounders. His career hospital and private practices he, together with as a clinician ranged through life insurance his long time friend and collaborator P M practice, medical specialist in the navy, consult- Sheppard, began a series of classical experi- ant physician, and later Professor of Medicine ments on the genetics of swallowtail butterflies, in Liverpool, and, finally, President of the

work which later stimulated his interest in on October 3, 2021 by guest. Protected copyright. Royal College of Physicians of London. His medical genetics. The success of the team of research contributions were equally broad young clinical research workers that built up based, spanning his classical work on mimicry round him left him less time for his clinical in swallowtail butterflies to his enquiry into practice, and he was appointed Reader in longevity by tracing and studying the lifestyles Medicine at the and, in of centenarians who had received congratula- tory messages from the Queen. He was one of 1963 on the retirement of Henry Cohen, he the first in this country to appreciate that became Professor of Medicine, a post that he medical genetics, far from being a discipline held until 1972. He founded the NuYeld Unit which focuses on rare and esoteric diseases, has of Medical Genetics, which he directed from a major role to play across every aspect of day 1963 to 1972. On the year of his retirement he to day clinical practice. This led him to estab- was elected President of the Royal College of lish the NuYeld Unit of Medical Genetics in Physicians of London, a post he held with great Liverpool, which became a stable for many distinction and flair until 1977. From 1977 to who went on to develop this field throughout 1983 he served as Director of the College’s the and elsewhere. Medical Services Study Group, and from 1983 But Cyril Clarke’s most important contribu- to 1988 was Director of its Research Unit. tion to medicine, and one that reflects his flair Among his many other activities he served as and willingness to chance his arm in problems President of the Royal Entomological Society which were often outside his field of expertise, and, much to his delight, President of the Brit- was his inspiring leadership of the Liverpool ish Mule Society. He spent his later retirement team that discovered how to prevent rhesus in Liverpool continuing his work on the genet- haemolytic disease of the newborn, one of the ics of butterflies and in a characteristically major advances in preventive medicine of the broad range of medical research.

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Cyril’s interests in butterflies, which started as he claimed, straight from the mouth of one of a childhood hobby, was reawakened while he his teachers at Guy’s, who, as he got older,

was serving in the navy and visited Australia. He restricted his personal pharmacopoeia to mor- J Med Genet: first published as 10.1136/jmg.38.5.281 on 1 May 2001. Downloaded from had a childhood ambition to breed the swallow- phia and sodium bicarbonate, and was not too tail butterfly, Papilio machaon, and he developed liberal with the bicarbonate. a technique for making them mate by hand. By As Professor of Medicine he led his depart- chance, he obtained a North American swallow- ment with a light touch, preferring to let bright tail, Papilio polyxenes, and was able to mate this youngsters go their own way, but always around

with P machaon. He produced F1 hybrids, and if they needed support. His remarkable flair then backcrosses, and hence discovered that and enthusiasm, and his ability to sniV out tal- their colouring reflects only a single gene diVer- ent and to pick research areas of importance, ence between the two species. was undoubtedly the major factor which led to read of this work and contacted Cyril and thus the wonderful achievement of the rhesus team, started a long standing and extremely produc- and to the success of the Department of Medi- tive collaboration on the genetics of mimicry in cine at Liverpool and its major influence on the tropical butterflies. The two of them also development of medical genetics. became interested in and industrial As a person, Cyril was a complex mixture of a pollution and followed up the observations of life long schoolboy, constantly bubbling with Bernard Kettlewell on the adaptive changes in enthusiasm and new ideas, and yet at the same the colouring of moths in relationship to time he could appear to be rather distant, so that pollution. Starting in 1959, and working every his students and junior staV sometimes found year up to 1994, Cyril and his colleagues caught him diYcult to approach and not a little terrify- moths in June and July using a mercury vapour ing. This was undoubtedly a reflection of his lamp. Overall, they collected 17 648 betularia innate shyness; as they got to know him better and were able to relate the proportion of his extraordinary warmth became apparent. He carbonaria to the level of pollution. was extremely loyal to his staV and supported There seems little doubt that Cyril’s interest them throughout their careers, usually behind in medical genetics was stimulated by his work the scenes and often without their knowledge. In on butterflies. It was Philip Sheppard who 1935, he married Frieda, or Féo as she was suggested to him that blood group genetics always known. Féo became an integral part of all might be a productive way into this field. Cyril Cyril’s work and his many other activities, which started by examining the relationship between ranged from crewing for him in his annual small blood groups, secretor status, and duodenal boat racing (not a relaxing pastime since Cyril ulcer and then turned his attention to rhesus had been an Olympic trialist and hated losing) to haemolytic disease. After his student Ronald breeding swallowtail butterflies in captivity. It Finn confirmed the observation that ABO was a remarkable partnership; Cyril never fully incompatibility between mother and fetus is recovered after Féo’s death in 1997. They are protective against haemolytic disease in the survived by three sons. newborn, and hearing of the transplacental pas- Cyril’s work was widely recognised. He was http://jmg.bmj.com/ sage of red cells from the fetus to the mother, elected FRS and received many national and Cyril and his colleagues evolved the notion of international awards. At the age of 88 years, injecting mothers with anti-rhesus antibody still busy at his research, he wrote that he (anti-D). Studies using male volunteers were would very much like to know why butterflies initially unsuccessful because they were carried have an XX chromosome complement in out with complete anti-Rh. But, at the sugges- males and XY in females, yet the latter live tion of Ruth Sanger, they were able to prevent much longer than the tempestuous XX males. immunisation in a further set of volunteers by “God moves in a mysterious way” he con- on October 3, 2021 by guest. Protected copyright. using incomplete anti-D. The story of this cluded. Certainly there can have been few success was heralded in a local Liverpool more mysterious phenomena than the multi- newspaper with the headline “Men of Mersey- faceted talents, flair, and complexity and side Mothers To Be”. The rest of this story is warmth of character of the man who wrote well known. these words. Cyril was a caring if slightly eccentric clinician, very much of the old school, who believed in minimal intervention. His advice to (This is an extended version of an obituary which appeared in his new house staV on the use of drugs came, The Guardian.)

www.jmedgenet.com Obituary 283 Cyril Clarke, Journal of Medical Genetics, and the foundation of clinical genetics J Med Genet: first published as 10.1136/jmg.38.5.281 on 1 May 2001. Downloaded from

Cyril Clarke became editor of Journal of persuaded to move to Liverpool from the Medical Genetics in 1969, five years after its Oxford School of Evolutionary Genetics, was inception, and he continued to edit it for the crucial in developing this basic work and in next 15 years. A glance at both the content and ensuring that it kept a vigorous scientific basis. the editorial board members of the Journal in Cyril’s lasting scientific reputation will those early years shows the range and quality of rightly rest on the prevention of rhesus haemo- its content and the calibre and diversity of lytic disease by immunological approaches, those he enlisted in running it. Basic science work of remarkable originality that should and clinical expertise were well balanced, logically have come from basic scientists, setting the pattern for the future. When I suc- paediatricians, or obstetricians rather than ceeded him as editor in 1985, it was indeed a from a clinician quite unconnected with the hard act to follow. field. Again, this immense success of “genetic Cyril’s great age (93 at his death) means that therapy” was far ahead of any other applica- most people working in the field now will have tions, to the extent that it is often no longer little direct (or perhaps even indirect) knowledge regarded as a “genetic” success and is increas- of his key role in founding and shaping what is ingly taken for granted. The book in which he now the specialty of Medical Genetics. His brought together all the key papers deserves to natural shyness and reticence have added to this, be better known.3 and while his autobiographical notes, written at How Cyril Clarke managed to achieve all of the age of 88 and published as “88 years of this 1 this from a background of “ordinary” general and that” are a delight to read, they are typically medicine and in a provincial university aca- unassuming and light hearted. demic base is to me both extraordinary and Like most people of true genius, he was far inexplicable. Anyone who had the pleasure of ahead of his time; I have only recently come to working in the David Lewis Northern Hospital realise how far ahead. He believed passionately in Liverpool (whose initial impressions in the that genetics should form part of all medical 1960s could be best described as Dickensian) practice and thinking; only now, with the would agree that it was not the natural nurtur- understanding of the genetic component of ing ground for academic genius. Furthermore, common diseases, is this beginning to happen Cyril only switched to academic medicine at and still only to a limited extent. the age of 50 and undertook all his key research As an adult general physician he saw genetics over the next 15 years, a “late developer” if ever

as applying equally to all age groups, not just as http://jmg.bmj.com/ there was one. a paediatric interest. A direct result of this has An equal puzzle is how he was able to remain been the development of UK Clinical Genetics part of the “medical establishment”, becoming as a balanced specialty with recruits from both President of the Royal College of Physicians on adult and paediatric medicine, in sharp con- retiring from the Liverpool Chair of Medicine. It trast to most of continental Europe and would be good to imagine that this in some way Australia. Most of those who worked with Cyril (“trained” would not be quite the right word) reflected success in persuading the College that and who went on to found departments in the genetics was important in medicine, but sadly I on October 3, 2021 by guest. Protected copyright. UK and North America came from and kept do not think that was the case. They certainly links with adult medicine, the value of which is recognised his scientific talent and his Rh work, now being appreciated. The close link with but few of his contemporaries there understood Victor McKusick’s Baltimore department rein- his ideas, even to a limited degree, and his “but- forced this. terfly work” was, I suspect, tolerated as the pas- Equally ahead of his time was Cyril’s recog- time of an otherwise great man rather than nition that “model organisms”, as they are appreciated for its scientific merit. now considered, could be used directly to gain Anyone who, like myself, had the privilege of insights into human disease. Although a working in Liverpool with Cyril Clarke, was number of the pioneer geneticists were keenly fundamentally influenced by the experience interested in both human disorders and basic and also by the friendship and support that genetics, none was a practising clinician. Many characterised his whole department. In my own of the insights to be found in his book “Genet- case, both friendship and scientific contact ics for the clinician”2 remain as relevant today continued over the next 30 years (in late 1997 as when it was written almost 40 years ago. His I received with a note his latest reprint on may not have been the most population genetics4 written aged 90!). Only orthodox choice for model organisms, but at after losing his dearly loved wife Féo, two years that time their population genetics and evolu- ago, did his own health rapidly decline. tionary biology were much better documented Cyril Clarke’s death does indeed, as David than that of Drosophila (and he would Weatherall states, mark the end of an era. undoubtedly have commented that they were Fortunately, though, his influence lives on in much more fun to work with!). His partner- the field of Medical Genetics today with its ship with Phillip Sheppard, whom he vigorous combination of clinical and scientific

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facets and its increasingly appreciated rel- 2 Clarke CA. Genetics for the clinician. 2nd ed. Oxford: Black- well, 1964. evance both to inherited disorders and to the 3 Clarke CA. Rhesus haemolytic disease. Selected papers and whole of medicine. extracts. MTP Press, Lancaster: MTP Press, 1975. J Med Genet: first published as 10.1136/jmg.38.5.281 on 1 May 2001. Downloaded from PETER HARPER 4 Grant BS, Owen DF, Clarke CA. Parallel rise and fall of 1 Clarke CA. 88 years of this and that. Proc R Coll Phys Edin melanic peppered moths in America and Britain. J Hered 1995;25:495-580, 675-87. 1996; 87:351-7.

Persisting memories of Cyril Clarke in Baltimore

The passing last Fall of Cyril Clarke brought of Medicine at Liverpool. During our visit to back memories of pleasant and productive Liverpool, Malcolm A Ferguson-Smith came interchanges between Liverpool and the Johns down from Glasgow to make arrangements for Hopkins Hospital over a 20 year period or his sojourn in the Moore Clinic which began in more beginning in 1957. Cyril was a central February 1959. At that time, he started what figure in those transatlantic collaborations in may have been the first hospital based cytoge- training and clinical research. netics laboratory in the United States. Medical genetics was institutionalised at Over the next 20 years or so, the large Johns Hopkins on 1 July 1957, when the mul- number of Liverpudlians who were fellows at tifaceted chronic disease clinic created by Dr J Johns Hopkins included Peter Brunt, J Michael Earle Moore became the base for a medical Connor, Brian Hanley, Peter S Harper, F genetics programme, the Division of Medical Michael Pope, Brian Walker, David Weatherall, Genetics. The Moore Clinic very quickly andJCWoodrow. Ronald Finn and “Johnny” became synonymous with medical genetics at Woodrow worked particularly with Julius R Johns Hopkins. Although the Medical Genetics Krevans pursuing the brilliant hypotheses of Division was a section of the Department of Cyril concerning the mechanism and preven- Medicine, its purview encompassed all ages tion of erythroblastosis fetalis. David Weather- and all specialties, with clinical care, research, all worked first with Ned Boyer in the and teaching, as in other specialty divisions. biochemical genetics section of the Moore The first visitor to the Moore Clinic from Clinic before establishing clinical connections Liverpool was Richard McConnell, who spent with Dr C Lockart Conley in the study of hae- a time there during a grand tour in Iowa and moglobinopathies and with others in the elsewhere in the United States, pursuing his department of Howard Dintzis in the study of interest in ABO/secretor in gas- basic mechanisms in the thalassaemias. http://jmg.bmj.com/ tric cancer and peptic disease. In 1976, while Cyril was President of the Anne and I first met Cyril and Féo in 1956 at Royal College of Physicians, Anne and I stayed the first World Congress of Human Genetics in in his flat at the College. During that time I Copenhagen. The friendship was solidified and gave the Lilly Lectures and acquired an honor- the exchange with Baltimore established in our ary MD from the University of Liverpool. It visit to Liverpool in early September 1958, was a rare privilege, in 1977, to receive a which included a visit to the butterfly laden Gairdner Award in Toronto at the same time as Clarke ménage. Cyril and Féo had been in did Cyril. on October 3, 2021 by guest. Protected copyright. Montreal to attend the International Congress In a few words it can be stated that Cyril left of Genetics in August 1958. Cyril confessed his mark on medical genetics by his penetrating serious withdrawal symptoms requiring him to and inquisitive mind and by his encouragement go to the Royal Vic to see outpatients! On that of a whole generation of students. Extending visit, arrangements were firmed up for the first from his study of butterflies, he was thinking of the Liverpudlians to come to the Moore and speaking about the role of polymorphisms Clinic, to acquire a BTA (Been to America) in multifactorial disorders, what we now call degree. That was David A Price Evans, who complex traits, far ahead of his time. during his stay in the Moore Clinic did much to We at Johns Hopkins are much indebted to initiate the field of pharmacogenetics, by defin- Cyril for the able protégés he sent to Baltimore ing the genetics of isoniazid metabolism. Price in the formative years of medical genetics here. Evans was Cyril Clarke’s successor as Professor VICTOR A MCKUSICK

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