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The power of partnerships: the Liverpool school of butterfly and medical genetics

  • DORIS T. ZALLEN (a1)

From the 1950s to the 1970s, a group of physician–researchers forming the ‘Liverpool school’ made groundbreaking contributions in such diverse areas as the genetics of Lepidoptera and human medical genetics. The success of this group can be attributed to the several different, but interconnected, research partnerships that Liverpool physician Cyril Clarke established with Philip Sheppard, Victor McKusick at Johns Hopkins University, the Nuffield Foundation, and his wife Féo. Despite its notable successes, among them the discovery of the method to prevent Rhesus haemolytic disease of the newborn, the Liverpool School began to lose prominence in the mid-1970s, just as the field of medical genetics that it had helped pioneer began to grow. This paper explores the role of partnerships in making possible the Liverpool school's scientific and medical achievements, and also in contributing to its decline.

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1 Mollison P.L. and Walker W., ‘Controlled trials of the treatment of haemolytic disease of the newborn’, The Lancet (1952) 259, pp. 429433; and Reali Giorgio, ‘Forty years of anti-D immunoprophylaxis’, Blood Transfusion (2007) 5, pp. 36.

2 Morrell J.B., ‘The chemist breeders: the research schools of Liebig and Thomas Thomson’, Ambix (1972) 19, pp. 146, 2; Geison Gerald L., ‘Scientific change, emerging specialties, and research schools’, History of Science (1981) 19, pp. 2040.

3 Ravetz J.R., Scientific Knowledge and Its Social Problems, Oxford: Clarendon Press, 1971, pp. 223233.

4 Clarke C.A., ‘Philip Macdonald Sheppard’, Biographical Memoirs of Fellows of the Royal Society (1977) 23, pp. 465500.

5 Clarke C.A., ‘The Navy to the rescue, or from Scapa to Sydney and home again, fifty years ago’, Journal of the Royal Naval Medical Service (1996) 82, pp. 151158. See also Cyril Astley Clarke papers, University of Liverpool Special Collections and Archives (subsequently ULA), D36/E.22.

6 Clarke C.A., ‘Hand pairing of Papilio machaon in February’, Entomologists’ Record (1952) 64, pp. 98100.

7 Clarke C.A., ‘Interspecific hybridisation between Papilio species of the machaon group’, Proceedings of the Royal Entomological Society of London, series C (1953) 18, p. 42.

8 Wants and Exchanges List, Amateur Entomologists' Bulletin (October 1952) 18, p. 3.

9 Sheppard to Clarke, 9 October 1952, American Philosophical Society Library, Philadelphia, Pennsylvania (subsequently APS), Ms. Coll. No 65, Series I, Box 5, folder: Clarke, Cyril A. #1.

10 Clarke to Sheppard, 14 October 1952, APS, Ms. Coll. No 65, Series I, Box 5, folder: Clarke, Cyril A. #1.

11 Clarke C.A. and Sheppard P.M., ‘Further observations on hybrid swallowtails’, supplement to Entomologists’ Record and Journal of Variation (1953) 65, pp. 112.

12 Sheppard to Clarke, 30 July, 1953, APS, Ms. Coll. No 65, Series I, Box 5, folder: Clarke, Cyril A. #2.

13 Zallen Doris T., ‘From butterflies to blood: human genetics in the United Kingdom’, in Fortun Michael and Mendelsohn Everett (eds.), The Practices of Human Genetics, Dordrecht: Kluwer Academic Publishers, 1999, pp. 197216, 198–202.

14 Cook Laurence, ‘C.A. Clarke, a modern Aurelian’, The Linnean (2003) 19, pp. 3242.

15 Bentall Ian Aird, H.H. and Fraser-Roberts J.A., ‘Relationship between cancer of stomach and the ABO blood groups’, British Medical Journal, 11 April 1953, pp. 799801.

16 P.M. Sheppard, ‘Cancer of stomach and ABO blood groups’, British Medical Journal, 30 May 1953, p. 1220. The secretor gene in its dominant form is responsible for producing soluble forms of ABO blood-group antigens (H is the form of antigen produced by type-O individuals) which appear in body fluids. In non-secretors, only trace amounts of soluble antigens are found.

17 Clarke to Sheppard, 1 June 1953, APS, Ms. Coll. No 65, Series I, Box 4, folder: Clarke, Cyril A, #2.

18 Over the years that followed, similar studies sought possible relationships between blood-group markers and other disorders such as gastric ulcer and mitral stenosis. APS, Ms. Coll. No 65, Series I, Box 18, folder: The Nuffield Foundation #1 , 1954–61.

19 Clarke to Sheppard, 1 June 1954, APS, Ms. Coll. No 65, Series I, Box 5, folder: Clarke, Cyril A. #1.

20 Ford to Clarke, 10 March 1955, APS, Ms. Coll. No 65, Series I, Box 5, folder: Clarke, Cyril A. #4.

21 Ford E.B., Genetics for Medical Students, London: Methuen & Co. Ltd, 1942.

22 McConnell Richard, ‘Sir Cyril Clarke at ninety’, Association of Liverpool Medical School Newsletter (1997) 20, pp. 12.

23 Sheppard to Clarke, 30 January 1956, APS, Ms. Coll. No 65, Series I, Box 6, folder: Clarke, Cyril A. #5.

24 Sheppard to Fisher, 25 April 1956, APS, Ms. Coll. No 65, Series I, Box 9, folder: Fisher, Ronald A (Sir) #2.

25 C.A. Clarke, draft of a history of the University of Liverpool Department of Medicine, 1958–1972, ULA, Cyril Astley Clarke papers, D36/B.21.

26 Some examples are Clarke C.A., ‘Prevention of Rh-haemolytic disease’, British Medical Journal (1967) 4, pp. 712; and Clarke Cyril A. and Finn Ronald, ‘Prevention of Rh-hemolytic disease: background of the Liverpool work’, American Journal of Obstetrics and Gynecology (1977) 127, pp. 538539.

27 For example, some Rh-negative mothers who are also blood type O will not develop antibodies against an Rh-positive foetus if that foetus is blood group A or B but will when the foetus is blood group O like themselves. Levine Philip, ‘Serological factors as possible causes in spontaneous abortions’, Journal of Heredity (1943) 34, pp. 7180; Nevanlinna H.R. and Vainio T., ‘The influence of mother–child ABO incompatibility on Rh immunisation’, Vox Sanguinis (1956) 1, pp. 2634.

28 Clarke C.A. and McConnell Richard B., Prevention of Rh Hemolytic Disease, Springfield, IL: Charles C. Thomas, 1972, p. 9.

29 Weatherall David, ‘Sir Cyril Astley Clarke, C.B.E. 22 August 1907–21 November 2000’, Biographical Memoirs of Fellows of the Royal Society (2002) 48, pp. 6985, 78.

30 Sheppard to the Nuffield Foundation, 12 February 1959, APS, Ms. Coll. No 65, Series I, Box 18, folder: The Nuffield Foundation #1, 1954–61.

31 These include Zimmerman David R., Rh: The Intimate History of a Disease and Its Conquest, New York: Macmillan, 1973; and Weatherall David, ‘Cyril Clarke and the prevention of Rhesus haemolytic disease of the newborn’, British Journal of Haematology (2012) 157, pp. 4146.

32 Another group – Vincent Freda, John Gorman and William Pollack – working in the New York City area, used the same anti-D intervention but based it on a theoretical premise, different from that of the Liverpool group, that large doses of antibody, passively administered, could depress the ability of a woman's immune system to detect and respond to the presence of Rh antigen. They achieved the same successful clinical result shortly after that of the Liverpool group.

33 ‘Top of the decade’, Time (26 December 1969) 94, p. 31. The prevention of Rh disease was included with such advances as the birth-control pill, the polio vaccine, kidney transplantation and dialysis, and human heart transplantation.

34 Harper Peter S., ‘Sir Cyril Clarke and Journal of Medical Genetics: an appreciation’, Journal of Medical Genetics (1985) 22, p. 417.

35 Sheppard P.M., Natural Selection and Heredity, London: Hutchinson University Library, 1958.

36 Comfort Nathaniel, The Science of Human Perfection: How Genes Became the Heart of American Medicine, New Haven and London: Yale University Press, 2012, pp. 163199.

37 The Moore clinic was a direct descendent of a clinic that originally was dedicated to the study and treatment of venereal disease, particularly syphilis. Once penicillin was found to be a successful treatment for syphilis, the clinic enlarged its focus to include an emphasis on other types of chronic disease and, under McKusick's direction, included the genetic components of such diseases. When he took over the clinic, McKusick renamed it in honor of his predecessor, Moore Joseph Earle. Harvey A. McGehee, McKusick Victor A. and Stobo John D., Osler's Legacy: The Department of Medicine at Johns Hopkins 1889–1989, Baltimore, MD: Department of Medicine, The Johns Hopkins University, 1990, pp. 8385.

38 Richard B. McConnell, ‘Blood groups and disease: an investigation of their associations’, Doctor of Medicine thesis, University of Liverpool, 1955.

39 Richard B. McConnell, interview by author, 6 May 1998.

40 McKusick to McConnell, 6 October 1957, Victor McKusick Collection, Alan Mason Chesney Medical Archives, Johns Hopkins Medical Institutions (subsequently CMA), Box 110B5-6 – Victor McKusick Papers: Old Moore Clinic Fellows, A-G-1960s, folder: Evans, David Alan Price.

41 McConnell to McKusick, 31 October 1957 (copy provided to the author by McConnell). The original letter is archived in CMA, Box 110B5-6 – Victor McKusick Papers: Old Moore Clinic Fellows, A-G-1960s, folder: Evans, David Alan Price.

42 McKusick V.A., ‘Persisting memories of Cyril Clarke in Baltimore’, Journal of Medical Genetics (2001) 38, p. 284.

43 Price Evans David A., Manley Keith A. and McKusick Victor A., ‘Genetic control of isoniazid metabolism in man’, British Medical Journal (1960) 2, pp. 485491.

44 A. McGehee Harvey, ‘Clinical investigation of chronic diseases: its successful pursuit in an outpatient setting’, Chapter 18 of Harvey, Research and Discovery in Medicine: Contributions from Johns Hopkins, Baltimore: Johns Hopkins University Press, 1981, pp. 266–292.

45 McConnell, op. cit. (39).

46 John McAnuff, interview by the author, 25 July 1991. See also Minns F. John (ed.), Wealth Well-Given: The Enterprise and Benevolence of Lord Nuffield, London: Alan Sutton Publishing, 1994, p. 263.

47 Zallen Doris T., ‘The Nuffield Foundation and medical genetics in the United Kingdom’, in Schneider William H. (ed.), Rockefeller Philanthropy and Modern Biomedicine, Bloomington: Indiana University Press, 2002, pp. 223238, 229.

48 Harper Peter S., A Short History of Medical Genetics, Oxford: Oxford University Press, 2008, pp. 293299.

49 John McAnuff (Nuffield Foundation) to Sir James Mountford, vice-chancellor, University of Liverpool, 2 July 1963, APS, Ms. Coll. No 65, Series I, Box 18, folder: The Nuffield Foundation #2 , 1962–67.

50 Clarke, op. cit. (25).

51 News and Notes, ‘Medical genetics at Liverpool’, The Lancet (1963) 282 (originally volume 2), p. 1074.

52 Other contributors to the building were the North West Cancer Research Fund (which supported a cytogenetics unit and an immunochemistry unit) and the university itself, which provided funds for a facility housing animals for research and for a Department of Radiodiagnosis.

53 P.M. Sheppard, Report to Nuffield Foundation, c.1959, APS, Ms. Coll. No 65, Series I, Box 18, folder: the Nuffield Foundation #1 1954–61.

54 Officer Lawrence H. and Williamson Samuel H., ‘Better measurements of worth’, Challenge: The Magazine of Economic Affairs (July–August 2006) 49, pp. 86110. Also at

55 C.A. Clarke, ‘Ninth (final) annual report (1971/72)’ (of the Nuffield Unit of Medical Genetics, Department of Medicine, University of Liverpool), ULA, Nuffield Unit of Medical Genetics, annual reports, D267/10.

56 Nuffield Grant, ULA, Cyril Astley Clarke papers, D36/D.18 and D.19.

57 Among these works are Clarke C.A., Genetics for the Clinician, Oxford: Blackwell Scientific Publications, 1962; and Clarke (ed.), Rhesus Haemolytic Disease: Selected Papers and Extracts, Baltimore: University Park Press, 1975.

58 See, for example, Pycior Helena M., Slack Nancy G. and Abir-Am Pnina G. (eds.), Creative Couples in the Sciences, New Brunswick: Rutgers University Press, 1996; and Lykknes Annette, Opitz Donald L. and Van Tiggelen Brigitte (eds), For Better or For Worse? Collaborative Couples in the Sciences, Basel: Birkhäuser, 2012.

59 Because she disliked her childhood nickname, Peggy, she and her mother selected another nickname, Féo, found in a novel. It became the name she used from her teen years throughout the rest of her life.

60 Weatherall, op. cit. (29), p. 75.

61 Miles Clarke, Stephen Clarke and Charles Clarke, interviews by the author, 16 September 2010.

62 McConnell, op. cit. (39).

63 Zallen D.T., Christie D.A. and Tansey E.M. (eds.), The Rhesus Factor and Disease Prevention, Wellcome Witnesses to Twentieth Century Medicine, vol. 22, London: The Wellcome Trust Centre for the History of Medicine, 2004, p. 36.

64 Cook, op. cit. (14); and Richard B. McConnell, ‘Order of Funeral Service’, ULA, D36/A.68, p. 20.

65 His findings, that the proportion of the three forms had not changed over the intervening years, were at odds with what had been observed in the Cothill colony near Oxford. Clarke C.A., Clarke F.M.M. and Owen D.F., ‘Gene frequencies in an artificial Wirral colony of the scarlet tiger moth (Panaxia dominula L.) in the four years after its rediscovery, 1989–1992’, The Linnean (1993) 9, pp. 1820.

66 Grant application from C.A. Clarke to the Nuffield Foundation, ULA, Liverpool archives, D36/D.18.

67 Clarke, Genetics for the Clinician, op. cit. (57), p. ix.

68 Clarke, Rhesus Haemolytic Disease, op. cit. (57), p. ix.

69 F.M.M. Clarke, ‘Some elementary statistics for the entomologist’, a series of six articles in The Entomologist on the meaning of statistical significance (April 1963) 96, pp. 73–76; the chi-square test (September 1963) 96, pp. 218–223; simple tests for genetic linkage (May 1964) 97, pp. 113–120; the Hardy–Weinberg law (January 1965) 98, pp. 7–9; the normal distribution (May 1967) 100, pp. 128–131; and the analysis of variance (July 1967) 100, pp. 181–183. The first of these papers appeared after the publication of Clarke's Genetics for the Clinician book, op. cit. (57), in which all of these topics are discussed. It appears likely that Féo Clarke worked with her husband on that book and then took the opportunity, from the knowledge she gained about statistics, to explain the relevant concepts to entomologists.

70 Clarke C.A., Clarke F.M.M. and Sheppard P.M., ‘Mimicry and Papilio memnon: some breeding results from England’, Malayan Nature Journal (1968) 21, pp. 201219; Clarke F.M.M., ‘Papilio memnon: a tailed “butlerianus” in the Malay Peninsula’, Malayan Nature Journal (1978) 30, pp. 551553.

71 Clarke C.A., ‘The prevention of “rhesus” babies’, Scientific American (1968) 219, pp. 4652.

72 P.M. Sheppard, recording describing prevention of Rh haemolytic disease, 18 March 1968, Genetics Society Archive (1968; SID I, 1–180) John Innes Centre Archives, Norwich.

73 Laurence Cook, Sally Thompson and Angela Urion, personal communications with the author.

74 Finn R., ‘Erythroblastosis’, The Lancet (1960) 1, p. 526.

75 Zimmerman, op. cit. (31), pp. 291 ff.

76 C.A. Clarke to David Zimmerman, 11 September 1973. A copy of this letter is inserted into Zimmerman's book, op. cit. (31), held by the library of the Royal College of Physicians in London. In that letter, Clarke states that an independent confirmation of Féo's role appeared in a book which was already in press before the Scientific American article came out: Jewkes J., Sawers D. and Stillerman R., The Sources of Invention, 2nd edn, New York: W.W. Norton & Company, 1969, pp. 348351. However, it appears from the acknowledgements in that book that the information came to those authors from Philip Sheppard, who had heard about the incident directly from Cyril Clarke.

77 Zallen, Christie and Tansey, op. cit. (63), pp. 40–41.

78 David Weatherall, ‘Past Masters’ column, ‘David Weatherall pays tribute to the man who asked him to eat asparagus in the name of research’, Times Higher Educational Supplement, 4 November 1994, p. 17.

79 Weatherall, op. cit. (29), p. 80.

80 Clarke, op. cit. (25).

81 P.A. Coventry and John Pickstone, ‘From what and why did genetics emerge as a medical specialism in the 1970s in the UK? A case-history of research, policy and services in the Manchester region of the NHS’, Social Science and Medicine (1999) 49, pp. 1227–1238.

82 Among these alumni are David Weatherall (Oxford), Rodney Harris (Manchester), Marcus Pembrey (London) and Peter Harper (Cardiff).

A travel grant from the Wellcome Institute for the History of Medicine made possible many of the oral-history interviews with the Liverpool doctors. The author is grateful to Stephen Clarke, Charles Clarke and Miles Clarke for their generous sharing of materials related to their parents. Archivists at the University of Liverpool, at the American Philosophical Society in Philadelphia and at the Johns Hopkins Medical Institutions in Baltimore provided valuable assistance in accessing key documents. David West, Bruce Grant, Margaret Rossiter and Richard Zallen made useful comments on drafts of the manuscript, as did the anonymous reviewers of the manuscript after submission.

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