Perspectives

Copyright Ó 2007 by the Genetics Society of America Perspectives Anecdotal, Historical and Critical Commentaries on Genetics Edited by James F. Crow and William F. Dove R. A. Fisher’s 1943 Unravelling of the Rhesus Blood-Group System A. W. F. Edwards1 Gonville and Caius College, Cambridge CB2 1TA, United Kingdom VEN if R. A. Fisher’s elucidation of the human blood- binatorial skills and his relations with A. S. Wiener, and E group system Rhesus in terms of the three linked to add a personal coda. It is best to take first the diagram loci C, D, and E had not proved to be substantially (Figure 1) from Fisher (1947) because it explains the correct, it would still have been an outstanding example relationship between the original Rhesus notation and of the power of analytical thought to unravel a complex that proposed by Fisher. As Fisher writes, ‘‘We may repre- array of genetical data. In fact, as a recent review relates sent the eight heritable antigen complexes geometrically (Avent et al. 2006), D is one gene (carrying the D anti- as the corners of a cube, while the six elementary antigens gen) and C and E are different splicing forms of another are represented by the faces; each allelomorphic pair of (CE carrying the C or c antigens and the E or e antigens). antigens is then a pair of opposite faces, and the three Fisher’s solution is recognizable beneath the modern faces meeting in any point specify the antigens in each molecular detail. complex.’’ (Ry) and (CdE) are in parentheses because The story of the unravelling of the Rhesus puzzle is the anti-d antibody had not yet been discovered (nor has told in chapter 13 of Joan Fisher Box’s R. A. Fisher: The it to this date); it was part of the brilliance of the hypothe- Life of a Scientist (1978). As well as describing the serol- sis that this haplotype and some of the missing antibodies ogy, Box gives a comprehensive description of the war- that the model predicted were later found. This is one of time circumstances, which in 1943 reunited in Cambridge the very few diagrams in the whole of Fisher’s work, Fisher and his former London colleague R. R. Race. Box surprising in view of Fisher’s geometric way of thinking. was able to draw on Race’s unpublished 1968 Fisher Next is Fisher’s solution as he wrote it out on the back Memorial Lecture ‘‘Blood Groups in Human Genetics’’ of a piece of Caius College notepaper (Figure 2), prob- in which he described the meetings with Fisher in The ably after dinner in College (where he lived) on the day Bun Shop, a Cambridge public house, where the inter- that Race had told him of his latest results when they pretation of the Rhesus reactions was discussed over met in The Bun Shop. It was presented to the Fisher pints of beer. Much later, he and his wife Ruth Sanger Memorial Trust by J. J. van Loghem and is reproduced told the story (Race and Sanger 1982), and on the with the permission of the Trust. The ‘‘CDE’’ notation occasion of the centenary of Fisher’s birth it was re- has not yet put in an appearance, but the tables may be peated by Clarke (1990) and Bodmer (1990), both of readily interpreted by reference to Figure 1. Note in whom also knew Fisher. Bodmer (1992) gave a fuller particular the two faces of a cube at the top of Figure 2 account still to the Eighth Congress of Human Genetics and the list of some of the genotypes and their reactions in 1991. Fisher himself described the purely scientific on the right, divided into ‘‘5 common,’’ ‘‘5 rare,’’ and ‘‘2 development in a lecture that he gave at Woods Hole, not observed.’’ Of this occasion Race and Sanger Massachusetts, in 1946: ‘‘The Rhesus Factor: A Study in (1982) wrote, ‘‘The immediate reaction was puzzlement Scientific Method’’ (Fisher 1947). and lack of understanding, especially on the part of The purpose of this article is simply to bring together Race; colours and even music were tried but did not in one place for the first time five illustrations that help; eventually unaided understanding alone came to belong to the story, to remark briefly on Fisher’s com- the rescue, and thereafter it was impossible to believe anything else.’’ Figure 3 is the beer-stained piece of paper on which, 1Address for correspondence: Gonville and Caius College, Trinity St., in The Bun Shop the following year, Fisher outlined his Cambridge CB2 1TA, United Kingdom. E-mail: [email protected] crossing-over hypothesis explaining the occurrence of Genetics 175: 471–476 (February 2007) 472 A. W. F. Edwards Figure 1.—The two notations for the Rhesus antigens from Fisher (1947). the rare antigens. He uses the CDE notation. The piece allelomorphic antigens are arbitrarily denoted by C, c, of paper was presented to the Fisher Memorial Trust by D, d, E, e, chosen to avoid confusion with any symbols so Ruth Sanger with the annotation, ‘‘This was the first far used’’ (presumably the allusion is to A and B of the writing down by Professor Sir Ronald Fisher of his very ABO system); the letter is dated May 17 and Race would elegant idea that the less frequent Rh chromosomes of course have seen the proofs of it by the time of the might have arisen by crossing-over in heterozygotes for meeting in The Bun Shop on June 22. Fisher and Race [sic] the more frequent chromosomes. He wrote it in (1946) record that the notation was Fisher’s idea, and ‘The Bun Shop,’ a ‘pub’ in Cambridge, on 22nd June Taylor and Race (1944) wrote, ‘‘The terminology 1944. The Professor is very short sighted and was not used in the present account of the Rh system [that is, aware of a good deal of beer on the table—the cause of the original terminology] will certainly not be perma- the marks on the lower part of the paper.’’ The figure is nent. Race (1944) has described a most ingenious and reproduced with the permission of the Trust. attractive scheme, formulated by R. A. Fisher, for the Rh In the telling of the story, the two sessions in The Bun genes, antigens and antibodies.’’ Shop have tended to be confused or at least conflated Race submitted his Ph.D. thesis ‘‘The Rh Blood (e.g.,Clarke 1990) but the evidence is that the first was Groups’’ (Race 1948) on March 24, 1948. It should be in late 1943 (as Race once said) and the second was a valuable source for any historian of serology. (On indeed in the summer of 1944. The date of the latter is examining the copy in Cambridge University Library, I significant, for Race’s letter to Nature, ‘‘An ‘incomplete’ find that I am the only reader ever to have consulted it.) antibody in human serum,’’ was published on June 24 Fisher noted that cDe could be produced by three (Race 1944). With his characteristic generosity toward different crossovers among the three commoner types his students (Race was registered for a Cambridge and that this was more common than the three rarer Ph.D.) Fisher did not co-author the letter in which Race types. From this, he suggested the chromosomal se- wrote, ‘‘The research arose out of a suggestion by quence DCE, with C and E being close together Professor R. A. Fisher,’’ adding, ‘‘The three forms of and separated from D by a longer distance (Box 1978, Figure 2.—Fisher’s 1943 solution to the Rhesus complex. Perspectives 473 Figure 3.—Fisher’s 1944 explanation of the rare antigens. p. 365). At the time, the evidence was not very strong, but it now looks as if, once more, Fisher was on the right track because, as mentioned earlier, it is now known that D is one locus, whereas C and E are alternative splice forms of a single gene. Next is a picture of The Bun Shop itself (Figure 4), Figure 5.—R. A. Fisher about 1943. kindly supplied by Sir Walter Bodmer and already larke published in C (1990). Sir Walter and I joined Because Fisher was reelected to a Fellowship at his old the Cambridge Department of Genetics at the start of college, Gonville and Caius, on assuming the Univer- Fisher’s last academic year as professor (1956–1957) sity’s Arthur Balfour Professorship of Genetics in 1943, and we both remember visiting The Bun Shop with he supplied a fresh photograph for the Fellows Photo- Fisher after his elementary lectures the previous aca- graph Album (Figure 5), contemporary with the eluci- demic year. It was pulled down not long afterward dation of Rhesus. It is reproduced by courtesy of the during the redevelopment of that part of Cambridge. Master and Fellows. (The redevelopment has itself since been pulled down and the site is currently undergoing another cycle of building; visitors to Cambridge should not be misled by THE COMBINATORIAL BACKGROUND the fact that there is now another Bun Shop elsewhere in That Fisher was an ace combinatorialist is obvious the city.) from even a cursory examination of his writings. His memorial window in the Hall of Caius College indeed reflects this by depicting a Latin Square (Figure 6, from the dust jacket of his book The Design of Experiments; Fisher 1935). This talent was deployed to great effect in the unravelling of genetic systems. In section 16 of his path-breaking paper, ‘‘On the correlation between relatives on the supposition of Mendelian inheritance,’’ Fisher (1918) considered the effect of ‘‘coupling’’ between two loci (that is, linkage) and, in particular, the two extreme cases of no linkage and complete linkage.

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