John Edwards, professor of human genetics at Oxford University, was the discoverer of ‘Edwards syndrome’, one of the most common conditions caused by an extra chromosome. When he entered academic medicine as a lecturer in Birmingham in 1956 genetics played virtually no part in the practice of medicine. The molecular structure of DNA had been solved only three years earlier, and the discovery that humans had 46 chromosomes and not 48 was made the same year that John was appointed lecturer. Today, genetics is at the heart of medicine and DNA is the basis of diagnostic pathology. John was one of the pioneers who helped to make this remarkable transformation possible.
The elder son of Harold Clifford Edwards, a distinguished London surgeon, John Edwards was educated at Uppingham school. He left with a distinction in physics and a passion for gliding, obtained during his time with the air squadron of the Officer Training Corps. The gliding club featured prominently during his time at Trinity Hall, Cambridge, and this, together with some uninspiring lecture courses, he regarded as the probable reason for his graduating with a third in the natural sciences tripos. However, he greatly enjoyed his time in the zoology department and this influenced his later career. He went on to clinical studies at the Middlesex and Central Middlesex hospitals and graduated in medicine in 1952.
Instead of moving on to pre-registration house jobs, he joined the Falklands Islands Dependencies Survey as a medical officer with an interest in zoology on board the research ship John Briscoe, spending nine months in Port Stanley and the South Atlantic. On his return he sought a junior house officer post, and worked with the neurologist Douglas McAlpine [Munk’s Roll, Vol. VII, p.349] at the Middlesex. A routine medical examination for National Service in the Army revealed a tuberculous lesion in one lung. Following six months’ treatment, employed partly in reading up on statistical methods, he took a second house job in gastroenterology (with Francis Avery Jones [Munk’s Roll, Vol.XII, web]) and then spent six months as a senior house officer in psychiatry at Knowle County Asylum. He became interested in brain pathology and this led to a senior house officer job in pathology at the Central Middlesex.
In 1956, using his statistical knowledge, he successfully applied for a lectureship in epidemiology at Birmingham University to work with Thomas McKeown [Munk’s Roll, Vol.VIII, p.311] and Lancelot Hogben in the department of social medicine. He was greatly influenced by Hogben and learned to apply statistics to information in the malformation register, namely to the epidemiology of dislocation of the hip and of neural tube defects. John pursued his clinical interests by going on ward rounds at the Children’s Hospital once a week and this led him to an interest in genetics. McKeown suggested that he join the new MRC unit in population genetics at Oxford directed by Alan Stevenson [Munk’s Roll, Vol.X, p.469], an expert in congenital malformations. John was at the unit from 1958 to 1960, but kept regular contact with the Children’s Hospital in Birmingham.
He resigned from the MRC unit in 1960 to take a year’s sabbatical at the Children’s Hospital in Philadelphia, where he consolidated his cytogenetics interests, interacting with Peter Nowell and David Hungerford. In 1961, he returned to the vacant lectureship at the department of social medicine, this time with a half-time connection with Douglas Hubble’s department at the Nuffield Institute of Child Health. John set up there a small cytogenetics laboratory to study Down’s syndrome and to provide a chromosome diagnostic service. Promotion to senior lecturer followed in 1965, and to reader in human genetics in 1966. At this point he took a year’s sabbatical at Cornell Medical Center and the New York Blood Center with James German. On his return, he was awarded a personal professorship in human genetics and moved the cytogenetics service and genetics clinic to the Women’s Hospital.
John was elected to the Royal Society in 1979 and in the same year was offered and accepted the professorship of human genetics at Oxford University following Walter Bodmer’s resignation. Other appointments included consultant to the University of Iceland from 1967, where he helped to establish record linkage of all Icelandic births from 1840. He was also visiting professor of human genetics at the Memorial University of Newfoundland from 1977, consultant in human genetics to the World Health Organization from 1972, and visiting professor at the University of Sydney in relation to his work on comparative mapping.
In 1959 Jerome Lejeune discovered the extra chromosome 21 responsible for Down’s syndrome. One year later John, working with David Harnden, discovered the next chromosome disorder due to an extra chromosome 18. This condition became known as ‘Edwards syndrome’. The discovery was no chance observation. It was due to sound clinical intuition. He appreciated that the pattern of multiple minor malformations and mental handicap in Down’s syndrome could be the clues that could lead to other chromosomal syndromes. Other less astute clinicians were looking at the chromosomes of Mendelian disorders and major malformations and finding nothing. Chromosome analysis in those days depended on bone marrow or testis samples, both requiring invasive and traumatic procedures. John developed a ‘painless’ skin biopsy method instead, which involved pinching a tiny fold of skin with forceps and slicing the exposed part with a sharp scalpel blade. He practised this on himself, producing multiple tiny scars on his knees. The method proved completely acceptable to his young patients.
In the years that followed John continued his interest in chromosome abnormalities and described patients with mosaic trisomy, triploidy and various translocations. He established a small laboratory for this work at the Nuffield Institute of Child Health in Birmingham. In one important study he personally analysed the chromosomes of 128 patients with Down’s syndrome born to young mothers, in order to determine to what extent inherited translocations and maternal mosaicism contributed to the frequency of the condition. Only one inherited translocation was found and he rightly concluded that routine analysis of affected children caused unnecessary distress and was unwarranted. When prenatal diagnosis was introduced later in 1970, the recurrence of Down’s syndrome in women with an affected child was found to be less than half a percent. The option of prenatal diagnosis, however, gave couples the reassurance necessary to contemplate further pregnancies.
John’s contribution to the development of diagnostic cytogenetics was very important, but he also made outstanding contributions to other aspects of human genetics including linkage mapping, genetic susceptibility to common disease, and comparative genomics. He attended all 11 Human Gene Mapping Workshops from 1973 to 1991. These workshops provided the chromosome maps that led eventually to the human genome project and the complete DNA sequence of the human genome in 2001. John’s contribution was to provide novel computing methods for assigning and ordering genes onto their specific chromosomes. He was an expert in statistics and mathematical genetics and wrote his own computer programmes. He insisted that his colleagues make their primary data freely available and was an early advocate for openness in human genetics. At the time when few human genes were mapped to chromosomes, John developed the novel idea of exclusion mapping using negative linkage which determined the chromosomal regions that could be excluded by the data.
From the beginning of his career John was interested in how to determine genetic susceptibility to common diseases such as diabetes and heart disease. His aim was to distinguish the effects of single genes of low penetrance from the combined effects of a multiplicity of genes. His ideas are encapsulated in a paper entitled ‘The simulation of mendelism’ (Acya Genet Stat Med 1960; 10: 63-70). This paper is considered one of his best. He returned to this theme on many occasions up to the last year of his life, with many critical papers on the proper use of sib-pair analysis, on haplotype mapping, and on various aspects of allelic association. He was an undoubted leader in this complex field.
John’s interest in the conservation of linkage groups between species led in the 1980s to a series of papers with Mary Lyon, Tony Searle and other mouse geneticists at Harwell, comparing the chromosomal homologies of mouse and human. He designed a graphical representation of homologies based on comparative mapping that became known as the Oxford grid. The grid revealed in simple form the large blocks of chromosomes in which groups of genes are conserved between the two species. With the help of Frank Nicholas, a database has now been created in which the genomes of many species, including farm animals, has been created. These grids are very valuable for evolutionary studies, as well as being a demonstration of the extraordinary conservation of chromosome structure within the animal kingdom.
Among clinical geneticists, John was an outstanding diagnostician and his clinical experience led to notable papers on the characterisation of X-linked hydrocephalus due to stenosis of the aqueduct of Sylvius, and on the delineation of Cornelia De Lange and Peutz-Jeghers syndromes. He ran genetic counselling clinics throughout his professional life and had an excellent rapport with his patients. They greatly admired him and appreciated the time and care he devoted to them. He was always extremely helpful to his clinical and scientific staff, and was a kind and generous supervisor of graduate students. He had a particular talent for inspiring his students and staff and it is agreed that this was one of his most important legacies of his time as professor and head of department in Birmingham and, from 1979, in Oxford.
It was always great fun to be with John. His conversation was full of amusing anecdotes and he always had an apt analogy to emphasise a particular point. I share with Sue Povey, Andrew Read, Dian Donnai and many others fond memories of extraordinary annual seminars, organised by John in the last week of January and held in the old genetics department library in the Oxford biochemistry building. A small group of colleagues were invited to contribute on a subject that John felt was ripe for discussion. Those who chose to use 35mm slides competed with inadequate blackout curtains and a temperamental projector, while others lounged on ancient sofas and decaying armchairs. But the output was some original and highly productive discussion and we always returned home refreshed with new ideas. This is just one example of John’s great ability to make us think constructively and for this, and for many of his other gifts, we will remember him with the greatest affection. He died from prostate cancer. He is survived by his wife, Felicity née Toussaint, a fellow medical student at the Middlesex, and his four children.
Malcolm Ferguson-Smith
[The Independent 17 November 2007;Brit.med.J.,2007 335 1269;The Times 17 January 2008]