JEROME LEJEUNE, a pivotal figure in medical genetics, is best remembered for his discovery 35 years ago of the chromosome abnormality which causes Down's syndrome.
His seminal paper, published in 1959, together with his French colleagues Marthe Gauthier and Raymond Turpin, was the first clear documentation of a chromosome abnormality in humans. This publication marked the introduction of clinical cytogenetics as an independent discipline, providing for the first time a definitive differential diagnosis, and rapidly becoming a most important clinical diagnostic tool in medical genetics.
In 1952, after completion of his medical education, Lejeune had become associated with Raymond Turpin, the Professor of Paediatrics at the National Centre for Scientific Research in Paris. He initially analysed the dermatoglyphics - ie the palm and finger prints (not to be confused with the modern type of DNA finger-printing) in children with Down's syndrome - and also researched the genetic effects of irradiation in humans (still a controversial subject).
It was, however, the study of the inheritance patterns of Down's syndrome in twins that led Lejeune to become involved in chromosome research. He was puzzled by the high concordance in identical twins in comparison to the extremely low concordance in non-identical twins. This did not fit in with expectations that the condition was caused by a single gene defect. He therefore postulated that the underlying cause may have been an abnormality affecting a number of genes on a chromosome, perhaps an abnormality in the number of chromosomes.
As a young medical doctor Lejeune's main research interest focused on mental deficiency, and early on he recognised the potential of chromosome investigations for the diagnosis of conditions associated with developmental delay. At the time he was working on his own, with relatively little support from his colleagues, and without much technological help.
By 1955 he was convinced that there must be an abnormality in chromosome number in sufferers from Down's syndrome, but at that stage he was not clear whether there was an extra, or a missing chromosome. One of the problems was the absence of a reliable standard for comparison, since there was then some uncertainty as to the normal chromosome number of man, although it had become generally accepted that there would be 24 pairs, a total of 48 chromosomes.
It is only when there are cellular divisions that the DNA is compact enough to be seen by ordinary microscopy. Lejeune developed his own technology for cell growth. He used cells from small skin biopsies from the patients, which he put together with extracts from chicken embryos. In the absence of an incubator, he strapped the test tube containing the cells plus the chicken extract to his own body. A few weeks later, there was enough cell growth for him to produce chromosome preparations.
Using slightly different technology, two research workers in Sweden, Joe Hin Tijo and Albert Levan, had in 1956 identified the correct chromosome number for humans as being 46, but it still took some time before Lejeune was able to clearly demonstrate that the children with Down's syndrome had an extra chromosome. Lejeune not only discovered the first numerical chromosome abnormality in man, but also the first chromosome deletion, which is the one seen in children who are developmentally delayed and have a peculiar cry, commonly described as 'cri du chat' ('cat cry'). Lejeune found that this was due to the deletion of a very small part of one of the longest chromosomes, and the syndrome is now called the Cri du Chat
Lejeune became the Professor of Fundamental Genetics in the Faculty of Medicine in Paris in 1964. He maintained his interest in chromosome research, but insisted on publishing his scientific papers in French. It was only relatively late in life that he learnt English, by aid of a linguaphone course. Much of his later life was dominated by his strong religious beliefs and devotion to Catholicism.
Lejeune was convinced that it would be possible to find an effective treatment for chromosome abnormalities, and wrote intricate papers to substantiate this view, in particular with respect to Down's syndrome. At the same time he crusaded against the prenatal Down's screening programmes, which had become commonplace since the early 1970s. The screening allows identification of foetal Down's syndrome with a view to offering termination of an affected foetus; for Lejeune this was a most unwelcome and contradictory outcome of his early and pioneering research.
WhenLejeune received the Allan Memorial Award in October 1969, he addressed the American Society of Human Genetics at San Francisco with a presentation entitled 'On the Nature of Men' with the motto 'To kill or not to kill, is the question (unknown)'. It was published in the American Journal of Human Genetics (1970), providing a rare opportunity for a non-French- speaking audience to become acquainted with Lejeune's work. He suggests that the genetic make-up of humans and the human chromosome picture must have 'appeared first in an extremely small group, even as small as one couple', implying that 'the old idea that human beings are brothers is not an ethical hypothesis or a purely moral goal but simply a correct expression of plain reality'. He further notes that 'the recognition of such brotherhood is very comforting but increases our concern as human geneticists for the destination of those unfortunate children who do not share equitably our chromosomal inheritance'.
In an interim section he proposes the establishment of a jurisdiction, a body of counsellors, a new Facility for Research and Applied Eugenics. He then outlines in three articles the statutes for such a new body, which must have startled the audience of mainstream geneticists, enthused and excited by the new provision for prenatal diagnosis now available.
There can be not doubt that Lejeune was a man of outstanding integrity, a highly disciplined and methodological scholar, as such much respected by his colleagues and the general public alike. He presented his views in a characteristically soft-spoken way, constantly expressing his deep and genuine concern for the disabled with Down's syndrome as one of the most common and outstanding examples.
There is a very long way to go before the vision and conviction of his work may be realised concerning the potential of medical treatment for these conditions, typically involving defects of hundreds if not thousands of genes. Nevertheless, the spirit of this man should continue to provide a stimulus for research into cytogenetics in general and gene therapy in particular.