A Tribute to Patricia Jacobs.

Presented to Patricia A. Jacobs, D.Sc., at the annual meeting
of the American Society of Human Genetics
Dallas, October 28-31, 1981.
Introduction by

The presentation of the William Allan Memorial Award is a special occasion each year for this Society. The award has been presented to distinguished human geneticists both from North America and overseas since 1962 and is accepted as one of the premier awards for the recognition of exceptional achievement in the field of human genetics. This year, our Society, for only the third time, has a woman president; moreover, it is unique this year that both the president and president-elect are women and also that, for the first time in its history, the Allan Awardee is a woman, a scientist of great distinction who has made exceptional contributions to her chosen field of study, human cytogenetics-Dr. Patricia Jacobs.

Pat, as she is known to many of us, was born in October 1934, in London, England, where her father worked for the I.C.I. Nobel Explosives division. On September 1, 1939, the whole division was transferred to the west coast of Scotland, and, of course, Pat, aged 5, followed. She received a Scottish public school education and after matriculating went to St. Andrew’s University to study botany.

She quickly transferred to zoology and came under the influence of a man who was then one of the youngest professors of zoology in the United Kingdom and who still holds the same chair, Prof. H. G. Callan, or “Mick” Callan, as he is more generally known. Callan, of course, is a cytogeneticist of lampbrush chromosome fame, and his “master” and “slave” hypothesis of gene regulation is well known

In 1956, Pat obtained her bachelor’s degree with first-class honours in zoology, her undergraduate thesis being on the meiotic process in Mantis religiosa, which was subsequently published in the Journal of Genetics with Callan. Pat’s early upbringing on the coast of Scotland gave her a love for the sea, the coast, and the islands, and this she maintains to this day, having her major residences on two islands on opposite sides of the world: Hawaii, an island of sunshine, flowers, sandy beaches, and hula dancers in the Pacific, where she spends 9-10 months each year, and Barra, an island off the west coast of Scotland, where she spends as much of each summer as possible. Her connections with Barra go back many years, as she spent many holidays there as a child.

The Isle of Barra is at the southernmost tip of that group of islands, The Hebrides, which protect the west coast of Scotland from the ferocity of the storms in the North Atlantic. In 1966, a team of scientists, led by Pat, from Edinburgh’s Western General Hospital MRC Clinical and Population Cytogenetics Unit descended on the island to carry out a chromosome study on all members of the population over the age of 65. Barra, like many other remote places, has a record of longevity among its population, as well as of keeping extensive genealogical records. Thus it was an ideal population in which to study the effects of ageing on the chromosomes and be able to follow up on interesting findings in descendant generations. Finally, in 1976, while on holiday in Barra, she found the property that she had been looking for for many years and purchased a home on the island.

On her return to England in 1957, she joined the staff at the Medical Research Council Clinical Effects of Radiation Research Unit as a scientist under the direction of Dr Michael Court Brown. It was around that time that I first met Pat when she was spending some time in the laboratory of Dr Charles Ford at Harwell and I was visiting that lab, which I had recently left. From that point on, Pat’s career never looked back, and by 1966 she was made a permanent member of the Medical Research Council’s scientific staff,
and although now in Hawaii, she still holds an honorary appointment with the British Medical Research Council. In 1966, she was granted the Degree of Doctor of Science from St. Andrew’s University for her work on human cytogenetics. The year 1970-71 was, in some ways, a turning point in her career. That year she spent a sabbatical with Dan Lindsley at the University of California at San Diego working on aneuploidy in Drosophila and getting back to first principles with an experimental organism which could be manipulated to answer questions in ways not possible with man.

Pat has been constantly productive in the 26 years since she began publishing, having produced a total of 116 papers in that time. I will now try to summarize what I feel to be her major contributions to our field. In 1958, she published with Ford and Lajtha one of the earliest descriptions of the human karyotype, which, together with those of other workers who had published by 1960, provided the data on which the Denver System of Nomenclature was based. 1959 marked a vintage year for early human cytogenetics, and a paper by Jacobs and Strong described the first example of the 47, XXY karyotype in Klinefelter syndrome and provided the first evidence for the possible role of the human Y in male sex determination. In the same year, Jacobs and her co-authors provided the first evidence of the 47, XXX female, which, following the Drosophila terminology, they
termed the “super-female.” Those were exciting days, in which the feelings of excitement were similar to those one can detect among molecular biologists today. In one year, the chromosomes of Down syndrome, Klinefelter syndrome, the triple X female, Turner syndrome, the first human chromosome mosaic, and the first double aneuploid (XXY/+21) were described, essentially by three groups: the Edinburgh group of which Jacobs was part; Charles Ford at Harwell, working with a group of clinicians from Guy’s Hospital and the Galton Laboratory; and the French group under Lejeune.

There is no doubt that priority for the discovery of the extra chromosome in Down syndrome must go to Lejeune, with rapid and independent confirmation coming from Jacobs and her co-authors, and the Harwell/Galton group, in that order. Priority for the XXY and XXX female goes to Jacobs and her coworkers, while priority for the first mosaic [8] and the first double aneuploid goes to the Guy’s Hospital/Galton/Harwell group [8], as does priority for the first XO female to be reported in man.

In addition to these chromosome abnormalities, Jacobs and her coworkers also examined the chromosomes in a case of testicular feminization and showed these to be XY, a first example of supposed sex reversal in man, now known to be due to a receptor defect.

In 1960, Jacobs was part of a group that reported the first fertile XO female; perhaps 10 are now known in the world. In many ways, these were halcyon years for human cytogeneticists. Skilled cytogenetics labs were few, accreditation exams had not been heard of, and it was a case of “Have Microscope, Will Examine Chromosomes,” and perceptive clinicians were only too ready to respond.

When discussing Jacobs’ career, one must say something, I believe, about the environment in which she was working at the time. This was the Medical Research Council Clinical Effects of Radiation Research Unit (now the MRC Clinical and Population Cytogenetics Research Unit), which was then under the direction of the late Dr Michael Court Brown, a gifted and farsighted clinician and epidemiologist. Court-Brown recognized very early that to make progress in this field one needed a team in which all the elements required for the study of chromosome disease at the population level were present and working together. In his view, such a team consisted of cytogeneticists, clinicians, and epidemiologists; and this he set about to develop. Thus from an early stage, the Edinburgh group was self-sufficient and not dependent on random referrals from friendly clinicians, but had a clinical arm that could seek out and evaluate the patients it needed.

During the early and middle sixties, a continued stream of high-class papers emanated from Edinburgh, many with Jacobs as senior author. An interesting observation was made by Jacobs, Court-Brown, and Doll, in a subsequent paper in 1963, which was that there is an increase in the frequency of aneuploid cells with age in lymphocyte cultures and that this occurrence is especially evident in females of 55 years and over and relates to an increase in the frequency of 45, X and to a lesser extent to 47, XXX, with age; while in males, there is less conclusive evidence that the Y is preferentially subject to loss or gain.

In a series of papers beginning in 1965, Jacobs and her colleagues examined the chromosomes of almost all of the male patients in the Scottish Maximum Security Hospital at Carstairs and found nine out of 315 patients to have a 47, XYY chromosome complement. This was the first description of a group of 47, XYY males. They concluded their first paper [14] with the statement that all these males were exceptionally tall, but that “at present, it is not clear whether the unusual frequency of XYY males found in this Institution is related to their aggressive behaviour or their mental deficiency or to a combination of these factors.” These initial studies have, of course, been followed up by extensive studies on 47, XYY males ascertained in various ways. Jacobs’ early observations of an increased frequency of XYY males in certain special security settings have been confirmed, but it has also been shown that many XYYs apparently develop
normally without special problems.

Some of Jacobs’ most interesting work has been done since she went to Hawaii, where she is a professor of anatomy and reproductive biology at the University of Hawaii Medical School. Her laboratory has produced a steady stream of papers on structural heterozygosity in man, chromosome mutation rates and the effect of chromosome abnormalities on reproductive fitness. In addition, a classic series of papers on the chromosomes in spontaneous abortions have provided data on the frequencies of the different chromosome abnormalities, their origin, and aetiology. In particular, Jacobs and her colleagues have provided evidence on the origin of triploids in man, and have shown that trisomics are usually maternal in origin, usually resulting from nondisjunction at meiosis I; that irrespective of the chromosomes involved, there is a high level of recurrence risk for trisomies; and, most interestingly, that hydatidiform moles, which are usually 46 XX result from the fertilization of an empty egg by a haploid sperm, which then duplicates without cytokinesis to restore the diploid number.

Credit must also go to Jacobs’ laboratory for the first method for the direct chromosome analysis of human spermatozoa by allowing them to fertilize hamster eggs and then analyse the chromosomes of the male pronucleus. In 1981, Jacobs reported on the fifth female with Duchenne muscular dystrophy to have an X/autosome translocation with breakpoints at Xp21  and argued convincingly that Xp21 is the site for the locus for Duchenne muscular dystrophy.

In this brief review, I have touched upon but a few of the firsts of Jacobs’ career. Above all, Jacobs enjoys her laboratory and time spent at the bench. In these days of photographic cytogenetics, where much analysis is done, not from the microscope but from the photographic print, Jacobs is old-fashioned. She believes in the direct analysis down the microscope in a good, old-fashioned way.

She has been one of the pioneers concerned from the very beginning with the nomenclature of human chromosomes. In 1960, she was a participant in the Denver conference; in 1963, in the London conference; in 1965, in Chicago; and in 1971, in Paris. In 1975, she became a member of the International Standing Committee on Human Cytogenetic Nomenclature and has been a signatory on each of the successive reports on this subject. As a former chairman of several of these meetings, no one was more aware than I of how much Pat’s participation and common sense contributed to the final consensus and agreement.

In 1972, she married Newton Morton, himself an Allan Award winner in 1963, whom she had met at the 1969 Birth Defects Conference at the Hague. Since then, they have published together and have brought to their science two totally different, but highly complementary approaches to the answering the many questions left in the area of human population cytogenetics.

Clearly, Jacobs has been an extraordinarily successful research worker. It is an honour for our Society to honour you, the 1981 Allan Awardee, and it gives me great personal pleasure to introduce to our Society Dr Patricia Jacobs, the 1981 Allan Award winner.

Originally posted in 1982 by the American Society of Human Genetics.

Where it all began, Patricia’s discovery of 47 XXY

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