2000 ASHG PRESIDENTIAL ADDRESS on Discovery, Genomes, the Society, and Society* Ronald G

View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Am. J. Hum. Genet. 68:819–825, 2001 2000 ASHG PRESIDENTIAL ADDRESS On Discovery, Genomes, The Society, and Society* Ronald G. Worton Ottawa Hospital Research Institute, University of Ottawa, Ottawa a year that might well be called “The Year of Our Genome.” What I want to do today is to look back over the last century and touch on some of the highlights, then spend a few minutes on the biggest event of the century—the Human Genome Project. I will then look at the future of human genetics and will end with some thoughts on the role of the Society in the new millennium. These thoughts will reflect discussions held at a retreat of the ASHG Board of Directors in the spring of 2000. Looking Back In reflecting on the past, one thing struck me, and that is the enormous amount of knowledge that has been forthcoming in a time frame that is miniscule in com- Ronald G. Worton parison with the time of human existence, or even com- pared with the span of the last millennium. Indeed, the principle of inheritance did not even emerge until the start of the 20th century, and it was not until 1915 that Dedicated to the memory of Roy Schmickel the architecture of the genetic material was first de- scribed. If we date the definitive elucidation of the phys- Fellow geneticists, old friends and new, I am truly ical basis of heredity to Morgan’s 1926 Theory of the honored to be your President in this first year of the new Gene, it tells us that, for the first 925 years of the last millennium, and a year that marks the 50th annual meet- millennium, the world was ignorant of this fundamental ing of the American Society of Human Genetics. A pres- principle. idential address to the Society is a difficult task. Some The second quarter of the century was not great for of your past presidents have reflected on topics that were human genetics. Quoting Dunn in his 1961 presidential important at the time; others have reviewed a decade of address (Dunn 1962), “progress in human genetics achievement or made predictions about the coming dec- seemed to have been impeded less by a lack of means ade. Those who have served in a year that marks a So- than by a lack of clear scientific goal, and this at a time ciety anniversary have used the occasion to reflect on when the major problems of genetics were taking a clear the Society and its role. None, however, have had the form.” While studies of fruit flies were revealing the prin- daunting task of standing before the Society on the 50th ciples of gene transmission, conservation, and evolution, “most observations on human heredity were not oriented anniversary of the annual meeting, in the first year of a in any clear way toward such problems. Matters of new decade, a new century, and a new millennium, in greater moment seemed to be the inheritance of ‘insanity’ and ‘feeblemindedness’ and other vaguely defined mental Received December 18, 2000; accepted for publication December 22, 2000; electronically published March 16, 2001. ills … pursued for immediate social ends.” Address for correspondence and reprints: Dr. Ronald G. Worton, As human genetics emerged from the eugenics period, Ottawa Hospital Research Institute, University of Ottawa, 501 Smyth the role of genes in disease was poorly understood, as Road, Room 4A-102, Ottawa, ON K1H 8L6, Canada. revealed by H. J. Muller in his 1950 presidential address * Previously presented at the annual meeting of The American So- (Muller 1950). Quoting an editorial in the Journal of ciety of Human Genetics, in Philadelphia, on October 4, 2000. ᭧ 2001 by The American Society of Human Genetics. All rights reserved. the American Medical Association, he noted that “until 0002-9297/2001/6803-0002$02.00 recently the prevailing view has been that mutation as 819 820 Am. J. Hum. Genet. 68:819–825, 2001 a direct cause of disease is extremely rare and of little factor VIII gene and stunned the audience with the enor- practical significance. Since observational data are lim- mity of the effort and the sheer size of the gene—180 ited to relatively few generations and since human cross- kb. Of course, to someone who has now spent more breeding experiments may not be performed, we shall than a decade working with the 2,500-kb dystrophin never be able to demonstrate with certainty that a he- gene, 180 kb seems downright civilized. reditary human disease arises from mutation.” This was Prior to 1985, it was not possible to predict the im- 1947, not the Middle Ages. pact that new technology would have on the cloning of The third quarter of the 20th century began a true human-disease genes by positional cloning. One of the golden age of genetics. Following the discovery of DNA first was the Duchenne muscular dystrophy gene (the as the genetic material in 1948 and the description of DMD gene), cloned by isolating DNA from band p21 its structure in 1953, rapid progress ensued to determine of the X chromosome. I had the good fortune to be the genetic code and the intermediate role of RNA in intimately involved in the identification of the DMD the process of manufacturing protein. The rapid gains gene (Ray et al. 1985) and, along the way, made lasting were all achieved in simple organisms, including phage friendships with my three erstwhile competitors and and bacteria—the age of human molecular genetics still sometime collaborators: Lou Kunkel, Kay Davies, and two decades away. Ed Southern. For human genetics, the third quarter of the century While speaking about the DMD gene–cloning effort, was the time when biochemical genetics, clinical genet- I want to acknowledge three colleagues who were crit- ics, and cytogenetics began to flourish. Building on the ical to the gene cloning and to my own career devel- work of the pioneers who studied blood groups and opment. The first is Christine Verellen, a friend and clotting factors, new technologies such as chromatog- colleague from Belgium, who demonstrated that an X: raphy and gel electrophoresis launched the discipline of 21 translocation in a young Belgian girl with muscular biochemical genetics. Victor McKusick, in his 1975 dystrophy caused the disease by breaking through the presidential address, identifies 1959 as the origin of both gene and inactivating the normal X chromosome (Ver- clinical genetics and cytogenetics (McKusick 1975). The ellen-Dumoulin et al. 1984). This young girl’s DNA discovery in 1960 of an extra chromosome 21 in Down became the substrate of our gene-cloning effort. The syndrome will stand as one of the landmark discoveries second is Peter Ray, a molecular biologist who joined of all time, and it was the driving force behind the later the cloning project shortly after it started and became development of prenatal diagnosis for genetic disorders. a valuable collaborator and friend for the next 12 years. The discovery of the sex-chromosome anomalies The third is Roy Schmickel, former head of the De- XXX, XXY, and XYY presented a special problem for partment of Human Genetics here at the University of researchers who wished to determine the true phenotype Pennsylvania, who provided critical DNA probes and without biasing the family’s treatment of the affected assisted us in cloning the X:21 translocation junction. individual. The controversy over newborn screening His tragic accidental death robbed the human genetics programs to identify and study such individuals was community and the city of Philadelphia of a great sci- politically intense and became the subject of John Ham- entific leader. This address is dedicated to his memory. erton’s presidential address in 1976 (Hamerton 1976). I couldn’t leave the 1980s without saying a few words The last quarter of the century can truly be called the about cystic fibrosis (CF). In 1983, a young member of era of human molecular genetics—beginning with re- our faculty consulted me about using RFLPs to map the combinant DNA technology that had surfaced at Stan- CF gene. My advice was to forget it, as I perceived it ford in 1976 and then gone underground, both figu- as a high-risk project and a potential drag on his career. ratively and literally, for 2 years to assess the safety of Little did I know then that Lap-Chee Tsui would map recombinant molecules. Early landmarks included Y. W. the gene within 2 years and clone it 4 years later. Clon- Kan’s demonstration that a polymorphism in the b-glo- ing the CF gene by Lap-Chee’s laboratory in collabo- bin gene could be used to predict sickle cell disease in ration with the groups of Jack Riordan and Francis utero (Kan et al. 1976) and the 1980 paper by Ray Collins was a true landmark. The set of three papers in White, David Botstein, and colleagues outlining how Science (Kerem et al. 1989; Riordan et al. 1989; Rom- RFLPs could be used as genetic markers to track and mens et al. 1989), which should be on the required map disease genes in families (Botstein et al. 1980). reading list of every graduate student in human genetics, Many of the early discoveries in human molecular laid it all out, demonstrated that it was possible, and genetics were reported at meetings of the ASHG, mak- opened the floodgates for a decade of positional cloning. ing this an exciting time to be a member of the Society.

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