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2016 William Allan Award Introduction: James Gusella 1

2017; Elsevier BV; Volume: 100; Issue: 3 Linguagem: Inglês

10.1016/j.ajhg.2017.01.016

1537-6605

David L. Nelson,

Mitochondrial Function and Pathology

Good evening. The Allan Award is our society’s oldest and highest honor. It was established in 1961 in memory of William Allan (1881–1943), who was one of the first American physicians to conduct extensive research into human genetics in his practice in North Carolina. I am especially honored to introduce this year’s winner of the Allan Award, James Francis Gusella. A native Canadian, Jim was born in the capital of Ottawa, ON, in the early 1950s and grew up with two sisters in an academically focused family. He earned a bachelor’s degree in biology from the University of Ottawa in 1974 and enrolled at the University of Toronto for graduate school. Jim joined the group of David Housman, who was interested in gene regulation and the biology of leukemia viruses. The Housman lab moved to MIT in Cambridge, MA, in the mid 1970s; Jim helped move the lab, took a master’s degree from Toronto, and transferred to MIT’s PhD program in biology. It was there that I first met Jim in early 1979, when I joined the Housman group for my PhD research. Like Jim, I began with studies of Friend leukemia virus but became interested in gene-mapping methods using emerging DNA technologies and somatic cell genetics. Jim pioneered the use of repetitive sequences to isolate human DNA fragments from specific chromosomes isolated from hybrid cell lines, providing probes to search for polymorphic restriction sites to refine linkage to disease mutations.1Gusella J.F. Keys C. Varsanyi-Breiner A. Kao F.T. Jones C. Puck T.T. Housman D. Isolation and localization of DNA segments from specific human chromosomes.Proc. Natl. Acad. Sci. USA. 1980; 77: 2829-2833Crossref PubMed Scopus (162) Google Scholar It was a heady time: we shared the small fifth floor of the newly developed Center for Cancer Research with the groups of Phil Sharp, David Baltimore, Bob Weinberg, and Nancy Hopkins. Presenting at weekly floor meetings was pretty intimidating. It seemed we worked 24/7. Jim was always in the lab—and often slept there. But we played hard too. I had been charged with buying a microcomputer for the lab—an early Apple II. As good geneticists, we introduced mutations into the code for a video game we liked just to see what the result would be. During lunches at MIT’s Pritchett Lounge, we would play the new Atari football video game and bruise and bloody the heels of our hands on the large trackball used to move the small X’s and O’s that represented the players. Jim has always been a huge sports fan. Into this atmosphere of unlimited potential came Kan and Dozy’s demonstration of restriction-fragment-length-polymorphism-based diagnosis of beta-globin mutations2Kan Y.W. Dozy A.M. Polymorphism of DNA sequence adjacent to human beta-globin structural gene: relationship to sickle mutation.Proc. Natl. Acad. Sci. USA. 1978; 75: 5631-5635Crossref PubMed Scopus (547) Google Scholar and then Milton Wexler’s Hereditary Disease Foundation commitment to identify mutations causing Huntington disease (HD). David and Jim were eager to work with Nancy Wexler, who proposed collecting blood samples from members of a large Venezuelan pedigree in which the disorder segregated. Jim tested the ability to transform lymphocytes by using blood I collected from my mother and three brothers on a trip home to Virginia at Thanksgiving. I occasionally wonder whether those lines are still in the collection. Housman, Gusella, and Wexler decided to attempt to find linkage with DNA markers, a seemingly impossible task requiring endless assessments of probes and Southern blots. Other voices cautioned that any such efforts should wait for a complete genetic map to optimize the search strategy.3Botstein D. White R.L. Skolnick M. Davis R.W. Construction of a genetic linkage map in man using restriction fragment length polymorphisms.Am. J. Hum. Genet. 1980; 32: 314-331PubMed Google Scholar Jim defended his dissertation, moved to the Harvard and Massachusetts General Hospital (MHG) Department of Neurology, and got to work. One of the first people Jim hired was his technician Rudy Tanzi. Rudy, a rock band keyboardist living in Providence, RI, commuted an hour each way to Boston to test probes for linkage in HD-affected families. Rudy went on to prominence of his own in Alzheimer disease. Jim’s wager was rewarded in the first 12 probes randomly chosen from a library of human DNA. G8, located on 4p, showed preliminary linkage to the HD mutation. Confirmation came with additional families from Mike Conneally’s collection in Indiana. Their paper, which published in Nature in 1983,4Gusella J.F. Wexler N.S. Conneally P.M. Naylor S.L. Anderson M.A. Tanzi R.E. Watkins P.C. Ottina K. Wallace M.R. Sakaguchi A.Y. et al.A polymorphic DNA marker genetically linked to Huntington’s Disease.Nature. 1983; 306: 234-238Crossref PubMed Scopus (1654) Google Scholar electrified the human genetics community by making clear that DNA markers would allow disease locus mapping in families that had resisted linkage with blood-group and other markers. Jim and the Hereditary Disease Foundation assembled a remarkable group, including Marcy MacDonald, who has collaborated with Jim for more than 30 years, to pursue the HD mutation as a consortium. It took nearly 10 years to find the expanded CAG repeat mutation in the gene now termed HTT5The Huntington’s Disease Collaborative Research GroupA novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes.Cell. 1993; 72: 971-983Abstract Full Text PDF PubMed Scopus (7046) Google Scholar (which was remarkably close to the original G8 probe), but an impressive array of methods was developed to facilitate the pursuit, and many of these proved important for the early stages of the human genome initiative. Efforts by many groups over the intervening 23 years have focused on therapeutics for HD, and impressive results are beginning to be realized in a variety of areas. Jim and Marcy have tenaciously focused on defining genetic modifiers in HD with an eye toward understanding why age of onset varies—delaying the onset of a late-onset disorder could provide an effective treatment. Their recent work with the extensive Venezuelan pedigrees has provided exciting potential targets.6Genetic Modifiers of Huntington’s Disease (GeM-HD) ConsortiumIdentification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease.Cell. 2015; 162: 516-526Abstract Full Text Full Text PDF PubMed Scopus (372) Google Scholar During those 10 long years pursuing the HD mutation, Jim and colleagues applied developing mapping methods elsewhere in the genome. He and Rudy focused on chromosome 21, and in 1987 they reported in Science the location of the amyloid precursor protein in a region linked to familial Alzheimer disease.7Tanzi R.E. Gusella J.F. Watkins P.C. Bruns G.A. St. George-Hyslop P. Van Keuren M.L. Patterson D. Pagan S. Kurnit D.M. Neve R.L. Amyloid beta protein gene: cDNA cloning, mRNA distribution, and genetic linkage near the Alzheimer locus.Science. 1987; 235: 880-884Crossref PubMed Scopus (1220) Google Scholar In addition, Jim either led or contributed to Mendelian gene mapping and/or discovery in neurofibromatosis types 1 and 2, amyotrophic lateral sclerosis, dystonia, Batten disease, paramyotonia congenita, von Hippel-Lindau disease, Wilson disease, familial dysautonomia, biotin-responsive basal ganglia disease, and many others. As the founding director of the Center for Human Genetic Research at MGH, Jim formalized the “genetic research cycle,” which begins and ends with the individual patient by progressing from phenotypic description to gene discovery, biological characterization, improved diagnosis, therapeutic development, and back to the individual patient. Jim remains very active; he co-founded the Developmental Genome Anatomy Project and led initial efforts to introduce whole-genome sequencing technologies for rapidly delineating classes of chromosomal aberrations that for decades had been defined by low-resolution cytogenetic techniques. He also participated in some of the most influential studies in neurodevelopmental genomics, including the initial definition of genomic segments associated with autism and other developmental abnormalities, such as 16p11.2 and 2q23.1, as well as individual gene discoveries, such as NRXN1. Sue Slaugenhaupt and Mike Talkowski wrote in their nomination letter, “Jim Gusella has transformed the field of human genetic research and has been at the forefront of many of its greatest achievements over the last 35 years.” Jim has done this with characteristic humility and grace. As long as I have had the great pleasure of knowing him, Jim’s focus has been on solving puzzles in order to help those afflicted with genetic disease. He is generous with his ideas and knowledge, and the success of his trainees is perhaps the greatest testament to his influence on the field. Jim has remained at MGH and Harvard since 1980. He and his wife, Maria Frangione, a pediatrician, raised three boys in Framingham, MA. It’s especially significant that Jim’s Allan Award is bestowed in Canada. As Marcy MacDonald commented, “Jim is the quintessential Canadian.” Among his other honors, Jim is a fellow of the American Association for the Advancement of Science and winner of the King Faisal International Prize in Medicine. He is the Bullard Professor of Neurogenetics in the Department of Genetics at Harvard Medical School and the Center for Human Genetic Research at MGH. He is also an associate member of the Broad Institute of MIT and Harvard and principal faculty member of the Harvard Stem Cell Institute. He has been a member of our society since 1984. Please join me in welcoming the 2016 recipient of the Allan Award, James F. Gusella.