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2016 William Allan Award: Human Disease Research: Genetic Cycling and Re-Cycling1

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2016 William Allan Award: Human Disease Research: Genetic Cycling and Re-Cycling1 ASHG AWARDS AND ADDRESSES 2016 William Allan Award: Human Disease Research: Genetic Cycling and Re-cycling1 James F. Gusella2,3,* school there. I was introduced to a typical university biology department and all kinds of diversity such as axo- lotls, halophilic bacteria, electric eels, and my personal favorite (because I spent a summer working on them in Donn Kushner’s lab), blue-green algae in Ottawa River fish slime. But really what I was captured by at the University of Ottawa was the bilingual beauty and logic of molecular biology taught by Gordin Kaplan, an eminent Canadian scientist who actually originated in New York City but spent his academic career in Canada and taught in both French and English. He used to alternate lectures in the two national languages. With his encouragement, after graduating from the University of Ottawa, I moved for graduate school to the Department of Medical Biophysics at the University of Toronto, where the Ontario Cancer Institute represented a truly interdisciplinary research environment set in the context of a medical treat- ment facility, the Princess Margaret Cancer Hospital. It was really an amazing experience to be within that setting and see both the basic research that was being done and the goal for which it was being done, i.e., patients with the medical problems it was trying to solve. Thank you, David, for that very kind introduction. I do However, on the day I arrived to do my graduate work, remember that early Apple computer game. We actually David Housman, my thesis advisor, announced that he created a much better game by putting those mutations was moving to the Massachusetts Institute of Technology in. The other thing I remember is the lunchtimes we spent (MIT), and I had to make a choice. I chose to go with playing Middle Earth along with Joe Kernan at Pritchett, him, so within a year we moved to MIT. It was a really also an experience. exciting time because I was moving into the nascent, Human genetics is essentially a cooperative endeavor, controversial field of recombinant DNA, which was just and I am really humbled and proud to be here accepting getting started at that point. It was also an interesting the William Allan Award. But the work that I have done time to be a graduate student because very shortly after I over the years has always been done with collaborators, arrived, fears of Frankenstein monsters and danger warn- so I would like to sincerely thank the many collaborators, ings caused the Cambridge City Council to place a morato- trainees, and dedicated technical staff who all helped me rium on all recombinant DNA work within the city limits, to reach this point, as well as helped to forward the partic- prompting some at Harvard to move to other institutions ular disease research that we were interested in. I’d also in order to be able to do their work. In my case, as a grad- obviously like to thank those who nominated me and uate student, I didn’t have that choice. I hung on, and a lit- said such nice things, as well as the selection committee, tle while later the City Council relented a bit; they allowed which chose me for this award. mammalian DNA cloning but only under the very strict It is particularly apt that I formally receive the Allan containment conditions of a P3 facility, where you had Award here in Canada. I did start out at the University of to gown up to do the work, and you had to use highly Ottawa. Having grown up in Ottawa, I decided to go to disabled vectors that were extremely difficult even to 1This article is based on the address given by the author at the meeting of the American Society of Human Genetics (ASHG) on October 19, 2016, in Van- couver, Canada. The audio of the original address can be found at the ASHG website. 2Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; 3Center for Human Genetic Research, Massachusetts General Hospital, 185 Cambridge Street, Boston, MA 02114, USA *Correspondence: [email protected] http://dx.doi.org/10.1016/j.ajhg.2017.01.008. Ó 2017 The American Journal of Human Genetics 100, 387–394, March 2, 2017 387 propagate. But it was an experience to spend time making without any prior knowledge of the nature of the genetic packaging extracts in the cold room to generate your re- defect or the altered protein product. It was very new combinant libraries and then having to gown up, go into because at the time, if you wanted to clone a gene, you a negative-pressure room, and work in a laminar flow had to know the protein sequence. So, there was no direct hood before you were actually allowed to use them. approach to a gene such as the HD gene, because you Well, I finally did graduate, but I actually didn’t accom- didn’t know what it was, and if you made a guess, you plish any of the gene-cloning goals that I had when I were likely to be wrong. But, we reasoned that we could had begun the work at MIT. Because I had started out work- find the chromosomal location. Then, once we knew ing on erythroleukemia cells, one of the globins was the that, we would clone the gene, we would figure out the obvious gene to clone, but these were quickly done else- mechanism by which the mutation worked to cause the where. So I moved on to a couple of other genes; at one disease, and ultimately we would use that information point, I was even trying to clone the soybean globin, leghe- to deliver benefit back to the families in terms of better moglobin, but plant DNA turned out to be really hard to diagnostics, disease prevention and management, and work with. In the end, I managed to graduate by cloning a rational mechanism-based treatment. This ‘‘genetic DNA from somatic cell hybrids, a cell technology whose research cycle’’ begins and ends with human patients, potential I had learned to appreciate from the work of but it also emphasizes the interdisciplinary, cooperative Lou Siminovitch in Toronto and Bud Baker in the lab nature of human genetic research in which we are all next door at MIT on Chinese hamster ovary (CHO) cell engaged, and if you think individually about what you mutants and by collaboration with Ted Puck and his col- are working on, it helps to position individual research leagues on CHO cells fused with human cells to segregate efforts into a larger context. human chromosomes.1 We found that we could make In 1980, this unbiased genetic strategy began with genomic libraries and specifically identify the human applying anonymous DNA variations, detected as altered DNA, so if you could create a human-rodent hybrid cell restriction enzyme cleavage patterns,3 in order to track with the particular human genomic region that you pieces of chromosomes through families and perform ge- wanted in it, you could clone the DNA from that region.2 netic linkage analysis. We were fortunate to be able to con- I graduated with my PhD in 1980, but a year after I had nect with Nancy Wexler. I pointed out that the part of the left Canada in 1975, Maria Frangione, also from Ottawa, NIH grant that was supposed to supply families was cut. It and I had been married, so she had moved down to Boston turned out that Nancy was at the NIH, where she was our to complete her medical training and pediatric residency. program officer for this grant. She got on a plane and went In 1980, we were faced with a decision—a tough decision down to Venezuela, where she started to collect blood sam- that was molded by many factors that I won’t go into. ples from this very large HD family that she knew about. She decided that she would join a group medical practice She also connected me to Mike Conneally, who ran the in the Boston suburbs, and I, despite the career risk, skip- HD Roster at Indiana University. The combination pro- ped a planned postdoctoral training position at the Califor- vided many, many families from all around the world, nia Institute of Technology and moved instead across the particularly in the United States. Nancy ultimately left Charles River to Massachusetts General Hospital (MGH), the NIH and went on to Columbia University and to where Joseph Martin, then the chief of neurology, encour- running the Hereditary Disease Foundation, which Milton aged me to start a lab to apply recombinant DNA tech- Wexler, her father, had started. Mike spent his years at niques to the fascinating mystery of Huntington disease Indiana University continuing with HD. (HD). When I first started, I had salary coverage for about The linkage effort led to the mapping of the HD genetic 3 months. Fortunately, the NIH Center grant that included defect to chromosome 4.4 It was the first time that an auto- my project was funded, although the part of the grant that somal defect had been mapped with only DNA markers was supposed to supply HD families was cut, so that and no prior knowledge. I remember the day in 1983 created an issue. However, I still had a job, and I was able that I read the gels and placed the genotypes on the pedi- to undertake a new approach to this devastating inherited grees. You didn’t need to calculate a LOD score.
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