HD Insights™

HD INSIGHTS: How did you first become interested in HD? SHOULSON: In 1973, I finished my residency in internal medicine and went to the NIH for a clinical research fellowship. I was part of the Public Health Service, and one of my jobs was working under Dr. Tom Chase, who ran the Experimental Therapeutics branch of the National Institute of Mental Health (NIMH), a research program involving patients with PD and HD. I had seen PD during my residency training, but I had never seen HD. In about two months I saw fifty to sixty HD patients and their families volunteering to participate in research. Shortly after, Dr. Chase was promoted to scientific director of the NIH Neurological Institute, and I, so to speak, inherited this wondrous research world for the next two years. I then returned to the University of Rochester for a formal neurology residency. By the time I joined the faculty in 1978, I had seen and cared for about 200 patients with PD and HD. So like most interesting things in life, these opportunities were just very serendipitous and fortuitous. HD INSIGHTS: You eventually became involved in the Venezuela project, correct? SHOULSON: Yes, from 1975 to 1977, I was involved in research at the NIH and met two really important people. One was Marjorie Guthrie, who was trying to get the word out about HD. I was in Washington, DC and watched her convince Congress and key thinkers in government of the importance of supporting HD research. She actually started a commission that I was part of, and that set the stage for the creation of the Total Functional Capacity scale that Dr. Stan Fahn and I developed between 1977 and 1980. While at the NIH, I also met Dr. Nancy Wexler, another important influence. Nancy had this crazy idea that perhaps we could use the "new genetics"—which at the time meant restriction fragment length polymorphisms (RFLPs)—to identify the HD gene in a large unexamined population of individuals with HD living along Venezuela's Lake Maracaibo. In 1980, Nancy and Tom went to Venezuela, and when they returned he said, "This looks like HD we see in the USA." Nancy recruited Dr. Anne Young, Dr. Jack Penney and me to the project. We were all junior faculty, Anne and Jack at the University of Michigan and I at the University of Rochester. I spent the next fourteen years traveling in February or March to Maracaibo, which was our headquarters for field research work. I sought to identify and characterize clinical phenotype and obtain biological samples, primarily blood, for DNA. HD INSIGHTS: What did it feel like when you heard from Drs. Jim Gusella, Marcy MacDonald and colleagues that they had identified a genetic marker? SHOULSON: We were surprised, because we had started in 1980, and by 1983 the linkage for the HD gene had been established and localized to the short arm of chromosome 4. Of course, establishing genetic linkage was different from identifying the gene itself. We were surprised at how quickly the linkage came, but also surprised at how long it took—ten more years—to identify and characterize the HD gene mutation. HD INSIGHTS: After identifying the gene, you started thinking about forming the HSG, correct? SHOULSON: Yes. Dr. Stan Fahn and I had experience organizing the PSG in the mid-1980s. In 1993, Dr. Jack Penney and I, supported by small grants from advocacy organizations, organized the first meeting of what was to become the HSG in Washington, DC. There were twenty of us from the US and Canada. The core leadership group also included Dr. Karl Kieburtz, who had recently completed our experimental therapeutics fellowship, and Dr. David Oakes, with whom I had worked closely in mounting the multicenter PSG "Deprenyl and tocopherol antioxidative therapy of parkinsonism" (DATATOP) trial. 1 The big decision we had to make was whether to meet again. We spent the next four or five years developing and refining the Unified Huntington's Disease Rating Scale (UHDRS) and applying it to clinical trials between 1994 and 1999. Thereafter, we took on the large-scale observational and clinical trials that helped set the standards for cooperative HD clinical research, such as "Prospective Huntington At Risk Observational Study" (PHAROS). 2 HD INSIGHTS: What was the biggest challenge in forming the HSG? SHOULSON: Well, I think the biggest challenge, besides the buy-in ("Are we going to do this?"), was actually doing something substantive. The old saying is, "The proof of the pudding is in the eating," meaning that talking about things and doing them are often quite different. We talked about a unified clinical research scale, but realized we didn't have anything like it and needed to develop such a tool. I remember that at a meeting in Boston in 1994, I got four groups together and locked each group in a room —figuratively speaking, of course—and said, "You have to come up with a scale for measuring the motor, cognitive, behavioral, and functional domains of HD." That was really the beginning. Copyright © Huntington Study Group 2014. All rights reserved. (continued on Page 18…) "'The proof of the pudding is in the eating,' meaning that talking about things and doing them are often quite different." H D I N S I G H T S HD Insights, Vol. 9 2

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