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2023 ASHG Lifetime Achievement Award: “If you want to go fast, go alone; if you want to go far, go together”

2024; Elsevier BV; Volume: 111; Issue: 3 Linguagem: Inglês

10.1016/j.ajhg.2024.02.004

1537-6605

Neil Risch,

Genomics and Rare Diseases

This article is based on the address given by the author at the 2023 meeting of The American Society of Human Genetics (ASHG). A video of the original address can be found at the ASHG website. This article is based on the address given by the author at the 2023 meeting of The American Society of Human Genetics (ASHG). A video of the original address can be found at the ASHG website. I'd like to start off by thanking especially Ophir Klein for his remarkable comments about me. I'm incredibly honored and feel very privileged to have received this award. And I'm not just grateful to Ophir, but also to the others who contributed to my nomination: Sarah Tishkoff, Nadav Ahituv, and Charles Rotimi and especially to the awards committee, who felt that I was deserving of this award. I am grateful to the Society for being my academic home for nearly 5 decades, accepting me, allowing me to serve in a leadership position, and honoring me more than once. I am also proud and grateful to the Society for its embrace of diversity in all of its dimensions and making it the highest priority for our future. This award originally was known as the William Allan Award, but the names of all the awards got changed this year to reflect exactly what they're provided for. This one is now called the Lifetime Achievement Award. I'm well aware that the first person to receive this award was Newton Morton in 1962 when he was just 32 years old. I started to wonder, what constitutes a lifetime of achievement? And how long does that take? So I took a look at all the recipients of this award over 60 years, from 1962 to 2023, to see if actually the age of the recipients had changed over that time (Figure 1). It turns out that it has. Back in the 1960s, the average age was in the upper 40s, but now the average age is 70. So the average age of a lifetime of achievement seems to have increased by 20 years over that period of time. I compared the age trend to life expectancy in the United States over the same period of time (Figure 1A, bottom line); the age increase appears to be even more than for the life expectancy in the United States (Figure 1A, top line). I also examined the ages of the Leadership Award recipients, previously known as the Victor McKusick Award. That one has a trend toward lower age. At the beginning there was an average age close to 80, but now the average age is down to 70, the same as for the Lifetime Achievement Award (Figure 1B). I also wondered if the Curt Stern Award, now the Scientific Achievement Award, initiated in 2001, showed an age trend. It does not (Figure 1C). I then realized when I had to put this talk together, knowing that this is the 75th anniversary of the American Society of Human Genetics, which is a landmark of course, that my lifetime of achievement is 50 years. This year marks the 50th anniversary of my entry into human genetics and genetic epidemiology. I also thought, in terms of a theme for this talk, what I really wanted to focus on. Many of you may know this famous proverb; it's believed to have originated in Africa: "If you want to go fast, go alone. If you want to go far, go together." In college I was a math major at Caltech. I then went for a year of graduate school in math at the University of Illinois when I realized that I didn't really want to do that anymore. In the summer of 1973, at home in Los Angeles, recognizing my crisis, my dad sent me to a guidance counselor friend of his. After some interest tests, the counselor suggested I consider the biomathematics department at UCLA. In August of that summer, I went for a visit. They had just initiated a new PhD program in biomathematics that was started by Carol Newton. Carol was an amazing woman. Carol had an MD from the University of Chicago and a PhD in physics from Stanford, one of the very few women at that time, as you can imagine, with that kind of a background. Carol really believed strongly in the important role of mathematical modeling in biology and medicine. When I went to visit, I had a remarkable conversation with her. She knew I was a diehard mathematician, so she told me about Ken Lange. Ken was not around at that time; Ken was actually in Hawaii, visiting Newton Morton, but really working with Robert Elston, who was also there at the time. I saw that Ken had been a PhD mathematician from MIT yet had done this transition to biomathematics. So for me, that made the transition okay. So I applied to the graduate program, and a week later I was accepted, and a week after that I started as the first graduate student. But what was truly transformational for me was what happened in the second quarter of my first year in the program, when I took my first class in genetics taught by Anne Spence and John Merriam. Anne was an absolutely inspirational teacher. Her lectures on human genetics were incredibly clear and enthralling to me. After two or three weeks in that class, I felt that I could predict the next lectures. I knew I'd found a home because I had discovered a subject I really loved. And as it turned out, both Ken and Anne were my graduate advisors for the years I was in that program. I also have to acknowledge my colleagues and friends. After I started, Mike Boehnke and Dan Weeks joined the program, also students of Ken and Anne's, so I wasn't alone, and we had other students as well. It was wonderful having friends in the department at the same time, and we've stayed friends over the years. My first job after graduation in 1979 was at Columbia University in the department of biostatistics, but also at the New York State Psychiatric Institute (which was my primary appointment). This was my introduction to psychiatric genetics, collaborating with colleagues there on various family studies and linkage studies, whatever was possible during that time, primarily of schizophrenia and bipolar disorder. But I also had the great fortune of meeting another individual, Ruth Ottman, who had recently been recruited as a junior faculty member to Columbia in the Sergievsky Center. Her focus was the genetic epidemiology of epilepsy. She constructed a family study of epilepsy, which went on for many years. I had the great privilege of working with her on so many studies: family-based studies, but also linkage studies, eventually to the point where she located a gene for an important autosomal-dominant form of epilepsy.1Poduri A. Wang Y. Gordon D. Barral-Rodriguez S. Barker-Cummings C. Ulgen A. Chitsazzadeh V. Hill R.S. Risch N. Hauser W.A. et al.Novel susceptibility locus at chromosome 6q16.3-22.31 in a family with GEFS+.Neurology. 2009; 73: 1264-1272Crossref PubMed Scopus (17) Google Scholar Now, things were not perfectly rosy while I was at New York State Psychiatric Institute because over time my funding there dried up. This then led to a "turning lemons into lemonade" story, something that had tremendous impact on my career. I was told that if I wanted to hang around, I needed to apply for a career development award, for which I had no experience. I had to have a mentor for that award, and at Columbia, at that point, there really were very few geneticists, and certainly no one doing the kind of genetics I was. But someone recommended to me that I meet with Zena Stein, an epidemiologist there. That was prophetic. Zena was a very prominent epidemiologist who sadly passed away this year at the age of 99. I met with Zena. I came to her office and we had a wonderful conversation. When I was at UCLA, I basically earned the equivalent of a PhD in biology and biostatistics in addition to biomathematics. I even had a year of medical school classes. I had done everything except one thing: I'd never studied epidemiology. After talking to Zena, she told me that if I wanted to be a genetic epidemiologist, maybe I should know some epidemiology. Made perfect sense. So that was the basis of my career development award. And fortunately, the reviewers agreed that I needed to learn some epidemiology, and that's exactly what I did. Fortunately, it was funded, and for the next two years I was at Columbia, I was able to train with Zena and especially her husband, Mervin Susser, another very prominent epidemiologist, and some of the other epidemiologists at Columbia. I was incredibly fortunate to have landed at Columbia University where they had this great group from whom I could learn epidemiology. To this day, I'm indebted to all of them for my perspective about human genetics, epidemiology, and genetic epidemiology. I got to appreciate and love epidemiology because I saw it as a sister field to population genetics, which is the other field that I gravitated toward when I was in graduate school at UCLA. Things were still not great at Columbia even though I had the career development award and I needed to start looking around for other jobs. I was sent a letter asking me if I would be interested in a position at Yale. I was living in New York and Yale was in New Haven, not so far away. But the job was in child psychiatry; they asked if I was interested in applying, and I said yes. So I came up to interview, which I thought went pretty well, and then I came up for a second interview. I then began to realize that perhaps that position wasn't the best fit for me. Leon Rosenberg was the chair of the Yale human genetics department at the time. After my second visit, we had a conversation. He said to me, "Neil, are you sure you want this job, in child psychiatry?" And I said, "Well, I'm not sure, but maybe yes." At that point, I had to be open-minded about the position. He then said to me, "Well look, if you could have any job here you wanted, what would it be?" And I said, "Well, what I would really like is a joint appointment in biostatistics in the epidemiology department and in human genetics." And he said, "Which do you want to be your primary appointment?" And I said, "Biostatistics." And he said, "Why?" And I said, "Because I'm not a lab person. Everybody in your department is a wet lab person; I don't do that. And I think I'm more likely to have students in biostatistics and epidemiology than in genetics." So he said, "Are you sure?" And I said, "Yes." And then he said, "Okay, done." And he did; he made it happen. He went to the chair of the epidemiology department and created a joint appointment for me in biostatistics and human genetics. And that's exactly how I ended up at Yale. I'm forever in his debt for making that happen for me. And from that point on, he became a lifelong friend and mentor to me until his recent passing. When I got to Yale, I had the opportunity to work with some wonderful people. Hongyu Zhao and Herping Zhang were in biostatistics while I was there, and I had many collaborations with both of them. In the human genetics department was Uta Francke. Uta was my go-to person for human and clinical genetics; just a brilliant woman. But the person I had the most kinship with going to Yale in the first place was Ken Kidd. Ken was a human population geneticist, and I was really looking forward to this opportunity of working with him. We did wonderful studies of linkage disequilibrium (LD) in the global samples he had collected, and we also shared some wonderful students. The other thing that was transformational for me at Yale was meeting Kathleen Merikangas. Kathleen had just come to Yale, also as a junior faculty member; she also had a career development award in psychiatric epidemiology but with a strong interest in genetics. This was back in 1984, so for about the past 40 years we've been collaborators and friends, a lifelong, wonderful relationship. I always have to talk about my students. I was actually right about my prediction to Lee Rosenberg: most of my students did come from epidemiology and biostatistics. Joellen Schildkraut and Elizabeth Claus were my first students, working on genetic epidemiology of cancer, Joellen on ovarian and Elizabeth on breast cancer, although Elizabeth was really a biostatistician. Joellen is now at the University of Virginia and Elizabeth at Yale and at Harvard, now a neurosurgeon as well as a biostatistician and genetic epidemiologist. Steve Gruber studied endometrial cancer and is now a world expert on colon cancer genetics at City of Hope. Jonine Bernstein also studied breast cancer and now is at Mt. Sinai in New York. Marjorie Marenberg, who went on to medical school, did a wonderful genetics paper on cardiovascular mortality in the Swedish twin registry. Laura Mitchell was interested in the genetics of birth defects. But I did also have two students from the genetics department, Laura Almasy and Sarah Tishkoff, both now at the University of Pennsylvania. Laura worked with me on genetic studies of dystonia, and Sarah was a graduate student with Ken Kidd; we worked together on LD studies in Ken's global samples. Both, of course, are now well known in ASHG. In fact, Sarah is now the president-elect! I have to also mention two additional individuals, Bernie Devlin and Kathryn Roeder. Bernie contacted me while I was at Yale and asked if he could do a postdoc with me. Bernie had a background, as I recall, not in human genetics, I believe it was more in plants, but he was clearly quantitative. I thought this would be a good opportunity for me to work with him, so I said yes, of course, so he came to Yale. What I didn't realize at the time was that it was a two-fer, because Bernie was married to Kathryn, whom I didn't know. She was starting at Yale as an assistant professor in the statistics department. So, as I said, it was a two-fer because I was supporting Bernie, but I was getting Kathryn for free! This turned out to be a wonderful relationship over the years I was at Yale. One of the most significant things we did was focus on DNA forensics. I was contacted by Lifecodes Inc., and ultimately the FBI, because the statistics they were calculating for DNA matches were being challenged in court. The statistics were considered unreliable because there was a "massive" deviation from Hardy-Weinberg expectations (homozygote excess) of the variable number tandem repeat (VNTR) loci that were being used. Lifecodes and the FBI asked for advice. So, Bernie and I decided, and ultimately also Kathryn, to take a look at their data. It turned out that we ended up with some Science papers as a consequence. What had been attributed to severe population structure and a huge excess of homozygosity wasn't really that at all. It turned out the VNTR loci that were being used were based on sizing of allelic bands on gels based on the number of variable repeats. If the sizes of bands (number of repeats) were close, the bands would end up near each other, and it was difficult or impossible to distinguish those heterozygotes from homozygotes. We showed that there was no homozygosity excess due to population stratification; it was just an artifact due to heterozygotes that had closely sized bands.2Devlin B. Risch N. Roeder K. No excess of homozygosity at loci used for DNA fingerprinting.Science. 1990; 249: 1416-1420Crossref PubMed Google Scholar But there continued to be subsequent challenges to the validity of the statistics. At this point we did another analysis. Analyzing the VNTR forensic databases, we calculated the probability of two random individuals from the database matching at N VNTR loci. Because of the highly polymorphic nature of the VNTR loci, it turned out that the probability of two unrelated individuals matching at three loci was already vanishingly small, and even smaller for more than three loci.3Risch N.J. Devlin B. On the probability of matching DNA Fingerprints.Science. 1992; 255: 717-720Crossref PubMed Google Scholar This was a great opportunity for me to collaborate with Bernie and with Kathryn, both of whom have gotten a great deal of recognition for their work since. I also had a wonderful opportunity to do some teaching of genetic epidemiology at the Banbury Center, Cold Spring Harbor. It was not inconvenient because I was at Yale, and I just needed to cross Long Island Sound to get there. Kathleen Merikangas joined me in organizing and teaching these summer courses over several years. We also had numerous guest lecturers who would come and participate. It was a great opportunity to train so many people in genetic epidemiology over those years; it's hard to remember them all, but two that I recall that have gone on to illustrious careers are David Allison, now Dean of the School of Public Health at Indiana University, and Sir Rory Collins, the PI and architect of the UK Biobank. When I was at Columbia in New York, I also had other genetics colleagues and friends at other institutions in New York. One was Cathy Falk, who was at the NY Blood Center. Cathy had been working with some neurologists at Columbia studying torsion dystonia. By this point I was now at Yale when Cathy introduced me to this group, who were at Neurological Institute at Columbia. I learned about the movement disorder idiopathic torsion dystonia (ITD), its elevated frequency in Ashkenazi Jews, its familial nature but uncertain inheritance. Cathy introduced me to Susan Bressman, who was a junior faculty member then leading the project. Susan had been collecting multiplex families systematically for a family study and also linkage analysis, which was done in collaboration with Xandra Breakefield at Harvard/Mass General Hospital in Boston, and Xandra's postdoc at the time, Laurie Ozelius. Of course, I was excited to join this project because it piqued my interest not just in linkage and positional cloning of the suspected gene but also segregation analysis to determine mode of inheritance and the population genetics associated with Ashkenazi ethnicity. We ended up doing a lot of studies together. First, we gave a clear demonstration that ITD was not recessive like all other Ashkenazi diseases, which it had been assumed to be, but actually was dominant, albeit with low penetrance, around 30%. Eventually, Laurie and Xandra found linkage on chromosome 9 and ultimately positionally cloned the gene (DYT1). This was also the beginning of lifelong friendships with these colleagues. In doing the positional cloning, we also observed that there was a founder mutation in the Ashkenazi population, and strong LD at the microsatellite markers used to map the gene that spanned many centimorgans. As a consequence, we realized that the mutation had to be of recent origin. So, we then attempted to date the age of origin of this founder mutation and the effective population size at the time, and came to the conclusion that it probably wasn't that old (maybe 14 generations) and went out on a limb, suggesting that the Ashkenazi population probably descends from a fairly small founder population of a few thousand individuals.4Risch N. de Leon D. Ozelius L. Kramer P. Almasy L. Singer B. Fahn S. Breakefield X. Bressman S. Genetic analysis of idiopathic torsion dystonia in Ashkenazi Jews: evidence for the recent descent of Ashkenazim from a small founder population.Nat. Genet. 1995; 9: 152-159Crossref PubMed Scopus (372) Google Scholar It turned out this was a Lithuanian Ashkenazi mutation, and subsequent work confirmed at least three bottlenecks in this population over the centuries.5Risch N. Tang H. Katzenstein H. Ekstein J. Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection.Am. J. Hum. Genet. 2003; 72: 812-822Abstract Full Text Full Text PDF PubMed Scopus (109) Google Scholar When our dystonia paper was published in Nature Genetics, the journal decided to commission an editorial about it, and who better to ask for an editorial than Arno Motulsky, who, of course, was a very prominent geneticist at the time and certainly interested in Ashkenazi genetics. While he had positive comments on our analysis, he also commented that "This leads to the startling conclusion that the effective population size of the founders of the current Ashkenazim may have been as low as a few thousand individuals."6Motulsky A.G. Jewish diseases and origins.Nat. Genet. 1995; 9 (199–101)Crossref PubMed Scopus (112) Google Scholar But, as he went on to say, "The power of the methodology and the somewhat sketchy historical data are clearly being stretched to the limit." The irony of this turns out to be that our estimate may have been a significant overestimate of the effective number of founders, as more recent studies suggest maybe a few hundred, not a few thousand, founders.7Carmi S. Hui K.Y. Kochav E. Liu X. Xue J. Grady F. Guha S. Upadhyay K. Ben-Avraham D. Mukherjee S. et al.Sequencing an Ashkenazi reference panel supports population-targeted personal genomics and illuminates Jewish and European origins.Nat. Commun. 2014; 5: 4835https://doi.org/10.1038/ncomms5835Crossref PubMed Scopus (120) Google Scholar Now, you might think this may have led to an adversarial relationship between the two of us. Actually, it was exactly the opposite. Arno and I became incredibly close friends and colleagues. We talked all the time because there was so much appreciation of each other in terms of what we do and what we know and our shared interests. Arno was such an incredible scholar. He knew everything, he read everything. I told him even my students, my postdocs, didn't read as much as he did. The man was an incredible fount of knowledge. Even though he passed at a relatively old age, I think about 94, he is still sorely missed. Also around this time, in 1989, I was invited to a workshop on genetic susceptibility to multiple sclerosis (MS) in Cambridge, England. At this meeting I met George Ebers, a neurologist and neurogeneticist at the University of Western Ontario in London, Ontario, Canada. George told me about some of the remarkable resources they had in Canada for studying MS and asked me if I was interested in collaborating. Yes! George was also collaborating with Dessa Sadovnick, a leading genetic epidemiologist at the University of British Columbia in Vancouver. So, for the next 10 years, I had frequent trips to London Ontario and Vancouver BC, and occasionally they would come to the United States. In Canada, they had a series of clinics throughout the country seeing the large majority of MS patients (around 27,000), along with extensive information about them, including family history. This remarkable opportunity gave rise to a great deal of genetic epidemiology research on MS, including family, twin, half-sib, and adoption studies, as well as molecular studies of multiplex families. During this time, George also had an exceptional PhD student working with him, Cristen Willer, who I also had the privilege to mentor. Cristen is now a prominent genetic epidemiologist and well known to ASHG as the 2021 Early Investigator Award recipient. During the time I was at Yale, I had also become acquainted and friends with Peggy Vance, a genetic epidemiologist at Duke University. In 1993, Peggy and her colleagues, including her long-time colleague Jonathan Haines, had discovered the strong association of the ApoE E4 allele with late onset Alzheimer disease (AD), one of the most significant genetic findings of the last century.8Corder E.H. Saunders A.M. Strittmatter W.J. Schmechel D.E. Gaskell P.C. Small G.W. Roses A.D. Haines J.L. Pericak-Vance M.A. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families.Science. 1993; 261: 921-923Crossref PubMed Google Scholar Peggy asked me if I was interested in collaborating on some of her Alzheimer's studies, to which I of course said, "Yes!" At a Gordon Conference in Newport, Rhode Island that Peggy, Jonathan, and I attended, Peggy shared some of her data with me; we were at the lovely beach there. As I was looking at it, I noticed that in addition to the E4 allele being a risk factor, the E2 allele was also underrepresented among the AD cases compared to controls. So, I said to Peggy, "Were you aware that the E2 allele is protective?" I showed her the data, and we ended up with a Nature Genetics paper.9Corder E.H. Saunders A.M. Risch N.J. Strittmatter W.J. Schmechel D.E. Gaskell P.C. Rimmler J.B. Locke P.A. Conneally P.M. Schmader K.E. et al.Protective effect of apolipoprotein E Type 2 allele for late onset Alzheimer Disease.Nat. Genet. 1994; 7: 180-184Crossref PubMed Scopus (1621) Google Scholar While I was in graduate school at UCLA, I kept hearing the names of the two most prominent genetic epidemiologists/statistical geneticists, Newton Morton and Robert Elston. Ken Lange had been in Hawaii visiting Newton Morton then but actually working with Robert Elston on his historic series of papers extending pedigree analysis. One of the great privileges of my career was getting to know and befriending both Newton and Robert, the two giants of the field. Robert was at Louisiana State University in New Orleans as the head of the department of biometry and genetics. Robert asked me if I would serve on the advisory board for his SAGE (statistical analysis in genetic epidemiology) resource, to which I of course agreed. So I got to make frequent trips to New Orleans. We had wonderful advisory board meetings discussing the latest of technologies but also great dinners at restaurants in New Orleans! These meetings continued after Robert moved to Case Western Reserve University as the chair of epidemiology and biostatistics, where we got to also sample Cleveland cuisine. At the same time, while I was at Yale, Newton Morton moved from Hawaii to Manhattan for a two-year stint as head of epidemiology and biostatistics at the Memorial Sloan Kettering Cancer Center. This was an incredible opportunity because now I could actually visit with Newton, work with Newton, and get to know him better, too. There are two recollections that I treasure about Newton's time in New York. First of all, he grew up in New Haven and his mom still lived there. One time he came out to New Haven to visit me and his mom, so I got to meet his mom too, a privilege probably not afforded to many. I also asked Newton if he would come to the genetic epidemiology class I was teaching at the time so the students could meet him. And he agreed. We got there a little early, sitting in class as the students arrived, wondering who this guest was. After all had arrived, I said to them, "I want to introduce you to our visitor today. This is Newton Morton." And then I just watched them as their jaws dropped. Yes, I got it, and mine too! Newton, of course, was a legend. And now the students were not just impressed with Newton but with me too because I actually knew Newton. Another significant colleague I met during my Yale days was Bronya Keats. Bronya was well known for her work on linkage mapping, Friedreich ataxia, and congenital deafness, and we collaborated on a number of projects. Bronya is only one of two people to train with both Newton and Robert, the other being my graduate advisor Anne Spence. Bronya and I became close friends, and this friendship has continued over the years. Also part of my group of colleagues/friends at that time were Stephanie Sherman and Tim Bishop, who also were trainees of Newton. I was at a meeting, probably around 1994, that David Cox was also attending. And David said to me, "Neil, would you be interested in a job at Stanford?" Lee Rosenberg had already left and gone to Bristol Myers Squibb. I tried to be coy in hiding my enthusiasm and said something like, "Yeah, I would consider it." But for me at that point in time, Stanford would be the dream job, for many reasons, not the least of which was because my parents were getting on in years, and it would make it much easier for me to visit them in Los Angeles and take care of things for them. So, I made several visits to interview at Stanford. The search committee included three Davids (Cox, Botstein, and Siegmund), along with Rick Myers and Uta Francke. Now, this is the second time I am mentioning Uta because, as it turns out, I was following Uta around! For good reason, not just because of her brilliance, but because she had good taste in places she worked. She worked hard to convince me to join Stanford, but it really wasn't that hard at all. I ended up having wonderful working relationships with all the members of that search committee. This time, my primary appointment was in the genetics department, but with courtesy appointments in statistics and health, research, and policy. Stanford, of course, had many legendary faculty, including Luca Cavalli-Sforza, Marcus Feldman, and Alice Whittemore, all of whom became close colleagues and friends. Luca and Marc were of course legends in human population genetics, my first love in graduate school, and Alice was my kindred spirit, starting her academic career as a mathematician before transitioning into epidemiology and genetics. The other remarkable thing about Stanford for me was the students. While I was there, I probably had several hundred students who took my courses in genetic epidemiology and statistical genetics. These students came from many different departments, primarily genetics, epidemiology, and statistics but also math, biology, and anthropology. To give just a glimmer of the remarkable students I had at Stanford in those days, in a single class in 1998 I had Jonathan Pritchard, Noah Rosenberg, Chiara Sabatti, Kristin Sainani, Holly Tabor, Hua Tang (all of whom are now Stanford professors), Eric Jorgenson (now at Regeneron), and David Elashoff (now at UCLA). Many of the students I had over my 10 years at Stanford are now luminaries in their fields. It was also during this period of time that David Cox and Rick Myers were involved with a company called Mercator. They asked me if I would be interested in working with them, because they were trying to clone the gene for hemochromatosis, which was known to be in the HLA region and a challenge to positionally clone.