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2020 William Allan Award address: genetics as a way of thinking—cultural inheritance from our teachers

2021; Elsevier BV; Volume: 108; Issue: 3 Linguagem: Inglês

10.1016/j.ajhg.2021.02.007

1537-6605

Mary‐Claire King,

Nutrition, Genetics, and Disease

This article is based on the address given by the author at the 2020 virtual meeting of The American Society of Human Genetics (ASHG) on October 26, 2020. The 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 2020 virtual meeting of The American Society of Human Genetics (ASHG) on October 26, 2020. The video of the original address can be found at the ASHG website. My heartfelt thanks to the Society for honoring me with the Allan Award. It comes from friends who know my work best, and there is nothing as important as that. In thinking about a presentation that would celebrate both the award and human genetics in this year’s unusual setting, I sought help from my friends. Aravinda Chakravarti suggested that I talk about our teachers. So this will be a story of inheritance; not of genetic inheritance, but of cultural inheritance. Three geneticists most enabled me to be part of this world: Curt Stern, Allan Wilson, and Luca Cavalli-Sforza. I will describe a little about the work of each of these extraordinary people at the time that I learned from each of them, and what learning from them meant to me. I met Curt Stern when I went to UC Berkeley as a graduate student in 1966 to study biostatistics (Figure 1). At the suggestion of my advisor, Jacob Yerushalmi, I registered for Dr. Stern’s genetics course for the last time he would give it before retiring, as then required at age 65. I’d been an undergraduate math major and had essentially no biology courses, but Dr. Yerushalmi said, “You cannot miss this. You will always remember this course.” He was right. I took Dr. Stern’s course and with Dr. Yerushalmi’s blessing, transferred to genetics for my PhD. I have never looked back. Dr. Stern’s course was magical. He came into class at one o’clock every afternoon (the course was five times a week) and wrote on the chalkboard the “puzzle for the day.” Sometimes the puzzle was graphic, sometimes a tricky cross, sometimes simply a question. I would look at the puzzle along with 150 other people, then 50 min later, I would understand how to solve it. It was great fun. One day during the course, I had a particularly sweet, short conversation with Dr. Stern. The class was in a large lecture room, and I liked to sit in front so as to see his writing easily. I had a class on the east side of campus just before Dr. Stern’s class, so I would hop on my bike immediately after my previous class, zip down the hill, and run into the Life Science Building, usually arriving just as Dr. Stern was walking in the opposite door. But one day, my previous class was over early, so I zipped down the hill as usual and was already seated when Dr. Stern arrived. He looked at me and smiled and said, “Am I late?” It was so endearing that I felt empowered to speak to him after lecture, to tell him how much I enjoyed his class. He invited me to join his graduate seminar for the next quarter, his last quarter as a faculty member. Dr. Stern’s graduate seminar was based on papers he had selected, all on the topic of mosaicism. In the 1960s, mosaicism was an active field in Drosophila, in plants, and in mammals. Dr. Stern was a leading person in the field.1Stern C. A mosaic of Drosophila consisting of 1X, 2X and 3X tissue and its probable origin by mitotic non-disjunction.Nature. 1960; 186: 179-180Crossref PubMed Scopus (1) Google Scholar,2Stern C. Tokunaga C. Nonautonomy in differentiation of pattern-determining genes in Drosophila, I. The sex comb of eyeless-dominant.Proc. Natl. Acad. Sci. USA. 1967; 57: 658-664Crossref PubMed Google Scholar Molecular biology was just being born, so while the questions being asked about mosaicism were conceptual (many of the same questions we are still asking now), the approach to answering them was based on genetic crosses rather than on molecular biology. In fact, mosaicism in Drosophila was perfectly suited to characterization using formal genetics.3Stern C. Gene expression in genetic mosaics.Genetics. 1969; 61: 199-211Google Scholar Dr. Stern had worked with Drosophila since the 1920s. He had grown up in Berlin and earned his PhD there at age 21. He was offered a fellowship at Columbia, so between 1924 and 1926, he was one of the members of Thomas Hunt Morgan’s Fly Room. A.H. Sturtevant, H.J. Muller, Calvin Bridges, and Curt Stern (the youngest of the group) shared a small room where they created Drosophila genetics.4Sturtevant A.H. Bridges C.B. Morgan T.H. The spatial relations of genes.Proc. Natl. Acad. Sci. USA. 1919; 5: 168-173Crossref PubMed Google Scholar, 5Stern C. An effect of temperature and age on crossing-over in the first chromosome of Drosophila melanogaster.Proc. Natl. Acad. Sci. USA. 1926; 12: 530-532Crossref PubMed Google Scholar, 6Stern C. Bridges C.B. The mutants of the extreme left end of the second chromosome of Drosophila melanogaster.Genetics. 1926; 11: 503-530Crossref PubMed Google Scholar Drosophila was soon discovered to have a superpower: the chromosomes of its salivary glands are enormous (they are polytene), so they could be visualized with the microscopy of the time. This discovery gave Drosophila geneticists a new tool to understand genetic phenomena at the cytogenetic level. For example, Dr. Stern showed that crossing over can occur during mitosis.7Stern C. Somatic crossing over and segregation in Drosophila melanogaster.Genetics. 1936; 21: 625-730Crossref PubMed Google Scholar,8Stern C. Doan D. A cytogenetic demonstration of crossing-over between X- and Y- chromosomes in the male Drosophila melanogaster.Proc. Natl. Acad. Sci. USA. 1936; 22: 649-654Crossref PubMed Google Scholar The linking of cytogenetics to formal genetics was a conceptual and practical breakthrough for the field, analogous to the linking of physical and genetic mapping today. Dr. Stern returned to Berlin in 1926, at the end of his fellowship period. Very fortunately, he was invited back to the U.S. in 1932, to Cal Tech, for what was intended to be a one-year visit. He told me that in late 1933, when it was time to return to Berlin, his family and friends in Germany said, “Don't come home. Stay in America. You absolutely cannot come home.” He took the advice, became a US citizen in 1939, and lived in America for the rest of his life. The class and seminar that I took from Dr. Stern were studies in genetics, not specifically human genetics. Human genetics in the 1960s was still observational. Based purely on observation, Dr. Stern had made major contributions to the field. As a young lecturer in Berlin in 1928, he introduced two concepts in a single elegant paper in Nervenarzt (The Neurologist). He wrote (to paraphrase), “Patients who present with the same clinical symptoms may have different underlying genetic causes.” And conversely, he wrote, “The same genotype may lead to different clinical phenotypes.”9Neel J.V. Curt Stern, 1902-1981.Annu. Rev. Genet. 1983; 17: 1-10Crossref PubMed Scopus (6) Google Scholar He was describing genetic heterogeneity on the one hand and pleiotropy on the other. Based on observation of human phenotypes and the genetics of what we would now call model organisms, he postulated two fundamental concepts of human genetics. Dr. Stern won the Allan Award in 1974. By then, he was suffering from Parkinson disease and his Allan Award presentation at ASHG was given by his former student, Jim Neel. In his introduction, Jim said that Dr. Stern’s legacy to his students was a love for genetics.8Stern C. Doan D. A cytogenetic demonstration of crossing-over between X- and Y- chromosomes in the male Drosophila melanogaster.Proc. Natl. Acad. Sci. USA. 1936; 22: 649-654Crossref PubMed Google Scholar To me, a specific meaning of this legacy was that we impact students whom we teach in class as well as students in our labs. I was not able to study with Dr. Stern as his graduate student, but what I learned in that first course and that first seminar have remained with me for more than 50 years. From 1969 to 1973, I was Allan Wilson’s graduate student (Figure 2). But before I was his graduate student, he saved me from leaving science. After transferring to genetics at Berkeley in 1967, I began to work in the lab of a distinguished bacterial geneticist. I had no idea how difficult it would be to learn, effectively on my own, how to do experiments. This bacterial genetics lab was very prominent, and I was grateful to be accepted there, but there was no culture of experienced people helping new people. I was completely overwhelmed. In 1969, Ralph Nader came to Berkeley to visit his sister. During his visit, he read California history and decided to undertake a project to investigate who controlled California’s land.10Ralph Nader Study Group Report on Land Use in California. (1973). Politics of Land. (Grossman).Google Scholar He needed a biologist as part of the team and offered me a job for the summer. I said yes, and had a fabulous time working with farm workers, learning about pesticide use and exposure, and about the practical realities of organizing a movement. At the end of the summer, Ralph offered me a job in Washington, DC in what became his Congress Project. I was going to take the job and spoke to Allan Wilson about making the move. We were already friends through political work. Allan strongly encouraged me not to drop out of school. “If you go to Washington, DC with Nader,” he said, “unquestionably you'll do good work. But you'll be going with a bachelor's degree. If you work on science-related issues, you won’t control the agenda, you'll always be working on projects designed by someone else. Stay in Berkeley,” he said, “finish your degree, and then you'll have the autonomy to work on the kind of projects you want.” I said, “Allan, none of my experiments work.” And he said, “Look, if everyone whose experiments failed stopped doing science, no one would be here.” “Allan,” I said, “That's easy for you to say, you're a very good biochemist. I'm reasonably good at writing equations, but not so good at doing experiments.” And he said, “Let's see if we can develop a project that is not too demanding experimentally, but will take advantage of the fact that you know how to write equations.” That became my project on molecular evolution in humans and chimpanzees. Allan was studying evolution using molecular clocks, measuring evolutionary divergence by the degree of separation of orthologous molecules from different species.11Sarich V.M. Wilson A.C. Quantitative immunochemistry and the evolution of primate albumins: micro-complement fixation.Science. 1966; 154: 1563-1566Crossref PubMed Scopus (105) Google Scholar He and his students had developed a way of quantifying immunological cross-reactivity of the same molecule (for example, lysozyme) in different species, comparing pairs of species that were relatively closely related and pairs of species that were more distantly related.12Prager E.M. Wilson A.C. The dependence of immunological cross-reactivity upon sequence resemblance among lysozymes. I. Micro-complement fixation studies.J. Biol. Chem. 1971; 246: 5978-5989Abstract Full Text PDF PubMed Google Scholar,13Prager E.M. Wilson A.C. The dependence of immunological cross-reactivity upon sequence resemblance among lysozymes. II. Comparison of precipitin and micro-complement fixation results.J. Biol. Chem. 1971; 246: 7010-7017Abstract Full Text PDF PubMed Google Scholar Using the same conceptual framework, the Wilson lab compared species with respect to the similarity of their DNA, quantifying the temperature and speed of re-annealing of bulk DNA molecules from the same species versus the same parameters for DNA from two different species.14Wilson A.C. Maxson L.R. Sarich V.M. Two types of molecular evolution. Evidence from studies of interspecific hybridization.Proc. Natl. Acad. Sci. USA. 1974; 71: 2843-2847Crossref PubMed Scopus (187) Google Scholar Allan suggested that as a third independent approach, I determine the proportion of individuals who were identical or different, within species and across species, with respect to electrophoretic mobility at each of multiple different proteins. Gel electrophoresis was quite new and enabled direct comparison of protein mobility based on proteins' relative size and charge. Allan had already tested the idea with dehydrogenases in birds.15Kitto G.B. Wilson A.C. Evolution of malate dehydrogenase in birds.Science. 1966; 153: 1408-1410Crossref PubMed Scopus (43) Google Scholar And critically, Margaret Dayhoff had recently published her Atlas of Protein Sequence and Structure, so we had direct knowledge of some human protein sequences.16Eck R.V. Dayhoff M.O. Atlas of Protein Sequence and Structure. National Biomedical Research Foundation, 1966Google Scholar What I didn’t appreciate, and perhaps Allan didn’t appreciate either, was that in order to compare multiple proteins in humans and in chimpanzees, I would need to convert dozens of different assays to work in electrophoretic gels. Very fortunately, Elo Giblett published Genetic Markers in Human Blood just at the right time,17Giblett E.R. Genetic Markers in Human Blood. Blackwell, 1969Google Scholar and I was able to adapt virtually all of her elegant protocols to my electrophoretic comparisons of human and chimpanzee proteins. I didn’t meet Dr. Giblett while I was a student, but when I moved to Seattle decades later, we became good friends. When Elo died in 2009, she bequeathed to me her original copy of Genetic Markers in Human Blood, with her notes penciled in the margins. The culture of the Wilson lab was inclusive and generous. After a while, I became fairly adept at various sorts of electrophoresis and could even teach others. My results showed very clearly that humans and chimpanzees were 99% the same in their protein-coding genes. The Wilson lab had already shown that identity at this level is characteristic of sub-species of other mammals (for example, mice) that are phenotypically indistinguishable. Obviously, this was a paradox, because we and chimpanzees are vastly more different than subspecies in anatomic features and in ways of life.18Wilson A.C. Bush G.L. Case S.M. King M.C. Social structuring of mammalian populations and rate of chromosomal evolution.Proc. Natl. Acad. Sci. USA. 1975; 72: 5061-5065Crossref PubMed Scopus (167) Google Scholar Allan and I published this story in 1975 in Science.19King M.C. Wilson A.C. Evolution at two levels in humans and chimpanzees.Science. 1975; 188: 107-116Crossref PubMed Scopus (1856) Google Scholar We presented the story as a paradox, with a hypothesis that at the time we had no way to test. We suggested that the critical events of human evolution are not so much changes in the sequences of protein-coding genes as changes regulating the timing of expression of those genes during development. In 2005, 14 years after Allan’s death, the complete chimpanzee genome sequence proved our hypothesis correct.20Chimpanzee Sequencing and Analysis ConsortiumInitial sequence of the chimpanzee genome and comparison with the human genome.Nature. 2005; 437: 69-87Crossref PubMed Scopus (1711) Google Scholar But Allan knew we had it right. Once evidence was clear, Allan was confident in his results. A great deal of Allan’s work in molecular evolution was extremely controversial, far more than the project with me. His most incendiary result was the prediction that humans and chimpanzees diverged 5 to 6 mya.21Sarich V.M. Wilson A.C. Immunological time scale for hominid evolution.Science. 1967; 158: 1200-1203Crossref PubMed Scopus (477) Google Scholar The orthodoxy at the time, based on fossil evidence, was that the human chimpanzee divergence was far earlier: 15 to 20 mya. Allan’s critical insight was that fossil evidence and molecular evidence both contribute to our understanding of human evolution, but not in the same way. Hominid fossils tell us where and when ancient hominids lived, but not what happened to them over evolutionary time. Allan told us, “All living species have ancestors, but not all fossils have descendants.” Molecular evolution reveals the ancient ancestors of living species.22Wilson A.C. The molecular basis of evolution.Sci. Am. 1985; 253: 164-173Crossref PubMed Scopus (90) Google Scholar His results, and the universal applicability of molecular clocks for evolutionary studies, have since been validated many times over. Beginning in the mid 1980s, the new super-power in genetics was PCR. Kary Mullis and Allan were good friends, so Allan knew of PCR from Kary’s first experiments with it.23Mullis K.B. Faloona F.A. Specific synthesis of DNA in vitro via a polymerase-catalyzed chain reaction.Methods Enzymol. 1987; 155: 335-350Crossref PubMed Scopus (3797) Google Scholar A interesting feature of PCR in its early days was that we cloned the PCR product before sequencing it. The cloning step was tedious and precluded large-scale experiments. Then Allan showed that the cloning step wasn’t necessary, that one could directly sequence PCR products.24Wrischnik L.A. Higuchi R.G. Stoneking M. Erlich H.A. Arnheim N. Wilson A.C. Length mutations in human mitochondrial DNA: direct sequencing of enzymatically amplified DNA.Nucleic Acids Res. 1987; 15: 529-542Crossref PubMed Scopus (266) Google Scholar Of course, direct sequencing made PCR infinitely faster to use. Allan was very proud of that technical innovation. It immediately went into the canon, without Allan being credited for it. Today probably few geneticists remember that PCR products were originally cloned. Another interesting feature of early PCR was its interpretation in the hands of an artist: Gary Larson. In the early days of PCR, before thermal cyclers were available, we set water baths at different temperatures, and transferred racks of tubes from one water bath to another to another. That worked well but was tedious and often kind of wet. During the days of water bath transfers, Gary Larson, who was another good friend of Allan’s, came to visit, watched us transferring racks from water bath to water bath, and asked what was going on. So Allan explained PCR and Kary’s work. A few days later on Allan’s office door a cartoon appeared. It showed three cave people sitting on a beach near tide pools, holding shells that they dipped into one pool, then another, then another. The title of the cartoon was “PCR in ancient times.” Allan was awarded a MacArthur Fellowship in 1986, very early in the MacArthur program. He didn’t live to test even a small fraction of his ideas; he died in 1991 at age 56 of leukemia.25King M.C. Allan C. Wilson, 1934-1991.Am. J. Hum. Genet. 1992; 50: 234-235Google Scholar His students and post-docs came from, and returned to, all fields of biology: Vince Sarich,10Ralph Nader Study Group Report on Land Use in California. (1973). Politics of Land. (Grossman).Google Scholar,20Chimpanzee Sequencing and Analysis ConsortiumInitial sequence of the chimpanzee genome and comparison with the human genome.Nature. 2005; 437: 69-87Crossref PubMed Scopus (1711) Google Scholar Linda Maxson,14Wilson A.C. Maxson L.R. Sarich V.M. Two types of molecular evolution. Evidence from studies of interspecific hybridization.Proc. Natl. Acad. Sci. USA. 1974; 71: 2843-2847Crossref PubMed Scopus (187) Google Scholar Steve Carlson,26Carlson S.S. Wilson A.C. Maxson R.D. Do albumin clocks run on time?.Science. 1978; 200: 1183-1185Crossref PubMed Google Scholar,27Wilson A.C. Carlson S.S. White T.J. Biochemical evolution.Annu. Rev. Biochem. 1977; 46: 573-639Crossref PubMed Scopus (976) Google Scholar Tom White,26Carlson S.S. Wilson A.C. Maxson R.D. Do albumin clocks run on time?.Science. 1978; 200: 1183-1185Crossref PubMed Google Scholar Becky Cann,28Cann R.L. Stoneking M. Wilson A.C. Mitochondrial DNA and human evolution.Nature. 1987; 325: 31-36Crossref PubMed Scopus (1858) Google Scholar Svante Pääbo,29Pääbo S. Gifford J.A. Wilson A.C. Mitochondrial DNA sequences from a 7000-year old brain.Nucleic Acids Res. 1988; 16: 9775-9787Crossref PubMed Scopus (319) Google Scholar Scott Edwards,30Edwards S.V. Wilson A.C. Phylogenetically informative length polymorphism and sequence variability in mitochondrial DNA of Australian songbirds (Pomatostomus).Genetics. 1990; 126: 695-711Crossref PubMed Google Scholar Linda Vigilant,31Vigilant L. Stoneking M. Harpending H. Hawkes K. Wilson A.C. African populations and the evolution of human mitochondrial DNA.Science. 1991; 253: 1503-1507Crossref PubMed Scopus (947) Google Scholar Mark Stoneking,28Cann R.L. Stoneking M. Wilson A.C. Mitochondrial DNA and human evolution.Nature. 1987; 325: 31-36Crossref PubMed Scopus (1858) Google Scholar,30Edwards S.V. Wilson A.C. Phylogenetically informative length polymorphism and sequence variability in mitochondrial DNA of Australian songbirds (Pomatostomus).Genetics. 1990; 126: 695-711Crossref PubMed Google Scholar Anna Di Rienzo,32Di Rienzo A. Wilson A.C. Branching pattern in the evolutionary tree for human mitochondrial DNA.Proc. Natl. Acad. Sci. USA. 1991; 88: 1597-1601Crossref PubMed Scopus (325) Google Scholar me, and many others. Allan taught us to be scientifically fearless. I was never a student or postdoc of Luca Cavalli-Sforza, but his help was terribly important to me (Figure 3). He enabled me to enter the world of human molecular genetics. Luca was an active member of our society. He won the Allan Award in 1987 and was president of ASHG in 1989. By the early 1980s, I was a young faculty member at UC Berkeley, working on the problem of inherited breast cancer using statistical approaches and linkage analysis. Luca, at Stanford, was beginning to apply the tools of molecular biology to human genetics. The possibility of examining human variation using restriction fragment length polymorphisms had just been published by David Botstein and colleagues, offering the opportunity to carry out linkage analysis and gene mapping much more effectively than with gel electrophoresis.33Botstein 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 Luca was actively exploiting these approaches. Luca had been very kind to me when I discussed the idea of inherited breast cancer in a seminar at Stanford. I had discussed statistical modeling of the population genetics of breast cancer using maximum likelihood estimation approaches.34Newman B. Austin M.A. Lee M. King M.C. Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families.Proc. Natl. Acad. Sci. USA. 1988; 85: 3044-3048Crossref PubMed Scopus (394) Google Scholar He had been critical, but positive. He also had come from mathematical genetics, as a young colleague of R.A. Fisher. With Walter Bodmer, Luca had written Genetics of Human Populations,35Cavalli-Sforza L.L. Bodmer W.F. The Genetics of Human Populations. Dover Publications, 1972Google Scholar which very strongly influenced my way of thinking about human genetics. He was just beginning work on The History and Geography of Human Genes,36Cavalli-Sforza L.L. Menozzi P. Piazza A. The History and Geography of Human Genes. Princeton Univ Press, 1994Google Scholar which was published in the 1990s and remains a masterpiece in our field. In his lab, Luca was beginning to integrate tools from molecular biology into medical genetics.37Johnson M.J. Natali A.M. Cann H.M. Honjo T. Cavalli-Sforza L.L. Polymorphisms of a human variable heavy chain gene show linkage with constant heavy chain genes.Proc. Natl. Acad. Sci. USA. 1984; 81: 7840-7844Crossref PubMed Scopus (45) Google Scholar I had no experience at all in genetics of human disease. Berkeley was enormously rich in molecular biology and biochemistry and genetics, but at that time, there was no infrastructure at Berkeley to link these fields to human medical genetics. Luca asked if I would like to spend some time in his lab. I had a small daughter, so there was no way I could move to Stanford for a formal sabbatical. But in those days, you could hop in your car in Berkeley and be at Stanford in less than an hour, so day visits were feasible. Luca showed me how to think about genetics of people in the same way that we thought about genetics of other species. That is, how to model mutation, selection, migration, and drift in human populations just like in populations of any other species,38Cavalli-Sforza L.L. King M.-C. Detecting linkage for genetically heterogeneous diseases and detecting heterogeneity with linkage data.Am. J. Hum. Genet. 1986; 38: 599-616PubMed Google Scholar with additional parameters for cultural transmission in human populations,39Feldman M.W. Cavalli-Sforza L.L. Models for cultural inheritance: a general linear model.Ann. Hum. Biol. 1975; 2: 215-226Crossref PubMed Scopus (21) Google Scholar then how to apply this perspective to gene identification for human disease.40Bowcock A.M. Crandall J. Daneshvar L. Lee G.M. Young B. Zunzunegui V. Craik C. Cavalli-Sforza L.L. King M.C. Genetic analysis of cystic fibrosis: linkage of DNA and classical markers in multiplex families.Am. J. Hum. Genet. 1986; 39: 699-706PubMed Google Scholar I was working with Luca in this informal sabbatical when we were asked by the grandmothers of the Plaza de Mayo in Argentina if we could help them with an urgent problem. The military dictatorship had just ended in Argentina, and the grandmothers hoped to prove the identities of children whom they believed to be their kidnapped grandchildren, the surviving children of their murdered adult children. We worked out the statistical parameters for the problem, a straightforward application of Bayesian statistics. The grandmothers thanked us and asked Luca to come to Buenos Aires to help them put the approach into practice. Luca didn’t miss a beat. He said to me, “I'm not the right person to do this, but you are. You've taught in South America, you can work in Spanish, you obviously know the genetics. But most importantly, you are the age of the murdered daughters of these women and your daughter is the age of their kidnapped granddaughters. You should go to Buenos Aires and sort this out.” So I did, making in June 1984 what I thought would be one symbolic trip.41Di Lonardo A.M. Darlu P. Baur M. Orrego C. King M.C. Human genetics and human rights. Identifying the families of kidnapped children.Am. J. Forensic Med. Pathol. 1984; 5: 339-347Crossref PubMed Scopus (21) Google Scholar More than 36 years later, the project continues. The tools that the grandmothers and I developed together42Ginther C. Issel-Tarver L. King M.C. Identifying individuals by sequencing mitochondrial DNA from teeth.Nat. Genet. 1992; 2: 135-138Crossref PubMed Scopus (152) Google Scholar are now used universally in forensics, including by the United Nations Forensic Anthropology team, which was created by young people from Argentina with whom we worked in the 1980s.43King M.C. My mother will never forgive them.Grand Street. 1992; 42: 34-53Crossref Google Scholar Across different eras, with different origins, and with very different personalities, my three teachers shared a worldview: they loved genetics and took seriously anyone else who loved genetics. Thinking back, this worldview was apparent in three ways, none explicit, of course. Each of them thought very critically about evidence, both their own and ours. Each of them took extraordinary time with us to explain their views, trying very hard to enable us to understand their perspective. Each of them was receptive to changing this perspective if the evidence was inconsistent with what they had thought, but you had to stand up for your evidence and argue it strongly and well. What mattered was the quality of the evidence and the consistency of the conceptual framework that you could build around it. Each of them was remarkably good at framing questions in testable form and at distilling from very complex ideas hypotheses that could be tested with available tools. Of course the tools were evolving quickly. Imagine what they could have done with current genomics tools. Each of them thought that no question was too big to ask. They understood that genetics is a way of thinking, that as tools get better and better, genetics will offer answers to truly fundamental questions of evolution, development, and disease. With current genomics tools, there should be no bounds to the questions we can ask and hope to answer. Each of my teachers left their students the legacy of fearlessness in asking questions. I hope we can do the same.