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Arno G. Motulsky (1923–2018): A Founder of Medical Genetics, Creator of Pharmacogenetics, and Former ASHG President

2018; Elsevier BV; Volume: 102; Issue: 3 Linguagem: Inglês

10.1016/j.ajhg.2018.02.005

1537-6605

Gail P. Jarvik, Mary‐Claire King,

Acute Lymphoblastic Leukemia research

Arno G. Motulsky, MD, a father of our field, was born in Germany on July 5, 1923, and died in Seattle on January 17, 2018, at 94 years of age. Through his research, writing, and mentoring, he was one of the founders of modern human and medical genetics. He created the field of pharmacogenetics. His life and career were in every way remarkable. His contributions as a scientist, physician, and mentor cannot be overstated. But first, he was a refugee.(Left to right) Arno with his siblings, Lothar and Leah, circa 1933. Provided by the Motulsky family.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Arno was born in 1923 on the Baltic coast of northern Germany in a region that had historically been benign for Jews. But when the Nazis rose to power in 1933, antisemitism was a central plank of their platform. Jews were immediately removed from civil service positions. By the next year, Jews were banned from the military, banned from marrying “Aryans,” and stripped of their German citizenship. By 1936, Jews were banned from most professions. November of 1938 brought Kristallnacht, internment of tens of thousands of Jews, and expulsion of Jewish children from schools. In 1938, Arno was 15 years old, and his dream to become a psychiatrist was ended by the expulsion. Out of school, he applied to enter Palestine as part of a youth program, but a heart murmur detected at the screening exam excluded him. The murmur was later found to be clinically insignificant, but by then it was too late. In early 1939, Arno’s family realized they had to leave Germany. Arno’s uncle lived in Chicago, but visas to enter the US required a long wait, regardless of a relative already here. So Arno’s father left for Cuba to make arrangements for the family to live there temporarily. In May of 1939, as the situation in Germany deteriorated, Arno and his mother, brother, and sister left Hamburg for Havana on the MS St. Louis. Despite the visas of the passengers, the ship was denied entry to Cuba. When the captain asked to land in a US port with the refugees, the ship was turned away from this country as well on the basis of a State Department decision that the Jewish refugees threatened US security. The St. Louis headed back to Germany. A few days before the ship was to land again in Hamburg, four countries agreed to take the refugees. By lots, the passengers were divided among England, France, Belgium, and Holland. (Ultimately, only those assigned to England were safe.) Arno’s family was sent to Belgium. A few months later, the Germans invaded Belgium, and despite having just received his US visa, Arno was arrested, ironically by the Belgians for being a German “enemy alien.” He was separated from his family and sent to a series of internment camps, after which he finally arrived at a cholera-, dysentery-, and typhus-infested camp near Gurs in Vichy-controlled southwestern France. Gurs was not an extermination camp, but thousands of prisoners died of disease or starvation. Arno was young and strong and, as he thought of it, “incredibly lucky” and survived to be transferred again, until he was finally able to leave France in June 1941. He crossed fascist Spain 10 days before his 18th birthday, after which it would have been impossible. He made it to Portugal and sailed to America to join his father in Chicago. It was 2 years before they learned that his mother, sister, and brother had escaped to Switzerland. Five years later, the family was reunited in Chicago. Until Arno was in his seventies, he did not publicly describe these events. He hesitated to speak up because, he said, “others had been through so much worse.” In recent years, with encouragement from his family and friends, he agreed to relate the history, to the Shoah project, in the human genetics literature1Motulsky A.G. King M.C. The great adventure of an American human geneticist.Annu. Rev. Genomics Hum. Genet. 2016; 17: 1-15Crossref PubMed Scopus (4) Google Scholar and, in a series of German interviews, to Deutschlandradio. In 2012, one of us (G.P.J.) was privileged to travel with him to the US State Department for a ceremony to honor the survivors of the MS St. Louis and diplomats from countries that accepted them as refugees—an apology, 73 years after the fact, for America’s failure. Over the last 20 years, we have had several opportunities to hear Arno weave his story together with that of his old friend Lissy Jarvik, MD, PhD, Professor Emeritus of Psychiatry at the University of California, Los Angeles (UCLA), and G.P.J.’s mother-in-law. A year younger than Arno, Lissy had made her way out of Holland in 1940 as the Germans invaded and was rescued from Vichy, France, with a Portuguese visa written, against his government’s orders, by Aristides de Sousa Mendes.2Fralon J.A. Graham P. A good man in evil times: The story of Aristides de Sousa Mendes – The man who saved the lives of countless refugees in World War II. Carroll & Graf, 2001Google Scholar Once in the US, Arno obtained a high school equivalency certificate thanks to his brief high school studies in Belgium and classes in a hodge-podge of subjects organized by teachers and professors among his fellow prisoners in French internment camps. (Arno described these classes as having no books or paper or pencils, “but we had each other and we had our brains.”) In 1943, he met his future wife, Gretel, in night school in Chicago, became a US citizen, and joined the US Army. The army needed doctors and sent him for premedical studies to Yale University and then to the University of Illinois at Chicago, where he completed his MD in 1947. Beginning as a physician scientist, he studied hemoglobinopathies with Karl Singer at Michael Reese Hospital in Chicago in residencies in medicine and hematology. During the Korean War, again in the army, he was stationed at Walter Reed Hospital in a unit set up by William Crosby and was assigned to study hemoglobin disorders that were affecting American troops. Arno specialized in the characterization of spherocytosis. In 1953, Arno joined the faculty of the Department of Medicine of the University of Washington (UW) and soon began introducing concepts of genetics into his lectures to medical students. He created the first US Division of Medical Genetics in 1957, the same year as the founding of the Johns Hopkins division. Shortly thereafter, Arno opened the genetics clinic at UW. He led the division until 1989. Arno was among the first to recognize that common complex human disease is influenced by identifiable and actionable genetic contributions. He most enjoyed pursuing these ideas with young colleagues. He was remarkably skilled at starting young investigators down novel and fruitful paths, often after first realizing the way to approach the genetics of complex phenotypes. To quote George Stamatoyannopoulos, one of Arno’s closest colleagues, “Arno had great, broad ideas.”3Jarvik G.P. 2016 Victor A. McKusick Leadership Award introduction: Stanley Gartler.Am. J. Hum. Genet. 2017; 100: 401-402Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar These ideas touched many fields of medicine. In 1957, Arno defined the genotype-dependent differential response to drugs in the context of drug-induced hemolytic anemia due to G6PD deficiency and of drug-induced prolonged apnea during anesthesia due to pseudocholinesterase deficiency.4Motulsky A.G. Drug reactions enzymes, and biochemical genetics.J. Am. Med. Assoc. 1957; 165: 835-837Crossref PubMed Scopus (309) Google Scholar In 1964, he gave this field a name: pharmacogenetics.5Motulsky A.G. Pharmacogenetics.Prog. Med. Genet. 1964; 23: 49-74PubMed Google Scholar The concept grew out of his work on the genetics and biochemistry of hemoglobinopathies and G6PD deficiency, including the protection offered by G6PD deficiency against falciparum malaria. Years later, he and his colleague Clem Furlong characterized the genetics of paraoxonase deficiency, which leads to differential sensitivity to pesticide poisoning.6Mueller R.F. Hornung S. Furlong C.E. Anderson J. Giblett E.R. Motulsky A.G. Plasma paraoxonase polymorphism: A new enzyme assay, population, family, biochemical, and linkage studies.Am. J. Hum. Genet. 1983; 35: 393-408PubMed Google Scholar Still later, Clem Furlong and G.P.J. showed that paraoxonase activity is associated with vascular disease.7Jarvik G.P. Rozek L.S. Brophy V.H. Hatsukami T.S. Richter R.J. Schellenberg G.D. Furlong C.E. Paraoxonase (PON1) phenotype is a better predictor of vascular disease than is PON1(192) or PON1(55) genotype.Arterioscler. Thromb. Vasc. Biol. 2000; 20: 2441-2447Crossref PubMed Scopus (287) Google Scholar In the 1960s, Arno was among the first to demonstrate that “natural experiments” could reveal the interaction between genes and the environment and that these observations could aid in the development of treatment for human disease. With his trainee Robert Sparkes, he proposed bone marrow transplantation as a therapy8Motulsky A.G. Anderson R. Sparkes R.S. Huestis R.H. Marrow transplantation in newborn mice with hereditary spherocytosis: a model system.Trans. Assoc. Am. Physicians. 1962; 75: 64-72PubMed Google Scholar and characterized environmental effects on hereditary spherocytosis.9Anderson R. Motulsky A.G. Adverse effects of raised environment temperature on the expression of hereditary spherocytosis in deer mice.Blood. 1966; 28: 365-376Crossref PubMed Google Scholar Arno subsequently demonstrated that murine spherocytosis could be treated by bone marrow transplantation,10Steinmuller D. Motulsky A.G. Treatment of hereditary spherocytosis in Peromyscus by radiation and allogeneic bone marrow transplantation.Blood. 1967; 29: 320-330Crossref PubMed Google Scholar the first success with this therapy in a free-living mammal. Bob Sparkes continued to study blood disorders at UCLA and published his last of 385 papers in 2012. In the 1970s, Arno’s studies of coronary heart disease with his trainee Joseph Goldstein established a new paradigm for the genetics of complex common diseases. Motulsky and Goldstein evaluated the lipid levels of survivors of myocardial infarction and their families, which allowed them to establish genetic types of hyperlipidemia and define familial hyperlipidemia as a new disease.11Goldstein J.L. Hazzard W.R. Schrott H.G. Bierman E.L. Motulsky A.G. Genetics of hyperlipidemia in coronary heart disease.Trans. Assoc. Am. Physicians. 1972; 85: 120-138PubMed Google Scholar, 12Schrott H.G. Goldstein J.L. Hazzard W.R. McGoodwin M.M. Motulsky A.G. Familial hypercholesterolemia in a large kindred. Evidence for a monogenic mechanism.Ann. Intern. Med. 1972; 76: 711-720Crossref PubMed Scopus (48) Google Scholar These studies were the foundation for the 1985 Nobel Prize in Medicine, awarded to Goldstein and Michael Brown for elucidating lipid genetics and biochemistry and the treatment of lipid disorders. Arno became interested in color vision in the 1960s, and beginning in the 1980s, he and his colleague Samir Deeb performed pioneering work illuminating the genetics of color vision. With their collaborators, they characterized the molecular genetics of this complex phenotype and understood the need to look across diverse populations13Motulsky A.G. Normal and abnormal color-vision genes.Am. J. Hum. Genet. 1988; 42: 405-407PubMed Google Scholar, 14Drummond-Borg M. Deeb S. Motulsky A.G. Molecular basis of abnormal red-green color vision: a family with three types of color vision defects.Am. J. Hum. Genet. 1988; 43: 675-683PubMed Google Scholar, 15Jørgensen A.L. Deeb S.S. Motulsky A.G. Molecular genetics of X chromosome-linked color vision among populations of African and Japanese ancestry: High frequency of a shortened red pigment gene among Afro-Americans.Proc. Natl. Acad. Sci. USA. 1990; 87: 6512-6516Crossref PubMed Scopus (40) Google Scholar and discovered both a common polymorphism and common genomic structural variation that affect how color is perceived.16Winderickx J. Lindsey D.T. Sanocki E. Teller D.Y. Motulsky A.G. Deeb S.S. Polymorphism in red photopigment underlies variation in colour matching.Nature. 1992; 356: 431-433Crossref PubMed Scopus (156) Google Scholar, 17Hayashi T. Motulsky A.G. Deeb S.S. Position of a ‘green-red’ hybrid gene in the visual pigment array determines colour-vision phenotype.Nat. Genet. 1999; 22: 90-93Crossref PubMed Scopus (80) Google Scholar Throughout his professional life, Arno served on, and often led, national and international venues on science policy and advocacy. He was particularly skilled in integrating non-scientists into these panels by teaching technical material that they needed to know to contribute actively. In 1977, he served as president of the American Society of Human Genetics (ASHG). In his presidential address, he summarized trends and directions in medical and human genetics.18Motulsky A.G. Medical and human genetics 1977: Trends and directions.Am. J. Hum. Genet. 1978; 30: 123-131PubMed Google Scholar He put the concept of sociobiology into context. He speculated on the role of genetics in common disease and the need to understand causal genetic heterogeneity. He addressed the genetics workforce, including the need to train clinical medical geneticists as the field evolved from basic science to translation across all fields of medicine. His address was presented 40 years ago and could have been written today. We will most remember Arno as a teacher and mentor of human and medical genetics. His educational legacy began more than 60 years ago with his creation of the Division of Medical Genetics and its clinic. A major goal of the division and clinic was to train the next generations of medical geneticists by integrating research and clinical practice. Clinical problems presented research questions, and research results were translated into actionable advice and treatment for patients. In 1976, Arno obtained one of the first training grants in medical genetics from the National Institutes of Health, and this grant is now in its 41st continuous year. The training grant sponsored both physician fellows and basic scientist postdocs, and trainees worked with mentors throughout the UW School of Medicine. Arno’s teaching was both formal and informal. His textbook Human Genetics: Problems and Approaches, initially co-authored with the late Friedrich Vogel and commonly called “Vogel and Motulsky,” was first published in 1979. It is viewed by many as the definitive textbook in human genetics and has had a great influence on the field worldwide for 35 years. The fourth edition was published in 2010 with Arno still as the principal author.19Speicher M. Antonarakis S.E. Motulsky A.G. Vogel and Motulsky’s human genetics: Problems and approaches. Springer-Verlag Berlin Heidelberg, 2010Crossref Scopus (16) Google Scholar Arno’s interest in Jewish genetic diseases and their origins led him first to edit, with Richard Goodman, Genetic Diseases Among Ashkenazi Jews20Goodman R.M. Motulsky A.G. Genetic diseases among Ashkenazi Jews. Raven Press, 1979Google Scholar and then to organize meetings and publish widely on this theme with co-authors in Israel, Europe, and America. Arno most loved informal teaching to individual fellows and young colleagues. He was the primary mentor of 48 postdoctoral medical fellows. Many of these trainees became leaders in medical genetics: Joseph Goldstein, Charles Epstein, Robert Sparkes, Judith Hall, George Fraser, Bonnie Pagon, Wylie Burke, Suzanne Cassidy, Jeff Murray, Thomas Gelehrter, John Mulvihill, James Evans, and Ephrat Levy-Lahad. Many other medical geneticists were not formally his trainees but learned from him in conversations and in clinic. Links to Arno as a teacher appear wherever one touches down in medical genetics. We think it likely that Arno has mentored, formally or informally, a large proportion of medical geneticists now practicing in this country and abroad. As with the other founders of our field, Arno welcomed women and men and young scientists of all ancestries as trainees. The diversity of our field is a tribute to this inclusive welcome. Arno became a model for successful mentoring not only in our field but also in higher education generally.21Nakamura J. Shernoff D.J. Hooker C.H. Csikszentmihalyi M. Good mentoring: Fostering excellent practice in higher education. Wiley, 2009Google Scholar The ASHG recognizes Arno’s contribution with the Excellence in Human Genetics Education Award, named for Arno and his friend Barton Childs. Arno received this award himself in 1999 and the sister award, the Honorary Medal for Outstanding Research and Education from the German Society of Human Genetics, 4 years later. Perhaps even more telling, three geneticists mentored by Arno have also won the ASHG Education Award. Until he was 92 years old, Arno continued to collaborate, write (with undiminished precision!), and publish. He was full of ideas for how younger generations of students and faculty could use current genomic technologies to answer long-standing questions.22Pierce S.B. Spurrell C.H. Mandell J.B. Lee M.K. Zeligson S. Bereman M.S. Stray S.M. Fokstuen S. MacCoss M.J. Levy-Lahad E. et al.Garrod’s fourth inborn error of metabolism solved by the identification of mutations causing pentosuria.Proc. Natl. Acad. Sci. USA. 2011; 108: 18313-18317Crossref PubMed Scopus (10) Google Scholar His wisdom was sought at weekly clinic conferences, journal clubs, and seminars. When he retired from public life 2 years ago, he remained warm and welcoming and eager for a good conversation. What an outrage (which we must speak about) that Arno was turned away from this country as a 16-year-old and what a gift that he made it back 2 years later. Everyone’s teenage experience remains with them forever, and Arno’s was no exception. About a year ago, Arno was watching with us a news report from South Sudan. A young woman was sitting on the sand in rags, emaciated, and in complete despair. Arno turned to us and said, “I know exactly how she feels.” Seventy-eight years ago, Arno Motulsky and Lissy Jarvik survived by grit and by chance. What would we have lost had Arno or Lissy died of starvation or typhus or a bullet or gas? How many like Arno and Lissy did we lose? How many more will we continue to turn away and lose?