NEEL, JAMES VAN GUNDIA

(b. Hamilton, Ohio, 22 March 1915; d. Ann Arbor, Michigan, 1 February 2000)

human genetics, radiation genetics, human mutation research, population genetics, genetics and public policy.

Neel was a founding member of the American Society of Human Genetics and played a critical role in the scientific and institutional development of human and medical genetics in the United States; he directed the program assessing the genetic effects of radiation on the offspring of survivors after the use of the atomic bomb in 1945; he created the Department of Human Genetics at the University of Michigan in 1956, one of the first such departments in the United States, and he chaired it for twenty-five years. An interdisciplinary thinker, with an interest in the relevance of genetic data to public policy, his work often addressed the biological and cultural future of the human species. His 1960s work with the anthropologist Napoleon Chagnon among the Yanomami Indians in Venezuela became the subject of a major international controversy shortly after his death.

Early Life James Van Gundia Neel (known as Jim) was born into a middle-class household in March 1915. When he was ten years old his father, Hiram Alexander Neel, died of pneumonia, and his mother, Elizabeth Minette Van Gundia Neel, moved with her three children from Detroit to Wooster, Ohio. For financial reasons a college education was not assured, but a scholarship to the College of Wooster made it possible and at Wooster he had the opportunity to study with the Drosophila geneticist Warren Spencer. Spencer’s teaching shaped Neel’s intellectual interests and professional future. In 1935 he went immediately from his undergraduate studies at Wooster to the University of Rochester, where he became the first American graduate student of the recent German émigré Curt Stern, another critical figure in the development of human genetics in the United States. (Neel’s obituary of Stern is cited below.)

Neel’s 1939 thesis at Rochester looked at temperature effects on gene expression. Using flies with abnormal patterns of bristles (hairlike appendages), he was able to characterize mathematical relationships between body size, bristle number, and known mutant gene forms. Even as he was completing this project, however, Neel was thinking of human genetics. As a graduate student he had taken three medical school courses (including anatomy) and had convinced Stern to offer a graduate seminar in human genetics. (Stern later wrote a textbook of human genetics, partially inspired by the keen interest of his student.) Neel did not immediately turn to human studies upon the completion of his PhD, however. On Stern’s advice, and with some reluctance, he accepted a position as an instructor in biology at Dartmouth College, going there in the fall of 1939. He stayed at Dartmouth two years.

In the fall of 1941 he was awarded a National Research Council fellowship to study at Columbia University with the prominent geneticists Theodosius Dobzhansky and Leslie Clarence Dunn. There Neel completed his first major scientific publication on a highly mutating line of flies (1942). It was also at Columbia that he made the decision to earn a medical degree: if he was going to study human heredity, he reasoned, he should understand human disease, abnormality, physiology, and anatomy. Concerned about the impending U.S. entry into World War II, he also believed that a physician could do more to help his country than a geneticist. He applied to the University of Rochester medical school just before the Japanese attack on Pearl Harbor of 7 December 1941, and he became a student there in the summer of 1942.

In October 1942, in Rochester, he met Priscilla Baxter, a recent graduate of the Smith School of Architecture in Cambridge, Massachusetts, then working as a mechanical designer at the Stromberg-Carlson Company. In May 1943 they were married, and they later had three children.

All medical students not exempted from service for physical reasons were given military commissions during the war. Due to the accelerated wartime pace of medical education, Neel completed his medical education at Rochester in September 1944, and became an assistant resident in medicine at Strong Memorial Hospital. Neel was the only member of the early group of scientific human geneticists in the United States to choose to earn both an MD and a PhD. Some influential students of human heredity in this period, such as Victor McKusick, were skilled clinicians with no formal training in laboratory genetics; others, such as H. J. Muller, were experienced Drosophilists who extrapolated from their work with flies to comment about human heredity. But Neel was both a physician and a geneticist, and his work reflected his commitments to both the laboratory and the clinic.

In 1945 Neel accepted a position at the University of Michigan at Ann Arbor, where he was to remain for the rest of his life. In 1947 he was one of the key participants in the creation of the American Society of Human Genetics, which formally came into being in 1948. He wrote the first paper to be published in the new society’s journal, the American Journal of Human Genetics, and he served the society as a member of the board of directors (1948–1950 and 1968–1970), vice president (1952–1953 and 1955–1957), and president (1953–1954).

One of his first major contributions to human genetics elucidated the nature of the inheritance of a complex genetic disease, sickle-cell anemia. Early work on thalassemia during his medical school days had alerted him to the possible importance of carrier states that result in a milder form of the full-blown disease. In 1948, he began working with African American populations in Detroit to understand an apparently similar genetic system. In his 1949 paper in Science, Neel demonstrated that the two forms of the disease, one mild, one disabling, reflected either heterozygosity or homozygosity for a single gene. Sickle-cell anemia, he demonstrated, was a classic Mendelian trait in which the heterozygous form had phenotypic effects, and the homozygous form constituted full-scale sickle-cell disease. Neel’s paper appeared in the same issue of Science in which sickle-cell anemia was characterized by Linus Pauling and his coworkers as a “molecular disease,” after they showed that the hemoglobin molecule in patients with the disease is characteristically elongated, thus producing the sickling of the cells.

In 1954 Anthony Allison demonstrated that sickle-cell trait, the heterozygous condition, conferred early immunity to a form of malaria endemic in Africa. This explained why the trait, and also the disease, were so common in populations historically living in malarial regions: those with sickle-cell trait had a survival advantage at an early age. Neel thus contributed significant insights to the understanding of a disease that remains the most compelling human example of what is called overdominance, or the heterozygote advantage, the condition in which a heterozygous genotype has a higher relative fitness than either homozygous form.

Atomic Bomb Studies Before the atomic bombs were dropped on Hiroshima and Nagasaki, Japan, on 6 and 9 August 1945, plans for studies of their physical effects on buildings and urban structures were already in place. But plans for studies of their biomedical effects on survivors were sketchy at best, partly because many of those involved in planning the use of these weapons did not expect that anyone heavily irradiated would survive the bombings.

Radiation was known to have biological effects, including genetic effects, as H. J. Muller had demonstrated with his studies of irradiated fruit flies in 1927, and some of those involved in the project to build the atomic bomb, code-named the Manhattan Engineering District, had been exposed to levels of radiation that produced illness or even death. (The physicist Louis Slotin died from the effects of a 1946 radiation burst at Los Alamos.) Secret research on the biological effects of radiation had been undertaken in several places during the war, including at the University of Rochester, where Neel was then a medical student, and Neel was vaguely aware that some secret work relating to radiation was underway there. Just after the bombings, he told a colleague who had been involved in the Manhattan Engineering District unit at Rochester that he would be interested in assessing the genetic effects of the bombs on survivors in Japan. This comment, apparently somewhat casual, eventually led to his appointment to carry out an exploratory visit to Japan as a medical corps lieutenant in November 1946.

By the spring of 1947, Neel was planning and directing the genetics study of what came to be known as the Atomic Bomb Casualty Commission (ABCC). He began a lifelong affiliation with the scientific study of the survivors, which continued long after his full-time work in Japan ended. Michigan was his base, but he returned to Japan regularly and continued to publish on the atomic bomb survivors and on other Japanese populations. The ABCC was a long-term, interdisciplinary U.S. study of the health of the atomic bomb survivors and their offspring, organized and overseen by the National Academy of Sciences, and funded by the new Atomic Energy Commission. With American, British, Australian, and Japanese staff at laboratories in Hiroshima, Nagasaki, and a “control” city, Kure, the ABCC examined survivors every year or so, tracking their illnesses and attempting to determine their risks as a result of exposure to radiation.

Neel’s genetics study involved examining every baby born to atomic bomb survivors, looking for abnormalities of structure or function, and determining whether these abnormalities were the result of mutation. The method involved comparing survivors with a statistically matched group of offspring from parents who had not been exposed to the atomic bombings. This would be a difficult assignment under any circumstances, in postwar Japan made even more difficult by virtue of the sometimes-strained social relationships between local residents and the occupying Allied forces, and the sensitivity of the questions addressed by the genetics research. Many Japanese expressed anger over the use of the atomic bombs by the United States, and the studies conducted primarily by American scientists and physicians were the subject of intermittent controversy for three decades. In 1975 the ABCC was renamed the Radiation Effects Research Foundation, and reorganized as a joint Japanese-U.S. program with more balanced funding and participation.

Neel’s genetics work in Japan, much of it carried out with his coauthor, the geneticist William J. (Jack) Schull, who joined him in Japan and in Ann Arbor in 1949, was both empirically rich and frustratingly inconclusive. In papers and reports spanning almost fifty years, Neel, Schull, and their colleagues attempted to construct compelling quantitative data about radiation risk for heritable mutations. As new technologies appeared—computing, electrophoresis, molecular genetics, and gene mapping— they were applied to the Japanese materials. But genetic effects remained elusive and unclear, and as several observers have noted, the most striking result of fifty years of work on these questions is that there is in no instance a statistically significant effect of parental exposure, in any of their studies (Schull et al., 1981). While compelling evidence of elevated cancer risk in the affected population emerged quickly, evidence for genetic effects was never clear or robust. The data from Japan at times even seemed to suggest that human beings were less sensitive to the mutagenic effects of radiation than were mice or flies, the primary experimental organisms used in radiation experiments (Neel and Schull, 1956; Neel and Lewis, 1990).

The work on the survivors produced data that were widely recognized as the most important available on the genetic effects of radiation in human beings, and that played an important role in the global, long-term assessment of radiation risk and the establishment of radiation protection standards. Neel and others involved in the study knew when it began that they would be looking not for unique radiation effects, but only for a possible slight increase in the types of defects that would normally appear in any population. They also knew that the numbers might be too low to yield statistically significant genetic results. They were convinced, however, that it was important to undertake the study regardless, because of the high public stakes in accurate scientific data about radiation risk.

In his 1994 autobiography, Neel identified the attempt to understand the genetic effects of radiation as one the most significant points of intersection between the science of genetics and societal concerns, and as the most comprehensive project in genetic epidemiology ever undertaken (p. 246). Certainly it was an unusual opportunity to test theories about mutation against the realities of human exposure to a known mutagenic agent.

The Thrifty Genotype and Amerindian Work In the late 1950s, Neel’s interests in human evolution led him to consider how environmental changes could transform a genetic trait from an advantage to a disease. His 1962 paper on diabetes mellitus as a “thrifty genotype” remains a key source for work in genetic epidemiology and is still frequently cited. It outlined one of his most provocative lines of research.

In that paper, Neel proposed that some modern diseases that seem to be obviously disadvantageous might have facilitated survival at one time in human evolution. In other words, an evolutionary strength could become, under different circumstances, a disease. His key example was non-insulin-dependent diabetes, a disease that even by 1960 was becoming a public health problem in the industrialized world. Neel suggested that the quick insulin trigger in this form of diabetes was a practical asset to people living on feast-or-famine regimes. With a near-starvation diet, the ability to conserve glucose is a major asset. If the pancreas secretes insulin quickly in response to elevated blood sugar, then glucose loss is minimized, which would be important to people with intermittently severe dietary restrictions. But with the rise of urbanized and industrialized societies, and an overabundance of access to food, this quick response became problematic. Neel and other observers made the comparison to sickle-cell anemia: perhaps the gene facilitating quick insulin response was most advantageous in the heterozygous form, a circumstance that would preserve the gene in the general population and explain the rising risk of diabetes in prosperous, well-fed populations. Since 1962, Neel’s thrifty genotype has been invoked frequently to explain the epidemics of obesity and non-insulin-dependent diabetes in populations all over the world.

In 1962, the same year that he published on the thrifty genotype, Neel traveled to Brazil to carry out his first fieldwork with isolated populations in South America. Neel may have been interested in South American Indians before 1955, but his relationship to Francisco Salzano played a critical role in the initiation of actual field research in Brazil, which then led to other studies in Panama, Costa Rica, and Venezuela. Salzano, a Drosophila geneticist then at the University of Rio Grande do Sul, came to Neel’s laboratory with a Rockefeller Foundation grant to study human heredity. One of his projects during his year in Ann Arbor was to prepare a summary paper on studies of Amerindian groups, and this paper, published in 1957, suggested some of the inadequacies of earlier studies, which generally dealt only with comparative blood grouping. Human population genetics research, Salzano and Neel agreed, should be much broader, encompassing studies of disease pressure, social practices of reproduction, diet, and environmental risks. The selection pressures shaping the lives and health of isolated populations, Neel proposed, provided some insight into the circumstances of human evolution.

Neel commonly invoked the threat of “civilization” as an urgent justification for his Amerindian studies. He said that the relatively few remaining primitive populations of the world were so rapidly being disrupted that his generation was almost surely the last to encounter any such groups in relatively undisturbed condition. He was also attracted to the “vanishing world” of the Amerindian, interpreting the grueling fieldwork that he undertook in remote and difficult-to-reach locations as a test of his own character.

For about thirty years, Neel and his colleagues and students from Ann Arbor carried out work in a large number of Yanomami villages, and with about twenty other tribes in South and Central America. The work was supported by the Atomic Energy Commission, which had also been paying for the work in Japan, on the premise that isolated populations, living in environments relatively free of industrial pollutants, could provide data about the elusive “natural” mutation rate of human populations. One result was the collection of about fifteen thousand blood samples, which revealed an unexpectedly high level of genetic variation in such isolated populations. Human genetic diversity, Neel’s work suggested, was maintained even in small groups, presumably by practices of kinship and marriage among local villages. Neel also proposed that the physiology of these remote groups was rapidly changing. The most isolated populations had radically lower blood pressure and glucose levels and very different patterns of infectious disease ecology, when compared with more urban populations.

In 1970 the work in Venezuela became the subject of one of the most widely used teaching films in the discipline of anthropology: The Yanomamo: A Multidiscipli-nary Study, a film favored by anthropologists to introduce generations of college students to fieldwork. Neel features prominently in the forty-five-minute film, as both narrator and participant. He tells the story of a trip to a village, the diets and habits of its inhabitants, and the research undertaken there. Accompanying him, and featured in the film, is the young cultural anthropologist Napoleon Chagnon, who began his work in the Amazon while he was a graduate student at the University of Michigan.

The Controversy over the Yanomami Neel had the distinction of becoming, only a few months after his death, the focus of a major international controversy. It was sparked by the journalist Patrick Tierney’s book, Darkness in El Dorado: How Scientists and Journalists Devastated the Amazon (2000), in which Tierney proposed that Neel, Chagnon, and other scientists working with isolated populations had engaged in unethical and even murderous behavior. Tierney claimed that Neel had intentionally used a “virulent” and outdated form of vaccine during a 1968 field trip to study the Yanomami living along the Orinoco River. Neel allegedly wanted to produce a measles outbreak that would provide a field test of his theories about the differential survival under disease pressure of those with male dominance genes.

Compelling evidence that the epidemic began before Neel reached the field, and that he provided rapid and responsible medical care to those affected, was very soon made public. Tierney’s claims about the vaccine itself were also quickly refuted by an appeal to scientific reports and documents from 1968, and by testimony from contemporary immunologists familiar with the vaccine used. Colleagues who had worked closely with Neel in South America testified to his humane treatment of those he studied, as did his own meticulous field notes, correspondence, and other archival materials. Public criticism of Neel was rapidly tempered, but the controversy itself, later focusing much more on Chagnon, continued to unfold. Organizations such as the National Academy of Sciences and the American Anthropological Association produced major reports about it, and it became the impetus for a widening debate about the proper treatment of populations under study around the world. An influential and respected researcher, the winner of numerous honors and awards, Neel became perhaps most famous for his role in this controversy some seven months after his death.

Geneticist Who Emphasized Environment Throughout his career Neel was markedly productive, publishing more than 650 articles and 10 books. These included a widely used textbook of human genetics, written with Schull (1954), an autobiography (1994), and several book-length reports about his work with populations in Japan (1956, 1965, 1991). He was a major force in shaping the field of human genetics through his teaching, his mentoring of postdoctoral students, and his public role in society. His honors included the Lasker and Allen Awards, the National Medal of Science, and membership in the National Academy of Sciences.

Unlike a later generation of scientists interested in human genetics, Neel was resolutely convinced that genetic health depended not on mining disease genes, but on improving the human environment. He sought to understand heredity as a guide to understanding how the environment should be organized so as to facilitate human health. In a 1974 lecture Neel observed that there was growing evidence that malnutrition in the early years of life affects intelligence. He proposed that if it is true that better nutrition improves intellectual performance, then any nation would have much more to gain from feeding its children well than it could possibly gain from conquering a dozen genetic diseases. The claim was an implicit criticism of the growing emphasis in human genetics on identifying disease genes, an emphasis that grew only more intense with the rise of the biotechnology industry and the Human Genome Project.

Neel was a complicated twentieth-century figure, a scientist who was interested in addressing major, and often sensitive, questions about evolution, human population genetics, and the human future. He became a human geneticist in the wake of eugenics, even writing an early paper based on data about the inheritance of red hair that he collected at the Eugenics Records Office in Cold Spring Harbor, New York. By the time of his death in 2000, the “complete” human genome had been mapped and genomic medicine was a social and political reality. His life thus spanned a period of dramatic and important scientific change, during which the field he chose became central to public support of the biological sciences and to the biotechnology industry. He was in some ways resistant to these changes, less interested in mapping genes than in understanding gene-environment interactions.

BIBLIOGRAPHY

Neel’s papers, including a complete bibliography of his publications, are held primarily at the American Philosophical Society in Philadelphia. Other materials relevant to his work are held in the ABCC collection at the Houston Academy of Medicine–Texas Medical Center Library, in the Bentley Historical Library at the University of Michgan at Ann Arbor, and in the archives of the National Academy of Sciences in Washington, DC.

WORKS BY NEEL

“A Study of a Case of High Mutation Rate in Drosophila Melanogaster.” Genetics 27 (1942): 519–536.

“The Inheritance of Sickle Cell Anemia.” Science, n.s., 110 (1949): 64–69.

With William J. Schull. Human Heredity. Chicago: University of Chicago Press, 1954.

With William J. Schull. The Effect of Exposure to the Atomic Bombs on Pregnancy Termination in Hiroshima and Nagasaki. National Academy of Sciences–National Research Council Publication 461. Washington, DC: National Academy of Sciences–National Research Council, 1956.

“Diabetes Mellitus: A ‘Thrifty’ Genotype Rendered Detrimental by ‘Progress’?” American Journal of Human Genetics 14 (1962): 353–362.

With William J. Schull. The Effects of Inbreeding on Japanese Children. New York: Harper and Row, 1965.

“Our Twenty-Fifth. ” American Journal of Human Genetics 26 (1974): 136–144.

With William J. Schull and Masanori Otake. “Genetic Effects of the Atomic Bombs: A Reappraisal.” Science 213 (1981): 1220–1227.

“Curt Stern, 1902–1981.” Annual Review of Genetics 17 (December 1983): 1–11.

With Susan E. Lewis. “The Comparative Radiation Genetics of Humans and Mice.” Annual Review of Genetics 24 (1990): 327–362.

With William J. Schull. The Children of Atomic Bomb Survivors: A Genetic Study. Washington, DC: National Academy Press, 1991.

Physician to the Gene Pool. New York: John Wiley, 1994.

OTHER SOURCES

Crow, James F. “Jim Neel—Some Memories.” Mutation Research 543 (2003): 93–96.

Lindee, M. Susan. Suffering Made Real: American Science and the Survivors at Hiroshima. Chicago: University of Chicago Press, 1994.

_____. Voices of the Dead: James Neel’s Amerindian Studies.” In Lost Paradises and the Ethics of Research and Publication, edited by Francisco M. Salzano and A. Magdalena Hurtado. Oxford: Oxford University Press, 2004.

Morton, Newton E. “Darkness in El Dorado: Human Genetics on Trial.” Journal of Genetics 80 (2001): 45–52. _____. Recollections of James Neel.” Mutation Research 543 (2003): 97–104.

Pauling, Linus, Harvey A. Itano, S. J. Singer, and Ibert C. Wells. “Sickle Cell Anemia: A Molecular Disease.” Science 110 (1949): 543–548.

Salzano, Francisco M. “The Blood Groups of South American Indians.” American Journal of Physical Anthropology 15 (1957): 555–579.

_____. James V. Neel and Latin America—Or How Scientific Collaboration Should Be Conducted.” Genetics and Molecular Biology 23, no. 3 (2000): 557–561.

Santos, Ricardo Ventura. “Indigenous Peoples, Postcolonial Contexts and Genomic Research in the Late 20^th Century: A View from Amazonia.” Critique of Anthropology 22, no. 1 (2002): 81–104.

Schull, William J. “James Van Gundia Neel, March 22, 1915–February 1, 2000.” In Biographical Memoirs, vol. 81. Washington, DC: National Academy of Sciences, 2002.

Tierney, Patrick. Darkness in El Dorado: How Scientists and Journalists Devastated the Amazon. New York: W.W. Norton, 2000.

Weiss, Kenneth M., and R. H. Ward. “Obituary. James V. Neel, MD, PhD (March 22, 1915–January 31, 2000): Founder

Effect.” American Journal of Human Genetics 66 (2000): 755–760.

M. Susan Lindee