James Neel

We write as a tribute to Jim Neel, whose accomplishments during his long and full life were a major factor in the development of modern human genetics. Although battling a string of formidable ailments, he was active and typically feisty to the end. Shuffleboard in the sun was not for him. It is more than a little ironic that the first two pages of the new millennium in [Am. J. Hum. Genet.], which he helped found, are devoted to his last paper. As demonstrated by his other papers published in 1999, even at 84 he was articulate, forthright, and knowledgeable as ever.

James van Gundia Neel was born on March 22, 1915, in Hamilton, Ohio. He graduated in 1935 from the College of Wooster (Ohio), where, under Warren Spencer, he investigated natural genetic variation in Drosophila. This laid the foundation for the scientific inquiry into the role of evolutionary forces particularly mutation in the genetic complexities of natural populations, which was to be the hallmark of his entire career. Jim did his graduate work at the University of Rochester (New York), pursuing genetic variability in Drosophila under Curt Stern. In 1939, with a newly minted PhD, he accepted a post at Dartmouth. There he discovered a Drosophila strain in which variability in bristle number seemed to be driven by a high mutation rate. This stimulated his lifelong general interest in mutation as a potent evolutionary force. However, with his leanings toward human genetics in particular and with war being imminent, Jim modified his career path by entering medical school at Rochester and was inducted into the U.S. Army. After residency in Rochester and a stint with the Atomic Bomb Casualty Commission (ABCC) in Japan, he assumed his lifelong post at the University of Michigan. Jim had high professional standards and did not seek personal attention, but he nonetheless quickly attained scientific prominence and eventually became the recipient of most of the important academic honors that can be bestowed on a biomedical scientist: member of the National Academy of Sciences since 1963 and recipient of the Lasker and Allen Awards and of the National Medal of Science. Over the years, he was called on for considerable national and international advisory service, although he had a remarkable ability to say no to things that he did not deem important.

Jim's first major contribution to human genetics involved the inheritance of sickle-cell anemia. In our molecular age, it is difficult to appreciate how difficult it was to discern the inheritance of these complex phenotypes, characterized by variable clinical severity in individuals of African descent. Using earlier insights from his thalassemia studies, Jim solved the problem by detailed analysis of phenotypic segregation. Controlling for ascertainment in carefully identified families, he showed that the sickle trait was the heterozygous condition and that sickle-cell disease was the recessive homozygous condition at a single Mendelian locus.

Just as he was starting his tour of duty in a U.S. Army hospital, Lieutenant Neel was summoned to Washington and was whisked onto a plane to Japan, to begin studies of the effects of radiation exposure in survivors of the atomic bombings. He arrived in 1946, just 15 months after the bombing, was a key person in the development of the scientific program, and was asked to stay on as acting director after his initial tour of duty. He thus played a leading part in establishing the ABCC (now known as the "Radiation Effects Research Foundation," or RERF) in Hiroshima, and he continued working there for decades, although from Michigan as his base.

Radiation dangers were paramount in the public mind at the end of the war. Muller had shown that ionizing radiation was mutagenic to the individual, and, for population geneticists, there were additional grounds for concern. In the prevailing theory of the time, mutation pressure was expected to introduce only a small number of deleterious mutations. These were predicted to be largely recessive, but in small populations such as had characterized our ancestry, the high probability of homozygosity would rapidly eliminate them. However, in the large, heterogeneous outbred human populations of today, with their diminished probability of homozygosity, a mutational "load" of recessive mutations could accumulate before the burden of their harmful homozygous effects was borne.

At the time there was no direct test for mutations (the DNA era had not yet dawned). Instead, in a "model of design and execution", the investigators developed a set of surrogate criteria related to birth defects and estimated the frequency of the various defects in offspring born to survivors, in relation to dose. Although the indicators were in the expected direction, the most striking result of this 40-years work was that "in no instance is there a statistically significant effect of parental exposure". Similarly inconclusive results were found in another classic mutation study, in which Jack and Jim used the comprehensive Japanese genealogical record keeping system to estimate the prevailing burden of recessive mutation, on the basis of the excess frequency of defects expected in offspring of inbred matings. Even the huge sample sizes available were insufficient for characterization of rare mutational events, especially with indirect and incomplete detection technology.

Jim's concern with the natural load of mutational effects and his realization that human population history was responsible for their amount and dispersion led to an interest in the study of humans in a more evolutionarily natural state, where those processes could be observed. He placed particular stress on the understanding of local microdemographic events through which the human evolutionary processes occurred.

Jim recognized that the cultural changes accompanying the progression from tribal society to urbanization had created novel environments for selection and that this contrast might reveal selective pressures, with consequences for human health. Reflecting this view was his "thrifty genotype" hypothesis, suggesting that in modern society susceptibility to diseases such as diabetes might be a deleterious consequence of genotypes that had formerly been advantageous in human ancestral environments, arguably one of the most influential hypotheses in genetic epidemiology.

Except for the few and the lucky, leadership goes beyond discoveries. Historians will trace the development of human genetics, now one of the most prominent of sciences, to a few determined and dedicated people. Jim Neel was a driving force among them. He was motivated by intellectual rather than by material capital. Lists of patents, citations, number of genes mapped will not tell his story. His legacy is the emphasis that he placed on the application of basic biological and evolutionary principles to genetic variation in natural populations and to the understanding of genetic etiology. This has shaped our science in a manner probably not wholly appreciated by those rushing pell-mell into biotechnology.

In his biography (Neel 1994) as a "physician to the genome" Jim lays out his vision for the future of our species. His views have received considerable attention. Taking a natural historian's perspective, Jim noted the current belief that genetic knowledge will contribute to public health by tailoring the genome to the environment. He warned that this will be a wasteful and probably losing proposition. As he repeatedly pointed out, the essential facts have been known for a century or more. Most of the complex multifactorial diseases really are just that, complex, not "genetic" in the usual sense. Their expression is heavily dependent on interaction with rapidly changing environments. [Jim believed that] much more effective and cost-efficient improvements to human well-being can be made by tailoring the environment to the genome.

He suggests that we keep our current love affair with mapping and cloning in perspective. In particular, he warns that excessive concern about genetic disease will become a trivial luxury if we do not avoid the specter of global overpopulation of the species to whose welfare he was so long dedicated.

This tribute is excerpted from K.M. Weiss and R.H. Ward, OBITUARY, James V. Neel, M.D., PhD (March 22, 1915 - January 31, 2000): Founder Effect, Am. J. Hum. Genet., 66:755-760, 2000. Please see this article for more information, photographs and references.

If you have any photos you would like to contribute to this page, please send them to the EMGS Webmaster. (Thanks to Mike Salamone for providing these historical photos from the EMGS archives.)