LITTLE, CLARENCE COOK

(b. Brookline, Massachusetts, 6 October 1888; d. Ellsworth, Maine, 22 December 1971)

mammalian genetics.

Little was the son of James Lovell Little and Mary Robbins Revere Little, a descendant of Paul Revere. He was educated at Harvard (B.A. 1910; Ph.D. 1914), taking his doctorate under William Castle, the first mammalian geneticist in the United States. He married Katharine Day Andrews on 27 May 1911; they had two sons and a daughter and were divorced in 1929. The following year he married Beatrice W. Johnson; they had a son and a daughter. He was a member of the American Academy of Arts and Sciences of the National Academy Science and received numerous honory degress.

In 1922, at the age of thirty-three, he became president of the University of Maine. Three years later he accepted the presidency of the University of Michigan, where he remained until 1929. In that year he founded the Jackson Laboratory in Bar Harbor, Maine. The original staff of the laboratory consisted of seven investigators, all of whom had been associated with him during his years as college president, and about an equal number of animal caretakers. During his twenty-seven years and become a world-renowned center for research in mammalian genetics and cancer.

From 1929 to 1945, besides his work as director of the Jackson Laboratory. Little was managing director of the American Cancer Society, twice president of the American Association for Cancer Research and an original member of the National Advisory Cancer Council created by Congress in 1937 to help established policies for the National Cancer Institute.

Little’s research was dominated by two interests: mammalian (especially mouse) genetics, and a search for the cause of cancer with emphasis on genetic factors in its etiology. His most lasting contribution to mammalian genetics was his developed of two of the earliest inbred strains of mice. Prior to 1914, while he was still in graduate school the potential of inbreeding for the production of uniform strains of plants and animals had gained general recognition among geneticists. It also was common knowledge, however, that inbreeding could cause loss of fertility and vigor. Despite the problems that this raised. Little started the inbreeding of one strain, subse quently known as DBA, while at Harvard, and a second, C57BL, a few years later. The mice were mated, brother with sister, for generation after generation. By the use of a sufficient number of animals and careful selection, he succeeded in establishing two healthy strains. While the two strains were obviously different from each other, in coat color and the incidence of cancer, the mice within each strain were strikingly alike. Throughout his career. Little insisted that his role as administration should not stand in the way of the steps necessary to ensure that these strains were maintained.

The genetic uniformity of these and other inbred strains has made them an indispensable tool in a great variety of research. In biology, they serve a function analogous to that of purified compounds in chemistry. Experiments can be repeated with the assurance that the experimental material will remain the same. The strains are widely and extensively used in laboratories throughout the world.

Another of Little’s major contributions to science also was initiated while he was in graduate school. It concerned the genetics of tissue transplantation In 1909, E. E. Tyzzer of the Harvard Medical School had reported on the growth of a transplantable tumor indigenous to one strain of mice when it was trans planted to a second quite unrelated strain, and to hybrid generations derived from crosses between the two strains. He concluded that the genetics of susceptibility to the transplants did not conform to Mendelian principles. In 1914, little published a paper in Science showing that a Mendelian inter predation was possible. In collaboration with Tyzzer, he carried out a second study that tended to confirm his interpretations.

When the Jackson Laboratory was founded the first project undertaken by the staff was a continuation of experiments on the genetics of transplan tation. The availability of inbred strains greatly enhanced the precision of the results. The results showed that susceptibility and resistance are de termined by at least twelve loci, with susceptibility being dominant. This work became the foundation of all subsequent studies in the genetics of transplantation.

Little’s third major contribution was the demonstration that, in strains of mice with a high in cidence of mammary tumors, the development of the tumors requires an agent present in the mother’s milk. The indication of this agent first came from genetic studies. The tumor incidence in hybrids be tween high-cancer and low-cancer strains seemed to be determined by the cancer incidence of the strain providing the maternal parent. The role of the mother was further established by foster-nursing experiments, which definitely proved transmission through the milk. While most of the experiments in this study were carried out by the staff of the Jackson Laboratory little played an important guiding role. Subsequent work performed elsewhere showed the milk agent to be a virus. These studies were thus an early step toward the recognition that viruses play a role in the etiology of many animal cancers.

A fourth research undertaking to which Little contributed, though almost entirely as an initiator, was a pioneering study in the genetics of behavior. The research at first was based on the use of four very dissimilar breeds of dogs but subsequently was shifted to mice. Once again, the great uniformity of inbred strains was proved to be an invaluable resource.

To an unusual degree Little combined the talents of an administrator with those of an innovative scientist. His considerable energies, his talent as a public speaker, and his ability to enlist the support of others made it possible for him to contribute significantly in both areas.

BIBLIOGRAPHY

I. Original Works. A complete bibliography of Little’s publications appears in George D. Snell, “Clarence Cook Little,” in Biographical Memoirs, National Academy of Sciences, 46 (1975), 240–263

II. Secondary Literture. Jean Holstein. The First Fifty Years at the Jackson Laboratory, William L. Dupuy, ed. (Bar Harbor. Me., 1979); Herbert C. Morse III, ed., Origins of Inbred Mice (New York, 1978); and George D. Snell, ed., The Biology of the Laboratory Mouse (Phil adelphia, 1941).

George D. Snell