It is a great privilege for me to describe the contributions of Clarence Cook Little to the origin, maintenance, and widespread use of mouse inbred strains. I wish he could be here to tell us in person about this fascinating business, for his recounting of the tales would add to the joy of all of us. " Prexy" -- I will have to call him by that name from here onward, since Clarence Cook Little is much too formal a title for such a friendly man -- was one of the world's best raconteurs, with a real relish for the interplay of human personalities.
I deem myself luckier than the other speakers this morning. They will inevitably feel constrained to be strictly scientific and objective and thereby will be overmodest in describing their personal contributions. Since I will be describing another person's role, it is appropriate for me to say that Prexy's character and personality, as well as his scientific acumen, contributed greatly to the origin and growing importance of inbred mice.
In preparing this account, I have asked many questions and received invaluable information from many people. I would like at this time to acknowledge special help from the direct memories of Elizabeth Fekete, Joe Murray, and George Snell; Joan Staats' invaluable archives and her Classified Bibliography of Inbred Strains of Mice; from the excellent biographical memoir on Little prepared by George Snell for the National Academy of Sciences; from the early scientific papers by the original Jackson Laboratory staff members; and from recent historical searches by Jean Holstein.
Three basic interests directed the scientific career of Clarence Cook Little: genetics, biological individuality, and cancer ( 1), but his influence went far beyond the scientific papers he contributed. Prexy was altruistic, charming, full of charisma, enthusiastic, idealistic, innovative, and in some ways unconventional and impractical but very persistent. He loved life. He had great powers of persuasion, but also appreciated and supported the efforts of his fellow man. Sometimes he may have placed two much trust in the altruism and idealism of others. He was a true "evangelist of science" and, to an extraordinary degree, his unique qualities fostered and shaped the history of inbred mice.
Clarence Cook Little was born in 1888 in Brookline, Massachusetts, where he grew up surrounded by a variety of animals, including dogs, cats, pigeons, and mice. His father introduced the long-haired dachshund to the United States, and both he and Prexy were much in demand as judges at dog shows. It is easy to see why he was attracted to biology when he was an undergraduate at Harvard College from 1906 to 1910. This was a heady period in the development of the new science of genetics. Following the rediscovery of Mendel's papers in 1900, biologists were eager to identify segregating factors (no one yet called them genes) and to check out the working of his laws on segregation and independent assortment in many different species. My uncle, George Harrison Shull, wrote a theoretical paper, "On the Composition of a Field of Maize" ( 2), about gene distribution in a cross-breeding species in 1908 when Prexy was a junior. Johannsen, in Denmark, had developed pure strains of beans by inbreeding through repeated generations of self-fertilization and was studying the interactions of genes and environment. The Bussey Institute of Harvard University, established in 1909 with William E. Castle as director, became a center for both plant and animal genetics, and at the Institute there was much discussion of genetic fixation by inbreeding. Sewall Wright, whom I regard as one of the deepest thinkers about principles of inbreeding and the types of characters fixed ( 3), was one of Prexy's fellow students and friends, as was E.C. MacDowell with whom he later worked at Cold Spring Harbor. Castle sponsored students working on genetics even earlier than 1909, and Prexy began working with him in 1907 on the inheritance of mouse coat color. Castle and Little published two papers from his undergraduate work ( 4, 5), the first establishing the pink-eye ( p) locus as distinct from dilute ( d) and albinism ( c), and the second deducing that dominant yellow ( Ay) is a lethal homozygote, not an easy conclusion in those days. That second paper, in particular, makes very exciting reading. No wonder The Jackson Laboratory has always welcomed student research trainees! Prexy also started in 1909 to mate brother-sister pairs to maintain his newly established homozygous dilute brown non-agouti stock. It would be very interesting to know when and how Prexy's major interest in his dilute brown non-agouti mice shifted from their coat color to their cancer incidence.
After graduation, he remained at the Bussey Institute to obtain his D.Sc. degree in 1914, and worked with E.E. Tyzzer at Harvard from 1914 to 1916. By 1915, he was arguing with Maude Slye in Science about the inheritance of cancer ( 6, 7). She followed incidence of cancer in long pedigrees of mice, but did not, of course, inbreed them, and never attached a Mendelian interpretation to her results. From 1915 on, Little and Slye continued to argue about heredity and cancer, and I enjoyed sitting in on such a confrontation in 1936. Prexy worked on genetic control of acceptance of tumor transplants with Dr. Tyzzer, and their work resulted in two papers based largely on crosses between Japanese waltzing mice and mice from the "most homogeneous stock of common (house) mice that had been bred at the laboratory of the Bussey Institution. All the present animals are direct descendants of a single pair of closely related dilute brown (silver fawn) mice obtained in the spring of 1909. From the start the stock has been kept free from any outcross and has therefore an unbroken stretch of more than twenty generations of inbreeding" ( 8). Also in 1916, Little, discussing the relation of heredity to cancer in man and animals, philosophized that animal studies "have proved beyond question that hereditary factors play an extremely important part in determining the incidence of cancer in mice," but "none of the material thus far employed in investigations with spontaneous tumors meets the requirement of 'homogeneity of genetic constitution' needed to determine the 'method of inheritance' of susceptibility to cancer" ( 9). By 1916, he must already have been dreaming of using his DBA mice for studies of mammary tumor susceptibility.
Prexy was in the U.S. Army during World War I, and following his discharge late in 1918, he decided to accept a position at the Carnegie Institute of Washington at Cold Spring Harbor, rather than to return to Harvard to work with Tyzzer. He wanted to devote full time to research on genetics and cancer in mice, and felt this would be more possible in a laboratory devoted completely to research than at a medical school. His correspondence at this time reveals that Tyzzer had maintained the DBA inbred stock through the war years, for which we must all be grateful (Holstein, personal communication). Prexy built up his DBA colony at Cold Spring Harbor and also started the development of a new "family" of inbred strains, descended from mice received from Miss Abbie Lathrop, a mouse supplier from Granby, Massachusetts. She seems, by the way, from records now in the possession of Joan Staats at The Jackson Laboratory, to have been a very responsible person who knew a great deal about the characteristics of her animals. In his line C, descended from Lathrop's stock, Prexy mated female 57 and female 58 to male 52. The descendants of female 57 became the C57BL inbred line, the descendants of female 58, the C58 inbred line. Prexy himself inbred the C57 stock, and his colleague, E.C. MacDowell (a former Castle student), developed the C58 line. (Later on, J.M. Murray was responsible for inbreeding the portion of the pedigree that eventually became C57BR and C57L.)
During the decade of the 1920s, Little became involved in educational administration and innovation, but insisted at the same time on continuing and expanding his research on genetics and cancer. At this period he seems to have been a central figure in an informal group called "Mouse Men of America," whose members exchanged information and mouse stocks and got together at scientific meetings. The membership, which grew to approximately 100, included Prexy and his growing research group, Halsey Bagg, L.C. Dunn, John Gowen, and E.C. MacDowell (J.M. Murray, personal communications). Some of the present-day subline differences may possibly be attributed to that extensive interchange of stocks not yet genetically fixed.
Little left Cold Spring Harbor in 1922 to become president of the University of Maine. His laboratory was set up at the Agricultural Experiment Station, and during the three years at Orono Joseph M. Murray, William S. Murray, and Arthur M. Cloudman joined the group as graduate students working with particular mouse stocks. Bill Murray's responsibility was the DBA stock, Joe's the C57BR stock. In 1925, Prexy became president of the University of Michigan, but one of his stipulations for accepting the position was that his research laboratory should be continued and enlarged. Graduate students and mouse stocks moved to Ann Arbor, where they were soon joined by Leonell Strong and his mouse stocks.
Here I must insert an aside, to say that I first met Prexy in 1925, because his daughter Louise was a University High classmate and close friend. I remember attending a Christmas party at the President's House -- in 1927 I think -- and admiring from afar Prexy's son Bob, who is here today.
At both Orono and Ann Arbor Prexy introduced fine new programs but, particularly at Michigan, he seems to have attempted too much too soon, and he met with considerable opposition. Although he had administrative problems, research blossomed in his laboratory, his graduate students were trained in the medical school and the zoology department, and new members were added to the group: John J. Bittner, Elizabeth Fekete, and Charles V. Green.
Prexy's move from Orono to Ann Arbor had been promoted by a group of Detroit industrialists who were also Mount Desert Island summer residents. When administrative storm clouds gathered at the University of Michigan, these friends asked Prexy what he wanted to do next. He wanted to build a laboratory devoted entirely to research on mammalian genetics and cancer, far from the confines of academia. They promised to support this endeavor, and Prexy resigned from the University of Michigan in the spring of 1929. I'm pleased to say, however, that he presented a very inspirational graduation address to the University High School class of 1929.
With Prexy's guidance, the original building of The Jackson Laboratory was constructed in the summer and fall of 1929. Gradually the mice moved in, and all the researchers (Bittner, L.C. Strong, and Prexy himself) were there by the spring of 1930. The research productivity of the first years at The Jackson Laboratory was very high -- it all must have been a good idea! For the purpose of this conference, it may be helpful to know how many and which inbred strains were then available at The Jackson Laboratory. I have used Joan Staats' Classified Bibliography to ascertain that the approximately 50 papers published between 1929 and 1936 reported work involving the following inbred strains: A, BALB/c, CBA, C57BL, C57BR, C57L, C58, DBA, N, and I; crosses between these strains, and interspecies crosses to Mus bactrianus and Mus wagneri; plus several different mutant genes. Two sublines were recognized in DBA; I know Elizabeth Fekete worked with DBA/1 and in 1937 George Woolley worked with DBA/212. C57BR/a and C57BR/cd were also distinguished. Little was directly responsible for the inbreeding of only the DBA and C57BL strains, but through the establishment of The Jackson Laboratory, he contributed greatly to the continuation and characterization of the whole array.
It was amazing that so much could be accomplished in the early years of The Jackson Laboratory, particularly as they were working under extreme financial difficulties. The year 1929 was not an ideal time for establishing what was intended to be a research institution supported entirely by private funds. Remember, there was no NIH, and no extramural granting capability way back then. I think we can attribute much of the success to Prexy's special qualities of persistence, charisma, enthusiasm, idealism, and interest in people. A particularly touching example is the publication in 1933 of the important paper on "The Existence of Non-chromosomal Influence on the Incidence of Mammary Tumors in Mice" by the staff of The Jackson Laboratory ( 10). That's team work! Incidentally, that publication was all based on DBA, C57BL (Prexy's own strains), and reciprocal crosses between them. When the supply of money dried up, as it did in 1932 and 1933, the staff voted to cut salaries back below "bare bones" budgets, lived as much as possible off the land, combined households, but continued to raise and study mice! That period of financial stringency had another effect on mammalian genetic research, which I feel has been very beneficial. The system I sometimes refer to as "Operation Bootstrap" was initiated then, I think following a suggestion by Bittner. Genetically controlled mice were supplied to outside investigators to support Jackson Laboratory research. That source of income pulled the Laboratory through a very tight time, and its continuation, gradually developing into more sophisticated arrangements, has become an important feature in the organization of biomedical research in the United States.
From all accounts I have heard, The Jackson Lab was a happy place in those early years despite the financial worries. Prexy's charisma held them together!
My assignment is to tell you about Prexy's contributions to inbred strains of mice, not to give you the entire history of The Jackson Laboratory, though the two are definitely related. By 1937, when I arrived at the Lab as an independent investigator, C.V. Green had died and Joe and Bill Murray and Leonell Strong had left for other positions (still mousy, I hasten to add). With the addition of new staff members George Snell, George Woolley, and Bill Russell, the research program became more diversified. After all, the genetic fixation that makes inbred strains useful for cancer research also fixes other characteristics that may well be studied to man's benefit. Prexy was interested in all the new undertakings, and very supportive. The Lab began to grow, with Prexy always responsible for obtaining funds. More formal student programs appeared, as well as visiting investigators, more mutant genes, and more inbred strains. We had become more systematic. One such effort you may want to hear about was carried out in 1937. From the beginning of The Jackson Laboratory, each staff member had maintained his own mouse colonies, though he would willingly supply a "breeding start" to others in or outside of the Laboratory, as geneticists have always done. Almost everyone had a colony of C57BL, and the incidence of minor anomalies such as small right eyes, malocclusion, and irregularities in position of the sacrum seemed to differ between colonies. Bill Russell had a huge pedigree chart tying together all of the C57BL colonies presently or recently at the Laboratory, and all of the stock which had been sent to outside investigators. There were 10 distinct sublines, many of them separated more than 20 generations previously. The big colonies in 1937 were C57BL/6, which Bill adopted, and C57BL/10, which George Snell maintained. The numbers were arbitrarily assigned of course. Within the sublines incidences of anomalies were similar, between sublines there were greater differences. Between 1937 and 1947, the Laboratory grew in physical size, number of staff members, and number of mice; it was a productive period, despite World War II, involvement in which led to the provision of large numbers of mice for study of tropical disease organisms.
Then came the drastic fire of October 1947 which resulted in destruction of most of the main laboratory and in loss of almost every mouse. That's when we came to appreciate the benefits of having provided inbred mice to other investigators. Letter after letter came in, offering stocks to help us get started again. Once more, Prexy's charisma kept the Lab together and, unlike the crisis of 1932-1933, this time the problem came at a particularly favorable time, if such can be said of a catastrophe. This was the beginning of growth of "big science," of research grants, of much more need for inbred mice. The destruction of The Jackson Laboratory mouse colonies, just when demand was increasing, led to much deeper appreciation by others of the former availability of these animal resources. In what I hope was a sensible plan, we accepted the offers of mice most closely related to our former stock, added some new special types that were generously offered, built up a common colony from which both in-house research colonies and animal resource colonies were derived, and arranged to carry out recharacterization of the life histories of mice from inbred strains in the common foundation colony. Prexy once more was the enthusiastic leader of a crusade with devoted followers. All experiments in progress were lost, and some staff members and assistants had to move to other laboratories for a short period, while those who remained at Bar Harbor first piled on top of each other at the Hamilton Station (site of behavior genetic studies of dogs and of rabbit genetics), then sat at desks on the open floor of a half-built animal house which was under construction at the time of the fire, and nursed the miniscule colonies of mice which began to trickle in. It was a wild time, but everyone seems to have loved it. And soon we had a new big, beautiful (for that time) mouse wing, and then new office and lab space and an auditorium. Phoenix rose from the ashes! The times were favorable, yes, but Prexy, with his energy, enthusiasm, power of persuasion, and vision, was the essential driving force.
Of course I speak from the biased viewpoint of a long-time staff member of The Jackson Laboratory. But I genuinely feel I am being objective in my conclusion that without Prexy Little the development of inbred strains of mice would have occurred much more slowly, and their use would have been much restricted. We all owe him a tremendous debt of gratitude.
1. Little, C.C. (1954). Genetics, Biological Individuality and Cancer. Stanford University Press, 115 pp.
2. Shull, G.H. (1908). American Breeders Association IV: 296.
3. Wright, S. (1922). U.S.D.A. Bull. 1090, 63 pp.
4. Castle, W.E., and Little, C.C. (1909). Science 30: 313.
5. Castle, W.E., and Little, C.C. (1910). Science 32: 868.
6. Little, C.C. (1915). Science 42: 218.
7. Little, C.C. (1915). Science 42: 494.
8. Little, C.C., and Tyzzer, E.E. (1916). J. Med. Res. 33: 393.
9. Little, C.C. (1916). Sci. Mon. 3: 196.
10. Staff of The Jackson Memorial Laboratory (1933). Science 78: 465.
See also
MGI.
See also
MGI.