"Happy are those who dream dreams and are ready to pay the price to make them come true."
- L.J. Cardinal Suenens
"The introduction of inbred strains into biology is probably comparable in importance with that of the analytical balance in chemistry."
- Hans Gruneberg
The inbred laboratory mouse has become an indispensable tool in numerous areas of biological and medical research. Many fields of investigation either had their origin or altered their direction in response to the availability of this remarkable creature. Our current realization of the potential of the inbred mouse has developed over a period of more than 70 years and reflects the dedicated research of many skilled and imaginative scientists. Perhaps because of the protracted period of time over which the utility of these mice became increasingly apparent and the attention given to striking developments arising from studies of recent investigators, the scientific community has never chosen to recognize the fundamental contributions made by the pioneering men and women responsible for the development of inbred strains, their worldwide distribution, and the early demonstrations of their potential for use in biomedical research.
On February 14, 1978, this oversight was partially corrected in the form of a historic awards ceremony paying tribute to those who made the most profound contributions to this field of science -- Drs. Clarence C. Little, Leonell C. Strong, Jacob Furth, Howard B. Andervont, Walter E. Heston, George D. Snell, Margaret C. Green, and Earl L. Green. The ceremony, attended by more than 200 students of various scientific disciplines, began with a series of talks, which comprise the first part of this book, by each of the honored scholars or their representatives. Dr. Elizabeth S. Russell spoke on behalf of Dr. Little who died in 1971. Dr. Margaret K. Derringer stood in for Dr. Andervont who was unable to attend for medical and personal reasons, and Ms. Jean Holstein spoke for Dr. Snell who contracted the "Russian flu" the weekend before the meeting. The ceremony closed with the presentation of medals ( Figure 1 ) and a monetary prize to each of the honored scientists. It was a grand occasion!
These collected talks, along with the presentation by another founding father of studies in inbred mice, Dr. Clyde Keeler, yielded new insights into the early history of mouse biology and should provide all students in this field with a perspective on this period of time which was not previously available. Additional references of major value in understanding the progress made in developing and using inbred strains are Dr. Keeler's 1931 monograph The Laboratory Mouse. Its Origin, Heredity and Culture ( 1), Biology of the Laboratory Mouse from The Jackson Laboratory ( 2), and articles by Staats ( 3), Heston ( 4), and Strong ( 5). Plans are also under way to publish a history of The Jackson Laboratory.
To those immediately familiar with the history of the laboratory mouse it will be clear that many gaps still remain in the literature on the people and events of early mousing. To name, at this time, others who made contributions of scarcely less importance than those of the award recipients would be invidious. I wish, however, to make two brief exceptions to this rule. These are to note the accomplishments of Dr. William E. Castle and Miss Abbie E.C. Lathrop, the former for his development of minds and the latter for her development of mice.
There are some remarkable similarities between the lives of these two people. They were born within one year of each other in small midwestern towns as children of school teachers. After obtaining their college degrees, both taught school for several years before moving on to other careers in Massachusetts. There, during the first decade of this century, they both became deeply involved in mammalian genetics and their pathways intersected. This fortuitous union resulted in the predominant use of the inbred mouse as a tool for studying "experimental evolution" for the next 70 years.
The story of William Ernest Castle's ( Figure 2 ) life is well known and his place in history secure. Castle was born in Alexandria, Ohio, in 1867. His interest in natural science, first expressed in his farm-boy childhood, was extended during his college years at Denison University under the tutelage of Clarence J. Herrick, professor of geology, zoology, and botany. Following graduation in 1889 he taught Latin for three years before moving to Harvard University to obtain a second A.B. degree and to work under the direction of C.B. Davenport.
In 1895, Castle obtained his Ph.D. degree under E.L. Mark, having worked on the embryologic development of Ciona intestinalis. Two years later, he received an appointment to teach at Harvard where he was to remain until his retirement in 1936.
A listing of Castle's publications reveals an interesting gap between 1900 and 1903. It was during this time that papers by deVries, Correns, Tschermark, Davenport, and Bateson -- all related to the rediscovery of Mendel's work -- were published. These writings irreversibly altered his direction and from Castle's point of view, "Here was where genetics began" ( 6). Thereafter, the work of Castle and his students and the history of mammalian genetics in this country are inextricably linked.
The opportunity for Castle to extend his advocacy of Mendelian principles to advanced students of biology came about with the opening of the Bussey Institution for Applied Biology in 1908 ( Figure 3 ). From that time until its closing (and his retirement) in 1936, Castle directed 16 students to completion of their Doctor of Science degree. Their names and the year in which they received their degree are shown as the "front" branches of the Castle family tree ( Figure 4 ). This construction originated from the contributions of Margaret M. Dickie on the occasion of Castle's 87th birthday and his investiture as an honorary trustee of The Jackson Laboratory ( 7). The "back" branches give a partial listing of the succession of visitors from the United States and other countries who benefited from Castle's formative influence in the development of mammalian genetics. These primary students have, in turn, been responsible for second and third generations of "Castlian" students, passing on the wisdom of the man and redeveloping the air of excitement which those at the Bussey experienced. This tree is far from being complete in the later generations, and I apologize to any who might feel slighted by not being included in its arborization.
Although only 13 of Castle's 246 publications were concerned primarily with mice, even a brief scanning of this family tree is sufficient to understand his pervasive influence on mouse genetics. Five of the award recipients from this meeting are found in branches of this tree -- Little, Strong, Snell, Heston and Earl Green -- as are a number of those who participated in the conference -- Keeler, Law, Russell, Bennett, Flaherty, Graff, Cherry, Potter, Staats, Hoffman, Hutton, and others. I am sure that many of the readers of this book will be proud, as I was, to work out their place on this abundantly fruitful tree.
Following Castle's retirement from Harvard in 1936, he moved to Berkeley to become a research associate in mammalian genetics at the University of California. There he continued his lifelong interest in color inheritance of mammals in studies of horses with a special focus on the Palomino breed. After a brief illness, he died on June 3, 1962.
Miss Lathrop's contributions to the development of inbred mice are much less well known but are nonetheless of major historical import. I am not the first to draw attention to her work as she is mentioned briefly in Biology of the Laboratory Mouse ( 2), Biology of the Histocompatibility-2 Complex of the Mouse ( 8), in a paper by Potter and Lieberman ( 9), and she was the subject of an article by Shimkin in Cancer Research ( 10).
Miss Abbie E.C. Lathrop ( Figure 5 ) was born in Illinois in 1868 to parents, both school teachers, who moved to Illinois from near Granby, Massachusetts. After receiving her degree from an unknown institution, she taught for several years before having to retire because of an illness which would later take her life, pernicious anemia. She moved to Granby around 1900 and, after a brief but futile fling at poultry farming, came upon the idea of raising small animals for sale as pets. "Her beginnings were small -- about as small as they could be, as she started with a single pair of waltzing mice which she got in this city [Granby, Mass.]. Her stock increased gradually and she advertised to buy mice. She received letters from people who thought she had them to sell, and she always made the effort to fill such stray orders. After she had sold 200 or 300 mice Miss Lathrop thought the resource of mouse farming as a business must be very nearly at an end, since the offspring from that number would be enough to supply pets for the entire younger generation, but the orders continued to come in." ( 11).
The source of the orders also changed drastically. Instead of receiving requests from mouse fanciers interested in obtaining creamy buffs, red creams, ruby-eyed yellows (very rare) or white English sables, she had orders for mice by the hundreds coming from research laboratories as far away as St. Louis and New York and as close as the Bussey Institute of Boston. It is more than likely that C.C. Little's classic studies on coat color genetics in mice, begun in 1907, were performed with mice obtained from Miss Lathrop's farm. Castle acknowledged, in a note sent to Dr. Michael Potter in 1958, that many of the mice used at the Bussey were purchased from Miss Lathrop ( Figure 6).
Abbie was initially confused by this increased interest in her mice, "but the truth came out that the mice are used in laboratories for scientific research as to the causes and treatment of various of the ills that human flesh is heir to. Cancer principally is greatly illuminated by the aid of these little creatures which are subject like people to the ravages of the fearful disease. In one of the cages of Miss Lathrop's mouse barn may be seen a lively little fellow with a lump upon his shoulder as big as a hickory nut. His days are numbered, for the cancerous tumor will strike a vital spot before very long and, with the delicacy characteristic of creatures low on the scale of life, he will probably succumb" ( 11).
This article was written in 1913 and clearly reflects Miss Lathrop's, by then, substantial scientific expertise in cancer research. At least five years earlier she had noted that her breeding program was being adversely affected by the development of "skin lesions," and mice were sent to a number of institutions purchasing the mice to determine the cause of the malady. For her, the most significant recipient of these ailing mice was Leo Loeb, then at the University of Pennsylvania. His diagnosis was "cancer" and by negotiations, as yet unclarified, it was arranged that experiments designed by him would be carried out by Miss Lathrop in Granby ( 10). This union proved extremely fruitful and, between 1914 and 1919, resulted in the publication of ten manuscripts (listed in reference 10). Their studies demonstrated that a) the incidence of mammary tumors varied among different families of mice, b) the incidence of tumors in crosses between high and low tumor families was like that of the high strain, and c) that pregnancy increased their frequency and that ovariectomy reduced it.
The careful records required to document these facts were kept in small hard-backed bound notebooks, now in the possession of Joan Staats at The Jackson Laboratory. A reproduction of one of the pages from these books is shown in Figure 7. These and other documents reveal that Abbie bred mice from the wild, foster-nursed mice, noted that the yellow coat color did not breed true, performed autopsies ( Figure 8, left), and had inbred mice to F12 by late 1915 ( Figure 8, right)! With approximately two and a half generations of breeding attained per year, this means that she must have started these lines around 1910, only one year after C.C. Little initiated the inbreeding of his dilute brown non-agoutis. One wonders if this effort resulted from her contacts with Loeb or perhaps with Little.
It is quite remarkable to recognize that these scientific feats were accomplished during a period when the demands on her time to care for the business of selling mice and other pets were at their peak. From around 1910 until her death in 1918, Miss Lathrop's barn and sheds contained more than 11,000 mice, several hundreds of guinea pigs, rabbits and rats, and occasional ferrets and canaries. The mice were housed in light-tight wooden boxes, filled with straw, and were fed on a diet of crackers and oats. "Every 2 months 25 barrels of crackers must be laid in stock to supply their appetites, and a ton and a half of oats is their monthly portion" ( 11).
Children of the town were hired at seven cents an hour to periodically clean the cages and were allowed free access to the always fresh cracker barrels as a bonus. The cages were watered daily "in little jars which are first boiled as a protection against disease germs" ( 11). Of particular interest, in view of Dr. Earl Green's comments (this volume) on the primitive mouse watering provisions which he found in Ohio as a student, is the observation that "on some of the [mouse] cages, Miss Lathrop has rigged a device for giving them water. It is a bottle with a feed tube, from which a drop constantly hangs down into the cage, and a thirsty mouse has only to stand on his hind legs to quaff a cooling drink" ( 11).
Abbie's forerunner of The Jackson Laboratory production unit sold mice to laboratories across the country. The market price varied according to the age of the mice, their color and other points, ranging from $10 to $20 per hundred. However, she continued to sell fancy mice as pets to the local children. In return for his 15 cents a child would receive a waltzing mouse or hooded rat and a brief lecture on pet care. "In schoolmarm fashion, she warned against neglecting the mice or handling them too much"( 12).
Miss Lathrop actively pursued her business and scientific interests in her mice until her death at the age of 50 in 1918. Her grave in West Cemetery, Granby, is marked by a simple stone. The little white house by the side of the road near Five Corners in Granby is all that stands of a reminder of the Granby Mouse Farm ( Figure 9). From time to time, there have been suggestions that a marker be placed at the farm to honor Miss Lathrop's accomplishments, but this has never been done. Nonetheless, the memory of Miss Abbie Lathrop will not soon be forgotten for almost all of us involved in mouse biology have daily reminders of her contributions in the form of today's inbred mice. Their roots, in many cases, can be traced back to ancestors who spent their lives in the wooden boxes of Miss Lathrop's farm ( Figure 10).
These and other inbred strains shown in this figure were the focus of the rest of the meeting and this book.
The basic science areas considered in this publication touch upon a wide spectrum of disciplines including cancer research, immunology, biochemistry, hematology, pharmacology, virology, cytogenetics, theoretical and applied genetics, and zoology. It was clearly impossible to cover all fields of investigation in which the inbred mouse plays a major role, but this sampling of these fields provides a cross section of scientific endeavors which are rarely included in a single program or volume. This format provided some unique opportunities for cross-fertilization among scientists involved in highly divergent fields of research and will give the reader of this text a taste of some of the more recent and intriguing developments in murine biology.
Finally, I wish to express my gratitude to those who did so much in helping with the planning for this meeting and publication of this book. I am personally indebted to Drs. Michael Potter, Wallace P. Rowe, and Lloyd J. Old for the many hours they spent providing advice, support, and encouragement. I also wish to thank Dr. Richard Asofsky for his enduring understanding of and many contributions to my peripatetic wanderings in science and the development of this program and publication. This effort would have been impossible without generous financial support from the Cancer Research Institute through Mrs. Helen C. Nauts, the National Institute of Allergy and Infectious Diseases through Drs. John Seal and Richard Krause, from the National Cancer Institute through Dr. William Terry, and the Division of Research Services of the National Institutes of Health through Dr. Joe Held. Joan Staats of The Jackson Laboratory and Ellen DiCarlo of the Holyoke (Mass.) Transcript-Telegram provided invaluable assistance in piecing together Miss Lathrop's history. Dr. William B. Castle, W.E. Castle's son and my professor of hematology in medical school, was very helpful in directing me to sources of information on his father's life and professional activities. Lastly, I wish to thank Academic Press for their courage in supporting this effort and to express my gratitude to Stoney Welsh for his multiple contributions to the development of the meeting and this book.
1. Keeler, C.E. (1931). The Laboratory Mouse. Its Origins, Heredity and Culture. Harvard University Press, Cambridge.
2. Staff of The Jackson Laboratory. (1966). Biology of the Laboratory Mouse. Second Edition. McGraw-Hill Book Company, New York.
3. Staats, J. (1976). Cancer Res. 36: 4333.
4. Heston, W.E. (1949). In Lectures on Genetics, Cancer, Growth and Social Behavior, p. 9. Roscoe B. Jackson Memorial Laboratory, Bar Harbor, ME.
5. Strong, L.C. (1942). Cancer Res. 2: 531.
6. Dunn, L.C. (1965). In "Biological Memories." National Academy of Sciences 38: 33.
7. Russell, E.S. (1954). J Hered. 45: 211.
8. Klein, J. (1975). In Biology of the Mouse Histocompatibility-2 Complex, p. 30. Springer-Verlag, New York.
9. Potter, M., and Lieberman, R. (1967). Adv. Immunol. 7: 91.
10. Shimkin, M.B. (1976). Cancer Res. 35: 1597.
11. Springfield Sunday Republican, October 5, 1913, p. 12.
12. Holyoke (Mass.) Transcript-Telegram, July 12, 1968, p. 14.
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MGI.
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MGI.
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MGI.
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MGI.
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PubMed.
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PubMed.