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Inbred Mice in Science

Leonell C. Strong

Leonell C. Strong Research Foundation, Inc.
San Diego, California

Those of us who have been in the field so long must keep reminding ourselves that genetics is still a young science, but in terms of its power to illuminate biology, it is a young giant precociously strong and rich in promise. Some of us have known this for a very long time; for many, the importance of genetics to all biological research is a brand new revelation. The distance this science has traveled from its infancy might well be measured by Francis Bacon's analogy of knowledge as a river, narrow at its source and easy of survey, but broadening eventually into a mighty body scarcely to be encompassed. Those of us who began our labors at the source, where the stream was narrow, can readily testify that genetics is today, by comparison, a river in flood.

But I would remind you that the broader the science-river grows, the more pressing is the need to recollect and review the principles and practices lying closest to its source, for though simple and few in number, these constitute the laws, the foundation stones of a science that a tyro cannot afford to lose sight of. This is particularly true of mammalian genetics, which has forged tools now shared by nearly all disciplines in biology. Perhaps our collections and recollections in this symposium will serve a useful purpose in restating the origins, the nature, and characteristics of these living tools, the inbred mice.

The potential importance of the mouse as a model system for experimental research had been recognized as early as 1889 when it was found that malignant tumors could be successfully transplanted in the species. A period of highly naive optimism followed. It was supposed by some that, with such a splendid tool available, all the ails of mankind might be expected to yield swiftly to science. Particularly bright was the hope that the great riddle cancer might thus soon be resolved.

The "mousers," led principally by the students of E.E. Tyzzer and W.E. Castle at Harvard, and a few others, were tinkering with various aspects of mouse genetics. Halsey Bagg at Memorial Hospital in New York had an interesting albino strain under study, and C.C. Little carried the mouse model idea to Cold Spring Harbor, where he continued work on a partially inbred strain of dilute brown mice but lost his colony in a paratyphoid epidemic. Maude Slye at the University of Chicago completed a brilliant study on the dominant-recessive question of cancer in mice, almost proving the genetic link, but then drew an upside-down conclusion by misreading her data.

Optimism gradually faded as it was found that results from experiments with mice varied so greatly that an investigator often could not even verify his own observations, much less expect a second researcher in another laboratory to do so. Cancer research again fell into the doldrums.

I need not tell a gathering of geneticists the trouble with mice was their individuality. Each mouse had a unique genetic constitution that proved equally unique experimental results, and there did not seem to be much hope for remedying these shortcomings. While the science of genetics furnished the theoretical means of standardizing animals through intensive inbreeding, nature's taboos against meddling thus with the order of things were held by such high authorities as W.E. Castle and his school to be invincible.

It is certainly true that the natural scheme for preservation of the species discourages incest in an extremely effective manner. In the grip of the debilitating ailments that surface through the pairing of recessive genes, an inbreeding species grows delicate and sickly, easy prey to disease. For stragglers able to survive these hazards, a barrier of sterility looms as the tenth generation of inbreeding is approached. Few scientists seriously believed that a viable strain of inbreds could be continued, even if briefly achieved.

In 1919, headed for a career in cancer research, I was a graduate student at Columbia University under the tutelage of the celebrated Nobel geneticist Thomas Hunt Morgan. Although Morgan was skeptical about the possible genetic link in the origin of cancer, I was impressed by the prevalence of the disease in my own family and by other scattered evidence and was determined to investigate that link.

In looking for a place to begin my research, I was impressed with Professor Morgan's achievements in the application of statistical methods to biology through the use of fruit flies. With them, Morgan et al. had, only a few years earlier, discovered the sex-linked chromosome. I became obsessed with applying these same techniques of quantitation to cancer research through the science of genetics. But the fruit fly would not serve my purpose; I needed a small mammal in which cancer naturally occurs, one both plentiful and cheap to maintain.

Except for its variability, the mouse was the best available candidate, among mammals second only to man in frequency and variety of spontaneous cancer. Regrettably, the frequency of occurrence was still all too rare; a single mouse with a spontaneous tumor was selling for $300 in the laboratories on the eastern seaboard. The use of mice in the number for quantitative research necessitated a ready supply at minimal cost.

From the outset, I was leery of the transplantation technique. It seemed to me that the host factor must be of prime importance in any attempt to understand the nature of cancer, and with transplants the host was ignored or somewhat neglected. Nonetheless, lacking alternatives, I launched an experiment to measure the effect of castration on the growth of transplanted tumors.

Actual engagement in the work led me to question anew the pitfalls of the method. How, I wondered, can you distinguish between the mechanisms of cancer and the mechanisms of rejection? Also a matter for concern was the unpredictable course of transplants; sometimes they grew and sometimes they did not. Even with the most meticulous work, the success rate varied between 10 and 40%. If the tumor did grow progressively, the growth rates of the same tumor in a series would vary. Could the reason be genetic?

These first gropings spurred a change of direction; work on the effects of castration was set aside in favor of a plan to attempt genetic analysis of factors underlying susceptibility and resistance to transplanted tumors. It had been my intent to use some of C.C. Little's experimental dilute browns for my study. Accordingly, I found an opportunity to spend the summer of 1919 with him at the Carnegie Institution of Washington at Cold Spring Harbor on Long Island.

After a brief pause during which I married Katherine Bittner from my native Pennsylvania, a honeymoon residence was set up in a tent on the Cold Spring Harbor grounds where married students were being housed for the summer. The paratyphoid epidemic destroyed Little's mouse colony just as we were settling in. This forced a drastic change in plans. I was obliged, instead of setting to work with the dilute browns, to capture wild mice and start sorting out their hereditary traits through the tedious processes of mate, wait, select, and mate again. (As a note of historical interest, I recall that the best lair of wild mice was under Oscar Riddle's pigeon coop.)

Out of fear that contamination would occur in the blitzed mouse colony at Cold Spring Harbor, we kept the wild mice under the bed in the honeymoon tent. Since cages were hard to come by, any wooden box, fitted with a screen-wire over, was pressed into use. (As I recall, wooden cheese boxes were considered prize finds.) The nutritional program for the mice consisted of bread scraps begged from the mess hall, combined with wild seeds gathered in the open fields and canned milk purchased out of a very slender budget.

Later that summer, Little learned that a pair of old dilute browns survived in Tyzzer's laboratory where the strain had been started. Tyzzer obligingly shipped them to Cold Spring Harbor, but Little, seeing their advanced age, despaired of their breeding and gave them to me. I assigned them a box and put them into the tent where the wild mice were now multiplying at a rate gratifying to me and alarming to Katherine. By a visitation of pure luck, one last creative spark ignited in the old pair, but since the resulting litter contained only one female, this point of revival for the dilute browns was tenuous.

Meanwhile, my attention had become engaged with the fascinating genetic events taking place among the evolving few scattered surviving mice. Even before the analysis had been completed, it was obvious the susceptibility and resistance to transplanted tumors were indeed genetically controlled. The unfolding results cemented my distrust of transplantation as a means of tackling the cancer problem. Unknown variables in the host and its tumor were being added to unknown variables in another host and its reaction to the tumor, and these were being hopelessly compounded by adding the unknown variables of rejection mechanisms to the equation. Obviously, reliable data could not be obtained or even hoped for with the mice available.

These experimental results and deliberations were potent forces bending my mind to the task of remodeling Mus musculus. I could not see how any real progress could be made until such a tool was fashioned. The arguments against such a project had been running in my mind for some time. Maybe the much-feared sterility barrier was not as absolute as was assumed. If sufficient numbers of mice were used, it might be possible to squeak through the critical generations. As for the predicted fatal delicacy (to which the experts attributed the fate of Little's colony), it seemed to me that once all the debilitating recessive traits had been bred out, there would be room to assume that an inbred strain could be as hardy as needed, provided adequate standards of laboratory hygiene were observed.

Just how I would finance the project, which would assuredly take a few years, I had no idea. At the time there were no multi-million dollar grants or leviathan foundations to support research. Private means sustained some who wanted to do research, but we were as poor as the church mouse of proverb. Even the educational program was being completed on borrowed money. But obsession pays small heed to arguments of reason. Somehow, a way would be found to do something that needed doing so much.

Foundations for the development of a better mouse were laid in the summer of 1920. One of Halsey Bagg's albinos, which he claimed were inbred but which proved to be nothing of the sort, was chosen as the "great white mother." Another albino, borrowed from C.C. Little and originating from a commercial colony at Storrs, Connecticut, was sire. The progeny were labeled simply, alphabetically, the A strain. Homozygosity was the chief aim. To her lasting credit, Katherine encouraged the enterprise and never once flagged in her encouragement and active help throughout what was to be an extraordinary ordeal in our lives.

In July 1921, doctoral work completed, we took a proliferating mouse colony to Annandale-on-Hudson in upper New York State, where I began my first teaching appointment in the biology department of St. Stephens (now Bard) College. It was an Episcopal institution and since the current rector lived on campus our entourage, now numbering three humans and about 400 mice, was installed in the vacant Episcopal manse at Barrytown-Four-Corners. Because no laboratory was available, the mice took up residence in the upstairs back bedroom of the manse. The intense musty-mousy odor that pervaded the house was no more of an inconvenience than many others endured during that period. The arrangement was at any rate convenient since it allowed Katherine, now expecting a second child, to care for Leonell, Jr., while continuing her services as chief caretaker and statistician for the mouse colony.

This serendipity was shattered abruptly just as winter set in. Word had reached local parishioners that the manse was being profaned by unspeakable creatures. An eviction notice for the mice was not long in coming, and they were transferred to the only alternative quarters, an abandoned chicken coop behind the biology building. By nailing several layers of tarpaper on the structure to keep out the cold and installing a galvanized metal floor to keep wild rats out, we transformed the chicken coop into the first Strong Laboratory for mammalian genetics. Its only refinements were a single electric bulb powered by a wire strung from the biology building and a borrowed potbelly stove, which later proved to be a villainous piece.

A strict brother-to-sister mating system was adopted for development of the inbreds, with the exception of a few mother-to-son matings. The hardiest pair in each descent was chosen to continue the line. Gradually the numbers of non-shared genes were reduced by this means. As the inbreeding animals lost hardiness and vitality, I expanded the numbers of breeders to increase the margin of safety. Efforts to guard the mice against disease required stringent sanitation standards, and the work of caring for the colony became an increasing burden. Recording of pedigrees was another ever-expanding chore.

But the mice progressed. Soon they were eating us out of house and home quite literally. Often it was only the college garden that ensured food for our table, and Katherine had already been scolded by Bernard Iddings Bell, St. Stephen's president, for taking too freely of the vegetables. Fortunately recognition of my work had begun to spread. Through the interest of James Murphy's group I was invited in the winter of 1922 to lecture at Rockefeller Institute. As a result, Simon Flexner, institute director, made available a grant of $2,500 to support the project.

The project, however, kept expanding. Shortly after initiation of the A strain, an outcross had been made between one of these albinos and a survivor from Little's dilute browns. Cancer, though infrequent, was known to occur in both ancestral stocks. This hybrid cross was designed to test the idea that an increase in variability ought to increase the incidence of spontaneous tumors, the rationale being that cancer is just one more variable. Continued hybridizing in this stock proved the prediction true. Subsequent mating of a cancer-bearing mouse with a normal one produced the disease in the telltale 3:1 Mendelian ratio in the F2 generation, a result that became the first laboratory proof that cancer is inherited -- and as a dominant trait contrary to Maude Sly's conclusion that the trait was recessive. This historic mating was the start of the so well known C3H high-tumor subline. At the same time, selection toward resistance to cancer, set up with this stock, produced the C12I, the CHI, and the CBA. The latter, selected for longevity, will still outlive any mouse in the laboratory.

It was impossible to pass up any interesting trait that appeared in the evolving mice, and thus a great many collateral lines were set up from mice showing characteristics that were thought to be of importance for further study. This haphazard expansion constantly strained the budget. By the third year of the work, application for funds was made to Columbia. Francis Carter Wood agreed to advance $200 in exchange for 800 mice of the evolving A strain, to be delivered in a year's time. To accept meant virtually giving away all of the animals needed for my own research program, but the situation was, as usual, desperate, so the deal was accepted.

As had been expected, a kaleidoscope of congenital defects began to appear in the mice in advanced generations of inbreeding. Cleft palate, cranial and skeletal malformations, blindness, and such lethal defects as spina bifida began to decimate the ranks of the mice as paring of recessive genes opened the Pandora's box of hereditary disease and disability in the evolving strain.

By the winter of 1924, a critical stage of the inbreeding experiment had been reached. Numbers dwindled as the mice moved into the advanced generations and sterility became widespread. Even so, a handful of mice of the 7th generation were successfully mated and their littering was awaited with high expectation.

It was at this point that the coal-burning potbelly stove betrayed us. A student helper in the lab, charged with stoking the fire and banking it for the night, was in a hurry to get away for some social event on a night when I was lecturing. He banked the coal too soon, and poisonous gasses escaped into the poorly ventilated shack, wiping out 80% of the mouse colony. Assessment of the damage the next morning showed that a lone pregnant female of the A strain had survived. By so slender a thread hung the "better mouse" ancestor of countless derived sublines used ever since in medical research throughout the world. It may be guessed that the days until that mouse littered were tense, anxious ones. Luckily, none of the sublines was entirely erased in the disaster, and in due time their numbers were multiplied to a safer level.

In the spring of 1925, I was offered an appointment at the University of Pittsburgh through George Gey's interest in my work. Higher pay and research facilities made it a tempting offer, but there were serious drawbacks to moving the mice, now in the most fragile stage of evolution. I decided to discuss the offer with Dr. Bell, who assured me that my best interests would be served by staying at St. Stephans. Thus I turned the offer down. It was therefore no small surprise to discover by way of a note tacked to the bulletin board at the end of the term that my appointment was being terminated.

No satisfactory explanation for this unhappy turn of events was ever made. My elective classes had more than doubled in my second year of teaching, and my work had been pronounced satisfactory in every way. It was a dismaying situation, too late in the year to hope for an appointment elsewhere. Letters to nearly every university in the country elicited no offer. Without savings, survival for our family was problematical; for the mice it was impossible. Contemplating the awful prospect of killing off the inbreds and abandoning the work, I considered abandoning science too; perhaps I should become a missionary.

Help came from an unexpected quarter. Professor Castle at Harvard, chief scoffer at the folly of trying to establish a strain of inbreds, sent word that he would take the mice into his laboratory at Bussey Institute. Sadly, he could offer me no position. Dean Edsel of the Medical School was abroad, so no appeal for emergency funds could be made. A request to the Rockefeller Institute for a grant to support the work at Bussey was deferred because Simon Flexner was also abroad.

The Strong family stored its furniture and once more moved into a tent, this one on the grounds of Bussey Institute. With two small children sharing it, it was no honeymoon tent this time. When the winter cold drove us out of it, we took to sleeping on the benches in the institute auditorium. Our endurance was pushed to the limit when Katherine required surgery for a spinal ailment.

Mercifully, Simon Flexner returned from his travels and quickly approved funds for a one-year fellowship at the Bussey Institute. During the stay at Bussey, the A strain, that ubiquitous pink-eyed mouse of laboratory fame was fully inbred. Individual mice were more alike biologically than identical twins.

For the first time, experiments with the mouse model system returned uniform, reliable, repeatable results with mathematical precision. As had been hoped, this blue-blooded mouse race proved the doom criers wrong by developing a new vigor once the threatening recessive genes had been bred out. They were more lustrous of coat, brighter eyed, and livelier than their wild ancestors.

Even more exciting for cancer research was the fully inbred C3H mouse. Not only had variability been eliminated, but in this subline, every female developed cancer of the mammary gland at approximately six months of age. By every known test of malignancy, the C3H is the most cancerous mouse in existence. Also in the complement of new mouse tools for quantitative research were the C12I and CHI with intermediate tumor appearance, and the long-lived CBA with low cancer incidence. Production of this cancer-resistant mouse had been designed as a means to apply comparative analysis between the cancer and non-cancer states.

Another crop of inbred sublines was begun in 1926 during the stay at Bussey. These included the F/St whiteface, valuable for a high incidence of leukemia in the older animals; I/St recessive; L/St, low incidence of mammary gland tumors, with lymphoblastoma, retinal opacity; and N/St with low tumor incidence and resistance to chemically induced tumors. Completing the lineup were Little's lost dilute browns, reconstituted from the ancient remnants of his colony and now fully inbred and pedigreed. It was my pleasure to present Little with a gift of breeding stock of his old line. I told him that I should not have saved them because it cinched his place in history as developer of the first successful inbred strain of mice. In turn, Little shared with me his newly established black C57 line, descendents of which still exist in my laboratory today.

Little had just become president of the University of Michigan and I accepted his invitation to help build a department of cancer research. The mouse colony, now commanding considerable attention in the scientific world, was moved to Ann Arbor in late June 1927.

Work toward stabilizing the inbred strains, and a half dozen experiments involving them, continued amidst a rising clamor from other investigators who wanted the mice for their work. When possible, a breeding pair was sent to anyone requesting them. Memorably, one of the first such pairs was a gift to Marie Curie. Keeping up with the demand, however, was far beyond the capabilities of my small laboratory. When it was impossible to fill requests for the mice, there were grumblings that Strong was uncooperative. A few even complained that I was trying to restrict scientific material for my own selfish use. These charges were never justified. Few people realized that the inbreds had been created in the first place as a means of opening my own scientific line of inquiry into the cancer problem. I was glad to share the mice, but I had no intention of abandoning my career in cancer research to become a supplier of laboratory animals for others.

In 1930, along with others from the Michigan faculty, I joined C.C. Little in founding the Roscoe B. Jackson Memorial Laboratory at Bar Harbor, Maine. When the expected private support for the laboratory evaporated in the great depression, we turned to the sale of the inbred mice to other researchers as a means of supporting The Jackson Laboratory. The numerous Strong inbreds plus Little's strains and a few others gathered from various sources comprised the inventory.

Intent upon building the institution and its trade, Little lectured widely on the virtues of the inbreds for research; his name became so closely associated with inbred mice that many assumed that he was their sole originator. The impression was further spread when Professor J.B. Haldane of London University paid a visit to The Jackson Laboratory to hear about our genetic wonders. I presented Haldane with a gift of the best breeding stock in my laboratory to take back to England. Apparently out of deference to Little as director of the institution that housed them, he introduced the mice into England as the "Little Inbred Mouse Strains." This error was not corrected until nearly a decade later when H.B. Andervont of the National Cancer Institute attempted to set the record straight at a Leeds genetics meeting.

The early confusion still continues in some quarters. Some think the credit belongs to Maude Slyde; others believe the inbreds to be the work of John Bittner, a graduate student of mine who took some of them with him to the University of Minnesota; and still others continue to suppose their author was C.C. Little alone.

When I left The Jackson Laboratory in 1933 to continue my cancer research at Yale, I left full stocks of breeders for all of my inbreds there, and these furnished a goodly part of the Jackson stock in trade until the great fire destroyed them. When the laboratories there were rebuilt and restocked, replacements for the Strong inbreds were obtained from various sources.

Figure 1 shows the distribution of Strong inbreds to other laboratories where mouse colonies were established for their propagation.

Many other sublines had their origin from a monumental cancer induction experiment carried out over more than a decade at Yale, in which injections of the carcinogen 20 methylcholanthrene into mice at an early age were continued in a line of mice for many generations. A cumulative effect of the carcinogen manifested in a greatly increased rate of mutation at many loci. As these mutants appeared, they were established as sublines. In all, 41 separate inbred strains have been in existence at one time or another. Most were studied and allowed to die out since it was impossible to support such sheer numbers. Others, thought to be of great potential value as research tools, were retained. Of these methylcholanthrene descents, only two remain in existence. These are the BRS subline, in which gastric lesions appear, and the polydactyly, a strain biologically unstable, bearing the pleomorphic gene LST. There is no demand for these strains, but I have thought them worth preserving for their potential value.

It has now been a very long time since the inbred mice made their debut as model systems for research. They were originally developed for the needs of genetics in relation to various aspects of cancer research, specifically to permit the application of quantitative analytical techniques. Their use in research has expanded immensely over the years.

For most, the procedures for their use have been sound, but in some instances it is obvious that errors in conclusions reported in the literature are traceable to insufficient training in the genetics of inbred mice on the part of researchers using them in other disciplines. There is, perhaps, time here to indicate caution. Only one illustration will be discussed.

In 1969, the pesticide DDT was listed as a carcinogen. The evidence for this conclusion appears to have been observation of an enhanced percentage of hepatomas obtained in the experimental mice. The observation led to the following conclusion: "The evidence for carcinogenicity of DDT in experimental animals is impressive" (Report of the President's Commission of Pesticides, 1969, p. 471).

Being a member of the commission, it was natural to inquire what strain of mouse had been used. It was replied that crosses had been made between females of C57BL/6 and males of either C3H or AKR, thus producing two hybrid stocks. This prompted a second question: Have all the variables been considered in the final conclusion drawn?

The variables properly to be considered were as follows:
1. It is well known that spontaneous hepatomas are of frequent occurrence in C3H and CBA inbreds. These strains probably received this trait from a common ancestor, the C/St.
2. Hepatomas are more frequent in males than in females. Here, a C3H male had been used for the production of the hybrid.
3. Hepatoma tumors are inherited as a dominant trait and hence could be expected to occur spontaneously in the F1.
4. The C3H mouse has an extremely high hereditary tendency to respond to chemical tumor induction with tumors of many types.
5. The heterosis obtained by hybridization, as in the case of the test animal used here, increases susceptibility to tumors in mice. Heterosis is a genetic phenomenon and its effect must be considered on the result obtained in any test involving hybridization, yet there is no mention of this variable in the case discussed.
In fact, there was no evidence of familiarity with any of these problems.

A more suitable mouse to test out the possibility that a given material is carcinogenic would be one with the lowest incidence of tumors, both spontaneous and chemically induced. These strains do exist and hybridization could also be used for any merits that process may be assumed to add to an experimental mouse.

Another approach that may be an even better test of carcinogenicity would be the use of two groups of test animals, one with high susceptibility and one with low. Then an average could be drawn. Perhaps "in mediocria firma" is a safer way.

When I resigned from the Pesticide Commission, the excuse of "insufficient time available" was true. But I think I might have resigned anyway, out of despair.

Had I remained purely a mammalian geneticist following the development of the inbred mouse strains, I believe I would have done several things to enhance their usefulness in all types of medical research. I certainly would have encouraged in every possible way the concept of using a minimum of two strains in the same experiment as a means to apply comparative analysis. I might wish that someone with the time to do so had followed up on the leads that were turned up in the application of this principle to cancer research in my own work and that of other investigators.

If the various inbred strains are arranged on a chart in order of their relative degrees of susceptibility and resistance to cancer, it is readily seen that they reflect a gradient from highly resistant through intermediate to high susceptibility ( Figure 2 ). This gradient appears to correlate with various levels of metabolic activity. High cancer susceptibility is accompanied by high levels of leukocytes and lymphocytes while the cancer-resistant state is associated with low levels of these two. A similar correlation is found in the degree of fluorescent pigments in the harderian glands. High fluorescence is present in high tumor susceptibility, whereas very weak fluorescence is found in the harderian glands of tumor-resistant strains. Perhaps a more comprehensive analysis of base line metabolic levels in various strains of inbreds compared with the gradient of susceptibility and resistance would yield a valuable profile. Certainly such a composite could amplify our understanding of the peculiarities of individual strains.

A matter of considerable concern to me is the amount of variation in characteristics now to be found in the same inbred mouse strain obtained from different sources. In recent years, an investigator interested in verifying my cancer control studies attempted to obtain several hundred C3H mice from a large commercial source; he reported to me that they could no longer guarantee the incidence of spontaneous tumors in their C3H mice. This and similar reports of great variation among inbreds of the same strain designation prompted me to suggest that the original Strong colony, where characteristics have not changed more than a tenth of a percentage point in half a century, might serve as the norm against which variation in derived colonies might be measured. Those receiving the proposal failed to see the need for such a yardstick. Perhaps this is because we have lacked a definitive statement of the variation and divergence problem. It is to be hoped that a study of the type presently being conducted by Dr. Hilgers of the Loewenhoek Institute in Amsterdam may emphasize the need for some standard. Otherwise I do not see how we are to maintain quantitative results from inbred mice.

Another startling and threatening practice involving the integrity of standard designations for inbreds arises from the production of germ-free mice. It is a well known fact that foster-nursed C3H mice, lacking the milk tumor virus, will have low tumor incidence. The inclusion of the letter f in the symbol was long ago designated to distinguish this important fact. Yet I have recently learned that a major supplier of laboratory mice is marketing germ-free (that is, foster-nursed) C3H mice without the f symbol to distinguish them from standard C3H. At first it was assumed that this supplier might be reintroducing the MTV into the otherwise germ-free stock, but this proved not to be the case. In short, this supplier has for several years been in effect selling C3Hf mice as C3H -- by the thousands. Considering the naiveté of many researchers without sufficient genetic training concerning the technicalities of the mice they use, we may legitimately feel some concern over the validity of experimental results being published where germ-free C3H mice were used with the mistaken belief that they were standard C3H high tumor mice. In defense of the practice, the supplier in question stated, "No one has ever complained."

If the inbred mouse is to retain its integrity and reliability as a tool for quantitative analysis in biological research, it is evident that the syndrome of characteristics for a given strain, identified by a given symbol, must adhere to a standard as unchanging as the international measuring devices for distance and time, so far as it is possible with living measuring devices, which the inbred mice assuredly are.

Secondly, broader dissemination of information concerning the genetics of inbred mice among researchers of other disciplines is essential if chaos is to be avoided. Ideally, a geneticist should be consulted prior to the commencement of any experiment where research animals are to be used, to make certain that the proper animal for the test is selected. Alternatively, an easy to use handbook as guide to the selection of the proper test animal for a given experiment needs to be compiled and made available to every researcher in the field of biology. Such a handbook should draw upon the expertise of geneticists deeply experienced with research animal models. Eventually, of course, we may hope for the addition of a more comprehensive course in genetics to the curricula of all schools where biology is taught, but you know and I know that such an enlightened move may be long in coming.


In writing my part of the history of the inbred mouse and taking a place in the symposium on the subject, I desire, at this time, to record and to give my sincerest thanks to the several assistants and associates with whom it has been my pleasure and opportunity of profitably working. Without their labor, loyalty to me, and dedication to the problem at hand, beyond the dictates of duty, far less would have been accomplished.

Among these co-workers, four have shown that extra loyalty and dedication to the origin, continuation, and distribution of an adequate experimental animal worthy of being used in quantitative biological research in cancer and innumerable other scientific problems.

These four were: Harold Woodworth (35 years); Harold Spencer, Jr. (13 years); Fred Johnson (7 years); and Henry Matsunaga (18 years) -- total, 73 years.

For these services to science while working with me, I shall be forever with appreciative memories.

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