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Biography as Related to Inbred Strains of Experimental Animals 1

Walter E. Heston

Fort Meyers, Florida

Soon after Congress passed the Bone Act establishing the National Cancer Institute in 1936, a Research Fellowship Program was set up to bring in a group of young investigators to complete the staff of this newly established Institute as soon as possible. These fellows were hired in 1938, and for two years, while the physical plant of the Institute was being built in Bethesda, they were placed for additional training in cancer research laboratories throughout the country.

As one of these research fellows, I was brought in as a mammalian geneticist and was fortunate to be placed for this two-year training period with Dr. C.C. Little at the Roscoe B. Jackson Memorial Laboratory at Bar Harbor, Maine. In no other two years have I learned more than in those two years at The Jackson Lab. There I received a good foundation in cancer research and, above all, I was well indoctrinated in the value of inbred strains of experimental animals, particularly mice, in medical research and especially in cancer research.

After choosing the genetics of lung tumors for my initial studies, I established a breeding colony of the high lung tumor strain A mice from animals received from Dr. J. Bittner who was on the staff of The Jackson Laboratory at that time. For a strain most resistant to lung tumors I chose strain C57L and established a breeding colony of this strain from animals received from Dr. Arthur C. Cloudman also on the staff there. Later I added a colony of strain C57BR from animals likewise received from Dr. Cloudman. In the spring of 1940, I was called in to the Institute in Bethesda and I shipped these colonies of individually identified mice along with the hybrids I had produced to Bethesda by Railway Express. Not one animal was lost in shipment. Subsequently, when I became involved in work on mammary tumors and hepatomas, I added strains C3H and C57BL to my breeding colonies from animals received from Dr. H.B. Andervont at the National Cancer Institute and still later other strains were added.

Since I was the one on the staff of the National Cancer Institute who specifically had received his degree in mammalian genetics, I assumed a special responsibility for maintaining my colonies of inbred mice and fostering the use of inbred strains in the research of the Institute. I had the full support of Dr. Andervont and my efforts were well received by my colleagues working with cancer. After all, one could not transplant experimental tumors without inbred animals. One day a few years later, however, in talking with Dr. R.R. Spencer, our director, it was decided that I might direct a comprehensive memorandum to the director of the National Institutes of Health, putting forth my ideas of the use of inbred strains in cancer research and also pointing out the value of the genetic approach and the advisability of using inbred strains in the research on other diseases carried out in the other Institutions of the National Institutes of Health. Accordingly, such a memorandum was formulated and sent. Within a few days I received from the director a half-page reply acknowledging me as a young investigator in cancer but implying that the other research at the Institutes was in good hands and was doing very well with the animals being used. This bothered Dr. Spencer more than it did me for he felt that he had been responsible for having put me into this somewhat embarrassing situation. Any misgivings I might have had about my brash actions were to be lifted a few years later when this director retired and a lecture series was set up in his honor. As the first speaker of the series a well known geneticist was selected.

One day in the early 1940s, Dr. Michael B. Shimkin who occupied an adjoining laboratory at the NCI received information that the inbred strains of guinea pigs at the USDA Beltsville Station were to be discontinued. These were of the original families with which Dr. Sewall Wright had done his monumental studies on the effects of inbreeding from which he derived the concept of the inheritance of threshold characters. These were the only inbred guinea pigs in existence and now, because of lack of space and financial support, they were about to be discarded. Dr. Shimkin immediately contacted Dr. Eaton who was in charge of the colonies, and Dr. Shimkin and I went to Beltsville and rescued the remaining breeding animals and brought them back to the National Cancer Institute where I set up breeding colonies. Aside from having a sense of their general potential value in medical research, we knew that they would be essential for any studies of transplanted tumors in this species and would be uniquely suitable for such studies as those later carried out with Robertson on the effect of ascorbic acid on the development of sarcomas. Unlike the mouse, the guinea pig can be made deficient in ascorbic acid. These families or strains included 2 and 13, and also family 35 that had a high incidence of polydactyly and family 32 that really should not have been called 32 for it had experienced some outcrossing. These latter two families were at such a low breeding level when we got them that it was impossible to get them going again. Years later, when he was in my laboratory, Dr. Sewall Wright poked his face in the cages and confirmed the identification of strains 2 and 13, not by their coat color, for both strains are tricolor, but by the shape of their noses. Strains 2 and 13 are still in existence and widely used.

In subsequent years inbred strains of rats were added to our breeding colonies from Dr. Dunning's colonies in Miami. These included strains A x C 9935, Marshall, and Fisher, all strains that Drs. Curtis and Dunning had been inbreeding for many years. In addition, we began inbreeding Osborne-Mendel rats and Buffalo rats that had been extensively used in medical research but up to that time had not been inbred. Years later, when a central animal breeding facility was set up at NIH with a geneticist in charge of the inbred colonies, all the guinea pigs and rats were transferred to this facility.

In the early 1940s, Dr. Margaret K. Deringer joined my laboratory, and about ten years later Mr. George Vlahakis joined us. To these two associates along with many other dedicated associates, technicians, and animal caretakers goes much of the credit for the work of this program. It was always the philosophy of the laboratory that probably the most important person on the team was the animal caretaker, and weaning and marking animals and making up new matings were considered the most important tasks of the laboratory and for this work I was always present until the day of my retirement.

Possibly of equal importance to our promoting the use of inbred strains of experimental animals was the part we played in the introduction of the use of the F1 hybrid. During World War II, instead of being placed in the Armed Forces, I was instructed to remain at the NCI and to work along with Drs. Lorenz, Deringer, and Eschenbrenner on the Manhattan Project. Our principal work was concerned with the effects of long-term, continuous exposure to low dosage gamma irradiation. It was my suggestion that as test animals we use an F1 hybrid because of its genetic uniformity, vigor, and long life. Since we already had a considerable amount of information on LAF1 hybrids from our lung tumor genetic studies, it was decided to use this hybrid. The program was extensive, involving thousands of such hybrids, and some of it attracted considerable attention. At one time we sent a group of several hundred uniform and individually identified LAF1's to the South Pacific for one of the tests of the atomic bomb. They made the round trip, arriving back in our laboratory for later observations of the effects of the irradiation without loss of an animal. The results of all of these studies demonstrated the value of the F1 because the tumors that arose in these very old animals occurred at ages beyond which inbred mice would not have lived. It also set the stage for the use of this particular F1 in subsequent radiation work. Unfortunately, this F1 was a rather poor choice in that both parent strains are poor breeders. Nonetheless, the studies did much to open up the extensive use of the F1 hybrid between two inbred strains as a genetically uniform, vigorous, long-lived experimental animal.

Work in our laboratory was also instrumental in introducing the use of the fostered strains. Bittner and others had shown that when newborn mice of high mammary tumor strains were foster-nursed by females of low tumor strains, few or none of them developed mammary tumors. For this reason, in the middle 1940s, we decided to start a colony of C3H mice foster-nursed by C57BL, the C3HfB, to be used in testing for the mammary tumor virus. We kept these animals in a healthy condition so that they lived to a very old age and, much to our surprise, the females were not free of mammary tumors as almost half of them developed mammary tumors at an advanced age. While we initially thought that these tumors were due to the high genetic susceptibility of the females plus the hormonal influence from their having had many litters, the observation of particles in the tumors of this line by investigators in Dr. DeOme's laboratory at Berkeley showed that this strain had a line of mammary tumor virus that was somewhat different from the milk-transmitted line. These and other observations opened the way to subsequent extensive studies of many fostered lines from various combinations and the lines of virus they retained. The C3H with the Avy gene, or C3H-Avy, is the highest mammary tumor strain we have ever had and the fostered strain C3H-AvyfB was particularly interesting in that it had an incidence of approximately 100% mammary tumors caused by a virus not transmitted through the milk but presumably genetically transmitted.

It was always the policy of our laboratory to send mice of any of our strains to any investigator who requested them. Since it was generally recognized that we had a rather clean colony, a reputation earned by our strict isolation of the colony, and possibly also since NCI always paid the shipping charges to insure prompt and safe delivery, we received many requests from researchers throughout the world. Consequently my wife was later to find out that my mice had become more widely known than I was. Much of the medical research of Japan today is done with strains of mice descended from my colony. This largely has been due to the efforts of Dr. Tatsuji Nomura in getting mice from us and setting up his own extensive production facility and even of his sister, Miss Michi Nomura, who first came to my laboratory to make arrangements for mice of our colony to be shipped to Japan. Through the years our mice were sent to establish breeding colonies in practically every country in the world and sent with almost no losses in shipment. In earlier days airline pilots took a special interest in our shipments of mice going to the far corners of the earth to be used in cancer research, often even taking them into the pilot's cabin to insure their safe passage.

Communication was always with the investigator who was to receive the mice to make sure that the breeding data did not get mixed up. An exception to this, however, was when Dr. Andervont and I sent C57BR and BALB/c to the U.S.S.R. These had to be transmitted through the State Department and, of course, they got mixed up, leading to a confusion of the Russian strains that did not get straightened out until about 15 years later when I visited the U.S.S.R. for the Cancer Congress in Moscow.

The day of retirement came for me on December 31, 1975, and a year later when all my research underway had been concluded, the Heston mice were no more. When word of my impending retirement got around, many came to me expressing concern about what was going to happen to my colonies of mice. It seems to me that it all worked out as it should have. I had always shared my mice with any who had asked for them so that any who were wanting to work with Heston mice had them. By this time even my associates had their own colonies. With my retirement there was clearly no longer a need for a colony of Heston mice. After all, of what value are a man's colonies of mice without the man.

1Address: 1380 Burgundy Drive S.W., Fort Meyers, FL 33907.

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