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How It Began

Clyde Keeler

Central State Hospital
Milledgeville, Georgia

First of all, let me say that I am happy to have a part in honoring some of my genetic colleagues who have made the greatest contributions to mouse genetics with their development and in-depth investigation of inbred strains of mice. These research activities have far-reaching implications for human and animal medicine, pharmacology, animal husbandry, and other biological fields.

It will be my role to say something about the environment and facilities under which the earliest mouse researches were carried out. I shall mention some of the individuals who served in those early days as supporting personnel.

The drama begins at the Bussey Institution of Harvard, spreading to the Station for Experimental Evolution of the Carnegie Institution of Washington at Cold Spring Harbor, Long Island, then to The Jackson Memorial Laboratory, and finally to laboratories in other parts of the world.

Benjamin Bussey answered the call of the sea in his teens and returned to Boston in middle life, fabulously wealthy. He bought an immense tract of land from the Weld family near Forest Hills and settled down to become a gentleman farmer, building his mansion on high ground. A few feet from his back door he shrewdly constructed a one-room school house which he gave to the county. This meant that the schoolmaster would live at the Bussey mansion where he would be available for reading and writing letters as well as answering questions about the complexities of terrestrial life with which Bussey was not completely familiar.

Benjamin Bussey imported pedigreed sheep and cattle from England. He raised wheat among other crops, employing the 100 male servants he brought ashore with him. They were all sworn to absolute secrecy as to their former activities on the high seas.

The Bussey will envisaged an agricultural school in great detail that eventually became the Bussey Institution of Research in applied Biology. The will stipulated that the design of the Bussey Building, a Gothic revival in style, that gave it a medieval, monastic appearance. It bore flying buttresses and its ve-ri-tas escutcheon was boldly carved upon the pediment of the portico. A tall flag-like iron weathervane was raised proudly aloft on the roof.

A single tree and a small barn wagonshed and horse stall hid behind the Bussey Building, that otherwise stood alone. A single tree graced the long driveway and under it on weekdays for many years Dr. Castle parked his model T with its brass radiator that he polished with xylol from time to time. On one occasion he absentmindedly tossed the xylol soaked rag onto the driver's seat and sat down on it.

The spacious interior of the Bussey Building was finished with uninspiring white plaster walls and extremely high ceilings. The long white hall on the second floor bore the only decorations: an unappreciated row of 21 famous Japanese prints strung up too high for temptation and therefore too high for artistic contemplation. They represented the complete series of "The Street Cries of Tokyo" and were the gift of Professor Uichanco of Manila, a former Bussey student.

The will described the precise spot on which the building should be erected, exactly so many feet back from the road. Apparently derived from Benjamin Bussey's former use of the word "shipmates," his will stated that students attending the Bussey Institution would be called "inmates." And so, we are honoring three "Bussey inmates" today.

The impressive building in Gothic revival appeared so ecclesiastical that several times lovelorn couples came holding hands and requested a priest to marry them. Once, while Prof. Castle was mating rabbits, such a couple arrived and asked for the marriage rite, mistaking the mild Harvard professor for a Catholic clergyman.

West of the Bussey Building there was a dog yard in which Clarence Little raised canines for his study of coat colors and Dr. Castle raised pigeons. In the early days the Bussey was bursting: a veritable menagerie of rats, rabbits, and guinea pigs. At one time it maintained a screech owl, a sparrow hawk, a tortoise shell male cat, and even a skunk which I deodorized alone because all prospective assistants suddenly found that they had pressing appointments elsewhere.

Aside from Dr. Castle, the Bussey faculty consisted of Drs. Wheeler and Brues in entomology, Dr. East in plant genetics, and Prof. Bailey in plant anatomy.

Dean William Morton Wheeler passionately hated genetics that had become so popular compared with his static entomology. He wrote a paper, "The Dry Rot of Our Academic Biology," from which I quote: "Genetics, what a promising bud, but oh how constricted at the base."

And again he fulminated that Nobel prize winner Thomas Hunt Morgan, the Drosophila geneticist, had "strained at a gnat and swallowed an hypothesis!"

This did not go down very well with Professors Castle and East, the Bussey geneticists.

Mr. Patch was the caretaker of the Bussey grounds. He was over 70 when I first knew him, having worked for the Bussey estate ever since he was 14. He had even known the last of the original 100 silent Bussey sailor men.

Mr. Patch plowed the ground and raised the cabbages and carrots that fed Dr. Castle's rabbits and, when the Bussey boys ate the discard rabbits from Dr. Castle's experiments, they snitched cabbage and carrots to cook with them. Mr. Patch had a key to Dr. Castle's office where the alcohol was kept and his Sunday morning visits appeared therapeutic. However, Dr. Castle had extreme confidence in Mr. Patch. Once Dr. Castle told me that if their opportunities had been exchanged, probably Patch would be a better professor and Castle a poorer caretaker.

The second member of the supporting team was Mrs. Kelley who hastened over to the Bussey each morning to greet the professors cheerily, and could be found flicking up dust from the furniture with an enormous instrument made of turkey tail feathers. She never quite mastered the vocabulary of the intelligencia, but she tried. On Monday mornings she distributed what she called the "immaculate towels," and on one occasion she came upon a box with a light in it, she soliloquized: "What's this? Why, it's an insinuator -- no, it's not an insinuator -- it's an inclabator."

Jovial Billy Reardon, caretaker of the rat room, was fresh off a freighter from Ireland. One day he came into the rat room and found AMA gold medalist Gregory Pincus with a pan in one hand and with the other he was dropping pinches of something from the pan onto a row of cages one after another. Billy dropped the heavy bag of feed that he was carrying, straightened up, and folded his arms.

"An' for Gawd sake, Pincus, an' what are ye doin'?"

"Oh, I'm just giving them a little clover."

"Well, I'm shore glad to know it. For a moment I thought ye was administering the hooly sacramint!"

The Bussey Building had a distinctive aroma, a none too delicate blend of mouse, rat, and rabbit, and one allergic medical student became so faint that he could not pass the threshold. One Bussey inmate wearing Billy Reardon's unwashed overalls was refused entrance to a fashionable Boston New Year's Ball.

A gray farm house served as the Bussey dormitory. There lived Mrs. Kelley, her husband, and her in-laws. There at one time also lived thirteen assorted doctoral candidates and postdoctoral researchers on fellowships.

After supper Bulgarian Doncho Kostoff might defend communism, or Dr. Hu might sit on the table with his legs folded under him and his hands held appropriately to expound on the nihilism of Buddhist nirvana. Doncho felt that the Soviet government was justified in shooting some 150 Moscow homeless waifs found to have hoof and mouth disease to prevent an epidemic. Doncho had published scientific papers in English, French, German, Bulgarian, and Esperanto.

Though Dr. Hu declared that all in this world is unreal and imagination, he carefully locked a typed draft of his two-volume thesis in a bank vault until the printers had issued his printed edition of The Phanerogams of China. We thought that thus was an extreme precaution for a thesis made of "nothingness" as its author declared.

Each student took his turn at cooking for a week, and there was an eternal soup on the stove to be quickly warmed up for between meals. It might start out with a ham bone and navy beans, mutate through many constitutions, as cans of this and that were added, to end up several weeks later as chicken and noodles.

One evening Dr. Meyers came down from the Bussey mansion at dusk and inadvertently kicked into a pair of amorous skunks. He buried his clothes, of course.

One night a thief reached through the window with a rake and stole Prof. Brues' pants containing his wallet. The police found and identified the pants the next day. We were all afraid that the Harvard Lampoon would hear of the incident. Just imagine the possible headline, and then shudder:

"Harvard professor's pants found in arboretum. Says they were stolen."

Aside from the ancient brass-framed microscopes, the Bussey equipment included an imposing cylindrical slide rule five feet long. There was a box calculator, an all-brass contraption of encased cogwheels, buttons, slides, and stamped numbers. There was a handle that, when tuned, suggested audibly some relationship to a McCormick thrashing machine. There was a versatile portrait camera and a carbon arc for photography.

Here mouse genetics, as we know it, was born with research on coat colors in mice by phenomenal Clarence Cook Little, Phi Beta Kappa, captain of the track team, collegiate title holder in shot put and discus, assistant dean of Harvard College in his senior year, and later founder of the Cancer Society and The Jackson Memorial Laboratory.

I have here a copy of Dr. Little's thesis study of coat color in mice, bearing witness to the author's connection with both the Bussey Institution and the Carnegie Institution of Washington Station for Experimental Evolution at Cold Spring Harbor.

Dr. Little exhibited a complete collection of stuffed mouse skins demonstrating coat color inheritance in mice at the International Congress of Genetics at Ithaca.

Mouse researchers always cooperated with the Mouse Fancy and so when the Boston Cat Club invited the Mouse Fanciers to hold a joint Cat and Mouse Show, a number of Bussey types of mice were exhibited. And it was there that a well known Mouse Fancier of the cloth was entrapped. It was really a conspiracy. An innocent looking young lady stepped forward and asked the minister:

"Aren't you afraid to handle mice?"

"Why, of course not, they can run all over your hands, like this, and are perfectly harmless."

"But aren't you afraid to put them on your shoulder?"

"Now, here is one on my shoulder, see!"

"Well, would you be afraid to have one on your head?"

The minister placed a mouse on his exceptionally bald head to demonstrate his bravery, and a light bulb flashed behind the decoy. The picture hit the press wires. Within a matter of several hours the papers hit the streets of the nation and the clergyman was no longer an employed Episcopal priest.

The Bussey was well represented at the Harvard tercentenary celebration with charts and models on exhibition in Cambridge.

There was a large chart depicting the known mutations arranged according to their linkages. There was a chart with ceramic mouse models showing the size effects produced by each of six recessive gene mutations in mice, studied by Castle, Gates, Reed, and Law.

There were large plaster models demonstrating degenerate retina and absent corpus callosum. Dr. Castle's rabbit skins were displayed and ceramic rabbit models showed their genetic relationships. Cat genetics was featured.

If mouse genetics was born at the Bussey, it was cradled at Cold Spring Harbor in the Carnegie Institution of Washington Station for Experimental Evolution. There we again meet C.C. Little, Leonell Strong, and E. Carlton MacDowell, a former Bussey inmate noted especially for his early studies of virus associated with leukemia in mice. There were Bea Johnson and Amelia Vicari. There was also from time to time Halsey J. Bagg, a student of behavior, who developed the famous Bagg strain of inbred albino mice. We published with Little on defects in the Bagg strain.

It was also with this strain of albinos that I was introduced in 1923 to mammalian genetics through my finding of what is now known as "degenerate retina," still our best animal model for retinal degeneration in man.

The Carnegie Station for Experimental Evolution was much better equipped than the Bussey with an office building separate from the mouse laboratories.

As a college student I had hitchhiked from Marion, Ohio, in the summer of 1920 to Cold Spring Harbor where I served as headwaiter, collected lobsters and starfish, and retrieved pig embryos in a slaughter house to pay for expenses and a ride back home.

There, in 1920, I met many outstanding geneticists. Charles B. Davenport ran the Experiment Station. Herbert Eugene Walter, Sidney Isaac Kornhouser, and H.M. Parshley were the mainstays of the Summer Field Course in Biology.

On the hill stood the Eugenics Record Office operated by Dr. Harry Laughlin and Dr. Muncie. Leslie Peckham was their factotum, who constructed family pedigrees for publications of the staff.

At the station for Evolution in Botanical Genetics was Albert F. Blakeslee, president of the American Association for the Advancement of Science, and his assistant, John Belling, inventor of the famous "Belling smear technique" for microscopy. These men and their summer assistants were doing spectacular research with the pig weed Datura stramonium, identifying various types characterized by three copies of particular chromosomes instead of two.

Hooper Hall contained the great dining room plus some dormitory space upstairs. The dining facilities served all personnel of the Record Office, the resident geneticists, and the summer course students.

Mrs. Davenport was dietician in 1920. That year she tried valiantly to stay within the budget by serving up Oscar Riddle's discard pigeons from his experiments on modification of the sex ratio. The menu said "squab." She dessicated these old birds. The diners merrily tapped out a tattoo chorus with their knives on the solid rib cages of these mummified atrocities, and the diners to a man, woman, and child returned the birds to the kitchen untasted.

Once again the dietician attempted to economize by having the carpenter armed with a sledge hammer do battle with Tetraceratops. He was the four-horned Algerian ram with which Dr. Davenport kept going his study of the "Inheritance of Supernumerary Horns in Sheep."

The carpenter eventually won. However, this was in the days before papaya tenderizers and, besides, Tetraceratops had a strong bodily odor. So his tough inedible chunks all went back to the kitchen. His life had been sacrificed in vain.

I leave to your imagination what happened when in the kitchen maggots were found in the cheese.

Because of my doctorate studies on degenerate retina in mice, I was asked by Dr. Howe in 1927 to join Howe Laboratory of Ophthalmology at the Harvard Medical School to teach and research in genetics, but after twelve years I resigned because I could not convince my conservative medical colleagues that genetics would ever produce anything of value to medical science. A few were sympathetic, but most were skeptical.

The head of my department, crusty old Prof. Frederick Verhoff, declared: "Heredity always runs out. You never see a defect in a human pedigree in more than two or three generations!" Once he even induced Dr. Howe to drop me from the payroll because "medical genetics has no future." The final report that I turned in must have been convincing because he promptly hired me back again with a $500 raise in salary.

Some medics maintained that medical school research should be confined to the human subject, and one colleague declared: "You can never convince me that immunity and susceptibility in man can be distributed according to a 3-1 ratio."

During my tenure at the medical school I kept my genetic experiments going at the Bussey. In mice I discovered the first genetic heart defect, studied coloboma iridis, corneal opacities, rosetted fur, discovered wavy2, as well as spine and tail anomalies. I examined hypo- and hyperglycemia, cystic kidneys, lethal anemia, harelip, hydrocephalus, and other defects.

I spread out to research glucose tolerance in Yale rats, blood groups in rabbits, sex deficiency in the tortoise shell male cat, and kidney stones in Dalmatian dogs.

Eventually my genetic interests led me into behavior genetics associated with coat color genes in rats, mink, and foxes where tameness may be synthesized by an appropriate combination of certain coat color genes. I extended these principles to man with my studies of albinism and red hair.

Shortly after I took my doctorate, Dr. Castle told me seriously that there was no future in studying mice because there were no more gene mutations in mice. They had all been studied.

Dr. East tried to get me to become a botanical geneticist! Nevertheless, my attitude was that it was merely a matter of many researchers being on the lookout for mouse mutations because there must be a whole spectrum of mouse mutations paralleling known mutations in man. So I wrote a small book to popularize mouse mutations. The accomplishments of our honorees show how wrong Dr. Castle could be at times.

In search for possible new mutations I went to China, Japan, and Turkey. I spent three days examining the thousands of stuffed mouse skins in the British Museum. I found blues, chocolates, pink eyed buffs, and albino types from all parts of the world.

When I finished my survey I thanked the curator for his kindness in allowing me to examine the British Museum mouse skins and told him that I had at the Bussey three varieties that he did not have, and that I would gladly send him specimens.

That little man became highly insulted and angered. He stretched several inches taller in his striped trousers and gray spats, looked down his nose at me, and screamed:

"Sir, if they are not in our collection, they do not exist!"

The ancient literature recorded that albino mice were used for auguries in Babylon, Egypt, and Troy long before the time of Christ. It was the same in China where all albino mice caught in the wild had to be turned over to the magistrates, and 26 such albinos are listed in Chinese history as found between 307 and 1641 A.D.

I wondered about the tiny Island of Tenedos at the mouth of the Dardanelles where stood the temple of Apollo God of Mice (Apollo Smintheus) since long before the Trojan War. Aristotle and other ancient writers told of the white mice raised under Apollo's altar. I went to Tenedos in 1930 and learned that in 1929 an albino house mouse was living in a garden shed a stone's throw from the site of the ancient temple of Apollo. Barring possible mutation, that could mean as much as 3,000 years of population inbreeding and with three generations a year the number of generations is staggering.

During this field trip to catch mice in Asia minor, I was captured and tried for espionage by the Turkish military. When it was learned that I was sponsored by a fellowship from Harvard University, the prosecution was incredulous.

The colonel who served as prosecuting attorney bluntly declared: "The government of Turkey maintains that there is no university on earth crazy enough to send a man half way 'round the world to catch mice!"

My interpreter bravely defended me with: "Yes, but there is one university crazy enough to send a man half way around the world to catch mice, and that is Harvard University in Cambridge, Massachusetts."

From the biomedical standpoint, our lowly housemouse must be awarded the title of "man's best friend."

Among the many uses of mice in pharmaceutical laboratories is drug research: first infecting and then trying to a cure. There is testing of drugs for carcinogenic and teratogenic effects as well as toxicity of their products. Drugs are tried out on mice before going to other Laboratory animals. Specialized strains of mice are employed for detecting diabetic agents, epileptic agents, and others. Mice are used to reveal behavior patterns and pattern effects of therapeutic drugs. Mice are involved in the standardization of sera.

A center for disease control employs mice to isolate virus, four types of fungi, for producing rabies antibodies, and for botulism titrations. They are used for the identification of the Hymenolepis tapeworm, Trypanosoma cruzi, and Echinococcus as well as the Toxoplasmosis parasite. Mice can separate pneumococcus from streptococcus viridans. There is a mouse test for Staphylococcus virulence, one for rat mite fever, and one for Leptospira of kidney and bladder. There are mouse tests for identifying rabies and equine encephalitis.

Elsewhere, mice are used to study weightlessness, radiation, toxic substances in chemical plants, and problems of the psychology laboratory. Man-mouse leukocyte hybrids are used in mapping human chromosomes. Mice are used in a pregnancy test. Mouse organ tissues are employed as substrates in the study of PKU and other human enzyme deficiencies.

Sminthophiles with curiosity might like to carry out modest but valuable experiments of their own on mice, employing simple apparatus. Perhaps some already do. In any case, old hands in the mouse genetics business will be glad to advise and assist the Mouse Fanciers.

Let me conclude with the observation that the ways of rodent geneticists are still often misunderstood by the laity. For example, one day a little old lady met me on the street and bubbled:

"Oh Doctah Keelah, I am so glad to see you. You know, this morning I saw the most horrible, big, old dead rat lying in the guttah, and, of course, I thought of you."

Then she became frustrated, blushed, and added:

"Oh, oh, oh, I didn't mean it quite that way. I meant that I thought you could use it in one of your experiments."

I judged that the conversation had gone far enough, so I did not stop to explain to the lady that I was really a mouse geneticist at heart and that in my opinion dead rats do not reproduce very well.

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