Search Magazine November 19, 2014

85 Years of Discovery

Muriel Davisson is a seventh-generation resident of Mount Desert Island, Maine, and the only MDI native so far to serve on the Laboratory’s research faculty. She earned an A.B. cum laude in zoology from Mount Holyoke College in 1963 and a Ph.D. in genetics from Pennsylvania State University in 1969. She was a college summer student at JAX in 1962, working with Drs. Paul Sawin and Richard Fox, and a research assistant from 1963 to 1964. She returned as a research associate in 1971 and retired as professor emeritus in 2012. She has been an eyewitness to more than half of JAX’s 85-year history, celebrated in 2014. Here, from her own unique perspective, are milestones of the Laboratory’s first eight decades of genetics research, discovery and medical contributions.

The founding

The Jackson Laboratory was founded in 1929 in Bar Harbor, Maine, by Clarence Cook (“C.C.”) Little. Dr. Little was educated at Harvard, where he did genetics research using laboratory mice with Dr. William Ernest Castle at the Bussey Institute. Dr. Castle might be seen as the father of mouse genetics, as the Bussey was the source of most early mouse genetic researchers, including Dr. Little and 17 other Jackson Laboratory scientists.

Convinced that genetically defined mice would be key to understanding cancer, while at the Bussey Dr. Little began developing the first inbred mouse strain, called DBA (for its coat color, dilute brown non-agouti). After receiving his D.Sc. in 1914, Little worked at Harvard and at Cold Spring Harbor Laboratory on Long Island, New York, where he began developing the now famous C57BL inbred strain, commonly called “black 6” and today the most commonly used mouse in global biomedical research. He became president of the University of Maine in 1922, and three years later moved to the presidency of the University of Michigan at Ann Arbor, where he remained until 1929, when he resigned to establish The Jackson Laboratory. A more detailed account of his career and of the first 50 years of the Laboratory may be found in The First Fifty Years at The Jackson Laboratory by Jean Holstein.

While in Michigan Dr. Little continued his research on cancer with his genetically defined strains of mice and connected with Michigan businessmen who would provide the funds for establishing the Laboratory. They may have become interested in his research from talks he gave to the summer community on Mount Desert Island while leading biology programs from the University of Maine in 1924 and 1925.

Roscoe B. Jackson, head of the Hudson Motor Car Co., and his brother-in-law Richard Webber, head of the J. L. Hudson Department Stores, were already partially funding Little’s research in Michigan. Land for the Laboratory’s Bar Harbor campus was donated by George B. Dorr, who was instrumental in establishing Acadia National Park. Funding for construction of a modest laboratory building and the first five years of operation was provided by Roscoe B. Jackson, Richard Webber and Edsel Ford, of Ford Motor Co. When Jackson died suddenly while traveling in Europe in March 1929, the Laboratory was named for him and remained The Roscoe B. Jackson Memorial Laboratory until 1963 when it was renamed The Jackson Laboratory, or JAX.

Dr. Little’s philosophy in founding JAX was that good research would come from a small group of scientists in an independent research environment with the freedom to follow their creative ideas, interact easily with colleagues and use genetically defined mice as research tools. Because of his conviction of the power of genetically defined mice to understand cancer, the subsequent emphasis on genetic research at JAX and the genetically defined mouse strains developed here, JAX has always been a center for mouse genetics and a mecca for mouse geneticists.

The early years

The fledgling Laboratory barely survived its first full year of operation following the stock market crash of 1929. As funds tightened, the original staff of 15 pulled together to conserve resources. The research staff included two brothers from Maine who had been Dr. Little’s students. To feed the staff, Dr. Joseph Murray provided vegetables from his family farm in Hampden, and Dr. William Murray led fishing expeditions. These difficult times established the Laboratory’s long tradition of cooperation and sharing.

Several important firsts occurred during JAX’s initial decade. In 1933 the entire staff published a paper on the maternal transmission of mammary tumors in mice, followed by co-author Dr. John Bittner’s paper identifying an agent transmitted in milk, later identified as mammary tumor virus. This work led to the entire field of study on how cancers are initiated by oncogenes in mammalian cells.

Also in 1933, JAX began selling mice from its inbred strains. The distribution of mice not only formalized the sharing of JAX mouse resources with other scientists, but also became a source of revenue for research and mouse breeding. In 1938 JAX received the first grant awarded by the newly established National Cancer Institute (NCI) at the National Institutes of Health (NIH). In 1941 JAX staff published the first book on mouse genetics and biology, Biology of the Laboratory Mouse, which became the “Bible” for researchers using mice as a research tool. Also in 1941 Dr. George Snell initiated and edited Mouse Genetic News, issued by the Laboratory and containing the original mouse genetic nomenclature guidelines, lists of inbred and mutant mouse strains, and laboratories with their mouse stocks. This newsletter became the predecessor of Mouse News Letter in 1949 through which JAX scientists shared pre-publication research data and information on mouse strains for most of the Laboratory’s first 50 years.

In 1947 JAX suffered a literal trial by fire. During the October 1947 Bar Harbor fire, which burned much of the northern and eastern side of Mount Desert Island, JAX was destroyed, including most of its mouse strains. (A few strains survived at Hamilton Station, an outpost in nearby Salisbury Cove.)

Financial and moral support flowed in swiftly after the fire, affirming the importance of JAX to basic biomedical researchers worldwide. A total of $483,000 was provided by the NCI, the American Cancer Society, the Maine Cancer Society and the Damon Runyan Foundation, including $123,000 from the Jackson and Webber families. The Ladies Auxiliary of Veterans of Foreign Wars provided support for a new library, beginning a long-standing association between the organization and JAX. Equally important, researchers returned breeding pairs of strains of mice they had obtained from JAX, and all but one of the pre-fire strains were re-established.

The spirit of surviving the Great Depression years probably helped Dr. Little and his staff face the aftermath of the ’47 fire. He is quoted as saying, as he stood looking over the devastated Laboratory site, “Now at least we can see the ocean.”

The ’47 fire had many positive after effects. The scientific community recognized the Laboratory’s importance to basic biomedical research and mouse genetic resources. The original Laboratory building was replaced with a better, more secure building. In the early 1950s an off-campus Foundation Stocks of Inbred Strains was established at JAX’s Highseas facility nearby. And finally, rustic, wooden buildings were built around the quadrangle just south of the main research building to replace the tents in which summer students had lived.

Although mice have always been the primary model organism at JAX, it should be noted that several other mammalian species have also had cameo appearances. Drs. Paul Sawin and Richard Fox did research using rabbits at Hamilton Station, and Drs. Paul Scott and John Fuller carried out behavioral research with dogs there. Deer mice, rats and hamsters all had brief tenures at JAX. Even axolotls, a type of salamander, lived on campus during Dr. Richmond Prehn’s tenure as director.

Milestones in the modern age

In 1956 Dr. Little retired and Dr. Earl L. Green became JAX’s second director. In 1958 the Morrell family donated land on the southern boundary where a production facility was built to enable expansion of the mouse-distribution program. The juxtaposition of large production colonies and strain inbreeding with genetic researchers generated increasing numbers of spontaneous-mutation mice and in 1959 the first formal funding for a mouse models program was obtained when Drs. Earl and Margaret Green were awarded a grant by the National Science Foundation (NSF) to support the Mouse Mutant Stocks Center.

Donation by the Morris/Hawkes estate of the Highseas summer “cottage” in 1951 enabled JAX to establish a precollege Summer Student Program to complement its college program. The first JAX/Johns Hopkins Short Course on Medical and Experimental Mammalian Genetics was held in the summer of 1960, co-directed by JAX’s Dr. John Fuller and Dr. Victor McKusick of Johns Hopkins.

When I joined JAX in 1971 as a research associate in Dr. Thomas Roderick’s laboratory, it was an exciting time in mouse genetics. Technology for visually identifying individual mouse chromosomes had just been developed, whereas previously only clusters of linked genes, called linkage groups, had been identified. Now these linkage groups were rapidly assigned to the physical chromosomes. Polymorphic biochemical markers had been identified in the 1960s and were being exploited to expand the genetic map of the mouse, and rapidly map genes and new spontaneous mutations to chromosomes. Perhaps most exciting was the discovery of extensive genetic conservation between the human and mouse genomes. Dr. Roderick and I joined the Comparative Mapping Committee of the Human Gene Mapping Workshops in 1977 and remained members or chairpersons until these workshops ceased in the mid 1990s.

The 1980s saw the beginnings of JAX’s lead role in mouse bioinformatics. Having collected and published mouse genetic information since the 1950s, Margaret Green in 1981 published a seminal and comprehensive book with descriptions of mouse genes and mutations, strain information, a map of the mouse genome and the genetic mapping data that she used to create it. Later in this decade databases and analysis programs initiated by Drs. Roderick, Janan Eppig, Joseph Nadeau and me coalesced to form the predecessor of Mouse Genome Database, which grew into Mouse Genome Informatics and is still the world’s single most comprehensive database on mouse genomics, attracting millions of visits each year.

In 1989 JAX faced yet another trial by fire, when the production facility was destroyed by a blaze that started in a mouse room being renovated by an outside contractor. After hearing a loud explosion, we stood at our windows in the research building watching in disbelief as a large column of black smoke and flames grew. Many of us rushed to the site and rescued boxes of mice from some of the breeding rooms in a “bucket brigade” until firemen refused us entry for our own safety. A few geneticists helped triage which surviving pups would be fostered to get the production strains up and breeding again as quickly as possible. True to the Laboratory’s tradition of cooperating and sharing, JAX researchers provided foster dams from their own colonies and assumed responsibility for providing resources to the worldwide research community.

In the fire’s aftermath, financial support poured in from around the world, including a large monetary gift sent by Japanese colleagues. Dr. Ken Paigen became the next JAX director six months earlier than planned. Called when he was about to board a plane back to California from Maine, he returned to Bar Harbor and took charge of the Laboratory’s recovery. Later Ken and I flew to Washington, D.C., and met with Dr. Judith Vaitukaitus, director of NCRR at the NIH, to make the case for rebuilding the production facility because of JAX’s critical role in providing resources for biomedical research. The NIH later awarded JAX two grants totaling $18.2 million for mouse facility construction. The outpouring of support reaffirmed how critical JAX was to the biomedical research community.

In the 16 years following the fire and rebuilding, research capacity was expanded by the addition of the Snell research wing in 1989, the north research wing in 1993 and the east research wing in 2006. In 2000 the Genetic Resources wing was built to consolidate resource programs – cryopreservation, genetic resource science, importation – and to provide space for large-scale projects.

The 21st century began the era of large-scale science, programs involving many scientists. Between 2000 and 2006, JAX scientists obtained funding for four such programs – a center to develop mouse models of neurological diseases; a center for new models of heart, lung, blood and sleep disorders; a Shock Center grant to expand studies on aging; and a genome dynamics center to study systems biology.

In the last two decades JAX has expanded beyond the Bar Harbor campus. A breeding facility at the University of California at Davis gave JAX a West Coast presence, providing space to expand contract breeding and to breed commonly used strains, while also enabling shorter shipping distances and times. Moving to a larger facility in West Sacramento, scientists at this campus began to provide contract research support to researchers at pharmaceutical and biotech companies, as well as universities, by helping with experimental design, doing the experiments (e.g., drug dosing and results assessment) and providing space for breeding mice.

In 2011 The Jackson Laboratory for Genomic Medicine was born when Connecticut approved a bond to bring JAX to its medical school campus in Farmington. The genome center, formally dedicated Oct. 7, 2014, will provide state-of-the-art genomic sequencing and analysis, giving JAX a much more direct connection to clinical research and human health.

When I joined JAX in 1971 the research facility consisted of what is now the core of the present research building with a mouse room wing on the east side. JAX had only the Bar Harbor campus and about 350 employees. Now in 2014 JAX has over 1,600 employees on campuses in Maine, California and Connecticut.

The future

In the early 21st century JAX is already making advances in understanding personalized medicine in the field of cancer research and treatment. The NSG mouse strain, developed by JAX’s Dr. Leonard Shultz, will be critical in furthering personalized medicine. In the PDX (patient-derived xenograft) program at the West Sacramento campus, NSG mice are already being implanted with patient tumor tissues and used to test the efficacy and safety of anti-cancer drugs. At this writing a collaborative breast cancer study in Maine between JAX and the Maine Cancer Initiative will help develop “avatars” – mouse surrogates for human patients. This collaboration will pave the way for patient-specific models to test alternative drug therapies for patients while they are undergoing initial standard treatment.

Under the leadership of Dr. Edison Liu, who became president and CEO in 2012, JAX has entered the field of genomic medicine. The Jackson Laboratory for Genomic Medicine in Connecticut is already bringing together JAX researchers’ genetic expertise and basic model organism research with scientists in many disciplines from around the world. Its state-of-the-art human genome sequencing will be critical to understanding the biological implications of human genome sequence variation and its role in individual responses to drug therapy. This research will firmly establish JAX as a world leader in genomic medicine and an even stronger participant in translational research – moving research findings in model organisms to patients’ bedsides.