Great Falls, Montana seems an unlikely spot for an independent biomedical research institute. This quiet town is certainly better known for the superb trout fishing in the Missouri River or as a jumping off point for the Bob Marshall Wilderness and Glacier National Park. There is no medical school in Montana and even the state’s research universities are a three-hour drive from Great Falls. Yet for nearly 60 years, research coming from the McLaughlin Research Institute has belied its small size.
The Institute began in 1954 with the arrival of Dr. Ernst Eichwald, recruited as a pathologist by the Montana Deaconess Hospital. As a condition of accepting the position, Dr. Eichwald, who directed a research program at the University of Utah, stipulated that a portion of the Hospital’s income from the clinical laboratory be set aside to help defray operating expenses and as a hedge against the day when National Institutes of Health (NIH) funding might become more difficult to obtain.
Ernst’s work in the Laboratory for Experimental Medicine, as it was then known, focused on the young field of tissue transplantation. Lacking a university, Great Falls did not have a ready supply of biologists or chemists looking for jobs, so he hired a used-refrigerator salesman from Sears, Bud Silmser, who seemed to be endowed with a good measure of common sense. In honing his skills at skin grafting using transplants within an inbred strain, Silmser had an unusually high failure rate. These turned out not to be technical failures, however, but rather rejection of male grafts by female mice – the discovery of the male-specific histocompatibility antigen, H-Y.
In addition to his clinical responsibilities and investigations into the genetics and immunobiology of transplant rejection, Ernst served as Editor of the journal Transplantation Bulletin and its successor, Transplantation, which had its editorial offices in Great Falls until 1967. Early work at the Institute, by Eichwald and later by Dr. Jack Stimpfling, played an important role in the eventual development of successful protocols for organ transplantation in humans.
Experiments in Education
Around 1956 an eager high school sophomore, Irving Weissman, approached Dr. Eichwald about the possibility of working in the lab. Irv was persistent and, after he made it clear that he didn’t expect to be paid, was allowed to help clean and change mouse cages. He quickly became more and more involved in the lab, learning the process and excitement of research, inspiring him to a career in science. Dr. Weissman is now the Virginia and D.K. Ludwig Professor for Clinical Investigation and Cancer Research at Stanford University and serves as Chair of the McLaughlin Research Institute’s Scientific Advisory Committee. In addition to after-school work, Irv spent much of his high school, college, and medical school summer vacations working on Dr. Eichwald’s research projects. The obvious enthusiasm and accomplishments of the young Weissman at the Institute led to development of a summer program for promising young high school students, selected on a statewide basis, to work and learn in the laboratory. The summer interns are active participants in the research programs at the Institute, and they learn, as no textbook can teach, the questioning process by which new knowledge is obtained. Most participants in the program have gone on to productive careers in science or medicine.
The success of the summer high school program has led its recent expansion to include college undergraduates and to develop a new initiative for area science teachers. All scientists at McLaughlin Research Institute serve as mentors in these programs. Service as an educational resource for the region is a vital part of the Institute’s mission. In addition to providing a start for the next generation of scientists, the education program provides a basic but crucial understanding for non-scientists of the nature of scientific inquiry and its implications for society; it behooves all of us in research to devote some of our time and expertise to pre-college education.
A Change In Venue
In 1964, Ernst Eichwald recruited Jack H. Stimpfling from the Jackson Laboratory in Bar Harbor, Maine to join him in the Laboratory for Experimental Medicine. Jack also was a leader in transplantation immunogenetics and his work with future Nobel laureate George D. Snell was pivotal for the genetic dissection of the mouse major histocompatibility complex, H2. Ernst and Jack worked quietly but productively until 1966 when the Deaconess Hospital moved into a new building on the south edge of town designed to allow them to compete more effectively with their in-town rival, the Columbus Hospital. Promised research laboratory and mouse space in the new facility did not materialize, however, and the two scientists moved their research programs into two abandoned mom and pop grocery stores, one of which is shown in Figure 1. The shelves served as adequate racks for mouse cages and the checkout counters worked as lab benches.
Through the urging of Great Falls physicians John Pfaff and Jack McGregor, Columbus Hospital under the Catholic Sisters of Providence realized that the orphaned laboratory presented an opportunity to support research (and perhaps provide the Hospital with a competitive edge in attracting patients). With support from local contractor John L. McLaughlin supplementing that of the Sisters, the McLaughlin Research Institute opened its doors in May 1967. The building provided excellent laboratory and mouse space for the two scientists, but soon after its opening Ernst Eichwald returned to the University of Utah where he became Chairman of the Department of Pathology. Ernst remained a valued friend and advisor to the McLaughlin Research Institute until his death in 2007.
After Ernst’s departure from Montana, Jack Stimpfling enjoyed his role as the sole scientist at the Institute while making major contributions in immunology and immunogenetics. Jack devoted his career to the identification and characterization of H2 recombinants, developing a panel of congenic strains with crossovers within the complex that were used by scientists worldwide during the golden age of immunobiology. By developing polyclonal, and later monoclonal antibodies to identify the rare intra-H2 recombinant mice, he added considerably to the value of the mouse resource. Jack’s application of genetics towards isolating and understanding the functions of the many molecules encoded within the complex was exemplary and far-reaching in its impact. Although unique in his ability to work so productively in such isolation, Jack enjoyed scientific and philosophical discussions with his many visitors and collaborators. “The Montana Institute for Immunology” meetings on several occasions were combined with the Immunobiology Study Section sessions. In one instance, research grant applications were packed in for review on mules to remote cabins adjoining the Bob Marshall Wilderness, much to the chagrin of some NIH bureaucrats. During Jack’s tenure, a cadre of scientists devoted to the Institute developed; in addition to Irv Weissman, this group included David Baltimore and Montana native Leroy Hood, both current members of McLaughlin’s Scientific Advisory Committee.
The research programs at McLaughlin Research Institute take advantage of the Institute’s historical strength in mammalian genetics. The animal facility is designed exclusively for mice, allowing efficient animal care, fewer demands for veterinary oversight, and, consequently, per diem rates lower than most other institutions. The mouse colony is maintained as a barrier facility and is free of viral pathogens; also included are quarantine rooms outside the barrier and an infectious disease area with individually vented cubicles. Animal technicians are active participants in the Institute’s research programs, providing services such as tissue sampling, neurological testing, surgical procedures, and record keeping. This provides relief from the tedium of cage changing for the caretakers and develops a sense of responsibility for “their” mice. Current census is approaching the capacity of approximately 15,000 mice. McLaughlin Research Institute was fully accredited by the Association for Assessment and Accreditation of Laboratory Animal Care in 1995. J. Douglas Coffin, who joined the Institute in 1993 following postdoctoral training under Tom Doetschman in Cincinnati, successfully established a transgenic mouse facility with both pronuclear and blastocyst microinjection capabilities. Genes have been ablated by Institute scientists using homologous recombination and numerous conventional transgenic lines have been produced. The shared application of mouse genetics to complex diseases and biological processes fosters interaction and collaboration among the scientists at the Institute.
A New Focus on Neurological Disease Research
Since Jack Stimpfling’s retirement in 1988, McLaughlin has grown from a one-investigator laboratory to a state-of-the-art facility with five research groups, under the direction of Dr. George A. Carlson. Like Stimpfling, Dr. Carlson was recruited from the Jackson Lab. Dr. Carlson applies his expertise in mouse genetics to understanding and modeling human neurodegenerative disease. He and his collaborators have made major contributions to understanding genetic susceptibility to prion disease and have developed transgenic mice that develop Alzheimer-disease like pathology and behavioral abnormalities. These mice are widely used for developing and testing new therapies. Dr. Carlson established a chemical mutagenesis program to detect genes active in pathways involved in neurological diseases. His latest work includes using stem cell cultures as well as transgenic mice to look at the mechanisms of dementing diseases.
Dr. Carlson’s work on neurodegeneration meant a change in the Institute’s focus – from immunogenetics to neurogenetics – and has attracted other scientists working in that field. Together this growing group brings a complementary variety of approaches to addressing the problems of degenerative nerve diseases, including Alzheimer’s and other dementias, Parkinson’s, prion diseases, neuropathies and multiple sclerosis.
The most recent addition to the faculty, Dr. Teresa M. Gunn (formerly the Robert Hovey Udall Assistant Professor of Genetics at Cornell University), joined the Institute’s faculty in 2009. Dr. Gunn’s research on the molecular mechanisms of neurodegeneration and neuropathies strengthens the Institute’s focus on degenerative brain diseases. Her work dovetails with that of the other investigators at MRI.
Dr. Deborah E. Cabin set up her laboratory at the Institute in September 2006, where she continues her study of the genetics of Parkinson’s disease. Dr. Cabin began this research in her previous position at the National Institutes of Health’s (NIH) National Human Genome Research Institute (NHGRI) in Bethesda, Maryland. She has been working with a transgenic mouse line that expresses a human gene which when mutated causes Parkinson’s disease. In the mice, it causes a motor neuron disease that should provide information about early stages of Parkinson’s.
Dr. John R. Bermingham, Jr. arrived at the Institute in October 1998 from the University of California, San Diego. Dr. Bermingham has successfully established an independent research program on the genetic control of Schwann cell differentiation and myelination. He has discovered a new gene family whose expression is modulated in response to nerve damage. This discovery was facilitated by Dr. Bermingham’s development of procedures to detect differential gene expression using tiny amounts of tissue.
Dr. John Mercer is an established geneticist/cell biologist who studies the molecular motors that transport organelles and proteins within the cell to where they are needed. Dr. Mercer was recruited from the University of Texas Southwestern Medical Center at Dallas. As a postdoctoral fellow under Scientific Advisory Committee members Neal Copeland and Nancy Jenkins at the National Cancer Institute, Frederick, he cloned the first non-muscle myosin gene to be described in mice. Mutations in non-muscle myosins can cause various genetic forms of deafness including Usher’s syndrome 1B (myosin 7a) and non-syndromic deafness B2 (also myosin 7a) and B3 (myosin 15). Since 2011, Dr. Mercer has been in Bangalore, India, helping to establish a mouse genetics facility as well as a lab at the Institute for Stem Cell Biology and Regenerative Medicine at the National Centre for Biological Sciences, as part of a collaboration between MRI and its former Scientific Advisory Committee member, Dr. James Spudich of Stanford University. The lab will focus on the role of mutated molecular motors in inherited diseases of the heart muscle called cardiomyopathies.
Doctoral Science Staff Changes
Pin-Xan Xu, PhD. was a Senior Scientist studying genes responsible for the development of eyes and ears that related to blindness and deafness at McLaughlin from 1997 – 2006. Dr. Xu accepted an appointment as Associate Professor in the Department of Human Genetics at Mount Sinai School of Medicine in New York City. “This was a very difficult decision to make, ” Dr. Xu said. “It is because of my success at McLaughlin Research Institute that my work is competitive enough to generate an offer like this, so this is a good reflection on the Institute.”
At McLaughlin from 1993 to 1999, Bill Crain, PhD. was a Senior Scientist studying gene expression in early mouse embryos, which related to birth defects and cancer. Dr. Crain retired from full-time laboratory research to spend more time working with his horses.
Dr. Douglas Coffin, PhD. was a Scientist studying growth of blood vessels and the relationship to different pathologies such as cancer and heart disease at McLaughlin from 1993 to 1998. Dr. Coffin accepted an appointment as Associate Professor for Molecular Genetics in the Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy and Allied Health Science at the University of Montana in Missoula, Montana.
In a lecture at the Institute given as the 20th century came to a close, Ernst Eichwald speculated on whether the time for “small science” had passed, but he argued that establishments like the McLaughlin Research Institute may well be an ideal setting in which curiosity, flexibility, and the fun of doing science can be maintained. Ensuring the survival of such an environment is difficult, but it is made easier by the dedication of the Institute’s supporters, particularly the members of our Scientific Advisory Committee. Each year the Committee convenes in Great Falls to discuss each investigator’s program, help foster collaborative studies, and provide advice on research directions and recruiting. In conjunction with the Advisory Committee meeting, scientists, students, physicians, and educators are invited to a daylong workshop. In most years more than 100 people participate. The lineup of speakers is impressive, including Advisory Committee members Jeff Frelinger, Irving Weissman, Neal Copeland, Nancy Jenkins, Leroy Hood, and David Baltimore along with an outstanding list of guest speakers.
It is clear that working in a very small, geographically isolated institution is not for everyone. However, it is equally clear that there are many outstanding investigators whose work can flourish in a collegial environment with minimal administrative impediments to research. We hope that McLaughlin Research Institute can continue to provide a place for the spiritual successors of Ernst Eichwald and Jack Stimpfling, working on the frontiers of science.
Building on their legacy of producing research results with a major impact on human health, the Institute is entering an exciting new chapter of improving human health.
Translating Basic Research into Medicine
McLaughlin Research Institute is playing a significant role in the development of an international trend towards translational research that applies genetic information obtained in the lab to medical treatments tailored to individual patients.
This new personalized medicine has been the longtime vision of MRI Scientific Advisory Committee member Leroy Hood. Dr. Hood, President and co-founder of the Institute for Systems Biology, has helped push medicine to the brink of revolution. An ongoing collaboration between Dr. Hood’s ISB and McLaughlin has produced promising possibilities for fighting Alzheimer’s and other degenerative brain diseases, and ISB has reached the stage of clinical trials. Their research has already moved medicine closer to the day when a simple blood test will reveal a person’s predisposition to disease and signal when disease is beginning. Such tests would enable very early intervention to prevent or slow the disease long before symptoms appear.
Work at McLaughlin, in collaboration with StemCells, Inc. (founded by Irv Weissman), has been instrumental in advancing another promising therapy for Alzheimer’s using brain stem cell transplants.
At this stage in its history, McLaughlin Research Institute is poised to help address the growing epidemic of dementia and other brain diseases.