She has come a long way. Today, scientists widely accept the theory that first met with laughter. Moreover, Dr. Griffin has moved on from explaining how Alzheimer's disease occurs and predicting who will get the disease to finding how to prevent it. The National Institutes of Health (NIH) recently awarded her and her colleagues at the University of Arkansas for Medical Sciences (UAMS) another $7 million to continue her work on Alzheimer's disease and related problems of aging.
Dr. Griffin earned a Ph.D. in physiology at the University of Rochester in 1974 and in the mid-1980s was doing research in developmental neurobiology at the University of Texas Health Science Center in Dallas. She noticed that the brains of patients with Alzheimer's disease and Down's syndrome had a similar excess of cytokines, immune signal proteins that cause inflammation and - sometimes - the death of neighboring neurons. Alzheimer's is a progressive, degenerative brain disease that causes severe memory loss and eventually death. She speculated that Alzheimer's disease occurs because of a cycle of cytokine-induced events in the brain, beginning with the release of amyloid, a protein fragment that is deposited as plaques, triggering release of more of these inflammatory cytokines. Interleukin-1 (IL-1) is chief among these cytokines and has subsequently been shown to cause further release of the plaque components, thereby propagating damage to an ever-expanding area of the brain.
Griffin wondered, If an excess of the cytokines in the brain fosters the development of Alzheimer's, and if the gene that produced that excess could be identified, could scientists "catch" Alzheimer's early enough to prevent it?
Her idea was a departure from the conventional wisdom about Alzheimer's disease. The leading researchers in the field, investigators at major universities, were focusing on the hypothesis that amyloid plaques were themselves directly responsible for damage to neurons. Funding agencies turned down Griffin's first requests for research grants.
"My idea was met with a cacophony of boos and guffaws," Dr. Griffin recalls now. A softspoken woman, Dr. Griffin chuckles when she remembers the early rejection of her hypothesis. She tells younger researchers that if they can't get funding for their wildest research ideas, to get funding for more conventional projects and "plug away on that novel idea in your spare time."
Dr. Griffin is professor and vice chair of the Donald W. Reynolds Department of Geriatrics in the UAMS College of Medicine and director of research at the Geriatric Research Education Clinical Center at the Central Arkansas Veterans Healthcare System.
After returning to her home state of Arkansas in 1986 as a professor in the Department of Pediatrics at the University of Arkansas for Medical Sciences (UAMS) College of Medicine, Dr. Griffin and her collaborators at UAMS first established in 1989 that Interleukin-1 is, indeed, over-expressed in the brains of persons with Alzheimer's disease. Just as importantly, they showed that IL-1 is over-expressed throughout the progression from Down's syndrome to Alzheimer's disease. (Persons with Down's syndrome typically develop Alzheimer's disease in later life.) Dr. Griffin and her colleagues reported the "cytokine cycle" in 1992. Next, they identified the variants of IL-1 genes that are associated with over-expression of the cytokine, B-amyloid precursor protein, the potential linchpin in the cytokine cycle, in 2000. Today a fairly rapid and inexpensive blood test can reveal the presence of those variants of IL-1.
Dr. Griffin and others also have shown that the over-expression of IL-1 can trigger several phenomena related to Alzheimer's disease. Scientists at several other universities have confirmed their discovery. Their findings were very exciting because IL-1 can be regulated with readily-available drugs.
Scientists now widely accept her theory that this chronic inflammatory response in the brain is an important factor in the development of Alzheimer's disease. In recent years other scientists have confirmed in multiple studies that individuals who take anti-inflammatory drugs regularly for other conditions are much less likely to develop the disease than individuals who do not take the drugs. Even more convincing, Dr. Griffin and her collaborators were able to show that people who have certain DNA sequences in the gene for interleukin-1 are more likely to get Alzheimer's disease. This finding was convincing evidence that interleukin-1 is a key factor in development of the disease.
Dr. Griffin is currently focusing on how these discoveries can help physicians stop Alzheimer's disease before its effects are severe. A Massachusetts genetics firm has joined her to search for drugs that could prevent or delay Alzheimer's disease. Interleukin Genetics (Nasdaq ILGN) will collaborate with Dr. Griffin and UAMS to identify possible drug treatments for persons who are at risk of developing Alzheimer's disease.
"Our idea is to detect the disease as early as possible and then intervene with drug therapies or alternative treatments before it reaches its very degenerative stages, so we can keep people functionally independent," she explains. Dr. Griffin and Interleukin Genetics will use functional genomics to determine how interleukin-1 gene variations alter inflammation in the brain, leading to Alzheimer's disease. Genomics is a discipline that identifies genes, their interactions, and their effects on biological processes. It promises to accelerate the development of new approaches to treating human diseases. This information, together with other genetic data, will be used to develop new drug therapies for individuals who have an over-expression of Interleukin-1.
Today, Dr. Griffin tells audiences they can reduce their risk of brain disease by having "a merry heart." She is co-director of the Alzheimer's Disease Center at UAMS, a professor in the UAMS College of Medicine, and a researcher at Central Arkansas Veterans Healthcare System. The National Institutes of Health (NIH) have supported Dr. Griffin's work since 1991 with grants worth $17 million through 2007.
An interdisciplinary research program on Alzheimer's disease has grown up at UAMS since Dr. Griffin first showed that IL-1 is a linchpin in the development of the disease. David A. Lipschitz, M.D., Ph.D., a South African geriatrician with a charismatic style, directs the Donald W. Reynolds Center on Aging and is chair of the department of geriatrics in the College of Medicine. Robert E. Mrak, M.D., Ph.D., has collaborated with Griffin on the cytokine studies for 11 years. Steven W. Barger, Ph.D., joined the department in 1995 as the first faculty scholar of the Inglewood Foundation, an endowment to UAMS aimed expressly at increasing its Alzheimer's disease research efforts. Cornelia Beck, R.N., Ph.D., a leading researcher on preserving independence in old age, directs the federally-funded Alzheimer's Disease Center at UAMS; Dr. Griffin is co-director of the center, along with Victor W. Henderson, M.D., M.S., who leads its clinical program. Charlotte Peterson, Ph.D., leads a research group that was the first to report a possible link between muscle loss and fat gain that may point to ways to reduce frailty in old age. John Hart, M.D., with co-investigators at Johns Hopkins University, has proposed a novel explanation for how we recall memories for objects that surround us, suggesting that objects occur in your memory by uniting the different brain regions that make up various parts of the object you are trying to remember. William J. Evans, Ph.D., has developed a fitness program based on one that helps astronauts reverse the effects of space travel. Sandra K. Pope, Ph.D., M.P.H., is studying the influence of dietary and genetic risk factors on cognitive decline over time. Jeanne Wei, M.D., Ph.D., recently left Harvard University Medical School to join the department as executive vice chair. Drs. Griffin and most of these scientists are affiliated with the Geriatric, Research, Education, and Clinical Core of the Central Arkansas Veterans Healthcare System, a program that has fostered research on aging since the mid-1970s.
The university also has geared up to do more breakthrough genetic studies. It collaborated with several other institutions in Arkansas to obtain $6 million from the NIH to create a network of high-powered research laboratories in the small rural state.
Dr. Griffin's collaboration with Interleukin Genetics may earn a profit for her and for UAMS, which trains many of the physicians, nurses, pharmacists, and other health professionals in Arkansas. University leaders hope that other high-tech health science research at UAMS will be an economic "engine" for the state, stimulating local industry and creating high-paying jobs for new generations of Arkansans.