31 Jul Marshfield Clinic charges ahead in genetic research
Clinic’s unique position gives it lead in cutting-edge field
MARSHFIELD, WI – TV writers formulating a new drama series on a world-class genetic research laboratory might have problems locating Marshfield on a map of Wisconsin.
But if they wanted a look at what is arguably ground zero for the burgeoning field of personalized medicine that genetic research is making possible, Marshfield Clinic would have to be their first stop. And with all that’s going on at the Marshfield Clinic Research Foundation (MCRF) and the Personalized Medicine Research Center (PMRC), they’d have to bring an extra notebook.
Because it has been a premier medical institution for decades, Marshfield Clinic is uniquely poised to bring genetic research to the bedsides of its patients largely because of three key advantages that act like blades of a propeller for the clinic’s research goals: A well-studied, stable local population; a world-class electronic database of medical records spanning decades; and well more than a decade of genotyping experience, which has gone hand-in-hand with the clinic’s role in the Human Genome Project, a monumental project which completed the final sequence of the human genetic map earlier this year.
“You put those three together, and it’s called personalized medicine,” said Dr. Michael Caldwell, director of medical research at Marshfield Clinic and principal investigator for the clinic’s Personalized Medicine Research Project. “It’s a research database that [we hope will] become a national resource for people to understand the genetic basis of disease and the genetic basis of response to medication.
“The idea is to put it together in a way that will allow not only our scientists, but scientists from other institutions, to begin to ask the appropriate questions and try to answer them – to try to do what we think will be a revolution in the practice of medicine.”
How that concept shows up at a patient’s bedside is a topic that can get pharmacologist, Dr. Russell Wilke talking a mile a minute about genetic polymorphisms and drug metabolizing enzymes.
In the shadow of the upcoming mammoth Personalized Medicine Research Project – in which the clinic plans to study variations in genes that might predict hundreds of adverse drug reactions in tens of thousands of patients – are two smaller projects that could have monumental impact on recipients of two of the country’s most prescribed drugs, one of which is the anti-coagulant coumadin.
Coumadin, a popular anti-coagulant used to a treat a variety of conditions that increase a person’s risk of developing blood clots, is the 34th-most prescribed drug in America. However, the drug is not without its risks—about 30 percent of the population has genetic variations in the liver enzyme that metabolizes coumadin in the body. The end result can be increased risk for adverse drug reactions, including too much blood thinning too fast leading to severe internal bleeding or even death.
Several groups around the country are working toward prescribing coumadin based upon a person’s genetic makeup. In Marshfield’s just-finished, yearlong study of 500 patients, the clinic charted how much coumadin they were taking and characterized their pertinent gene variations, all with the ultimate goal of helping physicians take the guesswork out of prescribing coumadin.
“Because it’s potentially a dangerous drug, we may improve clinical care by doing this type of study,” said Wilke, head of Pharmacogenetics at the PMRC. “Actually we plan to turn it around in the next year and study it prospectively, where we take the genotypes we have found to be associated with the inability to metabolize coumadin and genotype at the point of diagnosis and prescribe prospectively—the right drug in the right dose at the right time.”
Caldwell said Marshfield Clinic is well suited to do studies such as the coumadin project because of the nature of its patient base and the full range of disease it sees as home of those patients’ primary care physicians.
“We’ve got a population that cuts across all spectrums of disease,” he said. “The difference between studies that take place at Marshfield Clinic and studies that take place at universities is universities see a small spectrum of disease. Marshfield Clinic sees the full spectrum, from primary to quaternary care across all diseases, across all types of procedures. So as a consequence when you look at the whole population; you understand the population.”
Understanding the population then translates right back to better patient care and better medication prescriptions by merging phenotype information—a person’s visible characteristics—with their genotype information, which was never available before.
“The problem with coumadin is that we know that people respond differently to it; we know that it has big complications,” Caldwell said. “Now what is able to be discovered is a way of trying to figure out what right dosage to start somebody on.”
Which is a huge step, both in terms of better health for those individuals and the implications it holds for making theoretical laboratory results applicable in the field.
“So with solving the Human Genome Project … everyone’s sort of rushing to establish ways to implement functional genomics in the clinical world,” Wilke said.
The Right Mix
Catherine McCarty, a molecular epidemiologist and director of the PMRC, said that two fields of knowledge now can be blended at the clinic in unprecedented ways to get a leg up on disease. Epidemiology—which is primarily concerned with risk management before the onset of disease—typically has looked mainly at environmental and personal risk factors at the expense of genetic information, while geneticists largely have ignored environmental data.
“For the first time now, we’re able to develop the statistical tools to be able to put that information together and look at the relative contribution of genetics and environment in the development of disease,” McCarty said. “It’s so exciting. You can really practice primary prevention.”
Two areas have been found by the reviewers of recent research projects to be key for improving those studies—size and homogeneity of the study population. Marshfield has both going for it in its upcoming project, for which it already has gathered more than 10,000 vials of DNA samples and will have 20,000 by year’s end. The task dwarfs any similar project the clinic has undertaken thus far.
“We’re going to be looking at hundreds of polymorphisms [gene variations] in tens of drug metabolizing enzymes in tens of thousands of patients, interrogating our clinical medical record for association with various combinations of these gene polymorphisms and sequentially hundreds of adverse drug reactions,” Wilke said. “The permutations and analytic conundrums are daunting, but the clinical relevance makes it worth doing.”
The research will be the cornerstone of a national resource for genetic study that will have far-reaching social ramifications in how health care is practiced, Caldwell hopes.
“Let’s say I put you on a particular type of medicine,” he theorized. “The whole population would respond in a general way to that, but that doesn’t mean that you are going to respond like the majority of the population. There’s always been a tension between physicians and patients about that—‘Why isn’t this working?’
“I can’t hold you personally responsible for your care if I can’t predict how you should respond,” he said. “But if I can predict how you should respond or predict your predilection for disease … I can put some responsibility on you. I can’t do that now. I can do it now, and I do do it now, but I don’t have data to do it with.”
He will now.
Lincoln Brunner is a Stevens Point, Wisconsin-based freelance writer and a regular contributor to the Wisconsin Technology Network. He can be reached at firstname.lastname@example.org