Associate Professor Doug Coffin with some of his selectively bred mice.

From Mice to Mankind
Seeking Molecular Remedies for Disease

BY CAROLINE LUPFER KURTZ

Human embryos have a beating heart and circulating blood as early as one month of gestation. In fact, the cardiovascular system is the first functioning system to develop in any animal, according to Douglas Coffin, a molecular biologist and associate professor in UM’s Department of Pharmaceutical Sciences.

Since his days as a graduate student, Coffin has been curious about how genes control the step-by-step biochemical pathways of this development. His investigations, first in chicks and then in mice, eventually landed him at the Great Falls McLaughlin Institute and at UM in 1998.

The way development occurs in embryos, he says, can provide a map of the regulatory mechanisms at work in the normal course of events so that remedies can be developed for when things go awry, as in birth defects or disease. At the heart of his research is genetics.

“Genes are expressed at very specific times during development and then become silent,” Coffin says. However, they can become “switched on” again in certain pathologies, like heart disease, stroke or cancer.

Sometimes this is a good thing. During a heart attack, for example, an area of heart tissue is deprived of oxygen and dies. This triggers part of the system to turn on again to help repair the heart by generating new blood vessels to feed the muscle. The same thing can happen in stroke.

“Unfortunately, this repair system goes astray in tumors and in some kinds of arthritis, feeding the thing that is hurting us,” Coffin says.

Genes are blueprints for proteins. To sort out control of the body’s natural repair response present in heart disease, Coffin’s work focuses on creating genetically modified mice that either lack certain proteins or overproduce them. The mice then are subjected to different surgical procedures and analyzed for the presence of various growth factors — molecules known to help repair tissue. The idea is to enhance the growth of new blood vessels — angiogenesis — in heart patients, especially those who do not respond well to bypass surgery or angioplasty.

In recent years Coffin has collaborated with cardiac surgeon Carlos Duran, president of the International Heart Institute of Montana at St. Patrick Hospital in Missoula, and others in studies of how transmyocardial laser revascularization (TMLR) helps patients who do not respond well to other treatments to correct blocked arteries. With TMLR a laser bores tiny holes in heart tissue, spurring the organ to generate more blood vessels to compensate.

“We know TMLR works, but no one knows why it works on the biochemical level,” Coffin says. “We’d like to know how this surgery specifically affects the physiology of the heart so we can design drugs that could do the same thing but less invasively.”

Taren Grass, UM graduate student.

To discover which growth factors have the primary role in angiogenesis, Coffin and graduate student Taren Grass treated groups of mice with healthy hearts with a version of TMLR that uses a needle instead of a laser to perforate heart tissue. In some groups they also mimicked the damage that would occur during a heart attack. Both surgical approaches produced a significant increase in fibroblast growth factor 2, which resulted in new vessel growth near the wounded areas. In the heart- attack models, levels of vascular endothelial cell growth factor also increased. The researchers reported their results last year in the journal Coronary Artery Disease 2000.

Since then Coffin and Grass have extended their studies to models of heart disease that involve atherosclerosis and heart failure due to blocked arteries. They are studying ways to boost or facilitate regeneration of blood vessels in those areas.

“We have created mouse strains that are resistant to heart disease and obtained other types that are prone to it,” he says. “We are breeding these to see what happens with their offspring. In each case we know the exact genes we are working with” that confer the immunity or predisposition.
The vast majority of diseases involve more than one gene, he says. Most of his work is a matter of keeping track of which genetic levers are pulled and in what combination.

“We want to know how proteins are functioning in cells,” Coffin says. “We will watch which proteins are expressed or not and follow their effects in a cell. This may lead us to other molecular candidates that play a part in the resistance or prevention of heart disease.”

So far Coffin’s research has focused on the cardiovascular system and angiogenesis, but the work also has relevance for cancer studies. As with heart disease, Coffin says he can build models of cancer and genetically program them into mice to study how molecular regulatory systems malfunction in tumors. The identification of genes to experiment with is ongoing, he says, and recently received a boost from Professor Andrij Holian, director of UM’s new Center for Environmental Health Sciences.

“Professor Holian brings an array of new approaches to the identification of genes that could have a role in disease,” Coffin says.

One new project is to study genetic changes that occur in people who have been exposed to asbestos in Libby. Coffin and Holian are just beginning to look at blood serum and biopsies of damaged lung tissue from patients there to see how exposure has altered their genetic program. Discovering the biochemical changes that lead to cellular malfunction and tumors will give researchers new targets for therapies.

Coffin has another proposed project, in collaboration with Holian and Howard Beall, an assistant professor of pharmaceutical sciences, to study the effects of toxins at the Milltown dam on cardiovascular disease. And he is collaborating with neuroscientist Diana Lurie, a pharmaceutical sciences associate professor, on stroke studies.

Graduate students and pharmacy undergraduates carry out much of the day-to-day work in Coffin’s lab. Working in a research laboratory is of real benefit to them, he says.
“It adds a whole new dimension to their education. Teaching and research are mutually beneficial enterprises. They are what universities are all about.”

For more information about Coffin’s research, call (406) 243-4723/4759 or e-mail mouseman@selway.umt.edu.