MEDICAL BULLETIN

Math helps uncover genetic components of disease

Behind-the-scenes work benefits colleagues, patients

Robert C. Elston, Ph.D., admires the common areas of the new Wolstein Research Building.

If you ask Robert C. Elston, Ph.D., how he stumbled into a career as a mathematical geneticist, he’ll tell you it’s Adolph Hitler’s fault.

During World War II, Dr. Elston became an evacuee from London. He was sent to the countryside and took an interest in farming, which led him to an undergraduate degree in natural sciences and agriculture from Cambridge University.

But he didn’t have the capital to pursue farming, so he boarded the Queen Mary with 25 other students and set sail for America. Upon arriving in New York to begin a fellowship in animal breeding at Cornell University, he sat in on a pep talk about America. He bought a car and enjoyed the American way of life.

“When I got to Cornell, a professor asked me to stay and do Ph.D. work,” Dr. Elston said. “I said I was not there to get a degree.”

But the professor talked him into taking a test that was the gateway to pursuing a higher degree. He passed and soon found himself in an animal-breeding Ph.D. program. From there he completed some postdoctoral work in statistics at the University of North Carolina, but his visa status sent him back home for two years.

Determined to return to America, Dr. Elston’s interest in farming fell by the wayside as he pursued genetics instead. He said his story is not atypical of most people in academia who wind up in their specialty quite by accident.

“I’m too old to start farming now,” he said. “I don’t think I could farm in this country. The climate’s not right. I was trained to farm in England.”

The epidemiology community is thankful for that career detour. Dr. Elston, the director of the Department of Epidemiology and Biostatistics’ division of genetic and molecular epidemiology at the Case Western Reserve University (Case) School of Medicine, is now working to develop statistical methods for analyzing family and pedigree data to study the genetic component of certain diseases. He has been at Case since 1995.

Springboard for discovery

Although statisticians, who deal with scientific and statistical methodologies, don’t receive the same kind of press and public recognition that clinical researchers enjoy, their work often is the springboard for discovery. Dr. Elston said many diseases appear to result from a genetic predisposition, or from interactions between genes and the environment.

“What I do is mathematics. It’s back-ground, but it is helpful to the whole field,” he said. “It’s necessary work.

“In the division we are looking for genetic determinants of diseases, and the emphasis now is on complex diseases,” including colon cancer, fibromyalgia, lupus, intracranial and abdominal aneurysms, Alzheimer’s disease, end-stage renal disease, macular degeneration and cataracts, he said.

Dr. Elston said he works jointly with colleagues in other departments on linkage analysis—determining the location on a chromosome where a disease-causing gene resides—and statistical techniques—analyzing family “We’re developing new methods of analysis and determining the most efficient kinds of samples to get,” he said. “We’re analyzing data being collected with our collaborators.”

Dr. Elston also is the principal investigator of the Human Genetic Analysis Resource (HGAR), a National Institutes of Health (NIH)-supported resource that analyzes pedigree data with the Statistical Analysis for Genetic Epidemiology (S.A.G.E.) software package developed by the resource.

S.A.G.E., supported by a grant from the NIH’s National Center for Research Resources, is used in the genetic analysis of family and pedigree data. Researchers use the program to better understand the link between family disease history and genetics. Case’s Office of Technology Transfer licensed the software package in 2002, but researchers have used it locally, nationally and internationally for more than a decade.

Dr. Elston called the resource grant the glue that binds his group—Katrina Goddard, Ph.D., Sudha Iyengar, Ph.D., and Yuqun Luo, Ph.D., and, until her recent death, Jane Olson, Ph.D.—together. Every researcher in his division is working on some aspect of S.A.G.E., with the exception of Dr. Iyengar, who does more practical work, in terms of gathering and analyzing data of specific populations—but nevertheless uses the S.A.G.E. software.

“This is motivation for us to better develop statistical data to answer the questions she has,” Dr. Elston said.

Space will foster collaboration

Dr. Elston’s division has about 60 people, including faculty, staff and students. He said that although his group will be “bursting at the seams,” the new Iris S. and Bert L. Wolstein Research Building will provide much common space to foster more discussion and collaboration. One of the collaborators is Sanford Markowitz, M.D., Ph.D., a professor of cancer genetics at Case and a Howard Hughes Medical Institute investigator, who is studying familial cases of colon cancer. Dr. Markowitz, working to create a blood test to identify people who are susceptible to the disease before it develops in them, called Dr. Elston a “wonderful mathematical geneticist” at the Oct. 17 symposium opening the Wolstein Research Building.

Another major plus in moving the division from MetroHealth Medical Center to the Wolstein Research Building, Dr. Elston said, will be the ability to confine all classes to the Case campus. Before the building opened, many pre-doctoral students had to find transportation between MetroHealth and Case. Now they will be able to walk to all of their classes, as well as the library and other departments.

“We were cut off from the other departments before,” Dr. Elston said. “This is much more conducive to collaborations within the university. I’ve done some collaboration with a professor in the Department of Anthropology, but I’ve never seen where that department is.”

Through collaborations, Dr. Elston said, he wants to help researchers find ways to cure or prevent diseases.

“We are learning that most diseases have an important genetic component,” he said.

For example, he added, people may think of tuberculosis as a disease related completely to the environment, but susceptibility to this disease has a large genetic component, with heredity accounting for perhaps 50 percent of cases. Also, hypertension has a heritability of about 50 percent, although the public hears more about bad diet and exercise being the main culprits.

“The point is, if we can find the genes involved—because the genes do something, they control the metabolic processes by finding these genes—we find out what metabolic processes are involved in disease. We find targets for drug therapy,” he said. “Right now, there is a push, whenever you’re doing clinical trials and trying out a drug, to see what it does to something. Why not look at genetic markers at the same time, to tell us which genes may be involved?”

The benefit, he added, is determining how to make drugs work more accurately, developing better drugs, and finding alternatives to surgery to cure disease.