June 25, 2004

Systems biology yields insights that may aid cancer treatment

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Marc Kirschner, Ph.D., chair of the department of Systems Biology at Harvard Medical School (right), discusses a research poster with Vito Quaranta, M.D., professor of Cancer Biology at Vanderbilt (left), and Michael L. Simpson, Ph.D., of Oak Ridge National Laboratories.

Systems biology yields insights that may aid cancer treatment

Systems biology, a relatively new research approach, is yielding clues to one of the most difficult challenges facing cancer treatment: Why do some patients respond to cancer drugs, while others don’t?

By creating detailed maps of "signaling networks," linkages between various pathways of genes and proteins that resemble complicated wiring diagrams, scientists are beginning to understand more fully what goes wrong in disease at a molecular level — and how to fix the aberrant circuitry.

This approach to science, which pools the talents of mathematicians, engineers and computer scientists as well as biologists, pathologists and cancer specialists, promises to lead to a more individualized, and potentially more effective approach to diagnosis and treatment, experts say.

Within 10 to 15 years, technological advances will permit the early detection of disease from a single drop of blood, predicted Leroy Hood, M.D., Ph.D., president of the Institute for Systems Biology in Seattle. “Blood will be a window to distinguish health from disease,” Hood said last week at a Vanderbilt Summer Conference entitled "Mathematical Models in Signaling Systems."

About 100 scientists from throughout the world attended the two-day conference, which was organized by Emmanuele DiBenedetto, Ph.D., Centennial Professor of Mathematics and director of the Biomathematics Study Group, and Heidi E. Hamm, Ph.D., Earl Sutherland Professor and chair of the department of Pharmacology.

An example of the impact of systems biology is the discovery that the epidermal growth factor receptor, which is targeted by a new generation of cancer drugs such as Iressa, is a member of a family of at least four related receptors. These receptors can be “turned on” by more than 30 different molecules. They, in turn, can activate different pathways leading to abnormal cell growth.

This may explain why less than a quarter of patients with non-small cell lung cancer respond to Iressa, said David de Graaf, Ph.D., of AstraZeneca’s “Pathways” program in systems biology. “Inhibition of multiple receptors may be necessary,” he said.

Thanks in part to the sequencing of the human genome, “we now have an exquisitely detailed ‘parts list,’” said Adriano M. Henney, Ph.D., who directs the Pathways program. “Now we need to (get) the wiring diagram to understand how each component plays its role in responding to various stimuli and creating disease.”

If the systems biology approach is successful, “and it remains a big ‘if,’” Henney said in an interview, “… that will help us to change the way we go about putting new medicines into development, hopefully … reducing the size of clinical trials, the cost of clinical trials, (and) making sure we get medicines into the right patient at the right time.”

“In a different era there was a view, which is no longer tenable for complex organisms, that there would be a gene for everything … that we would find the gene that caused cancer and the gene that caused heart disease,” added Marc W. Kirschner, Ph.D., founding chair of the department of Systems Biology at Harvard Medical School.

“What we’re finding out instead is that genes are used over and over again … People have to understand how these genes work together in circuits, how they compensate for each other’s failures.”

Progress, however, “is going to require the training of a new kind of scientist,” Kirschner said, “… who really does combine the theoretical power of mathematics … with a real understanding of biology.”

The current lack of interdisciplinary training “reflects on some real deficiencies in our educational system, going all the way down into middle school or high school level, but certainly at the college level,” Kirschner said. “If this is going to be the frontier, how systems work, we have to have a much better way of presenting that to (students).”

The conference was supported by the National Academies’ Keck Futures Initiative, AstraZeneca, the National Institute of General Medical Sciences, the Biomathematics Study Group and the Vanderbilt Institute for Integrative Biosystems Research and Education.