Magic bullet

Cancer researcher Ulrich Bierbach hopes to forge out of platinum compounds ammunition against tumors.

Ulrich Bierbach: 'I want to explore all the avenues.'

or all its methodical rigor, scientific research involves a surprising amount of serendipity. Take cancer research, for example. During the Second World War, the Germans bombed an Allied cargo ship carrying mustard gas, a toxin used in chemical warfare. Some years later, an American oncology researcher named C.P. Rhoads linked that incident, through a study involving the men on board, with the toxin's ability to stop cancer growth. It was a breakthrough discovery: that small molecules could be used in cancer treatment, which led to rapid advancements in chemotherapy.

Another chance discovery can be credited, in a sense, with charting the course of Wake Forest chemist Ulrich Bierbach's career in cancer treatment research. In the mix-sixties, Bernard Rosenberg of Michigan State University sought to test the effect of an electrical field on the growth of E coli bacteria. He assigned a grad student to conduct an experiment by immersing platinum electrodes in solution and running electricity through them. But the student set the power level too high and the coils corroded. Rosenberg determined in ensuing tests that the platinum itself—not any electrical field—inhibited cell growth. This led to the development of a platinum compound called cisplatin, which kills testicular cancer cells and is the only chemotherapeutic compound known to definitively cure a form of cancer. It restored the health of champion bicyclist Lance Armstrong after his testicular cancer had spread to his brain and lungs, and it has saved the lives of untold millions of other men.

It is that kind of magic bullet that Bierbach, who has been recommended for tenure and promotion to associate professor, hopes to forge out of platinum compounds as ammunition against other forms of tumors. His promising work earned him this year's Award for Excellence in Research, presented at Founders' Day Convocation in February.

A native of Bremen, Germany, Bierbach obtained his master's and doctoral degrees at the University of Oldenburg. After a year of postdoctoral study in The Netherlands, he came to the U.S., spending, first, four years at Virginia Commonwealth University in Richmond, and then a year at the University of Minnesota before joining Wake Forest's chemistry department in 1999.

Bierbach describes his specialty as bioinorganic chemistry, which seems like an oxymoron until one realizes that inorganic elements are integral to living systems. Iron, for example, the most abundant metal in the body, is essential for breathing and oxygen circulation. Sodium, magnesium, calcium, zinc— each performs a vital life function.

Encouraged by cisplatin's success with testicular cancer, Bierbach and his research group—currently, four graduate students, three undergraduates, and one postdoctoral associate—are focused on finding platinum-based therapies for other forms of cancer. They collaborate closely with scientists at the School of Medicine and its Comprehensive Cancer Center, where Bierbach holds a joint appointment.

What makes platinum, among all metals, so promising? "It is a highly effective cross-linking agent," explains Bierbach, whose work is funded by a four-year, $901,000 grant from the National Cancer Institute. "DNA, as you know, is a double helix [in structure]—two intertwined spiral strands. When platinum interacts with DNA, it distorts the two strands, causing cell death. Normal cells can rejuvenate themselves over time, but cancer cells replicate too quickly to repair the damage, and they die."

Cisplatin also has been proven effective against ovarian cancer, but ovarian cancer cells become resistant to it over time. "Our goal," says Bierbach, "is to make a drug that can be used after cisplatin becomes ineffective."

Of the roughly 4,000 platinum derivatives that researchers have identified over the past three decades, only four have made it to clinical use. But that sobering statistic hasn't quelled Bierbach's optimism. "We are one of a very few labs that believes it can find [platinum] compounds that are sufficiently dissimilar to cisplatin to be effective with other tumors," he says. "Potentially, we think our drugs hold promise for effective treatment of brain cancers and extremely aggressive ovarian and lung cancers."

His strategy is to combine two independently active compounds—platinum and organic molecules—that, synergistically, yield therapeutic effects. There have been advances: one of his compounds has been shown in preclinical trials to date to be four to five times more effective than cisplatin in treating lung cancer, and he is confident that eventually it will prove a hundredfold more effective. But there are no shortcuts: the research demands painstaking synthesis and molecular structure analysis. "We must achieve a balance," he states, "between going straight to the goal—developing a chemotherapeutic agent—and exploring the basic science of why these molecules work."

It is that devotion to basic science that characterizes the academic quality of Bierbach's work. "We are not a drug development company," he says. "I want to explore all the avenues, even though they may not be all that promising. I want to learn from them."

But that's not to say that developing patentable drugs isn't on his radar screen. "My personal goal," he says, "is to get a compound into clinical trials in two to three years. That would be an accomplishment."

— David Fyten

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