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Progress, Fall 2004

This issue of Progress features four tales of researchers at the University of Michigan Comprehensive Cancer Center. To find answers, they're traveling to unfamiliar places, employing unusual approaches, conquering unwieldy data and creating undetectable devices, all intent on making cancer's future uncertain. The University of Michigan is one of the few places in the world where even one of these stories could take place; it may be the only place where all four could converge.Together, they illustrate that at U-M, cancer research isn't confined to a lab, or limited by words like organic or synthetic, big or small.They also show the power of collaboration -- in addition to the investigators profiled, countless other professionals play critical roles -- professionals in disciplines only collected in an institution with the depth and breadth of the University of Michigan.

These stories cast our Cancer Center's "comprehensive" designation in a fresh light. Each day we provide comprehensive care to every patient in every clinic. Our scientific pursuits are equally comprehensive.

Man Overboard: Diving for Answers with David Sherman

David Sherman’s laboratory in the University of Michigan’s new Life Sciences Institute looks much like any other research lab. Full of the familiar paraphernalia used to handle liquid chemicals, it’s what scientists call a “wet lab.” But Sherman’s work puts a whole new spin on that phrase. Sherman, Ph.D., is a John G. Searle Professor of Medicinal Chemistry in the College of Pharmacy and a professor of microbiology and immunology in the U-M Medical School. He pursues a quest only a handful of investigators in the world currently share: scouring the undersea world to gather substances with disease-fighting potential, then exploring their genetic origins to determine how they do what they do. His goal: to find new ways to create new drugs – including new cancer-fighters.

Coiba, Panama, July, 2004. David Sherman, PhD, collects sediment and plant samples at the water's edge.

“Many of the most successful clinical drugs used today – from the antibiotic tetracycline to the cholesterol-lowering statins – are produced by living cells,” explains Sherman. “The anticancer drug taxol is made from the bark of a tree.” Whether a rare tree’s bark, a piece of rubble from a remote coral reef or the dirt in his own backyard, they all hold the same mystery for Sherman. In his words, “each is full of organisms producing exciting chemistry.”

Sherman began his career as a synthetic chemist, creating duplicates of complex organic molecules. But he wasn’t satisfied with making copies of nature – he wanted to understand how nature did the work herself. Working alongside a pioneer in the field of bacterial genetics, he became one of the first to identify and characterize a set of genes involved in making a diverse class of organic antibiotics called polyketides.“We went from synthesizing drug-like molecules in the lab to studying the genes and corresponding enzymes that do the organic chemistry in bacteria that makes those molecules," he explains.

From that point on, he focused on finding natural substances with drug-like potential and understanding the genetics that drove them. But to prepare for that mission, some rather intense "cross-training" was required. "To study these systems," he explains, "you have to understand chemistry, then become a molecular biologist, then a bacterial geneticist, then a biochemist to really amount to something."

From laboratory to coral reef

Scuba diving -- a passion of Sherman's since his youth -- proved essential too, when the search for disease-fighting agents took him off-shore. "We know from twenty years of natural product chemistry that marine invertebrates produce fantastic chemistry. Right now at least twelve compounds in clinical trials or pre-trial testing for cancer come from these sources." The invertebrates Sherman refers to are soft coral and sponges -- the "innocent bystanders" -- of the undersea world. He postulates that, in an environment that seems to take survival of the fittest to new heights -- or depths -- there might be a reason why these creatures seem to be left alone by most all undersea life. Perhaps something defends them, and perhaps that same defense might prove equally powerful in the fight against cancer.

One of hundreds of potential cancer-fighters, the marine invertebrates off the coast of Panama are not only exquisite, but produce "fantastic chemistry," according to Sherman, who took this photo, as well as the photo featured on the index page, during an expedition to Cioba, Panama, withthe Smithsonian Tropical Research Institute in June, 2004.

"Our work with sponges is exciting," Sherman exclaims. "One of the most promising drugs, which is in trials now, comes from a sponge gathered from water between ten and 40 meters deep. An even more prolific producer of anti-cancer compounds is found at 300 meters -- a depth sane divers never attempt. We send submarines to harvest that material, which is expensive and environmentally tricky." Sherman's hypothesis is that it's not the sponge, but one of the microbes that lives symbiotically in it, that's the source of the potential drug.

But again, he;s interested in not just the cancer-fighting agent, but in the gene or genes that direct that organism to make the agent. "It's a short step from basic science to practical application," Sherman explains. "If you can find the genes and their associated enzymes involved in the synthesis of an anti-cancer drug, you can imagine manipulating those genes and enzymes to make lots of new drugs, working with other specialists studying specific targets to make something happen."

Brewing new treatments

Both the National Institutes of Health and a major pharmaceutical company are funding Sherman's efforts to make something happen. The goal is to develop a technology that begins with the genes and enzymes proven to be the organic instigators of cancerfighting drugs, and provides the tools to finish the job.Those tools would include synthetic "precursors" -- a library of diverse molecules that could be "fed" to the enzyme, producing new molecules at high levels in a fermentor. Each interaction with a different precursor would result in a slightly different potential drug to test. "This represents a brand new strategy for creating new drug molecules -- one with huge potential," says Sherman. "There are only a few people pursuing this approach -- maybe only a half dozen in the world."

"One of the major challenges in drug discovery is how to get your hands on the kind of chemical diversity needed to yield new drugs while balancing the huge risks and costs associated with bringing new drugs to market," he continues. "And using a fermentation process yields a much higher output of molecules -- you actually grow them, like you brew beer." As Sherman explains, "Drug development used to be a choice between totally natural or totally synthetic. Now we're combining the best of both worlds."

Unlike some scientists, running a race with their peers, Sherman's pace is set by nature. He sprints to catch up with the biological world. "I want to know how bacterial cells do their synthetic organic chemistry," he says. "They're way better at it than humans. It took me three years to make a synthetic drug for my doctoral thesis. That same product can be made in three micro-seconds by a living cell. What are they doing right?" Considering the enormous biodiversity of the marine world, Sherman's "lab" is filled with opportunities to answer that question, offering tremendous hope for the future of cancer treatment.

Read more about Dr.Sherman at http://sitemaker.umich.edu/davidhs; or visit his lab.

See additional photos from his recent expedition to Panama in partnership with the Smithsonian Tropical Research Institute at here.

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