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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