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DR. WILLIAM GERWICK - Scripps Institution of Oceanography Center for Marine Biotechnology and Biomedicine; Skagg's School of Pharmacy, La Jolla, CA
The Research: Fun With Algae and Other Tales
Bill Gerwick's laboratory
focuses on marine algae and cyanobacteria. The group conducts extensive fieldwork in areas ranging from
the Caribbean to the South Pacific to collect samples that are then tested for bioactive compounds with
pharmaceutical or agrichemical potential. The group also works extensively with the biochemical pathways
involved in the production of promising compounds, which Gerwick calls a "new dimension" of the natural
products field.
The group has been highly successful now in cloning and sequencing a number of biosynthetic pathways
at the genetic level and is working to harness and manipulate those pathways in useful ways, for instance
isolating an enzyme important in the production of a particular natural product and using it as a
standalone reagent to experimentally manipulate other organic molecules to produce new products.
 - VIDEO CLIP 1: "Research Focus of the Gerwick Lab"
 Why Algae?
Gerwick and his team initially became interested in marine algae as a source of new pharmaceuticals
because early efforts had shown them to be extremely rich in natural products with unique chemical
structures. "Any time you have a lot of structural diversity, it is a very lucrative and productive
group of organisms in which to investigate the possibility that some might be pharmaceutically useful,
" says Gerwick. In addition, he says, "I've long been drawn to marine algae and cyanobacteria as
life forms. They've just always intrigued me for their unique adaptations, their physiology, their
biochemistry, and ultimately their chemistry as well."
A Global Algae Hunt
The Gerwick laboratory group has collected algae and cyanobacteria samples from around the world.
Field locations have included the Indian Ocean, the South Pacific, the Atlantic and Caribbean, as
well as locations closer to home including the Oregon Coast and the Gulf of Alaska. As their work
has become more focused on cyanobacteria, the team has become increasingly focused on the tropics,
where these organisms are particularly abundant. Recent collection areas have included Curacao,
Madagascar, Panama, and Papua New Guinea. Because the work focuses on plants, the team can
typically collect from shallow water by simply snorkeling. At times they also use scuba down to
about 100 feet. The focus on shallow water habitats often also allows them to work right from
shore, simplifying collections, though they do at times work from boats.
Once samples are collected, Gerwick and his team take voucher samples for taxonomy, and when
working in another country they also take a deposit sample for the host country in hopes of
contributing to the building of scientific infrastructure in these locations. Subsamples are
also put in culture vessels to bring back living material to work with in the laboratory. The
bulk of the samples, though, are processed for chemical extraction and analysis using a sampling
protocol also used by Phil Crews that calls for
placing samples in alcohol (oftentimes simple cane alcohol when working in remote locations)
and adding seawater. The excess liquid is then poured off after a couple of days, once the
samples have been effectively pickled, and their chemistry preserved. Ultimately, samples
are subjected to a variety of assays.
Back at the lab, researchers test samples against cancer cell lines, as well as in simple brine
shrimp toxicity assay that offers a simple model for cancer cells. The group also tests for
neurotoxic potential by examining compounds' effects on sodium channels. Collaborators at
Novartis Pharmaceuticals also screen the samples for cancer, and Dow AgroSciences screens
compounds for agrichemical potential as herbicides, fungicides and insecticides. Academic
collaborators conduct further screen to detect potential for for fighting cancer, neurological
conditions, and tropical diseases such as malaria.
- VIDEO CLIP 2: "Global Protection Program"
- VIDEO CLIP 3: "Adventures in Specimen Collection"
A Bomp On the Shark's Nose
"We've had a lot of humorous and sometimes a little bit scary interactions over the years," allows
Gerwick, but the most memorable happened off the Pacific Coast of Mexico. Diving with Valerie Paul
(now at the Smithsonian marine Station at Fort Pierce, FL), Gerwick was at about 40 feet deep
collecting samples when a large shark came up from deeper water and felt compelled to swim straight
for the divers in a "very aggressive stance." Gerwick and Paul went to the base of an underwater
cliff as the shark came in aggressively circling in tighter and tighter circles. Gerwick was glad
to have with him a small poker that he had gotten in the habit of carrying while diving in the
Galapagos, where sharks are especially plentiful, though he had never been involved in a shark attack.
"This one actually came in for an attack and we had to bomp it on the nose," says Gerwick, "and it
did take off, fortunately." He turned to see that Paul had continued filming the entire episode,
ultimately producing some "quite amazing" film.
- VIDEO CLIP 4: "Sample Processing"
Success Stories: Curacin A, Somocysteinamide, and Scytonemin
The Gerwick team's study of algae and cyanobacteria has led to the isolation of a number of compounds
with pharmaceutical potential, among them:
Curacin A - In 1993, the group discovered a marine cyanobacterium while collecting in Curaao, the
crude extract of which showed potent cancer cell toxicity. Subsequently they isolated a compound
they named Curacin A that was responsible for
this bioactivity. Curacin A is a relatively simple compound known as a lipopeptide, which combines
amino acid and fatty acid components. It has garnered much attention, however, because of its unique
structure. "It's unlike anything else that's ever been found in nature," says Gerwick. Its mechanism
of action also appears to be unique. In animal models the compound was discovered to decompose quickly,
so it did not have the anticancer activity expected based on in vivo studies. However, the team has
successfully cloned the biosynthetic gene cluster that codes for the proteins used to produce
Curacin A and are working to express these genes in organisms more readily grown in the laboratory than
the source cyanobacterium. One of the goals of this work is to ultimately tweak this production system
to produce analogs of Curacin A that are more stable.
Somocysteinamide - Obtained from a mix of two cyanobacteria species ( Lyngbya majuscula and
Schizothrix sp.) this compound has also shown very potent cancer cell toxicity, particularly
against neuroblastoma cells. Gerwick allows, however,"It was one of the most perplexing detective
stories that we ever encountered." The problem was that somocysteinamide is quite unstable, so NMR
experiments revealed that the compound would change from one day to the next. The team had to work
backwards, looking at the structure as it changed over time to infer the natural product's starting
structure. A key challenge in working with the compound is that the cyanobacteria produce only very
small quantities, meaning sufficient quantities complete initial evaluations or to do in vitro testing
have not yet been available. Gerwick therefore believes that the compound would be an ideal lead for
a synthetic chemist to use to develop a technique for synthesizing larger quantities, though no such
work is yet underway.
Scytonemin - The story of scytonemin actually begins in the 1850s, when scientists first
observed that some cyanobacteria produce and exude from their cells a dark pigment into sheath
material that is normally clear. Most interestingly, this process was observed in response to
exposure to sunlight. The chemical structure of the compound responsible remained a mystery for
150 years. Then, a group of researchers at the University of Oregon came across the early reports
of the pigment and were studying the phenomenon. The group contacted Gerwick's team, which was the
first to investigate the pigment's chemical structure. What they discovered in scytonemin was
a promising and novel, but very complex, compound. Scytonemin shows potent anti-inflammatory
properties, which, combined with UV protection properties, is a promising combination for
potential use in a sunscreen. The patent on the compound is jointly held between the University
of California system and Oregon State University and researchers are working to achieve
a commercial licensing agreement for the compound.
- VIDEO CLIP 5: "The Discovery of
Somocysteinamide and the Need for Synthetic Chemistry"
From Tide Pools to Tenure
Bill Gerwick's love for the ocean and marine algae and cyanobacteria began when he was "a kid
poking around in tide pools," and his interest grew from there. As an undergraduate he attended
the University of California, Davis, and conducted phycology (the study of algae) research with
Dr. Norma Lang. He credits this work and Dr. Lang as the inspiration for his current career. After
finishing at Davis, he went to the Scripps Institution of Oceanography, where he did Ph.D. work
with Bill Fenical and studied the chemistry of macrophytic marine algae,
mostly brown algae. "That was tremendous fun," says Gerwick. He became increasingly interested in
biosynthesis and so, for postdoctoral research at the University of Connecticut, he explored that
topic, studying the biosynthesis of anti-cancer agents. Next he spent a few years in a junior
faculty position at the University of Puerto Rico in Rio Piedras, which he recalls as "a fantastic
opportunity for collecting marine organisms." Eventually he wanted to return to the Pacific West
Coast, so he took a position with Oregon State University, where he worked for over 20 years before
transferring to his current position at Scripps in 2005.
- VIDEO CLIP 6: "Growing the Microbes, Elucidating the Structures"
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