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Blue biotechnology wave

Nordic researchers are exploring bioactive compounds from the sea, looking for anticancer drugs, antibiotics, and more.

The Baltic and North Seas contain more than great herring. The oceans also hold a wealth of biotechnology resources. So far, nine marine-inspired drugs such as the breast cancer therapy Halaven, have been approved in the United States or Europe.
“This gives marine compounds an impressive success rate of one drug for every 2500 screened molecules,” says William Gerwick, professor at the Scripps Institution of Oceanography in San Diego.

Two anticancer compounds developed in the laboratory of William Fenical, director of the Center for Marine Biotechnology and Biomedicine at the Scripps Institution of Oceanography, are ready for Phase III clinical trials.
“We thought the ocean was cold, dark, not a source of rich materials. But today, more than 20 compounds for cancer are in clinical trials,” said Fenical in an interview for the Danish film company Kompas film.

Fenical, Gerwick, and other international experts in blue biotechnology—mining the sea for bioactive resources—met in November at the Technical University of Denmark (DTU). The occasion was a Marine Microbial Biotechnology symposium hosted by Lone Gram, a DTU professor, and Maria Månsson, a DTU researcher on a Sapere Aude postdoctoral grant.

Smooth sailing and choppy waters
Gram was part of a scientific team that collected thousands of promising marine microbes on the 2006-2007 Danish research expedition Galathea 3. This global sea voyage hosted a variety of projects, and Gram says they collected bacteria from “anything that was brought on board.”

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Galathea 3 getting ready to come to pier in Copenhagen. Photo credit: Thomas Bredol.

The Galathea collection of marine bacteria might yield new antibiotics. Maria Månsson and Nikolaj Vynne, also a DTU postdoctoral researcher, are analyzing potential antivirulence compounds made by Pseudoaltermonas bacteria from the collection. These and other compounds could lead to alternative antibacterial treatments. Of the approximately 77,000 microbial colonies tested on the expedition, three percent of microbes from seawater and nearly thirteen percent from living or inert marine surfaces inhibited the growth of a test bacterial pathogen.

Blue biotech can be stormy, however. Marine microbes are tough to grow. They might require high salt or other ocean-like conditions. They grow slowly and often aggregate in culture. Getting sufficient samples, especially of the secondary metabolites that are the most promising drug candidates, is a challenge. Marine organisms produce complex molecules, which is both a burden and a benefit. Complicated molecules can be hard to synthesize, making industrial scale-up difficult. However, symposium speakers said that intricate natural compounds are interesting to pharmaceutical companies that are disappointed in how few drug candidates have resulted from screens of small, simple compound libraries.
“Disruption of complex protein-protein interactions often requires very large compounds,” said Andrew Mearns-Spragg, founder and chief technology officer of AquaPharm Biodiversity Ltd, which is screening more than 10,000 marine-derived microbes for oncology and antibiotic drug candidates. Guy Carter, formerly with Wyeth-Pfizer and now CEO of Carter-Brennan Consulting, agreed. “The chance of a small, flat molecule succeeding as an antibiotic is low,” he said. “Drug discovery is now emphasizing greater biological complexity and more complicated chemicals. Natural products have an advantage: they are complex.” Marine compounds also have strong potential for bioactivity because so many marine organisms are symbiotic and produce compounds that affect their partner organisms.

What pharma wants from the sea
Marine compounds are exactly what pharmaceutical companies are looking for in potential drug scaffolds. However, the industry wants more than just raw molecules. In advice to scientists seeking corporate collaborations or funding, symposium speakers advised collecting as much preliminary data as possible. Having a molecule ready for Phase I testing helps pharmaceutical companies avoid time-consuming and expensive lead identification and optimization.

David Overy, of the University of Prince Edward Island and Nautilus Biosciences, suggested that academic laboratories interested in developing drug candidates collaborate. “Distribute experiments on mechanism of action, toxicity, and small animal testing of drug leads among a cluster of labs,” he said. A coordinated group of scientists might have access to small enterprise grants and government-provided services such as legal and business development expertise—all helpful for scientists considering working with a pharmaceutical company or starting a biotech company.

“Marine products have tremendous potential to reward a pharmaceutical company’s investment,” said William Fenical on day two of the symposium. Academic researchers can add value to compounds they discover by providing data on a molecule’s mechanism, cellular target, and potential for modification. Being able to supply quantities sufficient for testing, which means hundreds of milligrams of compound, will facilitate development. “Marine microbe-based natural products have advantages in all these areas,” said Guy Carter, “because they offer the possibility of altering compound structures through genetic engineering, and the possibility of large supplies through fermentation culturing and strain improvement. Marine products have the potential to reignite pharma’s interest in natural products.”

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DTU researcher Maria Månsson. Photo credit: Thorkild Amdi Christensen.