Cloned Gene from Sea Animal May Prove Key in Cancer Drug Development

Researchers at Scripps Institution of Oceanography at the University of California, San Diego, and their colleagues have taken a significant step forward in developing a new method to produce drug compounds with potential to treat various types of cancer.

In the current issue of the journal Chemistry and Biology, scientists at Scripps, the University of Minnesota and the Life Sciences Institute describe the development of "bryA," a gene that could help solve problems associated with the production of anticancer agents originally discovered in the marine invertebrate Bugula neritina.

"To be able to show that this gene really exists has been the Holy Grail for the last 10 years," said Scripps Professor Margo Haygood, a coauthor of the paper. "This takes us beyond just suspecting that a bacteria might be involved to actually having a gene that looks like the right thing."

Certain marine invertebrates such as Bugula neritina, a brown bryozoan animal with stringy tufts, live in a symbiotic relationship with bacteria that act as a chemical defense mechanism for the host animal.

In 2001, Haygood and other scientists in her Scripps laboratory found that such bacteria living in Bugula neritina were the source of bryostatins, a family of chemical compounds being closely studied for their potential as anticancer pharmaceuticals in leukemia, lymphoma and several cancers including colon, breast, ovarian and prostate.

One of the main obstacles impeding widespread bryostatin production is lack of a practical and economically viable method of producing the compounds. The bacteria cannot be grown in laboratories. And collecting vast numbers of the animals at sea would be environmentally destructive.

One way of solving this dilemma is to clone the genes involved in natural bryostatin development. In the Chemistry and Biology paper, the researchers describe the process by which they cloned a large complex of genes and singled out bryA, a gene for a catalyst the authors propose is active in bryostatin biosynthesis.

The researchers say it appears that bryA may synthesize a portion of the pharmacologically active component of bryostatin and therefore may be useful in developing clinically useful bryostatin byproducts.

"The isolation of bryA represents a significant step forward in understanding bryostatin biosynthesis and eventually harnessing bry genes to produce bryostatins and derivatives inexpensively and in abundant quantities," the authors write in the paper, one of the first studies that describes such a cloning achievement from a marine symbiont organism.

Haygood and members of her laboratory are now moving the research forward by attempting to use bryA to extract laboratory-developed bryostatin compounds.

Most cancer drugs work by killing rapidly growing cells, in many cases interfering with the body's normal processes. Bryostatin seems to be effective by "flipping a switch" that controls how cells behave in the body. In the case of leukemia, for example, it seems to bring the cells "to their senses" and make them behave like normal blood cells.

In addition to Haygood, research coauthors include Mark Hildebrand, Laura Waggoner, Sebastian Sudek, Scott Allen and Christine Anderson of Scripps; and Haibin Liu and David H. Sherman of the Life Sciences Institute (Sherman was formerly at the University of Minnesota). Haygood is a member of Scripps's Marine Biology Research Division and Center for Marine Biotechnology and Biomedicine and the Rebecca and John Moores UCSD Cancer Center.

The research was supported by the National Institutes of Health and the Department of Defense.