Novel Technique Aims to Boost Marine Drug Discovery

Looking to the seas to discover a new generation of cures for a variety of diseases, researchers at UC San Diego have developed a new method of deciphering how much biomedical potential marine organisms might offer.

In the March 29 edition of the Proceedings of the National Academy of Sciences, a research team led by Eduardo Esquenazi of Scripps Institution of Oceanography's Center for Marine Biotechnology and Biomedicine (CMBB) and UCSD's Division of Biological Sciences describe a novel approach to track how and when organisms produce molecules with potential human benefit. The method employs nitrogen as a biological tracer along with MALDI mass spectrometry, a laser-based analytical technique that can probe the inner workings of organisms.

Marine organisms obtained during field expeditions can produce exotic compounds unlike any from terrestrial plants and animals. They can generate a natural toxic product, for example, to ward off enemies in their habitat, yet the same substance might be used by researchers to kill cancer or treat other human diseases. But scientists hoping to extract such sources from sea life can encounter roadblocks in pinpointing exactly how these natural compounds are produced.

The method described in the PNAS paper offers a new way to discover and evaluate factors influencing the production of natural compounds and the timing of such production. The scientists say the approach, which can be executed with limited quantities, could become a novel tool in determining how environmental factors influence natural compound production and cultivating the compounds needed for drug discovery.

The research described in the paper focused on a genus of cyanobacteria, tiny photosynthetic sea organisms, and specifically jamaicamides, neurotoxic molecules discovered in 2002 off Jamaica's Hector's Bay by Scripps and UCSD Professor William Gerwick and his research team. Jamaicamides are thought to play a defensive role in nature, possibly to ward off feeding from fish. Such molecules, the researchers say, may also be effective against human cancers and tropical diseases.

"Marine cyanobacteria continue to surprise us in their capacity to produce an amazing diversity of exotic new natural product molecules; many of these are created utilizing biochemical reactions that are new to science," said Gerwick, a coauthor of the PNAS paper who holds a joint professorship in Scripps' CMBB and the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences. "Perhaps more importantly, some of these substances have powerful biological properties relevant to treating human diseases, such as cancer, inflammation and neurological disorders."

The researchers' experiments included adding nitrogen into laboratory cultures of cyanobacteria and testing growth under various conditions, including exposure to degrees of light and darkness. A technique called "MALDI-MS" (matrix-assisted laser desorption ionization mass spectrometry), allowed them to track the nitrogen through the growth process and identify how quickly nitrogen-containing molecules were created.

"This MALDI-MS approach could also be a valuable tool in efforts aimed at increasing natural product yields from laboratory cultures of cyanobacteria or other organisms with biomedical and biotechnological relevance, especially in cases where compounds are found in low abundance," the authors note in the paper.

"When we go into the field, we will collect a lot of material and we'll find a wide array of natural products. Some of these are found in very low amounts. This method has allowed us to monitor how quickly these particular cyanobacteria are making these molecules," said Adam Jones, a Scripps graduate student and coauthor of the PNAS paper.

"Cyanobacteria are valuable for their pharmaceuticals but can also be harmful in the environment, in instances such as cyanobacterial bloom events," said Jones. "This method can be used for identifying some of the triggers that cause the rates of compound production to increase for drug discovery purposes, but it may also be useful in determining how we can slow these rates to better understand how to limit negative environmental impacts of cyanobacterial toxins."

Coauthors of the paper include Tara Byrum, a staff research associate at Scripps' CMBB and Pieter Dorrestein, associate professor in the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences.

Support for the research was provided by a graduate fellowship from the National Institutes of Health Training Program in Marine Biotechnology, a graduate Fellowship from the Los

Angeles Chapter of the Achievement Rewards for College Scientists (ARCS) Foundation, NOAA, the California Sea Grant College Program and the National Institutes of Health.