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Sea slugs' chemical defenses may yield new medications, say CSUEB researchers

  • August 8, 2011

Down by the bay where tidal flats stretch, Cal State East Bay science students have gathered scores of half-dollar-sized crabs for a kind of aquatic culinary experiment. By offering the crabs a snack of sea slugs and other morsels tainted with a natural toxin, student and faculty researchers hope to learn more about the ecology of the sea floor and unlock the mystery of a marine-life poison that may one day help fight diseases such as Alzheimer’s.

The crabs are foreign to deeper water, such as the Puget Sound, home to the tainted sea slugs. There, colonies of coral with feathery orange stalks resembling old-fashioned quills, congregate. These virtually unmoving, unarmored soft coral have a few defense mechanisms; they can retract into the sand when touched and are also toxic, possessing a chemical in their tissue with similar effects to sarin nerve gas.

The soft coral also face an equally bright-hued, nearly-blind predator – festooned sea slugs that sniff out their prey with a pair of waving odor sensors. The sea slugs’ eyes, buried in the stalk, detect little more than light and dark.

It is these creatures (Tritonia diomedea) that James Murray, assistant professor of biological sciences at Cal State East Bay, has studied for more than 15 years. He is interested in neurobiology and behavior and carefully kept tanks of the sea slugs during the years he studied them in landlocked Arkansas from 2000 to 2007.

It was then that he was contacted by Daniel Nurco, a natural products chemist and lecturer at the University of California, Davis. Nurco was studying a chemical derived from the prey, known as sea pens. Interested in ptilosarcenone, whose action resembles some pesticides, Nurco wrote Murray to request shipments of sea slug blood and brain for enzyme tests. With student Nathan Shapiro, the Davis chemist also identified and published the toxin’s molecular structure.

The researchers were intrigued about understanding the natural toxin’s mode of action, such as how it is handled by predators like sea slugs or naive eaters like crabs – a marine equivalent of a laboratory mouse. Their insights may yield novel approaches to synthesizing useful compounds or new medicines.

Now Shapiro is pursuing an interdisciplinary master’s degree in organic chemistry and physiology at Cal State East Bay, having sought out Murray when he arrived here two years ago.
“I love science; I could never imagine doing anything else,” Shapiro said. “The program at Hayward was perfect.”
He continued working on sea pen studies, joining Murray to enlist collaborators Taro Amagata, an assistant professor who specializes in natural products chemistry at San Francisco State, and Monika Sommerhalter, Cal State East Bay assistant professor of chemistry and biochemistry. Sommerhalter’s graduate student, Vu Tran, is investigating how toxic compounds interact with biochemical systems.  Amagata provides purified extracts and tests. 

They are exploring the mystery, among other things, of how sea slugs tolerate consuming the apparently toxic sea pen. Clues they uncover may contribute to developing new medicines.

“The ultimate large question is about evolutionary behavior and co-evolution between prey and predator,” Murray said. “We’re interested in how sea slugs can eat toxins without being destroyed by them. Possibly, rather than make their own toxins, they can sort of steal them from their prey.”

That strategy is not uncommon in nature, as well as signaling, through bright coloration, a warning to would-be predators about potentially distasteful and sickening effects. There may also be antimicrobial benefits for the bearer to carry the toxins, similar to applying antibacterial soap to protect against skin infection.

Research in the 1970s indicated the toxin, when directly applied to nerves, mimics the action of nerve gas by blocking breakdown of a neurotransmitter, leading to an over-excited state that is quickly fatal at sufficient doses. However, if the toxin’s mode of action is to keep neurons fired up, it may be a promising natural source to modify into a compound to treat conditions such as Alzheimer’s disease, in which neurotransmitter production is reduced.
Sea slugs have a very limited dietary range. Oregon shore crabs, on the other hand, generally dine on algae but will eat almost anything. It is these crabs that Shapiro and student Mike Huynh have gathered along the shore near Hercules. At the lab, pieces of sea slug or sea pen were offered to the crabs.

Even after being kept without food for almost a month, the crabs refused both offerings. Crabs that were offered another option, chicken, did not refuse that meal. Now, extracts of sea pen and sea slug are being introduced into gelatin offered to the crabs to provide a uniform consistency and show that the rejection is not due to texture, Shapiro said.

The hypothesis is that the gelatin morsels will still be unpalatable, and refused. Since consumption may cause illness, Murray and Shapiro are on the lookout for changes in behavior if crabs or fish can be coaxed into consuming the material – for instance, by soaking the extract-laden gelatin in clam juice.

The mystery of how sea slugs have evolved resistance to the sea pen toxin is not yet unraveled. Test-tube studies by Tran, mixing a sea pen extract and nervous system enzyme together, show only modest inhibition, indicating the sea slug may have neutralized or sequestered the toxin.

It appears, through strong evidence gathered by Shapiro and Amagata, the sea slugs may store the toxin in their skin, a defense making them unpalatable and potentially dangerous to all but a few predators.

For slow, nearly blind sea slugs, tolerating sea pen defense chemicals minimizes competition for food, Sommerhalter noted. And, since the coral is a colony, it is not destroyed by losing pieces to occasional foraging.

Sea slugs have captured research interest due to their large, easily observed, and simple nervous system. Sea pens also attract interest due to having novel fluorescent proteins useful in biochemical experiments. (In other lines of research, Huynh is researching sea slug circadian rhythms, while CSUEB student Lucy Ogbu studied microbes that cause sea slug skin infections.)

The students of Murray and his fellow sea slug scholars occasionally present research at events such as poster sessions for the CSU Council on Ocean Affairs, Science and Technology (COAST), which funds part of the work, and the CSU Program for Education and Research in Biotechnology (CSUPERB).

Shapiro expects to graduate in about a year and hopes to one day teach pharmacology. He is grateful for his academic research experiences, saying, “It helped me to discover what I was really interested in and what inspires me. Jim is a great professor,” he adds. “He really challenges his students.”  

See a sea slug and sea pen in action in a movie by Murray, posted online.

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