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Stetten Lecture
'Ghoulish' Potion Shows Nervous System Function

By Alisa Zapp

On the Front Page...
At the Wednesday Afternoon Lecture scheduled for the week before Halloween, a researcher will decribe the deadly effects of a brew containing the funtional equivalent of cobra toxin, tetrodotoxin (puffer fish poison), and botulinum toxin. He'll also describe how this potent venom, found in marine snails, helps to reveal molecular mechanisms underlying nervous system function.


Dr. Baldomero Olivera

Dr. Baldomero M. Olivera, distinguished professor of biology at the University of Utah, studies the hundreds of neurotoxins produced by venomous cone snails. His research has already led to the development of a potent painkiller, now in clinical trials, that appears to vanquish pain that is unresponsive even to near-lethal doses of morphine.

Olivera will discuss his work and display a short video of a cone snail attacking and devouring a fish at the DeWitt Stetten, Jr. Lecture on Wednesday, Oct. 23. The lecture, entitled "Using Deadly Cone Snails to Learn Drug Design and Probe Nervous Systems," will start at 3 p.m. in Masur Auditorium, Bldg. 10.

Cobras, scorpions, and other venomous animals may use one primary chemical weapon to overpower their prey. Cone snails use an entire arsenal. Their venom contains 50 to 150 peptides, each of which wreaks havoc on the central nervous system of fish. Independently, the peptides stimulate responses that include jerky swimming, sudden whole-body rigidity, or even sleep. Together, they cause chemical shock, paralysis, and death.

Shells from some of the world's cone snails. Of the 500 species of cone snails found in tropical oceans, about 70 species produce poisonous venom. Some of these poisonous snails bury themselves in the sand and extend a worm-like tube from their mouths to lure nearby fish. When the fish bites, the tube releases a poisonous harpoon that injects neurotoxins into the fish. The snail then engulfs the paralyzed fish with an extendable stomach-like structure. Within 2 hours, the snail spits out all that is left of the fish -- bones, scales, and the used harpoon.

Olivera and his coworkers have extensively characterized about 30 of the peptides and have at least sequence information for more than 100 peptides. Each peptide recognizes and jams a specific ion channel or receptor subtype. So specific are the peptides for their targets that molecular biologists now commonly use the peptides as labeling tools. One peptide even enabled researchers to identify subtypes of voltage-gated calcium channels.

This specificity has obvious implications for the design of highly efficient drugs that have few side effects. Most drugs bind to their therapeutic target, but also bind to related molecules, causing a wide range of side effects. The snail peptides appear to bind only one target, and they do it with extremely high affinity.

"The average present-day drug binds its target more selectively than closely related molecules by a factor of ten, a hundred, or a thousand," Olivera said. "But with the snail peptide, you're talking factors of a million, a billion, or more."

Those numbers quickly piqued the interest of Dr. George Miljanich, now at Neurex Corp., a pharmaceutical company in Menlo Park, Calif. Neurex is examining one of the cone snail peptides for its ability, when administered directly into the spinal cord, to relieve intractable pain in people with cancer or AIDS. The trials are in phase II/III and have produced some dramatic results.

"It is gratifying that a peptide we discovered a little over 10 years ago is now relieving pain in patients," Olivera said. "There's every reason to think that some time next year it will probably be approved as a drug." Indeed, Miljanich said that Neurex plans to submit a New Drug Application to the FDA for the analgesic by the end of 1997.

As a testament to the specificity of the snail peptides for receptors in different areas of the body, Neurex is examining whether this same peptide, administered intravenously, can protect against nerve cell death following head injury or other trauma. These trials are in phase II.

Although Olivera's main thrust continues to be basic research, he encourages others to investigate direct medical applications of his work. Such applications seem almost as varied as the peptides themselves. Two groups of researchers are examining the use of another cone snail peptide as a diagnostic screen for Lambert-Eaton myasthenic syndrome, an autoimmune disorder triggered by lung tumors whose cells express specific calcium channels. A psychiatrist at the University of Utah is studying the peptides as possible treatments for psychiatric illnesses. Olivera suggested that the peptides might be developed to target key ion channels in cardiac and gastrointestinal systems.

"I think every one of the peptides could be a potential pharmacological agent, or at a minimum, a diagnostic tool," he said. After all, "the snail uses each as a very potent drug for its own purposes."

The snail peptides have additional qualities that bolster their potential as therapeutic agents. The targets of the snail toxins -- ion channels and receptors -- tend to be similar among all vertebrates, suggesting that what causes a neurological response in fish will cause some response in humans. The snail peptides are also much smaller, and therefore more easily manipulated as drugs, than toxins in snake or spider venom.

On a more basic level, knowledge provided by the cone snail studies may shed light on conditions -- such as schizophrenia, Alzheimer's disease, and epilepsy -- that involve abnormal function of receptors and ion channels in the nervous system. NIGMS has supported Olivera's work since 1979.

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