A pain drug far better than morphine has been developed by a crew of researchers at the University of Utah - and their collection of some of the world's oddest aquarium "pets."
These aren't the sort of pets you'd want to pick up and cuddle. They are cone snails, carnivorous mollusks that live in shallow waters of the Pacific Ocean and kill their prey with a cocktail of poisons.Depending on the species, they hunt fish or other snails. They may sting their victims with a harpoon barb at the end of a tendril, or they may first envelop them in a nightmare mouth that looks like a stuff bag for camping gear.
"The main thing is to kind of understand how one might be able to get better drugs with fewer side effects," said Baldomero M. Olivera, distinguished professor of biology at the U., who founded the lab more than 20 years ago.
"A component from Conus (the Latin name for cone snails) that Michael discovered when he was an undergraduate at Utah is already in use with patients. It's already in its advanced clinical tests."
By Michael he means Dr. J. Michael McIntosh, one of his former star undergraduate researchers who is now a psychiatrist with a medical degree from UCLA. Now that he has returned to Utah, McIntosh is searching for medical uses of cone snail toxins, called conotoxins.
"What's unique about the cone snails is that they provide a diverse array of compounds that are targeted to the nervous system," Mc-Intosh said, showing the Deseret News around the sprawling lab on the first floor of the U.'s biology building.
Through the eons, cone snails have evolved amazing ways to capture their prey. Nobody is certain how the 500 species developed poisons - and each type may cook up its own toxic brew - but the conotoxins are swift and sure.
"The marine snails themselves are one of the more successful predators in the ocean," McIntosh said. They are slow, unable to pursue if a fish happened to struggle free after a sting, so the jolt of chemicals must do its job immediately.
Their poisons "effect immobility within a second or two after striking, and they've done this by a combination effect," he said. "A typical snail may have 50 to 100 compounds, and they act in concert."
First the snail delivers a lightning jolt of paralyzing poison. It follows up with waves of other specific peptides that make the fish grow limp or overwhelm its sensory organs. Maybe some soothe the victim's nervous system so it won't struggle.
After the first blast, the other poisons "come in more slowly and complete the job," he said.
Lourdes Cruz demonstrated the snails' hunting tactics. With long-handled tweezers she held a goldfish near the purple gravel bottom of one of a dozen bubbling aquariums. Scenting the fish, a "hook and line" hunter snail plowed itself out from beneath the gravel.
Cautiously, it extended a long, pink, flexible tendril toward the fish.
The tentacle was its harpoon. It seemed to reach almost lovingly toward the fish's eye. When it struck, the goldfish jerked for an instant on the end of the strand, then grew limp and the tentacle drew it toward the snail.
A baglike mouth extended, enveloped the fish and pulled it inside the shell.
Another species of cone first extended its filmy bag of a mouth around a fish and harpooned it after it was inside. As the feeding continued, more and more cones became agitated and dug themselves out from under the gravel, galumphing slowly around the aquarium's bottom.
Cruz said last year a man was spear-fishing in the Philippines when he noticed a cone snail on the sea floor. In his village, cones are carefully prepared and eaten, and he took the chance that he wouldn't be hurt.
"It was a big, big shell that he saw," said Cruz, who shuttles between the U. and her laboratory at the Marine Science Institute at Dilman, Philippines. Like her, Olivera is from the Philippines, where cone snails are abundant.
"He put it under the garter of his trunks. So he got stung." He suffered a horrible headache and vision disorders.
The man got ashore before he went into respiratory and cardiac arrest. He was rushed to the hospital, where doctors were able to save him. The recovery took about two weeks, she said.
Cone snail poisons not only paralyze, but some cause "sensory anesthesia," McIntosh said. They also have specialized chemicals to more efficiently distribute the agents throughout the prey's body.
The hundreds of different toxins brewed up by cone snails may lead to developing many sorts of medicine: heart drugs, treatments for schizophrenia, anti-convulsant drugs, painkillers, anti-cancer agents, medicine to help victims of Parkinson's disease, stroke medications.
The great variety of toxins means the snails are a whole pharmacy of potent drugs, any of which may be exceptionally valuable to medicine if taken in the right doses. Since the drugs are precise in their action on the fish's cardiovascular system or neurological makeup, medicine made from them may not have side effects.
He explained that the human nervous system has receptors that are similar to each other but serve different functions. In pain treatment, morphine may block certain channels in the brain where it is intended to do its job, but because of the similarity to other receptors, different areas may be affected, too.
When those different areas are hit, the patient suffers side effects.
The receptors are like identical twins or triplets, he said. A neighbor might not be able to tell them apart - that's like the standard drug affecting similar receptors.
"What's special about the conotoxins is that they're more like the mother," able to tell them apart. A particular peptide that the snail makes may be able to strike a particular target and no other, leading to no side effects.
In the lab, teams study different phases of cone toxins, although the teams overlap. One group extracts toxins from the snails, using milking devices that are like basting syringes to extract minute amounts of the poison and then separates them into components.
Other scientists synthesize the compounds they are interested in. Another group works with biological and physical characterization, which is testing the compounds.
"We're then trying to determine what particular receptors - or ion channels or nerves - the compounds are acting on," McIntosh said.
Jeremy Karras, a junior majoring in biology, is helping to determine what certain chemicals do in the brain. Olivera - known to all as "Toto" - first had him work on calcium channels, and now he has expanded the work into different chemicals and peptides.
"Toto's lab is really cool, because there's all kinds of little biologically reactive peptides we can get from them," Karras said. It's also fun because he has been able to work "fairly independently on a lot of the projects that I've done."
In his research, Karras examines the brains of rats to discover the action of particular chemicals derived from cone poison. The brains are frozen, cut into slices and incubated in a solution that contains a cone peptide.
The peptide has been tagged with radiation. During the incubation, the cone poison binds to a particular site in the rat's brain.
"It will bind to the receptor" where the poison was designed to work, he said. The slice is placed on photographic film that is sensitive to radiation. The radioactive tag then exposes the film.
When he studies the film, the peptide shows up as an exposed spot. "It's basically to show where anatomically the thing binds," he said.
"You'll see, like, it binds in the hippocampus or the hypothalamus or something like that, and you know what that part of the brain does, so it gives you huge insight into what it might be doing or what its function might be."
It was just this type of research that led the lab to its greatest discovery so far, a peptide called SNX III. "Once it gets approval they'll come up with some flashy name," said McIntosh, its discoverer.
This is the painkiller that may be available in clinics everywhere next year. "It's been developed as a medication for chronic pain," Mc-Intosh added.
Cognetix Inc., a firm that spun off from the U.'s research, formed a partnership with a California company to develop and market the medicine. Based in the U.'s Research Park, Cognetix uses technology that it licensed from the university.
"It's about a thousand times more potent than morphine," said McIntosh, one of the scientific founders of Cognetix. Also, it does not produce tolerance the way morphine does.
It is the body's tendency to tolerate certain drugs that leads it to require stronger and stronger doses to kill pain. The bigger doses are more toxic and are more likely to cause addiction.
"This compound doesn't produce tolerance, so it's probably not addictive," McIntosh said. It is in Phase Three of clinical testing, in which the drug is tested on human patients. That is the last step before the Food and Drug Administration approves its general release.
"This is one compound," McIntosh said. "There are 500 species of snail, and they each make 100 compounds."