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Keeping up with the cones

Natural History; New York; Feb 2002;

by Aparna Sreenivasan;

Volume: 111

Issue: 1

Start Page: 40-47

ISSN: 00280712

Subject Terms: Mollusks Poisons Evolution Peptides

Abstract: The genus Conus includes more than 500 species, whose shells are embellished with a seemingly endless variety of intricate patterns. Cone snails have existed for 55 millions years, and the number of species of the venomous snail has been doubling every 6.1 million years.

Full Text: Copyright American Museum of Natural History Feb 2002

[Headnote] Chased by evolutionary biologists and pharmacological researchers, a tropical mollusk redefines "a snail's pace."

In the early 1900s a U.S. marine stationed in the Philippines found a beautiful shell near a coral reef. Thinking it would make a nice gift for his girlfriend back home, he carried it off, placing it on his shoulder to show his friends. As the young man walked toward his buddies, the animal inside the shell extended a needle like organ and stung him on the neck. Within minutes, the marine was dead.

The unfortunate American died from the sting of a cone snail, a member of the genus Conus. Collectors and beachcombers have long admired and coveted the snails' beautiful shells, risking a sometimes fatal sting to get them. The genus includes more than 500 species, whose shells are embellished with a seemingly endless variety of intricate patterns: repeating triangles or tiny cobblestone motifs, stripes, bands, spots. The length of the protoconch (the spiral on the wide posterior end of the shell) and the number of whorls differ by species, and the shells range from the size of a grape to that of a pear. To a collector, the allure of a mature, undamaged specimen-called a gem shell, and nearly impossible to find-cannot be underestimated. Despite the risk, people still pick them up.

"Cone snails don't have big jaws and sharp teeth, and they don't move very fast," says Baldomero Olivera, a University of Utah biology professor who studies these animals. "The only thing they have going for them is their venom." In a comparison among ten groups of carnivorous snails, Suzanne Lawrenz Miller, of the University of Washington, found that Conus are among the slowest, moving an average of 0.43 millimeters per second (some other meat-eating gastropods can move twice to ten times as fast). Thus, members of the genus must rapidly overwhelm their prey when they get the chance.

To detect prey, a cone snail uses its siphon, an organ that takes up water and directs it over the gills. Once the snail finds a target, it jabs the victim with its radula (a hollow tooth with a harpoonlike barb). Most mollusks use the radula to break up food, but the cone snail uses it to inject venom. A tether attached to the radula allows the predator to retract it quickly; the snail then draws the still-living prey through its proboscis and into its gut. If a fish were still able to twitch after the injection, it could escape before being swallowed, and another creature could swim up and eat it. And a worm-eating snail would be just a hungry snail if its prey could slip back into a burrow to die. The cone snail's venom must be quick-acting and extremely effective or, as with some molluscivorous species, be administered multiple times. Cone snails have existed for 55 million years, a relatively short time in evolutionary terms. Yet the number of species of Conus-the largest genus in the animal world except for insects-has been doubling every 6.1 million years. (Other rapidly evolving snail types have been doubling their numbers every 10.3 million years.) "And these rates are underestimates," cautions biologist Tom Duda, of the Smithsonian Tropical Research Institute in Panama, because the method does not account for Conus species that are now extinct. "I call them the fastest snails in the West," says Alan Kohn, a biologist at the University of Washington. Possibly driving the rapid expansion of the genus are its venoms, which are mixtures of peptides known as conotoxins.

Like a chef who compulsively varies a recipe each time he prepares it, a cone snail might never shoot out the same toxin combination twice. The genes controlling such variability may be important targets for natural selection, but other pressures might also play a role. "One hypothesis is that conotoxins are evolving in response to changes in diet," says Duda. Conotoxins' effectiveness comes from being adapted to particular prey species. Duda is investigating whether snail species with specialized diets produce highly specialized venoms. Another factor driving the increasing diversity of Conus might be their capacity to survive a long-distance drift. Although adults generally do not move far from their coral-reef homes, the minuscule larvae, floating with the oceanic plankton, sometimes end up in unfamiliar territory (some species' ranges extend from Hawaii and Tahiti to Africa's east coast and India; others, however, occupy areas less than one-tenth that size). As the transplanted snails grow up surrounded by prey that their parents never encountered, natural selection may favor those with toxin cocktails and feeding patterns that fit conditions in their new home; hunger would rapidly eliminate those that failed to assimilate. Distance and time could, on their own, account for a far-flung colonist population becoming distinct from its ancestor, but these variables-- even accompanied by a change in diet or habitat-- do not guarantee that a new species will arise. Kohn reports that C. miliaris, for example, feeds on a wide variety of organisms at Easter Island, where it is the only ecologically important Conus species, but that in the central Indo-Pacific, where it shares space with many other members of the genus, its diet is very specialized. In recent years, medical researchers have been looking for plants and animals whose naturally occurring chemicals-venoms included-might be used to treat disease. Until recently, sea sponges dominated the scene. Two successful drugs-cytarabine, used for non-Hodgkin's lymphoma and for a form of leukemia, and acyclovir, used for herpes infections-were derived from marine sponges. Such discoveries have encouraged researchers to rummage through the rest of the briny deep's offerings. Conus, with its hundreds of species and venoms, may be a new pharmaceutical gem. "When people tell me how beautiful the snails' shells are, I tell them that the real beauty lies within the ammal," says Joseph Schultz, a postdoctoral researcher at Stanford University's Hopkins Marine Station, who has traveled far and wide to collect Conus specimens for study.

The first indications that conotoxins might have therapeutic value came in the early 1970s. In Baldomero Olivera's laboratory, an undergraduate named Craig Clark developed a test that revolutionized the assessment of conotoxin effects. By injecting complex cone snail venoms directly into the brains of live mice, he elicited a variety of symptoms, including sleepiness, intense scratching, and hyperactivity. At about the same time, a high school student named Michael McIntosh established that the venom of C. magus, the magician's cone, induced seizurelike tremors in rodents. Thirty years later, McIntosh-now a biologist at the University of Utah-is still studying conotoxins.

Investigations of cone snail venoms have revealed that they inhibit motor control and that the paralysis induced by a sting represents the aggregate effect of several varieties of conotoxins. Some, the omegas, block the release of neurotransmitters; others, the alphas, prevent neurotransmitters from binding with target cells in muscles and nerves. Two other classes, the mu and delta conotoxins, specifically affect muscles, and a unique class known as conantokins targets the brain. The various conotoxins do not compete for binding sites. Each peptide in a snail's venom works by attacking a specific gateway controlling the action of nerves and muscles, either blocking it or forcing it open. There are many classes and subclasses of these gateways in the animal world, and they vary substantially between phyla. Remarkably, Conus manages to compensate by generating a plethora of different peptides. Selective pressures, working on the genes regulating conotoxin production, probably act on subtle changes in the structure of peptides. Just as an extra groove on a key allows it to fit one keyhole instead of another, the simple addition of a few amino acids allows a toxin to bind more tightly to its target.

Eventually, working with C. magus venom, McIntosh isolated omega-class peptides that cause spasms in mice. He also found that the type of nerve thus affected had been unknown before his discovery. A biotechnology company has now formulated an omega-class peptide into a drug that reduces severe pain in cancer and AIDS patients but does not produce the addictive side effects common to painkillers such as morphine. The drug is in the final stages of clinical trials, and the Food and Drug Administration has deemed it "approvable."

Another promising lead originated with Craig Clark. In the early 1980s, while investigating C. geographus venom, he isolated a conantokin that causes drowsiness. This molecule, held together by bonds that differ from the bonds in other conotoxins, is not shaped like most known cone snail peptides and does not bind with commonly targeted receptors in an animal's cells. As a result, venoms containing conantokins attack nervous and muscular systems in a variety of ways. McIntosh later took over the conantokin experiments and uncovered another interesting tidbit: the venom contains a component found in human blood-clotting factors but virtually nowhere else. Scientists later established that conan--tokins turn on a particular nerve "switch" in the brain. A pharmaceutical company in Salt Lake City is now pursuing this lead in hopes of formulating a new treatment for epilepsy.

But finding uses for these two peptides is just the beginning, according to Rob Jones, a senior scientist for the pharmaceutical company Cognetix. The possible range of treatments is limited only by the diversity of the peptides in cone snail venoms. Normally when scientists are drug hunting, they test piles of compounds whose functions are unknown, searching for one that proves useful. In this case, with many classes of conotoxins containing hundreds of peptides (the numbers of which, as Duda's work shows, are actually growing as species evolve), the drug hunters already know many of the functions of those peptide classes. Now they must determine which ones-from which species and in which combinations-can best ameliorate specific symptoms. "It is a backward approach to finding drugs," Jones says.

Zoologists and medical researchers have not been studying cone snails for very long. Western shell collectors have known about these mollusks for more than 200 years-even dueling over them at times, according to Jon-Paul Bingham, a Yale University postdoctoral researcher investigating Conus. But the demands of sustenance preceded those of medicine and beauty Indeed, communities in the Philippines and American Samoa have long considered cone snails a delicacy. No one has been known to die from eating them: digested peptides aren't dangerous. And in any case, Conus's foot, which is not connected to the venom duct, is considered the most flavorful meat on the animal. "When we asked the chief of an island in American Samoa if it would be OK for us to collect snails, he couldn't fathom why we would use them for research," says Joseph Schultz. "He thought we were getting dinner."

(see also list of Cone shells - by habitat and food preference)

CG and BGL , August 1996

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