Medicine from the Sea

From slime to sponges, scientists are plumbing the ocean's depths for new medications to treat cancer, pain and other ailments

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The work done over the years in medicinal botany has been a major spur for marine bioprospecting. More than 100 important drugs originate either as direct extracts or synthetic redesigns of plant molecules, including aspirin (from willow bark), digitalis (from the flowering herb foxglove), morphine (from opium poppies) and the antimalarial drug quinine (from the bark of the cinchona tree).

Researchers largely overlooked the oceans as a source of pharmaceuticals until the advent of scuba technology, first tested in 1943. Among the pioneers of marine bioprospecting was Paul Scheuer, an organic chemist and a refugee from Nazi Germany who ended up at the University of Hawaii at Manoa in 1950. He began to collect, identify and study an astonishing array of organisms—in particular, soft, sessile creatures. What intrigued Scheuer and others was that although such creatures possessed no obvious defense mechanism against predators—no teeth, claws, flippers to effect escape, or even a tough skin—they thrived. Scheuer and others assumed that the organisms had potent chemical defenses that might prove useful to people, so they began searching for the compounds using tried-and-true methods of biochemistry: grinding up specimens, dissolving the materials in various solvents, then testing the resulting extracts for a range of properties, including an ability to kill bacteria, to react with nerve cells or to attack malignant cells.

By the 1970s, the U.S. National Cancer Institute (NCI) and other research centers had begun to fund expeditions around the globe to collect marine samples. So far, the NCI has screened tens of thousands of marine extracts, and the institute continues to receive roughly 1,000 organisms from the field each year. David Newman, a chemist with the NCI’s natural products program, says the massive canvassing is necessary because only one out of every several thousand sub stances shows any promise. “You might expect to make a better return by playing Powerball,” says Newman. “But with drugs, when you hit it, you hit it big.”

The arduous process of identifying and testing marine compounds is about to greatly accelerate, some scientists say. Automated chemical probes will seek out interesting stretches of genetic material in a batch of seawater or ground-up sponge; then, the thinking goes, gene-copying techniques will enable researchers to produce an abundance of whatever compound the gene is responsible for. “Now we have more ways to find the gene clusters that produce these substances, and clone them so they can produce more,” says Bill Gerwick, an Oregon State University marine biochemist who studies blue-green algae from the Caribbean and the South Pacific. Recently, molecular biologist Craig Venter, president of the Institute for Biological Energy Alternatives, began sequencing the DNA of every microbe in the Sargasso Sea, a region of the Atlantic Ocean.

Most “discoveries” don’t pan out, either because test-tube results don’t translate to real-world problems or beneficial compounds also may produce harmful side effects. As a result, perhaps only one or two out of every hundred compounds that reach the preclinical testing stage yields a potential pharmaceutical—after anywhere from 5 to 30 years. “Both the beauty and the downfall of these compounds is that they are exotic and complicated,” says Chris Ireland, a University of Utah marine chemist.

A score of compounds derived from marine sources are being tested in clinical trials: one such compound, trabectedin, has been isolated from Ecteinascidia turbinata, a Mediterranean and Caribbean tunicate, whose colonies look like translucent orange grapes. Apharmaceutical company based in Spain, PharmaMar, is testing a drug, Yondelis, from this compound against several cancers. Another compound, contignasterol, is the source of a potential treatment for asthma being developed by a Canadian company, Inflazyme. The drug, based on a substance found in a Pacific sponge, Petrosia contignata, reportedly produces fewer side effects than current medications and can be swallowed instead of inhaled.

In the United States, a marine-derived drug that has been extensively tested for the treatment of chronic pain is Prialt. It is based on venom from a species of Pacific cone snail, whose poisonous harpoonlike stingers can paralyze and kill fish and humans. At least 30 people have died from conesnail attacks. Biochemist Baldomero Olivera of the University of Utah, who grew up in the Philippines and collected cone-snail shells as a boy, conducted the research leading to the discovery of the drug. He and his colleagues extracted a peptide from the venom of Conus magus (the magician’s cone). “I thought that if these snails were so powerful that they could paralyze the nervous system, smaller doses of the compounds from the venoms might have beneficial effects,” Olivera said. “Cone snails are of exceptional interest because the molecules they make are very small and simple, easily reproducible.” In January, the Irish pharmaceutical firm Élan announced that it had completed advanced trials on Prialt in the United States. The drug, acting on nerve pathways to block pain more effectively than traditional opiates, appears to be 1,000 times more potent than morphine—and, researchers say, lacks morphine’s addictive potential and exhibits a reduced risk of mind-altering side effects. One research subject, a Missouri man in his 30s who had suffered from a rare soft-tissue cancer since he was 5, reported to scientists at the Research Medical Center in Kansas City that his pain had abated within days of receiving Prialt. About 2,000 people have received the drug on an experimental basis; Élan plans to submit the data to the FDA for review and possible approval of Prialt, with a decision expected as early as next year. Other researchers are investigating the potential of cone-snail venoms, the components of which may number up to 50,000, in the treatment of nervous system conditions such as epilepsy and stroke.

Two antiviral drugs already on the market might be said to have been inspired by marine product chemistry: Acyclovir, which treats herpes infections, and AZT, which fights the AIDS virus, HIV. Those drugs can be traced to nucleosidic compounds that chemist Werner Bergmann isolated from a Caribbean sponge, Cryptotheca crypta, in the 1950s. “These are arguably the first marine drugs,” says David Newman.

Marine-derived products other than drugs are already on the market. For example, two essential fatty acids present in human breast milk are also manufactured by a marine microalga, Cryptocodinium cohnii. Infant-formula makers use the algae-derived substances in some products. An enzyme synthesized from microbes found in undersea hydrothermal vents has proved highly effective in decreasing underground oil viscosity—and therefore increasing oil-well yields. Already, automakers are using one compound, based on glues made by the common blue mussel, to improve the adherence of paint; sutureless wound closure and dental fixatives are other possible applications. New varieties of artificial bone grafts, produced from ground-up corals, possess a porosity that precisely mimics that of human bone tissue. Agroup of compounds with anti-inflammatory properties called pseudopterosins have been extracted from a Caribbean gorgonian (a soft coral) and are included in an antiwrinkle cream marketed by Estée Lauder.

With the field of marine products chemistry showing such promise, a new breed of hybrid scientist has emerged: scuba-diving chemists. They generally spend half their time shaking beakers in a lab, the other half scraping strangelooking things off underwater rocks. Jim McClintock, a University of Alabama at Birmingham marine-chemical ecologist, collects bottom-dwellers in the waters off Antarctica. A perhaps unexpected diversity of organisms thrives there, with more than 400 species of sponges alone. To explore that environment, McClintock and his co-investigators have to pry open sea ice eight to ten feet thick with chain saws, drills or even dynamite. They wear 100 pounds or so of diving gear, including special kinds of super-insulated diving suits, known as dry suits, and descend into deep, narrow holes—often with as little as a two-inch clearance in front of their noses. In this hermetic world, the water may appear pitch-black or gloriously illumined, depending on how much snow covers the ice overhead. Leopard seals, 1,000-pound predators that devour penguins and other seals, may demonstrate a hungry interest in the divers. Mc- Clintock recalls seeing a behemoth charging menacingly and surfacing through a crack in the ice to swipe at researchers topside. “I try to stay out of the food chain,” he says. Back at the University of Alabama, McClintock’s colleague, molecular biologist Eric Sorscher, screens Antarctic organisms for compounds; he has identified a few that may be tested for the treatment of cystic fibrosis. The Pennsylvania- based pharmaceutical firm Wyeth recently detected antibiotic and anticancer properties in extracts from Antarctic sponges and tunicates.


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