Drugs from the Sea

There's only one place left to find the next wave of supermedicines. Fortunately, it's where we should have been looking all along

By Rosie Mestel|Monday, March 01, 1999
RELATED TAGS: PHARMACEUTICALS, OCEAN
Outside the Scripps Institution of Oceanography in La Jolla, California, the sights, sounds, and smells are all of a seaside paradise--salty breezes, crashing blue green waves, picturesque piers, even people fighting gulls from their burgers as the wind whips napkins away. Inside, in biologist William Fenical's lab, it's good-bye to the sea's charms and hello to the smelly and slimy, the creepy and crawly, the disgusting and fascinating world of creatures scooped from that ocean outside, ground up, and thrown at every frightening disease he can think of.

This is the medicine chest of the next millennium--teetering mounds of agar-filled dishes smothered with fuzzy greenish growths, flasks full of brown nutrient broth layered with gray mold, beakers sporting pale, flabby eruptions like omelettes cooking in hell's kitchen. What's brewing in these potent pots? Stews of bugs--fungi and bacteria that once lived in ocean sediments, rotting driftwood, weeds, coral, sponges, and grasses. Although unappealing, any one of these containers might harbor a brand-new kick-ass cancer drug or a compound to wipe out some of the scariest viruses known to humankind.

Fenical's quest may be critical to the future of medicine. We need new drugs. The glory days of antibiotics are over. Bacterium after bacterium is gaining resistance to our arsenal. Doctors are desperate for compounds to attack cancer, Alzheimer's, AIDS, and a long list of other diseases for which there are limited treatments and no cures. Since that momentous day in 1928 when Alexander Fleming first noticed that a common mold blown in through an open window stopped staphylococcus bacteria from growing in a petri dish--his discovery of penicillin--researchers have been looking in increasingly exotic locations for the next strain of antibiotics. The search has intensified in landfills, septic tanks, swamps, chemical dumps, and trash piles.

But the returns are dwindling fast. "In the old days you could wander around a cornfield or up in a forest, take little dirt samples, bring them back to the lab--and what do you know? You'd found microorganisms that produce streptomycin, or actinomycin, or vancomycin," says Fenical, who is the director of the Scripps Center for Marine Biotechnology and Biomedicine. "Today when you do that you find streptomycin, actinomycin, or vancomycin--the same things. Of everything you find, 98 percent turns out to be something you've found before. It's costly; it's inefficient. And when you look at a graph and you see disease resistance going up and drug discovery going down, it's also downright frightening."

Fenical's lab of weird concoctions may be proof of his conviction that drug hunters need to look in new places. His answer is surprisingly simple: search the sea. Since the 1980s he has been plunging into the ocean to find the next wave of medicines. Already he and his colleagues have dredged up some promising candidates: chemicals that soothe swelling, from lovely tropical organisms called sea feathers; a compound from a bulbous yellow soft coral that disrupts cell division in cancer cells, like taxol, the breast cancer drug derived from yew trees; and virus-killing proteins from ocean molds that live in sea grasses.

Fenical is not alone in this effort. Just a few doors down from his lab, chemist John Faulkner has been in the business even longer, dragging molecules from sponges that might fight cancer, kill viruses, or help scientists better understand how cells in our bodies grow and divide. In labs around the world, the search on this new frontier has intensified. Today the list of novel potential anticancer drugs at the National Cancer Institute's Natural Products Branch includes more candidates from the ocean than from the land. Several promising drugs from the sea that might be used to treat leukemia--including one from a creature called Bugula, which clings to the bottoms of boats--are involved in human trials.

The ocean is by far the major habitat on the planet--it's 70 percent of Earth's surface," explains Fenical. "It's teeming with unique organisms. More than half the organisms in the ocean don't even occur on land."

That's the good news. The bad news is that it's difficult to know just where to look. When it comes to marine life, the rich history of ethnomedicine provides hardly any clues. There's precious little romance, either. Finding new compounds is a laborious process of trial and error, of collect, grind, and test. Still, Fenical and his colleagues have come up with strategies to narrow their search.

The first strategy is to go to a place where life is diverse and concentrated, such as a reef in the Caribbean. An environment rich in sea life is more likely to yield varied specimens. The next step is to try to gather what hasn't been studied before. "Don't even bother with this one," says grad student Helene Vervoort, pointing to a picture of a strange, spreading green blob--a sea squirt more properly called Lyssoclinum bistratum. She recalls pulling it up the first time she dove, only to be greeted back on the boat with "God, that green thing again!"

Hard corals aren't much use, either. Even if they weren't slow-growing and often off-limits because of environmental laws, they're well protected by virtue of their hardness. And hardness isn't the kind of defense researchers are looking for. They want to home in on creatures that use chemicals--not armor--to defend themselves. "We pay a lot of attention to ecology," says Vervoort. "We might say, 'Well, this one's interesting--there's no bacteria or algae growing on it, no other organisms settling on it--that thing must be producing something to keep itself clean.' Or we might spot an animal that looks delicate, and you would think it would be a good source of food for fish, yet it's not being eaten."

Fenical suspects that creatures loaded with biologically active molecules--the kind that they'd need to defend themselves chemically--could be the richest sources for all manner of drugs, many with unpredictable uses. Take the strange case of a glorious feathery sea fan called Pseudopterogorgia elisabethae. (While this creature looks great underwater, when dried it looks more like worn-out pink rubber bands.) "If you put a bit of tuna out on the reef, fish come from everywhere, and it's gone," says Fenical. "But if I grind up this animal and mix in some extract with the tuna, the fish will come up, take one bite, and go 'Yuck!' No way will they eat it."

Part of the sea fan's chemical arsenal, it turns out, is a family of molecules called pseudopterosins, discovered by Fenical and Bob Jacobs, a pharmacologist at the University of California at Santa Barbara. Pseudopterosins do more than make fish want to barf. In people, they soothe swelling caused by sunburn or chemical irritants. They do so by reining in a key enzyme involved in inflammation, and they do it with more clout than does hydrocortisone. Psoriasis, sunburn, and arthritis all involve inflammation, and one or more of the pseudopterosins might one day be the drug of choice to treat these afflictions. A biotech company based in La Jolla, Nereus Pharmaceuticals, has a license from Fenical and Jacobs--who hold the patent on pseudopterosin drugs--to investigate their power.

Fenical, meanwhile, reckons that a sea fan extract might be great as an additive to toothpaste or for soothing inflamed gums. The extract is already being added to cosmetics. The label of Estee Lauder's Resilience face cream lists P. elisabethae as an active ingredient, an addition that makes some sense: exposure to the sun triggers an inflammatory cascade in the skin, and if the extract limits the inflammation, it might also limit sun damage.

Of course, the hope is to hit the jackpot with far stronger drugs. Grad student Akkharawit Kanjana-Opas, who has come from Thailand to study marine microbes with Fenical, shows how he goes about screening for medicinal potency. In his hand he holds a vial with a trace of oily green goop, all that remains of liters and liters of a mashed-up fungus cryptically labeled CNK827, just one of 3,000 samples of ocean fungi he has screened. Thousands more will follow.

On his desk, next to a notebook neatly labeled "Marine Fungi Isolated from Mangrove Samples," sits a square dish filled with 96 troughs in 12 tidy rows. In each trough, Kanjana-Opas pipettes a droplet of Candida albicans, a disease-causing yeast. Then in goes a droplet of a pretty dye called alamar blue. If the yeast cells start to grow, the liquid will turn red.

Next comes an extract, in this case a fungus dredged from sediments in a swampy coastal mangrove forest. A sample goes into the first row. Into the seven other rows go increasingly more diluted samples of the same brew. When all the troughs are filled, the plate is put in the incubator overnight. By morning, Kanjana-Opas will know whether any of his samples show promise as killers. Most of the troughs will be pink, indicating the extract hasn't done much. Promising candidates will be blue, showing that they killed off the yeast in a reasonably diluted concentration. The same method is used to screen for compounds that might work on cancer cells or herpes.

If a promising candidate turns up, there are many more steps. In the case of a potential cancer killer, researchers test the drug against a set of different cell lines developed by the National Cancer Institute and derived from colon cancers, breast cancers, leukemias, and others. The trick is to ferret out drugs that kill a range of cancer cells but leave healthy cells unharmed. Next, the compound must be purified, its molecular structure must be determined, and either a drug company or the National Cancer Institute has to decide to fund testing on animals. Finally, the drug must be tested on people. At any stage, testing may be dropped, and for reasons as simple as the drug's being either too toxic or too weak.

Although that outcome is common in the drug development business, Fenical is excited about a substance he discovered several years ago, called eleutherobin, in a remote shallow sea off the coast of Australia. It comes from a mottled yellow pickle-shaped soft coral. Eleutherobin stops malignant tumors from growing in much the same way taxol does, by binding to a protein called tubulin and disrupting cell division. Several other compounds under development show similar behavior, including one extracted from a sponge and one from a Mediterranean coral.

The continuing nemesis of experimenting with sea drugs is supply--getting enough material to test, let alone produce, a drug. In the case of eleutherobin, researchers got lucky. In 1997 a group headed by chemist K. C. Nicolaou at the Scripps Research Institute managed to make the drug in the lab, using cheap starting materials: cardamom and dill.

In many cases, it's simply too hard to make a drug from scratch. The chemistry is too complicated. What then? Microbes can be grown in vats if researchers can figure out what to feed them, but other substances can prove more daunting to reproduce. When researchers became interested in halichondrin B, a promising anticancer chemical from a sponge fondly known as "yellow slimy," they had to collect a whole metric ton of sponges to derive 300 milligrams of drug--the amount needed to begin preliminary trials. They'd never have been able to do it if the National Cancer Institute hadn't put out a "Help! Where can we find more yellow slimy?" call to marine biologists. Word came back that the sponge thrives off the coast of New Zealand. Now researchers are trying to farm the plant in Wellington Harbor.

Another critter, called Bugula (the boat clinger), is also under cultivation. The organism grows in shallow water almost anywhere, yet only three known populations of Bugula actually make bryostatin 1, a potent drug that's involved in dozens of clinical trials as a treatment for everything from leukemia to kidney cancer. Bugula can grow in vats on land and in the ocean on wire mesh. Despite the recent progress, no marine drug has reached the pharmacy shelf. That, however, is no surprise. It took more than two decades, from gathering crunched-up Pacific yew bark to FDA approval for treating breast and ovarian cancer, for taxol to make it to market. And Fenical is not discouraged. In fact, he is passionate about the possibilities: "If we need new drugs, where are we going to go? Space? No." He pauses and waves his hand expansively out the window toward the wide blue Pacific. "It's sitting right there. It's diverse as hell. And it's waiting for us."
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