Diving for Drug Discovery
Pharmaceutical research is taking to the high seas
Inside the ribbon worm, as it slinks along the ocean floor, is a chemical compound that could help people suffering from Alzheimer’s disease. Within the tiny, slimy body of the sea slug, there’s a compound that has the potential to treat lung cancer. From miniscule bacteria to massive coral reefs, marine sources are increasingly regarded as sources of possible new medical treatments — if researchers can navigate formidable financial and environment obstacles on the way to the pharmacy.
Marc Slattery, a marine biologist by training, looks to sponges and coral as possible sources of drugs. As stationary species in the open ocean, these organisms have developed many chemical defenses to protect themselves. Slattery studies whether those chemicals could protect us, too. Maybe the same compounds that fend off fish could battle viruses, kill bacteria, and even fight cancer.
“These organisms are producing some nasty sorts of chemistry,” Slattery explains. “If you focus on the biotech side of things, there may be a drug in that” — or, he suspects, many.
After a long history of success on land, pharmacognosy — the search for substances in nature that have pharmaceutical potential — is finally getting its sea legs. Slattery, a pharmacognosy professor at the University of Mississippi, is one of the researchers scouring the oceans for cures. The ocean is awash in chemical compounds that are rare on land, and scientists believe some of those compounds have the potential to become valuable pharmaceuticals. Two marine-derived drugs are already in use — an anti-tumor medication derived from sea squirts and a painkiller from a cone snail — and more than a dozen others are in clinical trials. Researchers don’t think the ocean will provide a cure for every malady; their work is a complement to, not a substitute for, conventional drug development efforts. Since so many ocean species have never even been studied, researchers guess that a multitude of useful marine compounds have yet to be found.
“All of this discovery, it’s the same as the early explorers that went around the world finding new lands,” says William Fenical, director of the Center for Marine Biotechnology and Biomedicine at the Scripps Institution of Oceanography in San Diego. “We find new substances that have the potential to be important in the future of human life.”
But researchers worry that damage to the oceans could mean some species — and whatever chemicals they produce — will be lost before they’re found. Ocean acidification, warming water temperature and pollution all threaten sensitive corals and the symbiotic species that live on the reefs. Says Michael Lesser, a coral reef biologist at the University of New Hampshire who collaborates with Slattery, “We could lose something that could have great value to us as human beings, and not even know it.”
The terrestrial world has yielded cures for millennia, many of which have found their way into modern drugs. Ancient Greeks chewed on willow bark to relieve pain and inflammation; a chemical in the bark, salicylic acid, was used to make aspirin. South American tribes turned to cinchona bark, which contains quinine, to lessen the symptoms of malaria. Even penicillin was isolated from a common species of household mold.
Over the past few decades, some scientists have chosen to focus on the ocean because it offers more unexplored possibilities. Slattery jokes, “We still have a lot to check out in marine systems, whereas they’re sort of running out of plants to try.”
Marine organisms produce different compounds than their land-dwelling counterparts. Ocean waters are filled with chemicals less common in soil or air, like bromine and chlorine. As a result, Slattery says, many marine species have evolved to incorporate those chemicals into their biological compounds by making their own modifications to the chemical structure.
Some sponges Slattery has studied, for instance, defend themselves with terpenes, the same class of chemicals pine trees use to ward off hungry insects. The sponges incorporate bromine into the terpenes to form “new and unusual structures” substantially different from terpenes native to trees.
To decide which sponges and coral to investigate, Slattery and his colleagues go scuba diving. In reefs from the Bahamas to Palau, they watch how species interact. On an excursion in the Pacific, they noticed that fish tended to avoid a certain sponge, Stylissa massa. It’s a big, bright orange sponge, and “if you’re looking for food as a fish it seems like that’s the first thing you’d cue in on,” Slattery says. “Yet we rarely see anything swimming by it.” When a species sparks his interest this way, Slattery extracts a golf-ball sized bit of tissue to take back to his lab.
Back in his Mississippi lab, Slattery isolates compounds in his samples and tests them against a disease-causing bacteria, virus or fungus. Stylissa massa, for example, has yielded a promising compound called palauamine, named for its island of origin.
Scripps’ Fenical, on the other hand, focuses on the many microbes living in the ocean floor. “If you pick up a piece of the bottom about the size of a sugar cube, you have one billion microbial cells to study,” he says. Fenical and his colleagues sail to various parts of the ocean, including areas near the US Virgin Islands and the California coast, then lower small sampling devices that grab onto a bit of the ocean floor and haul it back to the surface. He’s come back with a variety of chemically rich bacteria called actinomycetes.
If a compound seems effective against a certain pathogen, it’s put through a range of preclinical tests — and, if it still shows promise, through three phases of clinical trials overseen by the US Food and Drug Administration. Once a drug gets to clinical trails, “it doesn’t matter whether that sample comes from a marine environment, a terrestrial environment, or even the moon,” Slattery says — it goes through the same tests for safety and effectiveness.
Two compounds Fencial’s team has found are in clinical trials as cancer drugs, and more are in preclinical trials as antibiotics.
The vast majority of compounds taken from the ocean don’t become drugs, however, which is one of the reasons marine efforts are only a small part of overall drug discovery. Many compounds aren’t useful against particular pathogens, and others are found to be toxic during testing. A chemical from another Pacific sponge that Slattery found was highly effective at treating a fungal infection that often proves fatal to AIDS patients. The problem was, nobody could figure out how to give patients the drug. Pills, injections, nothing seemed to work; the human body couldn’t absorb it. “It’s almost like a rock,” Slattery says, “It just does not go into the human body in any way, shape or form.” After three years of research, he realized the compound wasn’t a feasible drug.
Funding, too, is a major obstacle. Developing a new drug costs hundreds of millions of dollars, says Alejandro Mayer, a marine pharmacologist at Midwestern University in Downers Grove, Illinois. That’s far beyond the scope of usual research grants doled out to marine biologists; a biotechnology or pharmaceutical company must be willing to fund the project.
This high cost is a key reason why there are just two marine drugs currently on pharmacy shelves. Yondelis is an anti-tumor drug derived from a chemical found in ascidians, small marine animals commonly called sea squirts. Prialt, a painkiller that Slattery says is “10,000 times more powerful than morphine and doesn’t have all the side effects,” came from a species of cone snail. Drugs currently in clinical trials, like those from the sea slug and ribbon worm, draw on sponges and bacteria as well, and are aimed at not only cancer and Alzheimer’s, but ADHD, schizophrenia, asthma, and other diseases.
The sources of marine drugs, while at risk, could be a rallying cry for those working to save the oceans. Sandra Brooke, Coral Conservation Director of the Marine Conservation Biology Institute in Bellevue, Washington, says the potential for marine drugs “is one of the big hooks” when explaining why coral conservation is so important. Since any compound used on a large scale as a drug will be synthesized rather than extracted from the sea, she says, marine drugs are unlikely to further damage reefs. As for how the oil spill in the Gulf of Mexico will affect drug discover efforts, Brooke says, “the short answer is, we really don’t know.” Scientists aren’t yet sure what effect the spill and dispersants will have on the gulf’s biodiversity.
Scientists have been searching for drugs in the ocean for only a few decades, and much remains to be discovered. “Think about how vast the ocean is, how different the ocean is” from place to place, Fenical says. “This is an enormous undertaking that will take one hundred years to have a sense of how it’s going to work.”
Slattery is optimistic about the field’s long-term potential. “I think over the next decades, you’re going to see more marine [drugs] filtering onto pharmacy shelves,” he says.