Testing the Waters

AMY WRIGHT HAS made more than 200 trips to the bottom of the sea. She made those voyages in a submersible vehicle operated by her employer, Florida Atlantic University’s Harbor Branch Oceanographic Institute, in Fort Pierce, Fla. The descent in the submersible—a small submarine with room for four people—was always in darkness, to preserve power in the external lamps. Once they reached their destination, sometimes over a half mile beneath the ocean’s surface, the lamps would flick on and reveal a strange world: huge bottom-feeding fish, a menagerie of oddly shaped sea sponges and other marine invertebrates. Once, during a dive off the Galapagos Islands, Wright watched as a jellyfish suddenly illuminated itself in the inky depths, turning bright red. “It glowed like an alien spacecraft,” she says.

Wright took the plunge over and over in a quest to discover new medicines. As director of the natural chemistry program for the institute’s Marine Biomedical & Biotechnology Research (MBBR) division, she belongs to a small but devoted coterie of scientists who believe that the ocean’s extraordinary diversity of animals, plants and microbes represents a massive and still largely untapped source of chemistry that could produce life-saving drugs.

Seagoing scientists have landed some important catches. Since 1969, the U.S. Food and Drug Administration has approved six marine-based medicines. The first, cytarabine (Cytosar-U), came from a sea sponge found in the Caribbean and is now a mainstay in the treatment of acute myeloid leukemia, as well as other forms of leukemia and non-Hodgkin’s lymphoma. Another medicine derived from a marine sponge, eribulin mesylate (Halaven), was approved by the FDA in 2010 and has assumed an important role in the treatment of metastatic breast cancer; research shows that the drug significantly prolongs survival in patients who no longer respond to standard chemotherapy regimens. The most recent addition to the marine formulary is another cancer drug, brentuximab vedotin (Adcetris), which contains a tumor-fighting compound based on a toxin produced by the Indian Ocean sea hare, a snail-like mollusk. The FDA approved brentuximab vedotin in 2011 for the treatment of Hodgkin’s lymphoma and systemic anaplastic large cell lymphoma in patients who haven’t responded to other therapies.

And more marine pharmaceuticals could arrive soon. In February, the U.S. Food and Drug Administration granted priority status to the review and approval process for trabectedin (Yondelis), a treatment for advanced soft tissue sarcoma that’s already available in many other countries. Derived from a sea squirt, the drug could be commercially available by the end of the year.

“These are exciting times for marine pharmaceuticals,” says Alejandro Mayer, professor of pharmacology at Midwestern University in Downers Grove, Ill., and editor-in-chief of the journal Marine Drugs. Mayer monitors the pharmaceutical industry pipeline for marine-based experimental compounds and says there are now more than two dozen in clinical trials. Most are candidates for cancer therapies. But Mayer notes that there are chemicals that could help treat heart disease, immune and neurological disorders, viruses and many other conditions. Some hold out hope that the sea could even offer solutions to a particularly crucial problem: antibiotic resistance.

NATURE HAS LONG been a source of pharmaceutical products. Aspirin—based on salicin, found in the willow tree—may be the most obvious example, but there are countless others. The cancer drug paclitaxel (Taxol) is derived from the bark of the Pacific yew tree, and many antibiotics, including streptomycin, tetracycline and vancomycin, came from compounds produced by soil bacteria. Between 1981 and 2010, almost three out of four new drugs originated from, or were inspired by, naturally occurring compounds.

Just a tiny fraction, however, came from the sea, and that puzzles William Fenical. “Most of the world’s biodiversity exists in the ocean,” says Fenical, distinguished professor of oceanography and pharmaceutical science at the Scripps Institution of Oceanography of the University of California, San Diego. “A milliliter of seawater holds more than a million microorganisms. And there are a billion microorganisms we know very little about in a cubic centimeter of bottom sediment. And we’re not developing those?”

Fenical is widely regarded as the dean of marine pharmacology in the United States. He arrived at the Scripps Institution as a researcher in 1973 with the idea of searching the sea for compounds with medicinal properties—a neglected field of research at the time, even though the FDA had approved cytarabine a few years earlier.

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Fenical’s requests for funding often met with derision, but he found enough to make his first inroads. He spent much of the 1970s simply trying to figure out what kinds of marine organisms he should be studying. He began with red algae, aware that years earlier Japanese researchers had discovered it contains bromine, which is found in the ground and seawater and belongs to a group of nonmetallic elements called halogens. Fenical was eventually able to show that algae and other sea organisms use bromine and other halogens, such as chlorine and iodine, to make what are known in the scientific community as natural products. While that phrase may call to mind organic grocery stores, to scientists a natural product is essentially a secondary metabolite—a chemical made by an organism that is not essential to the organism’s primary life processes but that conveys a distinct survival advantage.

Fenical’s discovery countered the skeptics who doubted that marine organisms might contain biologically valuable compounds. And it gave hope that there was unique chemistry to be discovered in the sea, because exceedingly few land organisms use halogens to make natural products.

Fenical set up his own lab in 1977 and has collected and identified thousands of previously unknown sea compounds. After earlier investigating sea plants and animals, he and his team now focus solely on marine microbes, which they extract from sediment they dig up in the Pacific. “There’s an almost unlimited supply of microbes and we know that they make unusual things,” says Fenical. For instance, his researchers recently discovered that a rare marine bacterium in the genus Serinicoccus produces a compound, which they named seriniquinone, that causes melanoma cells to self-destruct within three hours of treatment.

Teams searching for drug candidates in the ocean all have their own methods for isolating promising microbes, but the process normally boils down to a few key steps. Scientists studying sea sediment begin by mixing a gram or so of the diluted muck on a petri dish with growth factors and nutrients. “Then we watch to see what grows over the next few days or weeks,” explains University of Aberdeen organic chemist Marcel Jaspars, who heads PharmaSea, a consortium funded by the European Union that is searching for drug leads in extreme marine environments such as the Arctic Ocean. If the culture flourishes, it’s then put through a series of filters to separate biologically active chemicals from contaminants or other inactive elements. (The steps are similar with sea plants and animals, such as sponges, which are ground up, treated with solvents, then run through filters, a process Amy Wright compares to making coffee.)

After isolating a new strain of microbe, says Jaspars, “we try to find out if it has any chemical talent.” He and his colleagues conduct a genetic analysis of the microbe, and run it through a mass spectrometer, an instrument that measures the mass and concentration of its atoms and molecules to determine whether the organism is producing novel structures. Next, the microbe is tested in laboratory assays, or disease models, to find out whether it might kill cancer cells or infectious bacteria, for instance, and determine whether it’s toxic. If testing suggests a marine compound is safe and has important biological qualities, it can then go to an organic chemist, who will use the microbe as a model to synthesize an experimental drug.

A 2015 analysis published in Marine Drugs found that anti-cancer compounds represented more than half of the new marine natural products discovered from 1985 to 2012. One reason for that dominance is that the National Cancer Institute (NCI) has been screening natural products, including those from sea organisms, since 1983. Chemist Kirk Gustafson, head of a natural products chemistry section at NCI, studies terrestrial and marine natural products, and he has found that those from the ocean have a diverse chemistry, certain examples of which seem to be suited to fight cancer.

Gustafson offers marine sponges and their associated microbes as an example. “They’re very primitive, but they have evolved to have highly sophisticated chemistry,” he says. Like many marine invertebrates (such as coral and some sea squirts), sea sponges are sessile—that is, they attach themselves to the ocean floor and remain fixed in one place. “They can’t run, so one of the selective strategies they have to survive is to chemically alter their local environment,” says Gustafson. Sessile invertebrates manufacture toxins that ward off predators, and evidence suggests that they also produce growth inhibitors that prevent other species of invertebrates from taking root nearby and stealing their sunlight and nutrients.

Growth inhibitors are an example of a secondary metabolite, which organisms produce to help them survive. “If one function of a secondary metabolite is to inhibit the growth of a competing species,” says Gustafson, “then maybe it can hit a similar target in a mammalian tumor.” Last summer, Gustafson and several colleagues reported in Marine Drugs that a sponge called Acanthella cavernosa produces alkaloids (organic chemicals containing nitrogen) that help stabilize a protein called PDCD4 that suppresses tumors. (Recent studies have shown that PDCD4’s tumor-suppressing function is lost in some aggressive cancers.)

Amy Wright is one of several scientists funded by NCI who are searching the seas. She and her colleagues are currently looking at a number of promising compounds, including several that might treat pancreatic cancer, which has a five-year survival rate of less than 7%. Wright also did some of the early work identifying the chemical structure of trabectedin, the cancer treatment now being considered by the FDA.

A Spanish company, PharmaMar (mar is Spanish for “sea”), developed and patented trabectedin, which it has licensed in several markets to Janssen Research & Development, a division of Johnson & Johnson. Janssen is currently seeking FDA approval of trabectedin to treat an unusual form of cancer called soft tissue sarcoma (STS), and it is already available for treatment of advanced STS in 77 countries.

George D. Demetri, director of the Center for Sarcoma and Bone Oncology at Boston’s Dana-Farber Cancer Institute, has been studying trabectedin since 1998 and has treated many patients with the drug through the FDA’s expanded access (sometimes called “compassionate use”) program, which permits the use of investigational drugs. Demetri says about one in five patients with advanced STS, who have few other options, responds well to trabectedin, which can shrink about 8% of tumors and has durably stabilized many others, occasionally for more than four years. If and when the drug gains FDA approval, Demetri hopes to study whether trabectedin might offer some benefit in earlier treatment of STS. Trabectedin is also approved in many countries for use in combination with other chemotherapies for treating relapsed ovarian cancer.

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AFTER CANDIDATES for new cancer treatments, the next largest category of new marine natural products reported in the scientific literature each year is antibacterial compounds, or antibiotics. “Discovering primary antibiotic activity can be fairly easy,” says Fenical, who estimates that 1% to 2% of new compounds his group identifies and tests have the ability to kill infectious bacteria, at least in a petri dish. Most of those flunk further testing, however, because they’re too toxic or they lack other properties needed for development  as antibiotics.

But Fenical believes that a microbe found in the sediment of the ocean floor near Santa Barbara could defy the odds. The previously unknown bacterium produces a compound that Fenical’s group named anthracimycin after discovering that it inhibits growth of Bacillus anthracis, the bacterium that causes anthrax. Last year, they reported in the Journal of Antibiotics that anthracimycin also kills methicillin-resistant Staphylococcus aureus (MRSA), the notorious bacterium that causes potentially fatal infections and doesn’t respond to most antibiotics. And anthracimycin performs this feat in live animals, not just a petri dish.

Fenical, like many in the field, has been greatly concerned by the lack of interest from the National Institutes of Health for funding research on marine-derived antibiotics. He thinks that’s especially unfortunate considering how serious the problem of antibiotic resistance has become. According to the Centers for Disease Control and Prevention, at least two million Americans become infected each year with bacteria that resist treatment with antibiotics, and more than 23,000 die from the infections.

Fenical hopes that a pharmaceutical company might take an interest in developing anthracimycin, but he’s realistic about the prospects. Most large drug companies have abandoned antibacterial research units because of their low profitability, says David Shlaes, a former vice president for infectious diseases at the drugmaker Wyeth (acquired by Pfizer in 2009) and author of Antibiotics: The Perfect Storm.

Moreover, the few large pharmaceutical firms that still had teams studying natural products—from the land or from the sea—have given up those efforts, too, even after a three-decade run during which naturally occurring compounds accounted for most newly approved drugs. The process is now generally seen as too costly and time consuming, says Shlaes. With the advent of high-throughput screening and other technological advances, big drug companies prefer to scan massive compound libraries for drug leads. At the same time, however, some small and medium-size pharmaceutical startups have shown renewed interest in developing natural products into drugs.

Among Fenical’s lasting legacies could be the many biologists and chemists he has trained who are continuing to search for new marine drugs. One of Fenical’s former students is biochemist Tracy Mincer, who recently set up a lab to study marine natural products at the Woods Hole Oceanographic Institute in Woods Hole, Mass. In one current research initiative, Mincer and a colleague, biochemist Kristen Whalen, are studying antibiotic adjuvants—compounds that make existing antibiotics more effective against resistant bacteria. One way to do that is to shut down an infectious bacterium’s efflux pumps, which shuttle toxins—including antibiotics—out of a cell. Mincer, Whalen and several colleagues recently discovered a compound derived from a marine microbe (found on a piece of plastic debris floating north of Bermuda) called Pseudoalteromonas piscicida that clogs efflux pumps in resistant strains of bacteria. “When you shut down the pumps, a weak antibiotic can become more effective,” says Whalen. “You bolster its potency.”

Mincer has applied for NIH funding to launch a collaboration with Marcia Goldberg, an infectious disease specialist at Massachusetts General Hospital. Mincer’s lab has built a library of 5,000 extracts produced from marine organisms. A few display antibiotic activity in the lab, and Goldberg hopes to further test them using a variety of assays, including disease models for infectious diseases. “Over the next three to five years,” says Goldberg, “I hope we’ll have a number of promising compounds to move forward to the next stage of drug development.”