Jewels in the Mud
A marine biomedicine pioneer leads explorations of the oceans to battle drug resistance and disease
By Mario C. Aguilera
Put simply, NPI-2358 sucks the life out of tumors. The drug hinders the functioning of blood vessels within them, and, deprived of nourishment, they die.
William Fenical of Scripps Institution of Oceanography at UC San Diego knows all about such drugs in the fight against cancer. But Fenical also knows that NPI-2358, or "Plinabulin," is different. Fenical and members of his laboratory discovered a microbe on the surface of a seaweed in the Bahamas that led to the development of Plinabulin, a synthetic derivative. Developed by Nereus Pharmaceuticals Inc., Plinabulin, now being tested in humans, is different from conventional cancer drugs: It targets established blood vessels in solid tumors such as lung cancer and tends to leave healthy cells alone.
Plinabulin is one example of a novel drug born in the ocean with enormous potential to wipe out disease. It also embodies the essence of Fenical's research career as a scientist and tireless evangelist of marine-based medicines and their promises for cures.
Fenical, a founding father of the field of marine biomedicine, knows that humans face an epidemic of pathogenic bacteria and diseases that have become resistant to modern medicines. Examples range from illness caused by the bacterium Staphylococcus aureus — an infection now resistant to 88 percent of all antibacterial drugs—to war-related sicknesses that proliferate on the battlefield.
To treat such diseases, where will tomorrow's new drugs come from? Fenical believes the answer lies in the oceans and their vast resources. The oceans cover 71 percent of the planet. Across that immense space, spread along the expanses of the ocean deep, new treatments for the sake of humanity's future await discovery.
The Wonder Years
Fenical describes his childhood years in Chicago as "classic 1950s." It was a time when world-changing events were set in motion that permanently captured his imagination. New developments for ocean exploration flourished in that decade. Jacques Cousteau and his engineering partner were refining the Aqua-Lung, the forerunner of modern scuba diving equipment, which afforded broad access to the wonders beneath the sea surface. Fenical credits a formative visit to an uncle in Tampa, where the young boy spent countless days with mask and snorkel, becoming entranced by the sea.
Fenical never gave up his love for the ocean and diving. Throughout his education, including doctoral studies in organic chemistry at UC Riverside and subsequent university teaching positions, he kept diving. The sea's beckoning became stronger year by year, culminating at the moment he quit a job in the oil industry.
"I said to myself, 'Life's too short, I need to find some way to work in the ocean!,'" Fenical said.
Off he went, pursuing his curiosity about the mysterious chemical structures that might be found in marine environments. He began expounding his ideas to his fellow academicians.
"One colleague said to me, 'Why do you think there are any interesting chemical compounds in the ocean?' and I said, 'I don't know, but it makes sense. And nobody's ever done it. Somebody's got to get in there and work.'"
With an understanding that scientific knowledge of the oceans in the 1950s and '60s was in its infancy, Fenical dedicated himself to finding out if indeed the oceans held natural resources worth identifying and studying.
When he arrived at Scripps in the early 1970s, the idea of developing medicines from marine sources was virtually unheard of. In the early days he and his colleagues made mistakes. They studied the wrong types of plants and animals. They employed the wrong laboratory procedures. But with the mistakes came progress and eventually credible scientific knowledge. In 1973, Fenical published a landmark paper in the field of marine biomedicine in the Journal of the American Chemical Society that showed that life in the ocean produces bizarre and highly bioactive natural products.
Successes then snowballed, and, in Fenical's words, "the field went boom!"
Early in the young field of marine biomedicine, the intricacies involved in identifying a novel chemical compound with medical potential could consume a scientist's life for six months. Today, with a broad knowledge base and modern technology, it might take a week or two.
By the time he founded the Scripps Center for Marine Biotechnology and Biomedicine (CMBB) in 1998, Fenical headed a vibrant laboratory with students, post-doctoral researchers, and other scientists, all focused on discovering novel medical sources from the sea. Living in environments that are often dark, cold, and drab, the tiny denizens in ocean bottom mud now seem most likely to change the future of medicine, the team believes.Next Page: EXOTIC BIOPROSPECTING
Alexander Fleming's 1929 discovery of penicillin from a soil fungus spurred a boom in the pharmaceutical industry. For the next 50 years, researchers looked in terrestrial environments—from low-lying woodlands to snow-covered mountaintops—for natural microbes that produce new antibiotics in a similar fashion. More than 120 antibiotics were developed in succeeding decades to treat infectious diseases.
"There was no greater scientific discovery than that of penicillin," said Fenical. "This was the foundation, the ultimate, in my view, of using the evolutionary consequences of chemistry from nature and applying it to human needs."
Though penicillin was considered a wonder drug in its heyday, in time bacteria emerged that proved resistant to its potency. With the majority of land-based environments sufficiently exhausted of new sources, the pharmaceutical industry virtually pulled the plug on finding new terrestrial antibiotics. By the early 1990s most pharmaceutical companies had abandoned the search altogether.
Thus, Fenical looks to the seas. Across settings that span from mild to extreme and are home of the broadest biodiversity on the planet, he seeks to determine which organisms in the ocean make potentially therapeutic products and which don't.
"These are novel, unique organisms—plants, animals, and microbes—that have a different genetic composition (than terrestrial organisms)," said Fenical. "Unique genes equals the production of unique compounds."
A marine organism living in the deep sea, for example, might produce a distinctive compound to defend itself from predators. Could such a compound be adapted to repel a human disease such as malaria? Could its unique chemical structure be reformulated to fight a neurological disease such as Alzheimer's?
To find out, Fenical probes the vast seafloor—and its unglamorous mud. He vigorously pursues bacteria from the order actinomycetes. Nearly 80 percent of antibiotic medicines have come from soil-based actinomycetes and now Fenical is hunting their marine cousins.
His group and collaborators discovered a unique marine actinomycete genus they call Salinispora off the Bahamas in 1990. Over time they cultivated thousands of strains of the bacteria, which led to the first drug from the Salinispora family, now in clinical trial testing at Nereus, a San Diego-based firm and longtime collaborator. The drug could one day treat myeloma and lymphoma, cancers that afflict white blood cells in bone marrow and the body's immune system.
More recently, Fenical, his team, and collaborators unearthed a new genus of bacteria living in shallow sediment not far from his Scripps laboratory in La Jolla. Crude extracts of Marinispora have revealed potent antibiotic activities against drug-resistant human pathogens. The finding has produced four new compounds, the "marinomycins," members of a new antibiotic class. Early tests of this "Mar 3" actinomycete reveal encouraging antibiotic results against methicillin-resistant Staphylococcus aureus, or MRSA, an infection proliferating in hospitals and other health care facilities.
"Drug resistance is growing at an alarming rate," said Fenical. "So we continue to explore, and now we have found at least 14 different groups of organisms that occur in the ocean and appear not to occur anywhere else on land."Next Page: BRANCHING OUT
As CMBB director, Fenical works alongside colleagues who are expanding beyond medicine to apply biological and chemical knowledge to topics from agriculture to new transportation biofuels.
To fully realize his early dreams of capitalizing on the ocean's potential, Fenical is boosting his portfolio as explorer, researcher, and teacher with an expanding role as collaborator. He works with scientists based in Fiji, Guam and other Pacific islands in hopes of discovering all-new antibiotics.
Closer to home, Fenical is increasingly branching out through the UC San Diego campus and its world-class School of Medicine, including the Moores Cancer Center and Skaggs School of Pharmacy and Pharmaceutical Sciences. Working with Victor Nizet, chief of the new UCSD Division of Pediatric Pharmacology and Drug Discovery, and his own center's Paul Jensen, Fenical is working through a $2 million federal research grant to develop new antibiotics to treat drug-resistant diseases.
"CMBB is a completely unique arrangement on a worldwide basis," said Fenical. "Nowhere else is there a frontline marine science institution intimately connected with a frontline school of medicine. Nowhere have those collaborations been built that afford exploitation of the ocean and subsequent development of drugs, even to the stage of clinical trials in our own hospital."
Further, through a new contract worth up to $29.5 million from the U.S. Department of Defense's Defense Threat Reduction Agency, San Diego-based biopharmaceutical company Trius Therapeutics Inc. will identify natural products discovered by Fenical to develop new antibiotics against disease-causing microbes for applications ranging from military biodefense to prevention of hospital-acquired infections.
Fenical and Jensen also partnered with Steve Bennett, Scripps director of business development, and UCSD's von Liebig Center for Entrepreneurism and Technology Advancement to launch a start-up company spun off from UCSD to license promising drug leads. In the long years from discovery to final product, the price tag for development of a drug is now estimated at $1 billion, Fenical said. Rather than watch many potential drug prospects fail due to lack of funding during a critical development period known in the business as "the Valley of Death," Fenical and Jensen hope their new early-stage company will build a financial bridge to drug maturity.
Nearly 40 years after arriving at Scripps, Fenical says things are just getting started.
"The oceans are extraordinarily biologically complex," said Fenical. "Potentially it could take several hundred years to fully understand and develop their medical resources."
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