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The Research: Marine Natural Products Research

Dr. William Fenical is one of the founders of the marine natural products field. He is currently the director of the Center for Marine Biotechnology and Biomedicine (CMBB), based at the Scripps Institution of Oceanography in La Jolla, California. Scripps is part of the University of California, San Diego, and several other departments at the university are also part of the CMBB. The CMBB focuses on the discovery of new medicines from marine sources and on developing the ocean as a frontier for the future by training young people to explore and become excited about what the ocean can bring to the field of human health. Fenical is also a member of the UCSD Cancer Center, as much of his work involves collaborating with cancer physicians.

Fenical's research focuses on the discovery and development of marine natural products as potential treatments mainly for cancer and infectious diseases. His work in the field, which began in the 1960s, has covered a wide range of organisms including algae, corals and sponges, but his current focus is on marine microorganisms. He studies not only their medical potential, but also basic questions about their biology such as where they grow and the roles they play in the ocean.

- VIDEO CLIP 1: "Program Overview, Collaboration within UCSD; New Focus on Marine Microbiology"

Sediment Collection Devices

A critical challenge Fenical and his colleagues faced once the potential of deep-sea sediment microorganisms became clear, was how to collect samples, as no appropriate sampling devices existed. Oceanographers had been collecting sediment samples for many years, but the tools they had developed were not appropriate for rapid replicate sampling. Using existing equipment scientists were able to collect at best only a few deep samples in a day, but because sediments are typically quite patchy, multiple samples were needed to ensure that a reasonable cross section of microorganisms present could be collected. Another challenge was that existing equipment had to be deployed from ships, which are expensive to operate and not readily available in remote areas. So, Fenical and his team began to develop miniaturized portable sampling tools that allowed them to collect a large number of samples in a single day from whatever boat might be available. They began by modifying simple devices designed for collecting lake sediment samples that would freefall then collapse on impact with the bottom to grab a sample and then be retrieved. By adding weights and high-tech lines that are strong but lightweight, the group is now able to take samples down to about 3,600 feet. They have adapted an electric fishing reel for retrieval. The devices can be easily transported on a plane and deployed from small boats, allowing Fenical global access.

Early on the group collected samples in the tropical Atlantic and near their home base in La Jolla, where deep canyons are found close to shore. They have since sampled at locations such as Palau, Guam, Hawaii, Mexico, the Egyptian Red Sea, and Australia. They have also developed similar devices that take core samples, allowing examination of deeper sediments and stratified changes in microbial communities from the aerobic surface sediments to the anaerobic sediments farther down. However, these corers require retrieval by more sophisticated devices. Fenical ultimately hopes to be able to collect samples from much greater depths, because the ocean is on average about 12,000 feet deep. To do that, his team is developing a remote sampling device that can be dropped without tether then retrieved using a timing device or weight release to return it to the surface.

- VIDEO CLIP 2: "Evolution of the Deep Ocean Sampling Program"

Ownership

How to Raise a Deep-Sea Microbe

Pioneer Days

As one of the pioneering founders of the marine natural products fields, Fenical struggled during the 1970s against the widespread perception that there was little if anything of medicinal value in the oceans. "It was discouraging to press forward because of that," he says, "and difficult for young people who had a vision to look at this field to get a job." Nonetheless, a handful of researchers, mainly chemists, persevered. In addition to doubting the ocean's biomedical importance, some potential funders suggested that the work was more about lounging and diving in the tropics than drug discovery. To overcome this hurdle, Fenical and colleagues in about 1979 invited one funding agency representative along on an expedition to Tres Marias on Mexico's Pacific side. The reprentative ended up in a near shark attack, averted when another diver shoved a camera into the shark's mouth and hit him several times with a club. After that, says Fenical with a laugh, he consistently attested that the field was dangerous, but, more importantly, he came away from the trip with a clear understanding that the researchers were working very hard despite their enviable field locations.

As the field progressed, chemists like Fenical, who were learning needed biology as they went, were making fascinating discoveries. "Very slowly, we began to see the presence of molecules that no one had seen before," says Fenical, "compounds that contained unusual elements even. " For example, the researchers found that bromine, a noxious gas, was actually incorporated by enzymatic processes into organic molecules in the ocean, largely as molecules that provided defense. Finally, by the 1980s, thanks to several drug discoveries, it was becoming clear that the ocean was indeed an important biomedical resource. By the end of that decade, says Fenical, the pharmaceutical industry began to make some investments in the field, mainly by collaboration. Fenical points to growing support, for instance from the National Institutes of Health, which recently awarded his lab a major marine biotechnology training grant, as a sign that recognition for the importance of marine natural products is now growing. "I'm happy after some 30 years or more that now we're really looking at a resource that's understood, appreciated and being developed at a rapid pace," he says.

- VIDEO CLIP 4: "Marine Natural Products Research, Then and Now"

Success Stories

One of Fenical's earliest successes was the discovery and development, along with Bob Jacobs of a group of unique anti-inflammatory agents called the pseudopterosins, which were isolated from the soft coral Pseudopterogorgia. Though still in development as a topical pharmaceutical product, the pseudopterosins were licensed by the Estee Lauder company, which developed a series of popular skin care products based on them called Resilience. Production of the products requires collection of the coral from the wild, a fact that initially caused dismay among some environmentalists, Fenical says. However, once he and his colleagues had the opportunity to explain the collection process, the work was used as an example of how conservation-sensitive new products could be developed from coral reefs. Rather than destroying the whole coral, the collections involve pruning or "feathering" about 80% of the corals, leaving a viable branchlet on the reef that, like a plant, regenerates, often to a more luxurious state than prior to pruning.

More recently, Fenical's lab group has developed two potential cancer treatments from compounds produced by marine microorganisms. The first, called Halimide, was isolated from a microorganism that lives on marine algae. It is a fast-acting anti-cancer agent with the unique property of entering into a tumor's blood vessels and causing them to collapse, therefore removing the blood flow and causing the tumor to die within a few minutes. A second product, called Salinosporamide A, is proving more potent than most anti-cancer agents on the market, Fenical says. It targets a small bundle of enzymes in the middle of cancer cells called the proteosome and inhibits their function dramatically, even at sub-nanomaolar levels of compound. Salinosporamide A is a product of a newly discovered genus of microorganisms called Salinospora, that live in the deep ocean sediments. Both these products are licensed to and being developed by a small San Diego biotechnology company called Nereus Pharmaceuticals, which Fenical helped to found and currently consults for. A key focus of Nereus is the identification of drug candidates derived from marine microbes. These lead products are expected to reach clinical trials soon.

- VIDEO CLIP 5: "Development of the Pseusopterosins, Halamides, and Salinosporamide A"

Near-Fatal China Expedition

Having traveled the world in search of marine natural products, Fenical has been involved in a number of tricky situations, but none so memorable as one that occurred on an expedition to China. He and colleagues had been invited to collect samples there in the early '80s, long before anything resembling free scientific exchange between the U.S. and China had been established. There were no hotels, so upon arrival in Beijing, they had to stay at rooms in the Communist party headquarters. They worked from Hainan Island, which at the time was almost completely isolated and unknown but would in 2001 become the focus of international attention as the landing site of a U.S. surveillance plane damaged during a collision with a Chinese jetfighter.

While collecting algae samples working from Chinese fishing boats not far offshore, Fenical recalls hearing an enormous explosion and his ears ringing. He and his dive buddy looked at each other in confusion but neither knew what had happened. They thought perhaps something had happened to their scuba equipment but could find no problems, so they surfaced. About 50 yards away, another part of the team was working from a separate boat. Fenical and his buddy soon learned that Chinese fisherman using dynamite, a relatively common practice in some parts of the world for stunning fish for collection, had dropped dynamite near two of the divers. At the time Fenical surfaced, both were laying unconscious on the bottom. One of the wounded divers woke up and had the presence of mind to grab the mask that had blown off him, clear it, and find his regulator. He then grabbed his still unconscious partner and took him to the surface and got him breathing again. The team took them quickly to the island, but the hospital there was extremely primitive and lacked the medicine or expertise to treat the divers' injuries.

The most critically wounded diver had only 10-15% of his lung function and the team knew it had to get him to better facilities in Hong Kong, some 300 miles away. Because of the nature of the injuries, an embolism was a serious concern and so the team felt they could not fly the diver out on an airplane because the altitude change could cause problems. So, they instead set about finding a way to get him off the island by helicopter, which proved an exceedingly complex task. As "luck" would have it, there was a pair of military helicopters on the island and a pilot there offered to do the flight, but for days made excuses why they would have to postpone departure. Finally, the team realized that the helicopters were not even functional but instead simply painted nicely to give the appearance of military capabilities.

Finally, with help from the British Embassy in Beijing, the researchers made arrangements with a British Petroleum exploration team working nearby to come get the diver in its huge jet helicopter. Nothing like the sophisticated craft had ever been seen on the isolated island, so thousands of residents met it at the airport to see the spectacle. Fenical and his team had a difficult time just getting the injured diver to the helicopter through the crowd, but clearing the crowd for takeoff proved impossible. The pilot had to simply start the engine, whose blast knocked quite a few villagers down, but no one was injured. The drastic measures proved justified as the diver, treated in Hong Kong by a doctor trained in Belfast who specialized in bomb blast victims, completely recovered.

Education

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