From Nature, A Past And Future

Courtesy of William Fenical

SCOURING THE SEAS Fenical holds the "mud missile" aboard a boat.

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Natural Products, Anniversary

Courtesy of William Fenical

PAST AND PRESENT In a 1960s photo, Varro Tyler, ASP's first president, holds a flask containing a fungal culture.

Lloyd Library & Museum

PAST AND PRESENT Today, Fenical's team has coaxed several strains of deep-sea bacteria to grow in the lab.

On the open ocean, a small fishing boat bobs on the rolling waves. The team of scientists on board has set out from a remote atoll in Fiji, and they are out to find new chemistry in the inky Pacific depths. That takes some specialized tools, including a 6-foot-long metal probe with a precisely calibrated system of weights and small buoys, not to mention a lot of patience. Devised by William Fenical and a team of engineers at Scripps Institution of Oceanography, the probe is designed to plunge to the ocean floor, pick up a sediment sample, and then drop its weights and float back to the surface. Fenical has a variety of such devices, each with its own nickname-the "mud snapper," for example, or the "mud missile."

Fenical's coworker, microbiologist Paul Jensen, is aboard the boat, and he knows it can take nearly half an hour for the probe to descend to the bottom, plus more time to grab some mud and come back up. So the team keeps waiting. But that day, the device never resurfaces. It seemed to have gotten stuck somewhere, perhaps with never-before-seen molecules trapped inside.

Thousands of scientists worldwide embark on similar pursuits to find bioactive chemicals in nature. Those chemicals, called natural products, have the potential to unlock new chemistry and biology and to become new drugs. Promoting these scientists' work is the job of the American Society of Pharmacognosy, a leading professional society for natural products researchers. This year, ASP, as it's known to its nearly 1,200 members, is celebrating its golden anniversary. This summer, the society held its 50th annual meeting in Honolulu, attended by an all-time high of more than 650 researchers, including heads of seven of the world's natural-product-related professional societies.

Although ASP's overall mission of promoting science and fostering community has stayed the same, today's ASP is a different group from the 88 scientists present at the society's founding in 1959 at the University of Illinois, Chicago. A theme throughout ASP's history has been bringing new groups of researchers into the fold and, through their ideas and tools, moving the science forward. Fenical's mud missile missions to the ocean floor, which have led to two molecules now in clinical trials, are only one such innovation. Researchers who spoke with C&EN say it is critical that natural products researchers embrace new technologies and explore new environments to propel the field into its next 50 years.

When ASP was founded, penicillin, a compound from a mold, had already ushered the world into the antibiotics age, and scores of folk medicines had already been extracted from plants. ASP began as a society of academic researchers studying plant natural products. Over the years, researchers looking at marine organisms and terrestrial and marine microbes joined ASP, along with industry researchers and scientists who study nutraceuticals, which are foods and food-derived products believed to provide health benefits, and traditional medicines. Despite the growth, ASP retains a tight-knit-family dynamic, says Ben Shen, who studies natural product biosynthesis at the University of Wisconsin, Madison. "Every time I go to an ASP meeting, I come back pumped. I get excited about research all over again because of all the enthusiasm and support there," he says.

ASP's broadening in both research and member makeup is evident in the pages of the society's flagship journal, the Journal of Natural Products, says JNP Editor-in-Chief A. Douglas Kinghorn of Ohio State University College of Pharmacy.

Since its 59th volume in 1996, JNP has been copublished with the American Chemical Society, in the start of a fruitful relationship between ASP and ACS, Kinghorn says. The journal was once copublished with the Cincinnati-based Lloyd Library & Museum and was called Lloydia. ASP recently reestablished a relationship with the Lloyd Library, which now maintains the society's archives.

Even as ASP celebrates the past, its members are looking toward the future. ASP "is constantly trying to renew the scientific establishment's view of natural product research," says Guy Carter, assistant vice president for chemical and screening sciences at Wyeth Research and immediate past-president of ASP. For the Honolulu meeting, each speaker was asked to speculate about future directions, says meeting coorganizer Roy K. Okuda of San José State University. "We want to be prospective as well as retrospective," he says.

The future was also on the minds of natural products researchers, including several past-presidents of ASP, who gathered last April at the National Institutes of Health, in Bethesda, Md., for a symposium and workshop organized by John M. Schwab, a program director at the National Institute of General Medical Sciences, and chemical biologist Jon Clardy of Harvard Medical School. The group advocated melding natural product science with the latest tools of other fields, such as genomics, genetic engineering, bioinformatics, and synthesis (Nat. Chem. 2009, 1, 261).

Interdisciplinarity is key, Fenical says. Traditional methods of isolation and chemical structure determination alone are no longer enough to be innovative. "If you use the same old tools without innovative methods, you're going to make the same old discoveries," he says.

Fenical's oceangoing probes don't usually get lost. When a new glop of seafloor arrives at the lab, his coworkers optimize culture conditions for the microbes they find within and set about sequencing genomes, analyzing biosynthetic pathways, and more. "Today, we're not just finding out that a natural product has anticancer activity; we may know a new natural product's biological target in a matter of days," he says.

Genomic tools also reveal "hidden" natural products, says Bradley S. Moore of the University of California, San Diego, a collaborator of Fenical's who studies natural product biosynthesis. With the right context, genetic sequence information can help scientists determine whether an organism has dormant biosynthesis pathways and figure out a way to get those pathways working as efficiently as possible. Molecular biology tools can also help researchers reengineer biosynthesis pathways to quickly study natural product analogs, he says.

Molecular biology can also help researchers obtain more of a scarce natural product, Shen adds. "If we understand biosynthetic pathways at a genetic level, we can go beyond what we learn from understanding them at a chemical level alone. We can manipulate these pathways and optimize them," he says.

Other researchers are using ecology to tease out small molecules' natural contexts in their native environments. They are then using that information to determine a natural product's bioactivity while also looking for new systems to study. For example, Julia Kubanek, a chemical ecologist at Georgia Institute of Technology, exposes seaweeds and other marine organisms to predators in order to turn on chemical defense systems, which can also flip on hidden biosynthetic pathways. "We're trying to be smarter about how we discover new chemistry," she says.

Clardy also finds new chemistry by exploring ecology. In collaboration with ecologist Cameron R. Currie at the University of Wisconsin, Madison, he explores the symbiotic relationships between insects, bacteria, and fungi and has uncovered new natural products by delving into the strange bedfellows' chemical communication (C&EN, April 13, page 5). "What's special about natural products is that they have an evolutionary history-that they've been selected to do something in biology," he says. Whether or not their application in the human world relates to their native function, it's undeniable that many natural products have had great success as drugs, he says.

Natural products continue to provide new drug candidates. However, in the decades since ASP's founding, many large pharmaceutical companies have moved away from dedicating significant resources to basic research on natural products.

The shift has to do with a decrease in infectious disease research, historically a fruitful area for natural-product-based drugs, and an increase in high-throughput screening technologies, which aren't readily compatible with natural product purification and identification processes (Science 2009, 325, 161). Today, Wyeth is the only U.S.-based company with a major presence in the natural products area. Some non-U.S.-based firms, such as Novartis, continue to have a strong presence in natural products research. New business models in this area are still emerging and are likely to involve the burgeoning community of biotech companies.

In the short term, this shift is leading to concerns about employment for scientists in the natural products area, Schwab says. But the long-term outlook is bright because new natural product discovery strategies are revealing heretofore unknown families of molecules with the prospect of unprecedented bioactivities, he adds. This might lead to brand-new therapeutic modalities, he says.

"If you use the same old tools without innovative methods, you're going to make the same old discoveries."

Pharmaceuticals aside, natural products can make their mark in many areas, notes Jef K. De Brabander, a synthetic organic chemist at the University of Texas Southwestern Medical Center. For instance, some natural products make great biochemical tools. The natural product leptomycin is too toxic to be useful as a drug, but because it blocks the export of proteins from the cell's nucleus, it's invaluable for researchers who study that process, he explains.

Natural products can also play a role in conservation efforts, says Mark Hay, a chemical ecologist at Georgia Tech. Humans are dependent on natural systems for cleaning air and water supplies, but the impact of rising populations and increased consumption is compromising how these delicate ecosystems work. "The language for understanding and mediating those processes is written in chemistry, and an understanding of how natural products work in the real world gives us insights into how we might fix things," he says.

A critical part of ASP's future, and of the field's future, lies in training young scientists worldwide in cutting-edge technology and giving them the support they need to succeed, Fenical says. "The strength of any society is in its young people," Moore agrees.

ASP isn't alone in embracing this mission. Programs including the NIH-led and interagency-funded International Cooperative Biodiversity Groups Program, which partners U.S. natural product researchers with scientists abroad, are as well. The program has a strong training component-it helps bring scientific infrastructure and the latest techniques to the resource-rich locales where natural products come from.

For his part, Fenical tries to imbue his young colleagues with enthusiasm for natural products research. "I tell my students, 'You're the only person in the world who's seen this compound, and you can be proud that you've made this discovery,' " he says. "In a way, it might be how the early explorers felt when they found new land that wasn't even on the charts. Natural products can give you that feeling."

Some time after the fruitless Fiji trip, one of the University of the South Pacific's Fiji campuses fielded a phone call from a local fisherman. He offered to return an unusual catch from a recent excursion back to the campus. Someone had printed a contact phone number on it, likely with a permanent marker, Jensen recalls. He was happy to have the probe back, although this time, it didn't snag a useful sample. Maybe next time.