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Reported by Nick Zagorski
November 17, 2004

The lush tropical rainforests and colorful coral reefs of our planet have long been a source of promise in the fight against cancer and other diseases. Even today, these regions, though shrinking rapidly, remain a mystery. They house an amazing biodiversity of microbial, plant and animal life which produces a dizzying array of protective chemicals, such as the toxins secreted by tree frogs, cone snails, and the plant Ricinus communis, source of the deadly ricin. And somewhere under that forest canopy or coral bed, one or more species in that mass may produce the next great cancer drug. But what is the best way to find it?

Since 1960, the Natural Products Branch (NPB), a branch of the Developmental Therapeutics Program of the National Cancer Institute (NCI), has devoted itself to finding these chemicals by setting up a repository of plant and animal samples from around the world. The NCI Natural Products Repository currently houses some 170,000 extracts from samples of over 70,000 plant and 10,000 marine organisms collected from over 25 countries, as well as over 30,000 extracts of diverse bacteria and fungi. This repository is being considered as a source of novel compounds to add to the 500,000 compounds envisaged for the NIH Roadmap Molecular Library.

After over 40 years of screening these extracts, a critical arsenal of important cancer drugs has been developed. The fleet is led by the flagship drug Taxol®, which is used for the treatment of several cancers, notably breast and ovarian, and includes other FDA- approved drugs such as: the camptothecin analogs, topotecan and irinotecan, vinblastine and vincristine, and the microbial-derived anthracyclines such as doxorubicin and the bleomycins. Several other promising compounds also are currently being tested in clinical trials against cancer and AIDS. Overall, though, these samples haven't produced the cornucopia of efficacious anti-cancer agents that many would have hoped for.

Gordon Cragg, D. Phil., chief of the NPB, notes that the quest for therapeutic natural products can be akin to "looking for a needle in a haystack." "In the first group of extracts studied from 1960 to 1982 that gave us two anti-cancer agents, Taxol and camptothecin, over 114,000 extracts were investigated." Cragg says part of the problem with plant collections is that the sources for many of these natural products reside in developing countries, where, historically, cancer has not been a health issue. "If we were looking for an anti-malarial agent or treatments for other diseases affecting the local populations, we could use the knowledge of local healers to guide the collections, but for cancer we pretty much just grab any species we can find, and cover a broad taxonomic range."

Still, Cragg points out that over 60 percent of the current anticancer drugs are derived in one way or another from natural sources, and, thus far, natural products chemistry has proved superior to that of de novo combinatorial chemistry. Also, with NCI maintaining an open repository, its samples are free to be studied by other researchers for the treatment of any human disease, subject to a Material Transfer Agreement protecting the rights of the countries of origin. And with about 90 percent of the tropical and marine species still untapped, there continues to be optimism that a new anti-cancer agent is around the corner.

However, natural products research needs to turn over a new leaf; continued collection, extraction, and screening of natural samples is not enough in this changing world. Collecting animal and plant samples remains a costly and time-consuming process, and as the ecosystems housing these species continue to disappear and thousands of potential novel chemicals are never tested, the collection becomes a race against time. All the while, many drug-resistant cancers and microbial pathogens have emerged as a result of the ongoing drug therapies, so new drug discovery remains critical.

Science is becoming increasingly interdisciplinary, and natural products research is shifting that way as well. Natural products chemistry increasingly collaborates with synthetic chemistry, and vice versa, which works to the strengths of both fields. "Nature made these molecules for a reason," says Cragg, "and no matter how good chemists are, they couldn't ever dream these molecules up. But if they use the natural compound as a template, then they could rationally tweak it to try to improve it." The cholesterol lowering drug Lipitor®, a synthetically modified version of a fungal-derived chemical, is one such success story.

Cragg also believes that examining combinations of products, as often done in cancer chemotherapy, is also worth expanding; in nature, the organisms regularly use a variety of chemical defenses, often involving structural variations of the same basic chemotype. "Of course," he says, "The advocates of traditional medicine we encounter have been telling us this all along. They ask: 'why are you wasting time separating individual compounds out? Everyone knows you need the whole extract'." Indeed, herbal remedies for many illnesses have become a big business. However, Cragg is concerned about quality of production and care. "When you isolate a pure chemical, you know what you've got," he says. However, with crude extracts, the exact chemical content is unknown, so different samples will contain varying proportions of active constituents, and will not work the same way. "Even in the same forest," says Cragg, "two trees of the same species a few hundred yards apart can vary widely in their chemical content."

One important shift may be locating new sources. Tropical plants were initially the focus of natural product searches; starting in the 1990s, the focus moved more towards marine organisms. Now, the newest area to study is the rich population of microorganisms from extreme environments, especially bacteria and fungi. With their rapid genetic adaptability, microorganisms have developed unique biochemistries and can be found in every possible environment: hot springs, deep-sea vents, even in the frozen tundra. And while human impact has destroyed much of the plant and animal ecosystems, humanity has actually created novel habitats for many microorganisms. "Novel bacteria can be found at the bottom of a polluted lake, or even in the middle of a toxic waste dump," notes Cragg. There are already several effective bacteria-derived anticancer agents, and other microbial products are undergoing clinical trials in the United States and elsewhere. With less than one percent of microorganisms cultured and studied, this taxonomic kingdom holds even more potential than the plants and animals. And since microorganisms generally have such short life spans at ambient temperatures and consequently rapid genetic turnover, novel strains continuously emerge which may produce novel compounds.

Microorganisms hold other advantages as well. From a maintenance perspective, they are easier to store and work with in a laboratory. From a molecular biology perspective, they are even more advantageous. "Microbes are intriguing," says Cragg, "because their genes responsible for the synthesis of constituent active compounds are located together in clusters, the so-called biosynthetic gene clusters. So we can identify which genes are involved in producing each compound." Several research groups are trying to use this knowledge and mutate the synthesis genes, which cause the bacteria to make slightly different molecules. "In essence, the bacteria are doing the work of the combinatorial chemists," says Cragg.

Scientists also are exploring the possibility of inserting clusters of foreign genes involved in the synthesis of plant and animal natural products into bacteria, thus enabling the synthesis of useful molecules readily in the lab. This capability would ease the cost of acquiring raw materials and protecting habitats. This gets a bit trickier, though, since locating all of the genes involved in synthesizing compounds from higher organisms is more difficult.

Natural products research at the NCI has been robust for over 40 years, and numerous cancer patients have already benefited from some of the fruits of this labor. However, with hundreds of thousands of samples still waiting to be discovered and new technologies that can be used to enhance the discovery process, researchers are optimistic that examining new natural products will continue to turn up even more useful drugs to treat cancer.

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