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Vol. LX, No. 8
April 18, 2008
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STEP Forum Explores Natural Product Drug Discovery

On the front page...

Your cold capsule. Dad’s aspirin. Nana’s eye drops. We may take such therapies for granted, but safe and effective medications don’t grow on trees—or do they? In fact, their sources may. Since modern chemistry has not kept pace with the need to treat many illnesses, scientists are returning to nature as the inspiration for new drugs.

Mother Nature is making a comeback.

“The NIH has always played an important role in the discovery of drugs to improve public health,” moderator Chris Ketchum told the crowd in Natcher Conference Center, where a recent Staff Training in Extramural Programs (STEP) forum explored “Drug Discovery: Is Nature the Answer?”

Continued...


  Panel members include (from l) Dr. Alice Clark of the University of Mississippi, Dr. William Gerwick of the Scripps Institution of Oceanography at UC-San Diego and NCI’s Dr. Gordon Cragg.  
  Panel members include (from l) Dr. Alice Clark of the University of Mississippi, Dr. William Gerwick of the Scripps Institution of Oceanography at UC-San Diego and NCI’s Dr. Gordon Cragg.  

Ketchum welcomed panelists Dr. Alice Clark of the University of Mississippi, Dr. William Gerwick of the Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences at UC-San Diego, Dr. Peter Lipsky of NIAMS and NCI’s Dr. Gordon Cragg. Together they tackled the scientific, technical, ethical, legal and economic aspects of bringing a natural product from discovery to market.

In a comprehensive overview, Clark led with definitions (see sidebar) and likened natural product (NP) drug discovery to navigating a maze. Challenges include shortages in bulk supply; multiple compounds must be teased apart in “bioassay directed fractionation”; and the eternal question—funding. Her timeline of the odyssey from discovery through clinical trials and finally to market “looks very nice and linear,” she cautioned, but the process is intricate and the tab runs high.

“To get a single chemical entity ready for a human clinical trial,” she said, “costs $750 million to $1 billion and takes from 10 to 15 years.” She called for getting more NPs into the pipeline both as potential treatments and “as probes for exploring cell biology.”

Are there computer algorithms for isolating NP compounds? No, Clark said. Nonetheless, the scientific process demands that compounds be isolated and tested singly. “That’s the heart of natural product work.”

Gerwick told tales of “bio-prospecting from the field”—in this case, the ocean.

“It’s a great time to be a natural products chemist,” he said, touting marine microorganisms as “very rich.”

Lyngbya bouillonii is among the cyanobacteria, or blue-green algae, harvested as a possible source of new drug therapies. The “snapping shrimp” is one of the characters in the saga of natural products used in drug discovery.

Top, l:
Lyngbya bouillonii is among the cyanobacteria, or blue-green algae, harvested as a possible source of new drug therapies.

Top, r:
The “snapping shrimp” is one of the characters in the saga of natural products used in drug discovery.

Consider the sponge. Not the rectangular store-bought kind, but the sea sponge, a primitive invertebrate. These squishy critters are the source of many promising leads for the treatment of cancer and other diseases; a small colonial ocean creature called a bryozoan yields the source for bryostatin, now under investigation as an anti-cancer agent.

Dr. Peter Lipsky said natural products have a rich history in medicine.
Dr. Peter Lipsky said natural products have a rich history in medicine.

“Another stunning discovery,” said Gerwick, “is the sea hare, a marine mollusk that feeds on cyanobacteria [blue-green algae].” These ancient inhabitants of diverse ecosystems possess “a virtuosic ability to create molecules” and yielded the dolastatins, several of which show promise as potential anticancer drugs. They are the Earth’s oldest natural products chemists. However, there is growing evidence that, in both of these cases as well as many more, the actual producers of these potentially useful medicines are bacteria, including cyanobacteria that live in association with, or are eaten by, marine invertebrates.

“The point,” he continued, “is that these are giving us fundamentally new chemotypes,” some of which have “fantastic biological activity.” Along with his team, Gerwick’s mission is to find, retrieve, preserve and analyze these samples— assuming the scientists can evade saltwater crocodiles in murky mangrove water.

It’s not just the level of basic supply, he said, where things get complicated. When an NP has unusual structural features, how do you characterize the genes involved in its biosynthetic pathway and their encoded enzymes? “There are lots of problems,” he says, “but it’s exciting.”

NIAMS’s Dr. Peter Lipsky observed that, when introducing NPs to the bedside, he saw in his colleagues a “prejudice difficult to overcome, especially in clinical settings.” Yet “surveys show that between two-thirds to three-quarters of our patients take natural products...[which can generate] an ‘us-versus-them’ mentality.” His talk worked to bridge that gap.

Natural Product vs. Drug

A natural product is an organic compound, one produced by a living organism, probably to improve its chances of survival. For example, a flower’s vivid color and aroma attract pollinating insects. By legislation, some botanicals are categorized as dietary supplements, not drugs.Intended as dietary supplements, they cannot legally make “drug claims.”

A drug, according to the FDA, is an article to be used in the diagnosis, cure, mitigation, treatment or prevention of disease.

In rheumatology, “there’s a rich history of borrowing drugs from every area,” he said, “and some of the ones that get used come from natural products.” That history continues with the thunder god vine (in Chinese, lei gong teng).

The vine, which can reach almost 40 feet, produces white flowers and red fruit with three “wings.” The leaves, flowers and outer skin of the root are poisonous, but the root pulp is used medicinally and has a centuries-old history in Chinese herbal medicine.

“The Chinese use it to treat fever, lupus, rheumatoid arthritis, worms and inflammation,” said Lipsky. But there are problems: “No quality control. No two [samples] are the same and there are few controlled studies. No mechanistic studies to see how it works. Yet [the Chinese] have enormous clinical experience suggesting that something [therapeutic] is going on.”

He tackled those problems both logistically and scientifically, and for the first time lei gong teng’s anti-inflammatory actions and active components were investigated and summarized according to Western standards.

Lipsky shepherded the drug through phase 2a/2b clinical trials, but “we needed a stable source for phase 3. Going to China got problematic.” Rutgers University experts developed a way to grow the vine hydroponically in greenhouses, then to clone it for high production. And now, Lipsky said, “We believe the FDA may approve.” Thunder god vine holds significant promise.

NCI’s Cragg, former chief of the Natural Products Branch in the Developmental Therapeutics Program, brought historical, legal and ethical aspects to bear on the question of NP drug discovery.

“We need to recognize the contributions of traditional knowledge,” he said. “This can be abused; we’ve got to be aware of that.” For example, turmeric, long used in Ayurvedic medicine in wound-healing, became U.S. patent 5,401,504 until the Indian government filed, and won, a challenge on the grounds that the patent lacked novelty.

“Researchers should be aware of traditional knowledge associated with their products,” Cragg stressed, “and respect [intellectual property rights].” He pointed out how the U.N. Convention on Biological Diversity, with 150 signatories, “was never ratified by the U.S. Senate...yet because it covers conservation, sustainable use and equitable sharing of benefits, it stands as an important international treaty.

“We must share with the host countries,” he stressed, “because they do the conservation.”

And they have sovereignty over their own biological resources. Cragg and NCI’s Dr. David Newman worked with colleagues at the NCI Technology Transfer Center to develop the NCI Letter of Intent, later to become Letters of Collection, as well as memoranda of understanding and tech transfer agreements for benefit-sharing; these serve in basic and commercial research agreements.

NCI has also invited scientists from 65 source countries to visit NCI-Frederick and hosted scientists from 22 countries for training and collaboration. The exchange is a fruitful one.

“NCI helped get the cancer cell line screening program involving NP drug discovery going at the Federal University of Ceara in Fortaleza, Brazil...the university collaborates with many centers in Brazil, where there is great biodiversity,” Cragg reported. “It takes high ethical standards and a lot of good will and trust.”

In the panel discussion, Lipsky chimed in on the global note: “The advances made in drug discovery are unavailable to 90 percent of the world’s population,” he said. “The opportunity to develop botanical extracts, besides providing for us, could also offer high quality drugs for the rest of the world. We have a moral obligation to pursue that.” NIHRecord Icon

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