Nature's Drugs

Swimmers in the coral reefs of the Philippines know to stay away from Conus magus. The sea snail may be small--just a few inches long--but it's deadly mean. One dose of its venom can paralyze the passing fish that make up its diet. To drugmakers, though, the potency of its toxin is sheer poetry. Scientists who recently broke down the poison discovered--and copied exactly--a chemical compound that blocked nerve cells from sending signals to the brain. Result: Prialt, a new painkilling drug 1,000 times more powerful than morphine, the most potent analgesic now available to medicine.

That marks one more triumph for mankind's ingenuity, and a comeback for Nature as well. The development of Prialt, which reached the market earlier this year, neatly demonstrates the latest twist in our relationship with the global ecosystem. As the flow of new drugs down the research pipeline slows to a trickle, pharmaceutical companies are turning again to the natural world for inspiration. Researchers now talk of promising new drugs derived from a vast range of living organisms--everything from Brazilian snakes to Hawaiian mollusks. "The industry is in crisis," says Graham Dutfield, an authority on the bioprospecting business at Queen Mary College in London. "The companies are throwing masses of money at research but just not getting the returns. That's why they are looking at different options."

Blame the vanity of science. Back in the 1980s, the industry's smartest brains reckoned that a purely technological approach--so-called combinatorial chemistry--could replace trial-and-error or the well-informed hunch as the primary source of new products. Machines would mechanically mix and match the basic building blocks of chemistry, throwing up tens of thousands of variations that could be tested automatically for their therapeutic potential. "The big companies just plugged away at screening large libraries of compounds," says Ian Paterson, a chemistry professor at Cambridge University who recently coauthored a new paper on the renaissance of natural products. "The idea was that if you bought enough lottery tickets one would give you a billion-dollar drug." Not so. Even today, it's tough to predict how a wholly artificial product will react with the real flesh-and-blood world. The number of new drugs approved by the U.S. Food and Drug Administration fell from 53 in 1996 to just 23 last year.

Nature, aided by evolution, may often be just as efficient in turning up leads. Living organisms have spent eternity learning to cope and compete with one another, developing structures that are often hugely complex and potent. "Nature has done about 3 billion years of work for you," says Chris Molloy, business-development manager at Singapore-based MerLion, a leading company in the field, which maintains a "library" of 100,000 strains of microorganisms and 38,000 plant samples. "The genome of natural products doesn't waste time in producing molecules that don't interact with biological systems." Big business now takes the point. MerLion has struck partnership deals with several of the world's biggest pharmaceutical companies, including Merck and Schering-Plough.

For older researchers, of course, it's a return to familiar territory. About half of the products in today's medicine chest originated in nature, including some of the top performers. Aspirin was originally synthesized from willow bark, known to reduce fever for more than 2,000 years. The breast-cancer drug Taxol was cribbed from the bark of the Pacific yew. But in the past the sheer complexity of nature's formulas meant they were hard to analyze in the lab, let alone reproduce in drugs for the mass market.

No longer. Scientists have refined a battery of techniques for breaking down some of the trickiest compounds. Think only of the rapid advances in chromatography, the technique for unscrambling mixtures by watching the rate at which the different compounds can travel. "In the last 10 years, the equipment we have at our fingertips has increased many thousandfold in its sensitivity," says Jon-Paul Bingham, a biochemist at Clarkson University in the United States. Gene research is also providing scientists with insights into the composition of millions of organisms, allowing them to isolate whatever may be valuable in a future drug. Says Lars Ekman, research boss at Elan Pharmaceuticals, the company behind Prialt: "The scientific community is at last at a point where we can start to understand the action mechanism of naturally occurring drugs."

At the same time, researchers have a better idea of what targets to aim at. It's now increasingly possible, for example, to identify the exact point in the human system where a newly identified compound can work its magic. Find the trigger for the disease, and it's easier to disarm. Prialt, for example, was found to head straight for one of the several channels in the spinal cord which takes pain impulses to the brain.

These days drug companies are beginning to use natural products as templates, tweaking them to create synthetic compounds. If nature provides the inspiration, it's almost always possible to enhance a compound's effectiveness in the lab. (Don't think about using actual extracts from a plant or creature for your wonder product: environmentalists shudder at the thought of plundering rare species.) At the Eisai Research Institute in Massachusetts, for example, scientists have created a modified version of a compound called Halichondrin B, derived from a New Zealand deep-sea sponge, which is proving an impressive performer against human tumors in clinical trials. For its part, Bristol-Myers Squibb is now testing a drug called Ixabepilone, a modified version of a bacterium found in garden soil, in patients with advanced breast cancer. Novartis has several anticancer agents derived from nature in its pipeline. And at Wyeth, Rapamune, isolated from Easter Island soil and used to prevent kidney rejection after transplants, is one of the company's fastest-growing drugs. Says Chris Shaw, professor of drug discovery at Queen's University Belfast, "What we are seeing now is just the tip of the iceberg."

A dark cloud in this trend is that pollution, global warming and other human-induced changes threaten biodiversity--and with it a treasure trove of potential new drugs. So far scientists have identified and given Latin names to 1.7 million species, but it's reckoned the final number could be at least 10 times as high. "What we are finding now is that we are only just scratching the surface of biodiversity," says Ben Shen, professor of Pharmaceutical Sciences at Wisconsin-Madison University. "The question now is whether we can access it before it's too late." Its venom may be strong, but the sea snail still needs defending.