ROSY PERIWINKLE, native to Madagascar, has yielded compounds used to treat Hodgkin's disease and leukemia.

From the plant-choked jungles of Malaysia to the coral reefs of the Caribbean, scientists are combing the planet for cures to our most intractable maladies. Such bioprospecting is tedious workon average only one in thousands of natural compounds tested shows pharmaceutical promise, and only a handful of those ever make it to market. Yet despite the high risk of failure, researchers press on, driven by the realization that with millions of years of experience under her belt, Nature is the ultimate chemist.

Indeed, nearly half of all human pharmaceuticals now in use were originally derived from natural sources. Perhaps the most famous example is aspirin, which evolved from a compound found in the bark and leaves of the willow tree and was later marketed by Bayer starting in 1899. Some 50 years later, scientists identified anticancer compounds in the rosy periwinkle (right), which pharmaceutical heavyweight Eli Lilly subsequently produced for the treatment of leukemia and Hodgkins disease. Other well-known examples include the cancer-fighting Taxol, isolated from the Pacific yew tree, and Aggrastat, an anticoagulant based on the venom of the saw-scaled viper from Africa.

Today many other compounds taken from Nature's medicine cabinet are showing promise (see sidebar). And with thousands of species as yet untapped for their chemical potions, it's tempting to compare bioprospectors to the proverbial kids in a candy store. But in fact, those sweet rewards sometimes come at tremendous cost. Researchers are increasingly finding themselves at odds with traditional healers in many parts of the world, who have long made use of plants and animals to treat various ailments, and with Nature herself, who does not typically part with anything without ecological consequences.

That there is a need for new drugs to combat AIDS, Alzheimer's and other ailments, however, goes without saying. In addition, researchers are under mounting pressure to find compounds to replace those that have become less effective. With bacterial resistance on the rise, for example, the world desperately needs new antibiotics. The same holds true for cancer drugs, which can lose their potency in a patient over time. And Nature may still be the best place to hunt for such lifesaving compounds.

Finding the Needle in the Haystack

With about 10 million species inhabiting the earth, how do scientists determine which ones contain potential panaceas? In many cases they are screening randomlya process that yields on average one useful drug for every 20,000 samples analyzed. But other researchers employ a different strategy, consulting indigenous people when possible. According to Conservation International, studies have shown that plants identified by locals are in fact up to 60 percent more likely to have pharmaceutical potential than their randomly collected counterparts.

Recently plants and sessile or slow-moving marine invertebrates such as sponges, corals and sea slugs have attracted particular attention because for these organisms, running away from a predator is not an option. Instead they have chemical defenses. And with a little tweaking, the potent toxins they produceas well as those manufactured by certain poisonous snakes, frogs and land invertebratescan actually save lives.

DRUGS FROM PLANTS. Many drugs in use today have their basis in wild plants. A selection of these are shown here.

Of course, targeting a promising compound is only the first step. Before developing a drug from it, a renewable resource for the compound has to be established. This task poses an enormous barrier. Because these compounds often come from rare or slow-growing organisms, or are produced in minute quantities, harvesting the source organisms in sufficient amounts may be unrealistic.

To address this problem, researchers usually try to make synthetic derivatives. But sometimes synthesis proves impossible, or uneconomical, as in the case of Ecteinascidin-743, an anticancer compound currently in clinical trials that comes from a creature called a sea squirt. Scientists from CalBioMarine Technologies in Carlsbad, Calif., have developed a method of culturing the animal, going so far as creating an artificial version of the mangrove roots it settles on in the wild. In other cases, simply culturing cells from the source organism is sufficient.

Once developed, these drugs, as with all proposed pharmaceuticals, must pass a battery of rigorous test that evaluate their safety and efficacy in animals and then humans. This step, too, can take its toll, especially on start-up companies. Take, for example, the case of Shaman Pharmaceuticals, a once-promising company armed with a product poised to treat people suffering from chronic diarrhea. Their drug, Provirderived from the sap of croton, a common Amazonian treedid so well in two years of clinical trials that the FDA granted it fast-track status, requiring only one final Phase III trial instead of two. When the FDA later decided to demand a second Phase III trial, though, Shaman couldn't afford it. Today the company sells dietary supplements.

Bioprospecting or Biopiracy?

In addition to the difficulties posed by the research itself, the scientists and pharmaceutical companies hunting for natural miracle drugs face critical ethical dilemmas. In Brazil, for example, officials have expressed concern over the possibility that the scientific demand for plant samples has led to plant smuggling. And indigenous groups around the world worry that in the race to patent Nature's million-dollar molecules, science is stealing their intellectual property.

Indeed, according to a report that appeared earlier this year in the Atlanta Journal and Constitution, even a project that aimed to share future profits with the native peopleMayans in Mexico's Chiapas statehas floundered, owing to disagreements over who owns the plants, folk knowledge and commercial rights to whatever drugs might result from the collaboration.

Other efforts to ensure these often poorer nations benefit from visits from bioprospectors have had happier outcomes. In South America's Suriname, for instance, Bristol Myers-Squibb, scientists and conservationists from the Missouri Botanical Gardens, the Virginia Polytechnic Institute and Conservation International helped to establish a four-million-acre reserve. Conservation International has also been active in helping the governments of Madagascar and Indonesia to develop policies aimed at maintaining national sovereignty over their biological resources.

On the Horizon

Bioprospecting during the past decade has yet to turn up a blockbuster drug, but a number of naturally derived pharmaceuticals are being evaluated in human trials. These include compounds ranging from Immunokine, derived from the venom of the Thailand cobra, which may effectively combat multiple sclerosis, to calanolide A, an anti-HIV agent retrieved from a Malaysian plant. Ziconotide, a potent pain reliever extracted from the tropical marine cone snail, has come particularly far and is awaiting FDA approval. Once approved, Ziconotide will become the first marine-organism-based pharmaceutical.

In many cases, though, the environments in which potentially healing organisms live are being destroyed. Estimates place the number of species screened for their medicinal properties at a mere 1 percent, yet each year more than 30 million acres of tropical forest are lost. Human activity is taking its toll on the oceans, too, in the form of pollution and overfishing. Such large-scale destruction of our planet's complex ecosystems will no doubt come back to haunt usif for no other reason than the fact that with every species lost, Mother Nature is taking potentially lifesaving chemical formulas to the grave.