TORTUGUERO NATIONAL PARK, Costa Rica – Carlos Bettancurt cuts the motor and we glide soundlessly toward the bank of the Parismina lagoon, part of the vast network of rivers and canals that crisscross this wildlife sanctuary.

Doused liberally with DEET to ward off mosquitoes and swathed in hats, longsleeved shirts and pants, we step ashore and follow Carlos, a trained Costa Rican naturalist-guide, along the path that he originally hacked out of this steamy jungle six years ago.

We are hunting on this sweltering January afternoon, not for the elusive jaguar or for the huge crocodiles we spotted earlier along the riverbank, but for something both less dangerous and potentially far more valuable – medicinal plants, which grow in abundance in rainforests all over the world.

Most of what Carlos knows about jungle medicine he learned from his grandmother, who is in her 90s now and unable to accompany us. As we alternately take notes and swat bugs, Carlos shows us a platanilla plant, which, when made into a tea, is said to induce abortions. He points out a type of sour cane that, when chewed, is supposed to help with liver and lung problems. And a broom tree, parts of which are said to stop bleeding.

So, why haven’t the big pharmaceutical companies been able to find medicines in the jungle as easily as Carlos? Despite the seeming promise of”bioprospecting” for drugs in rainforests, professional drug hunters have reported no blockbuster drugs after 10 years of looking. Merck & Co. even terminated its landmark bioprospecting contract with Costa Rica in 1999 after producing no commercially viable products – though the company says it’s still analyzing samples.

The difficulties are somewhat ironic, in light of the fact that human beings have always used natural products as medicine, and 80 percent of people in developing countries still do. Chimpanzees and other animals, too, eat certain types of foliage when they’re sick that they wouldn’t ordinarily eat as food, noted tropical ecologist Dan Janzen of the University of Pennsylvania.

Indeed, about 50 percent of all human pharmaceuticals in use today – from simple aspirin to powerful cancer chemotherapy drugs such as vincristine and Taxol – originally came from natural sources.

But modern “bioprospecting” in rainforests, coral reefs, deserts and other exotic locales has been slow going so far. It’s partly because modern drug development is such a costly, plodding process, often taking a decade or more to complete testing and regulatory approvals before the first prescription is written.

But the rainforest fizzle also may reflect unrealistic expectations about companies’ abilities to turn the folk remedies of people such as Carlos’ grandmother into the safe, reliable medicines that Western consumers expect.

Bioprospecting took off in earnest in 1991 amid great hopes when Merck entered into an agreement with Costa Rica’s National Biodiversity Institute, a private, nonprofit group that had been co-founded in the late1980s by Janzen. Under that novel agreement, Merck gained access to some plants, fungi and environmental samples from Costa Rica’s protected rainforests, and the Costa Ricans got the right to royalties if any marketed drugs resulted.

The romantic ideal of bioprospecting gained more steam in 1992, when 177 nations (although not the United States) ratified the Biodiversity Convention, an agreement that outlined ways for rich nations hunting for medicinal gold to share the wealth with cash-poor, plant-rich nations; and just as important, preserve natural habitats and indigenous populations in the process.

The need to protect such habitats was – and still is – acute, said Katy Moran, executive director of The Healing Forest Conservancy, a nonprofit group based in Washington. The equivalent of a football field of rainforest is lost every second  to industries such as logging, cattle raising, and oil and mineral extraction,  she said.

Bioprospecting has helped to preserve some of the land, said botanist Joshua Rosenthal, who heads the International Cooperative Biodiversity Group program, an effort started in 1993 at the National Institutes of Health to enable American scientists to work with other countries in bioprospecting ventures.

In Surinam, for instance, combined efforts by the US government, Bristol Myers-Squibb, conservationists and scientists from Virginia Polytechnic Institute and the Missouri Botanical Gardens helped the Surinam government set aside 4 million acres as the Central Surinam Reserve a year and a half ago, Rosenthal said.

The disappointing news, however, is that so far – and it really is too soon to judge – bioprospecting has yielded no major new drugs. Some are believed to be in the pipeline, but pharmaceutical companies remain close-mouthed.

“If they  get a lead, they won’t tell you,” Janzen said.  “They don’t want the competition to know what area they are looking in. 

The industry trade group, Pharmaceutical Research and Manufacturers of America, has acknowledged that companies may be reticent to talk about bioprospecting in part because they don’t want to be perceived as stealing the flora or the intellectual property of indigenous people. But the lack of publicized results also reflects the fact that companies are putting more effort into high-tech drug discovery using genomics to design drugs from scratch  rather than combing nature for medicine.

In comparison to lab-based genetic research, bioprospecting is a hit-or-miss proposition fraught with obstacles, as biologist Steven King, chief operating officer of Shaman Pharmaceuticals in South San Francisco, can attest.

Shaman Pharmaceuticals started up in 1989, armed with a short list of a dozen promising medical plants that company officials knew grew in specific regions, such as the  northwest Amazon basin in South America. One plant in particular, which contained a molecule the Shaman scientists dubbed SP303, seemed to be highly effective against diarrhea, just as indigenous healers had said it was.

Encouraged by the US Food and Drug Administration to do the research that could get this extract approved quickly as a prescription drug, the company launched human studies, including one on 400 patients at 25 US medical centers. The results were encouraging, King said, but apparently not quite good enough. The FDA demanded another study, but Shaman didn’t have the $15 million to $20 million to do it.

The result? Shaman is now reorganizing in the face of bankruptcy and has decided to market its once-promising prescription drug as a dietary supplement, for which prior FDA approval is not necessary. The product is now sold in health  food stores, under the rather drab name, NSF, for normal stool formula. The good news for Shaman, King said, is that the food supplement seems to combat not just traveler’s diarrhea, but irritable bowel syndrome as well.

Despite such bumps in the road, there is still considerable optimism that bioprospecting will yield new pharmaceuticals because of the sheer numbers of plant species in the world, many of which are as genetically complex as humans.

“Plants contain enormous numbers of genes and, if you multiply the number of  species times the genes, the number is huge,” said biochemist Malcolm Morville, who runs Worcester-based Phytera Inc., a biotech company.

“Plants can’t move,” he said, which means the only way plants can adapt to threatening changes in their environment is by turning on or off certain genes. “That’s why plants are of interest because, genetically and chemically, they’re some of the most sophisticated species on Earth.” Sponges and some other marine organisms use the same defenses.

“Nature produces many wonderful molecules for various reasons as a form of chemical defense,” said Gordon Cragg, chief of the natural products branch at the National Cancer Institute, which has been testing extracts from nature as potential cancer-killing agents for 45 years.

“You comb through nature, collect a whole range of plants, marine organisms and microorganisms, and then test extracts of these substances to see if they kill cancer cells in the test tube. The extracts often are mixtures of hundreds or thousands of chemicals. You have to try to isolate the one or two chemicals that are responsible for killing cancer cells.”

This, not surprisingly, can be a long and tedious process, and one that may seem far removed from the muggy, buggy reality of a Costa Rican rainforest.

But it is a path well worth pursuing, said Mark Plotkin, a Tufts University-trained ethnobotanist who now heads the Amazon Conservation Team, a Virginia-based group dedicated to protecting biological and cultural diversity.

“Western medicine is the most successful, sophisticated method of healing ever devised, but it doesn’t have all the answers,” he said. “Rainforest shamans claim they can cure – not just treat, but cure – some of the things we can’t. Doesn’t it make sense to go ask these guys what they have?”

SIDEBAR: Some Drugs From Nature Show Promise

Although drug researchers haven’t hit the jackpot, they are developing some promising medicines from plants, insects, marine organisms, soil bacteria and other natural products.

Researchers from Abbott Laboratories are now conducting trials in human volunteers of a painkiller called ABT-594, which the company believes is about 50 times better than morphine in relieving both chronic and acute pain, yet is not addictive. Abbott scientists had already synthesized ABT-594 for other uses when they learned that John Daly of the National Institutes of Health already had discovered the powerful painkiller in the skin of a tiny Ecuadoran tree frog.

An Argentine soil microorganism has already been turned into an approved drug that fights antibiotic-resistant bacteria, Syncercid. And Neurex Corp. is working on a painkiller made from cone snails that live in tropical oceans.

Meanwhile, esearchers at Arizona State University have begun human testing for a cancer-fighting drug, bryostatin, made from a marine weed that grows off the California coast. The researchers also see anti-cancer promise in a blue-green algae found near Guam, and have begun safety testing of a drug derived from it.

Finally, a Malaysian plant may produce a potential drug to combat AIDS, called calanolide A, which is now in human testing.

For more information, a good source is  “Medicine Quest” by Mark J. Plotkin (Penguin Putnam Inc. New York) or check out www.amazonteam.org.

Consumers Believe Soy Is Good Food, And Research Shows They’re Partly Right.

Americans have fallen in love with the humble soybean. Convinced that in its many incarnations – tofu, soy milk, dietary supplements – soy can prevent everything from heart disease to hot flashes to cancer, consumers have sent soy sales soaring.

In the 12 months ending in October 1999, supermarket sales of soy foods were up 45 percent over the previous year, to nearly $419 million, according to Spins, a San Francisco market research company.

But is soy really as beneficial as people believe and as some ads say?

The most solid evidence of soy’s benefit comes from studies of cholesterol. In October, the US Food and Drug Administration was convinced enough of its benefit to begin letting manufacturers put health claims on soy products indicating that soy may lower heart disease risk.

Some studies suggest soy can fight hot flashes and may lower the risk of breast and prostate cancer. But paradoxically, the very ingredients that make soy beneficial may endow it with risks.

Soybeans are legumes that are rich in plant estrogens, specifically, genistein and daidzein, which are substances known as isoflavones. Like the estrogens that humans make in their bodies or buy by prescription, phytoestrogens may drive cell proliferation – a red flag that means soy could theoretically spur cancer growth, particularly breast cancer, which is often driven by the hormone estrogen.

In general, because soy isoflavones are weak estrogens, they may be taken in by molecules known as estrogen receptors, possibly blocking the stronger estrogens made in the body.

In premenopausal women, this means that plant estrogens may protect against breast cancer by blocking a woman’s own, stronger estrogens; in postmenopausal women, who have less estrogen than younger women, adding plant estrogens to the diet could yield an overall increase in estrogen levels, a possible concern for women who have or may develop breast cancer.

So how do the plusses and minuses of soy stack up in all areas of health? Much of it depends on individual risk factors for various diseases. Here’s the latest data to go on:

Cholesterol. Overall, human and monkey studies suggest that soy reduces cholesterol 10 to 15 percent, a figure that reflects a grab-bag of studies on tofu, soy powder, extracts, and supplements. Specifically, soy lowers LDL or “bad” cholesterol, and countries where people eat a lot of soy tend to have lower heart disease rates, as well as lower cholesterol.

To get the beneficial effect of soy, a person has to eat at least four servings containing 6.25 milligrams of soy protein a day, as part of a diet low in saturated fat and cholesterol, the FDA noted.

In other words, soy provides “a definite, but modest reduction” in cholesterol, says Dr. Sherwood Gorbach, a professor of community health and medicine at Tufts University School of Medicine, who has also developed and patented a soy supplement called Healthy Woman.

Bone density. Here, the studies are mixed, with some showing a protective effect and others not. Some preliminary data suggest soy may restore bone loss, but this is not proved.

Hot flashes and other menopausal symptoms. Again, the data are mixed. Some data suggest soy reduces hot flashes by 40 to 50 percent, says Dr. Machelle Seibel, an endocrinologist at the Fertility Center of New England in Dedham and medical director of Inverness Medical, Inc., which makes SoyCare supplements.

But hot flashes often improve by 20 to 30 percent on placebo (or dummy drugs), too, he notes, adding that in some women, soy probably adds 20 to 30 percent to the benefit from any placebo.

On the other hand, Margo Woods, a Tufts nutritionist, has just completed a study of 85 women and found no difference between soy protein and placebo – both reduce hot flashes by about 25 percent, she says.

As for vaginal dryness, another common menopausal symptom, at least one study shows soy helps some women.

Prostate Cancer. Epidemiological studies from Asia suggest that men there are less likely than American men to get prostate cancer and die of it. One possible reason is that soy isoflavones may inhibit an enzyme that converts the hormone testosterone to its chemical cousin, dihydrotestosterone, which can spur prostate cell growth.

In a few case studies of men with prostate cancer, high doses of isoflavones seem to reduce the number of cancer cells, notes Seibel. So far, however, there’s no solid evidence for using soy to treat prostate cancer.

In fact, despite encouraging data from animal studies that suggest soy isoflavones also act as angiogenesis blockers (which stop blood vessel growth around tumors), so far, no company appears to have asked the FDA to approve a health claim for soy on the grounds that it may fight prostate – or any other – cancer.

Breast Cancer. This is the diciest area of all because some research suggests that soy prevents breast cancer, while other indicates that, at least theoretically, it could increase it.

On the one hand, strong epidemiological evidence from Singapore and elsewhere shows that Asian women have a three- to five-fold lower risk of breast cancer than American women, though whether this is due to eating soy is unclear. At the very least, it would seem to suggest that high, lifelong soy consumption lowers the risk of breast cancer risk.

In fact, Japanese women with breast cancer typically continue to eat soy as part of their diet – and their survival rates are better than those of American women with breast cancer.

Furthermore, research suggests that in postmenopausal women, the levels of estradiol, a natural estrogen made in the body, decrease while women take soy, suggesting that soy may be protective against breast cancer, says Woods of Tufts.

The mere suggestion that soy might increase breast cancer risk rankles some soy researchers, including Gorbach of Tufts. “That’s a ridiculous contention,” he says. “Everywhere in the world where soy is consumed, the amount of breast cancer is remarkably decreased.”

Still, in the interests of full disclosure, here’s another side of the story.

When human breast cancers are transplanted into mice who are then given varying doses of isoflavones, strange things happen, says Tufts biochemist Barry Goldin. At high doses, the plant estrogens inhibit the growth of human breast cancer cells, while at lower doses, they may enhance it.

At the University of California in San Francisco, Dr. Nicholas Petrakis, an emeritus professor of preventive medicine and epidemiology, has also studied American women given soy and found some had an increase in the number of hyperplastic, or potentially precancerous, breast cells as well. This does not prove that soy raises the risk of breast cancer, he cautions, but it does suggest that soy probably has a “stimulatory estrogenic effect.”

Also troubling is a 1998 study of nearly 50 premenopausal women published in the American Journal of Clinical Nutrition. The women were randomly assigned to continue their normal diets or to add 60 grams a day of soy supplements (containing 45 milligrams of isoflavones) for 14 days. Those who added soy had a greater increase in proliferation of breast cells.

Bobbie Hayes , a nurse in the menopause consultation service of Harvard Vanguard Medical Associates, puts it this way: “We don’t feel [soy] is completely benign.” It may be that soy is protective in Asian women who consume it all their lives, she says, but not for American women who start taking large doses at menopause to combat hot flashes.

At the National Cancer Institute, Dr. Peter Greenwald, director of the division of cancer prevention, adds that women who take soy are “taking an estrogenic compound. We know estrogens promote breast cancer and cell proliferation. So there is a theoretical risk.”

Unfortunately, he adds, so far “we have no evidence” from clinical trials on either “the benefits or the harm of soy. If women are taking it to combat hot flashes, I would not see a problem with short-term use – a year or six months.. . .I think the longer you go, the less sure we are without studies.”

Bill Helferich, a professor of nutrition at the University of Illinois, shares that concern. If given early in life, he says, isoflavones can cause breast tissue to differentiate, just as estrogen does – a good thing because the more differentiated breast cells are, the less likely they are to become cancerous.

On the other hand, if taken later in life, when tiny tumors may already be starting to grow, plant estrogens may cause those tumors to grow faster, he says.

Of particular concern, Helferich says, is women who take the prescription drug tamoxifen to prevent breast cancer but who want to switch to soy. That makes no sense, he says, because tamoxifen is a proven way to reduce cancer risk and soy is not.

So what’s the bottom line in terms of breast cancer? Given that nobody has proved that soy reduces or raises breast cancer risk, much less that the supplements have the same risk-benefit profile as soy food, the prudent course might be for women to make decisions about soy just as carefully as they would about prescription estrogen. Among other things, that might mean talking to your doctor about taking soy for a limited period of time to combat hot flashes, then stopping.

And what about food versus supplements? Alas, once again, there are no good data, but Woods, the Tufts nutritionist, says that “people should increase their consumption of soy as a food,” she says. “It’s better than hamburger or fried chicken.”

Most of the data showing a benefit to soy come from studies of food, not pills. “We have no data on what happens when you take phytoestrogens as supplements. . . I think taking supplements is too big a leap from the data on food.”

If you want to add soy to your diet, try adding about three ounces of tofu or its equivalent a day, which will give you 45 milligrams of soy phytoestrogens, the amount that’s believed to be beneficial to the heart.

If you prefer supplements instead, you should aim for about 45 to 55 mg a day. And it may be best to break this into two doses, one in the morning, one at night.

Here’s how we tested some of the leading brands of St. John’s wort, the popular herbal antidepressant.

We went to a CVS store in Cambridge, Mass., and bought the following products: CVS’ house brand; Natrol; NatureMade; Nature’s Resource; Quanterra; and YourLife. In addition, we obtained a bottle of Herbalife, which is sold privately through distributors.

We placed several pills of each brand in two sets of unmarked, identical-looking bottles and coded each brand. The CVS brand, for instance, became BG-001 (for Boston Globe), Herbalife became BG-002, etc.

We then sent one set of coded samples to an herbal testing company in Ithaca, N.Y. called Paracelsian, Inc. and hired it to do biological assays. The goal was to see whether each product worked – as judged by its ability to block the “reuptake” (or absorption) of both serotonin and dopamine, two neurotransmitters involved in depression, in rat brain cells in a test tube.

We sent the other samples to a testing company called PhytoChem Technologies, Inc. in Chelmsford, Mass., and hired it to do a chemical analysis of each of the products. The goal was to see if the products had as much hypericin, an ingredient in St. John’s wort, as the labels indicated.

In addition, unbeknownst to either company, we included an eighth set of pills in each set, placebos, or “dummy” pills, supplied to us by the Massachusetts College of Pharmacy. This was a way of testing the tests – a placebo should not pass the biological assay (and it didn’t) nor should it have a chemical profile like that of real St. John’s wort products (and again, it didn’t.)

After we got the results, we analyzed them with the help of independent scientists, including Paul S. Blum, a neuroscientist in Cambridge, Mass., who helps drug companies develop new drugs, and Timothy Maher, director of pharmaceutical sciences at Massachusetts College of Pharmacy.

We also discussed our results with the manufacturers of all the products we studied and herbal industry spokespeople.

Details of the testing methods: In the biological analysis, Paracelsian compared each product to Prozac and Zoloft (prescription antidepressants known as selective serotonin reuptake inhibitors) and to a “reference” herbal product, the Perika brand of St. John’s wort, which has been shown to inhibit the reuptake of the neurotransmitters serotonin and dopamine in rat studies, and to reduce mild to moderate depression in some people.

Prozac and Zoloft work by blocking the reuptake into brain cells of serotonin, and to a lesser extent, by blocking dopamine as well. Paracelsian’s assumption was that if St. John’s wort works, it may act by this same mechanism, that is, blocking neurotransmitter reuptake.

The Paracelsian scientists took cells from rats’ brains and put them in a test tube with a sample of St. John’s wort. They then added serotonin and calculated how much was left in the test tube after several minutes. The more that is left in the test tube, the better the antidepressant effect.

The Paracelsian team then repeated this for dopamine.

In the chemical analysis, PhytoChem did two tests on each sample – a spectrophotometric assay (called DAC 1991) and HPLC, or high performance liquid chromatography.

In the first, PhytoChem passed light through each sample.

Because scientists know what wavelengths of light hypericin absorbs, they can calculate how much hypericin is in a product – the more light absorbed, the more hypericin the product contains. For each sample, PhytoChem did this test twice and then averaged the results. PhytoChem also compared each result to the amount of light absorbed by a known control substance.

In the second test, the HPLC, PhytoChem injected each sample into a stainless steel column packed with silica (like powdered glass or sand). The silica was then treated with a special surface coating. The individual substances in St. John’s wort were then separated based on how well they stuck to this coating.

As individual compounds are separated out and leave the column, they can be detected by the absorption of light. The resulting pattern of peaks exiting the column at particular times and different intensities of light absorption produce a “chromatogram” – essentially a “fingerprint” of the constituents of a particular plant. The “fingerprint” of St. John’s wort is clearly different from that of, say, ginseng.

(We used only the first type of chemical testing, the spectrophotometric method, to gauge the amount of hypericin in each product. We did not use the HPLC test results to calculate hypericin; we used it only in a qualitative sense. It showed that all of our sample products except the placebo had the typical St. John’s wort fingerprint.)

Strengths of our study: We used two different companies for biological and chemical testing and independent consultants to help analyze the results. We blinded the testing companies to the identity of the products. We also did not tell them we had submitted placebos. And we bought the products as any consumer might – in a popular drug store.

Drawbacks of our study: Our study was not a clinical trial in humans, we did not re-confirm our results with other testing companies, and we did not test all available brands, including two major products, Kira and Movana.

The Paracelsian assay may not test the correct mechanism for St. John’s wort. While some scientists think St. John’s wort works by blocking serotonin reuptake, others are unconvinced. That means some samples that flunked the Paracelsian test might pass a test based on another mode of action.

The PhytoChem analysis isn’t perfect, either. It tested our samples for hypericin, which scientists used to think was the active ingredient in St. John’s wort. Now, some scientists think the active ingredient may be a chemical called hyperforin.

Still, hypericin is the ingredient manufacturers use to standardize products and it’s the one that’s touted on the labels.