Nature's brew

In any other place, Eric Irvin would not have been too concerned about the cut on his leg. But he was trekking deep inside a remote Peruvian rain forest in the shadow of the Andes Mountains.

Even minor cuts can be dangerous in a rain forest where high humidity keeps wounds from properly healing.

Nothing I tried seemed to help," Irvin said.

Irvin was there as one of the organizers of the Amazon Healthcare Expedition, a continuing-education program sponsored the University of Washington's Schools of Medicine, Nursing and Pharmacy. They were there to teach participants about the medicinal and nutritional properties of rain forest plants and how they might advance the prevention and treatment of disease.

The kit of treatments the team had brought along for the expedition earlier this year weren't working for Irvin's cut, so one of the guides suggested that he try using the sap from the local dragon's blood tree. It was a homespun remedy that had been used for centuries. Irvin was curious and decided to try it.

He applied the sap. The wound healed perfectly.

Irvin's experience is but one example of why there's renewed vigor in the search for potential drugs in the natural world. Researchers are traveling to the ends of the earth in their quest for new natural compounds that have healing properties, sometimes in unlikely places.

One major area of focus is cancer. Scientists in Atlanta recently announced they had found a natural compound made from magnolia tree cones that appear to block a pathway for cancer growth. And Fred Hutchinson Cancer Research Center's Dr. Jim Olson, whose lab is perfecting scorpion venom as a cancer-fighting tool, is traveling with other researchers to Australia next year to search for similar compounds among that country's notoriously dangerous critters.

Olson and many other scientists know they're not breaking new ground — man has been using natural remedies to treat illness from the very beginnings of civilization — but with newer technology, they're more likely to find compounds that work.

The organized, systematic research into the use of natural compounds as we know it today began in the 1950s and 60s. By 1971, President Nixon had declared a war on cancer with the National Cancer Act. Almost immediately, cancer research increased across all sectors, including research into compounds derived from natural sources.

Dr. Jim A. Duke was one of the early leaders in the field. As the former director of the United States Department of Agriculture Medicinal Plant Resources Laboratory, he conducted research into crop diversification and medicinal plant utilization and later worked in Colombia and Panama.

"We felt we were getting close to some breakthroughs and had done some fantastic work, but the program ended," Duke said.

Though the war on cancer was started with the same enthusiasm that drove the moon landing, the momentum couldn't be maintained in the declining economy and corresponding policy changes of the late 1970s and early 1980s. Federal research into medicinal plants was shut down in 1982, and cancer treatment research shifted to the development of synthetic compounds. But in the background, advancements continued to be made on natural compounds, and Duke was certain that interest would return.

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A tree bark breakthrough

Early in the 1960s, a USDA-funded botanist collected bark from a Pacific yew conifer near Packwood, Wash. Over the next 20 years, researchers found that the yew's bark contained a compound with cancer-fighting properties. The compound, originally known as Taxol, entered the pharmacological net and advanced through mice screening and into clinical trials. A 1988 phase 2 trial demonstrated effectiveness against melanoma and ovarian cancer.

It was not an easy journey. Public concern, expressed through the media, was that natural cures were archaic; researchers were accused of primitivism. There were ecological concerns as well, with fears that the commercialization of Taxol would cause the extinction of the Pacific yew, a rare, extremely slow-growing native conifer.

Slowly, over time, the compound, now known as Pacilitaxel, became widely used as an effective treatment. It's also synthesized now instead of being taken from the Pacific yew.

"It was a landmark event," Duke said. "People were now aware that natural compounds could work. The search was on again."

Duke has traveled across the globe in search of plants and foods that have medicinal properties; he has written about his discoveries and is currently working on a book about Amazonian herbs with particularly good health benefits. He believes there is a simple reason for the effectiveness of using natural compounds as the basis for treatments.

"Every biological organism on Earth evolved from the same base compounds," Duke said. "So my genes will recognize the compounds in naturally derived pharmacological agents and accept them. But my genes can't begin to know synthetic compounds."

The result, according to Duke, is treatments with fewer side effects and negative reactions than synthetically derived compounds.

Seeking cures in unlikely places

Olson, a member of the Clinical Research Division at the Hutchinson Center, also sees tremendous potential in natural agents.

"The diversity that comes from plants and animals is much greater than we have been able to generate in a laboratory. And through evolution, some of these molecules have been optimized and have excellent bio-distribution properties," Olson said. "Optimization that might take years of research in a laboratory has already been accomplished by hundreds of thousands of years of natural evolution."

As a researcher and a clinician who treats brain-cancer patients at Children's Hospital & Regional Medical Center, Olson has learned to trust the properties of natural compounds. But while other researchers have scoured the world for plants that hold curative properties, Olson is searching anti-carcinogens in creatures that bite back because the study of natural toxins and venoms holds a great deal of potential.

He points out that synthetic agents have not had much success in passing through the blood-brain barrier. Many natural neurotoxins, however, pass through easily. Species such as the cone snail have developed venoms that stay in the bloodstream long enough to pass the blood-brain barrier.

"I'll be looking for cone snails, spiders and scorpions; anything we can find with powerful neurotoxins," Olson said about his trip to Australia. "Then, I'll be looking at ways to modify those compounds so we can use them for imaging certain populations of neuro-cells in the brain. I believe that this will ultimately be helpful in studying neurodegenerative diseases and delivering therapeutic treatments."

Olson's lab already has developed a process to identify brain cancer cells with diagnostic imaging by using chlorotoxin (a small protein) from scorpion venom and a substance known as Cy5.5, which has fluorescent properties. When they are bound together and injected into a mouse, the compound nicknamed "tumor paint" attaches itself to cancer cells and lights them up so that they are seen by diagnostic imaging technology.

The compound is remarkably precise in its ability to define the margins between cancer cells and normal brain cells, much more so than magnetic resonance imaging. Olson's lab also found that the compound lit up other cancers. They're now awaiting permission to conduct clinical trials.

"This whole idea stems from the fact that these natural compounds have evolved in nature to get into the brain and affect neurons," Olson said. "They have surpassed the capabilities of what most pharmaceutical companies can do."

For Olson, the importance of finding effective natural compounds is frequently brought home in his clinical work.

"Every day, I go over to Children's Hospital and use Vincristine, a chemotherapy drug derived from the periwinkle plant. That treatment is helping keep kids alive," he said.

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Nature doesn't yield its secrets easily

It's not always easy to identify effective natural compounds. Even when they are located, it can take decades to bring them to market; Pacilitaxel took nearly 30 years from discovery to commercialization.

And for every compound like Etoposide, an effective chemotherapy drug derived from the American mayapple, many more compounds turn out to be ineffective for medicinal use.

Some natural compounds, though effective, may not be suitable for commercialization. The dragon's blood sap that Irvin used on his cut has long been known to have curative properties, but attempts to commercialize it have failed.

"The complexity of natural compounds is often a challenge," said Dr. Julian Simon, of the Hutchinson Center's Clinical Research Division. "That complexity makes it hard to change or tweak a natural compound if it does not quite reach the desired effect."

In synthetic compounds, a formula can be altered during the research and trial process. Natural compounds have proven to be less adaptable.

"So often in the use of natural compounds — it either works or it doesn't," Simon said. "In a synthetic compound, we can adjust; this is not true of most natural compounds. The match has to be nearly exact."

The other challenge is location.

"In the lab, you can create what you need," Simon said. "In nature, you have to go out and find it."

But the pursuit is well worth it, Duke said.

"Every time I visit the Amazon rain forest, I'm struck by the diversity," Duke said. "In 1982, we did a study that showed that it has the greatest biologic diversity on the planet."

Duke said the greatest challenge in finding effective natural compounds is locating new species. He points out that there are perhaps 5,000 chemicals in each species and nearly 98,000 species on the planet. That's a lot of chemicals to find and study. Obviously, the more you investigate, the better the odds of finding something new.

That's why he worries about protecting the planet's biological diversity, afraid that new species might be destroyed before they are ever discovered.

"There is still so much to find; we can't risk losing new species or destroying known ones," he said.

Potential cures, near and far

North of downtown Seattle, a small park meanders along two of the city's neighborhoods. Just off the main pathway, in a shaded area, there's a small Pacific yew, its scraggly limbs covered in moss. Farther along is a small patch of periwinkle.

There are cures and treatments all around us, in plain sight and hidden from view. Today, a new generation of researchers is attempting to unlock nature's secrets.

They know it won't be easy to identify the next new compound, a novel cure, and they know they'll have to step out of their labs to find it.