Miércoles 27 de Julio de 2005, Ip nº 119

Pharmacy Island
Por Claudia Kalb

Danley Pearson left his job as a machinist in utter agony two decades ago. Sixteen-hour days of hauling and lifting submarine and airplane parts had battered Pearson's back. He had two herniated discs, sciatica and enough pain to fill a 767. Over the years, Pearson, of Arrowhead Villas, Calif., tried muscle relaxants, injections and a slew of pain relievers, but the torment persisted, and the drugs' side effects—constipation, dry mouth, sexual dysfunction—made every day a misery. "I couldn't lead a normal life," he says. Then a little snail changed everything.

In 2000, just when he was ready to give up on finding relief, Pearson's doctor told him about a clinical trial for a new drug called ziconotide (brand name: Prialt). The drug, given through a pump implanted in Pearson's abdomen, had two unique characteristics: it was 1,000 times stronger than morphine and was derived from an unusual source—a beautiful but deadly cone snail found in the Indian and Pacific Oceans. The mollusk's venom, it turned out, was not only good at killing marine prey, it could also block pain signals in the human spinal cord. Pearson, 54, says he hopes he can stay on the drug forever. "I feel more normal now than I have in 20 years," he says. "I'm pretty much pain-free."

Modern medicine has made enormous strides in recent years, but brutal diseases like cancer, diabetes, heart disease and HIV still kill millions of people, and new treatments are desperately needed. In their quest for cures, researchers are trekking through forests and diving deep into oceans to collect nature's loot—from the jungles of Madagascar to the waters off Palau. As they docked near Miami in April, scientists from Harbor Branch Oceanographic Institution in Ft. Pierce, Fla., walked the decks of their boat, giddy with excitement. During a two-week expedition through the Florida Straits, their submarine had scooped up a cornucopia of 250 organisms, among them several intriguing new specimens: mysterious sponges with translucent tentacles, a sea fan adorned with unusual lumps. "I'd never seen anything like that," says Harbor Branch's Amy Wright.

Could one of these strange new organisms have medicinal powers, maybe one day leading to a breakthrough drug? Researchers at the National Cancer Institute's Natural Products Branch in Frederick, Md., are betting on that possibility. Since 1986, NCI has amassed close to 100,000 plant and marine samples from around the world. On a recent spring afternoon, NCI's David Newman opened one of 10 giant walk-in freezers, where shelves are stacked high with Ziploc bags and cloth sacks. Inside? A treasure trove of nature's creations: reddish orange coral, a dark green starfish, brown twigs. In a lab nearby, every sample will be crushed into a powder, then made into extracts to be tested against human cancer cells. The extracts are also part of a lending library of sorts, available to outside scientists for evaluation against other conditions, like viral diseases and infections. So far, some 4,000 extracts have shown "significant activity" in the NCI lab, deeming them worthy of further study. The odds of discovering a blockbuster in the freezer are exceedingly low, but, says Newman, "you never know what you're going to find."

Newman is especially excited about a compound called Halichondrin B, known among scientists by its nickname, "yellow slimy." In preliminary lab tests at NCI, Halichondrin B, derived from a New Zealand deep-sea sponge, obliterated human tumors. At the Eisai Research Institute in Andover, Mass., scientists created a modified synthetic version of the active component in Halichondrin B, dubbed E7389, which is now making its way through human clinical trials. It's still far too early to tell if E7389 will make it to market. But early data from 61 patients with a variety of solid tumors show "significant evidence of anticancer effect," says NCI's Dr. A. Dimitrios Colevas.

Over the course of pharmaceutical history, terra firma has offered a plethora of medicines. Aspirin comes from willow bark, penicillin from fungus, the cancer drug Taxol from the Pacific yew tree. Today, researchers are also turning to the vast and unexplored galaxies of the ocean. "There's literally a pharmaceutical gold mine there to investigate," says George Miljanich, of Elan Corp., Prialt's manufacturer. William Fenical, a pioneer in marine research at the Scripps Institution of Oceanography in La Jolla, Calif., has been hunting for microbes, the tiniest specks of life, in ocean sediment since 1990. He's hoping that two of his compounds, developed by a biotech company he cofounded called Nereus, will soon be tested in humans. In animal tests, one has shown activity against multiple myeloma, the other against breast cancer. "The potential of marine microbes is beyond any expectations I've ever had," says Fenical.

Despite the enthusiasm, cultivating drugs from nature is a long and unpredictable process. Aware of these challenges, many pharmaceutical companies put Mother Nature on the back burner in the 1990s, focusing instead on man-made compounds constructed from scratch in the lab. But today, even pharmaceutical execs admit that the approach has not lived up to its promise as a tool for drug design. With a limited number of medications in the pipeline, nature may be making something of a comeback. "The complexity and diversity of natural products can't be matched by even the most innovative human scientist," says Greg Vite, of Bristol-Myers Squibb. "I think we're going to see a resurgence of interest in natural products."

Today, drug companies use natural products as templates, tweaking them to create synthetic compounds, as Eisai did with Halichondrin B. Bristol-Myers 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 senior scientist Guy Carter.

Big Pharma has plenty to gain from a successful drug. But who reaps the rewards when the medication is derived from a far-off land? After a controversial past, the research world has become more sensitized to the rights of host countries. The development of a compound called prostratin is a prime example. In the mid-1980s, Paul Cox, of the Institute for Ethnomedicine, in Provo, Utah, learned about a tree bark in Samoa that local healers used to treat hepatitis. Cox shipped samples back to NCI, where lab tests found activity against HIV; today prostratin is in the final stages of animal testing by the AIDS Research Alliance in West Hollywood, Calif. Should the drug make it to the clinic, the Samoan people will receive 20 percent of any commercial profits. "My sense all along was that the knowledge I got from healers was intellectual property," says Cox.

And then there's the property of the earth. Responsible scientists know that conservation is a key piece of the medicinal treasure hunt. "We're very sensitive," says David Sherman, of the University of Michigan, who scours the oceans. "We only take what we absolutely need." At the University of California, Berkeley, chemical engineer Jay Keasling is seeking new ways to tackle the supply problem once an active compound has been isolated. Keasling has injected the genes from the antimalarial plant, artemisinin, into E. coli bacteria and yeast. These microbes, known for their ability to propagate, act as nature's own drugmaking factory. The goal, says Keasling: "You don't have to harvest the rain forest or the seafloor to get the products."

Any drug, whether it's derived from the sea or a test tube, comes at a price. Prialt can cause unsteadiness, dizziness and memory loss, and it costs about $19,000 per year. For Danley Pearson, however, the payoff is worth it. After decades of suffering, he's out walking his dog in the hills. Thousands of miles away from the Indo-Pacific snail, light-years ahead of his pain.

  26/07/2005. Newsweek Magazine.