A Bitter Pill
The modern medicine chest is packed with stories of lifesaving drugs ingeniously drawn from unlikely species. So why haven’t drug companies—or conservationists— been able to cash in on nature’s pharmacy?
By Richard Conniff
Twenty years ago this past October, environmentalists around the world celebrated a landmark deal between a major drug company, Merck, and Costa Rica’s National Biodiversity Institute, INBio. Until then, the standard practice had been for drug companies to collect biological specimens anywhere they wanted, ship them home to study, and (if they were very lucky) develop one or two of them into miracle drugs—all without the source country ever being aware of it. But instead, Merck was now paying $1.1 million up front for bioprospecting rights and promising a royalty from any drugs that resulted.
For environmentalists, the best part of the deal was that a share of any payment would go to protect the habitat itself. The rest of the world was furiously demolishing forests and wetlands, converting them to short-term cash crops like soybeans, hamburgers, and shrimp. But suddenly, a Fortune 500 company was putting money behind the idea that nature intact might have a higher value. One economic analysis even put a number on it: bioprospecting for drugs would increase the value of some habitats by more than $3,600 an acre.
Other economists warned the added value was likely to be no more than $25, but the dream of earning “green gold” by tapping “the mother lode in Mother Nature” quickly spread worldwide. In Rio de Janeiro in June 1992, the Convention on Biological Diversity for the first time recognized the need to preserve a multitude of habitats and species as a matter of both international law and the good of humanity. It also stipulated that a fair share of the benefits should go to the countries where this diversity flourishes. It seemed like the beginning of a new era in drug discovery, international development, and habitat preservation alike.
It was also too good to be true. In 2008, Merck quietly abandoned its search for new drugs from the natural world, shifting its attention to synthetic compounds and vaccines instead. Then last year, as if to mark the anniversary of its Costa Rican folly, the company gave away its entire library of natural compounds—100,000 extracts representing 60 percent of all known plant genera, ready to be screened for the next big miracle drug. And it wasn’t just Merck: Pfizer, Eli Lilly, Bristol-Myers Squibb, and most other Big Pharma companies have also abandoned the direct search for drugs from the natural world. “We lived under the assumption that the rainforest was full of medicinally useful compounds like vincristine,” says James Miller, vice president for science at the New York Botanical Garden. Derived from a plant in Madagascar, the rosy periwinkle, that drug had turned leukemia and lymphoma into survivable diseases. “And nobody found the next vincristine.”
Miller holds out hope that drugs from the natural world may yet have their day. But bioprospecting since the Merck deal has so far failed to produce a single new blockbuster drug. Instead of the widely anticipated golden age of drug discovery, new drug approvals over the past decade have sunk to a 25-year low. Nor has any major drug contributed revenues to the preservation of the habitat from which it was originally derived. On the contrary the Convention on International Trade in Endangered Species says 64 plant species are currently threatened by overharvesting for medicinal uses.
What went wrong? The track record for green medicines had previously been almost miraculous. Though neither doctors nor patients generally realize it, about half the drugs they depend on come directly or indirectly from the natural world. The list starts with aspirin (now produced synthetically but first found in the bark of the willow tree) and includes all the antibiotics, almost all the anticancer drugs, and many of the leading cardiovascular medicines, among others.
The medicine chest is packed with stories of the most unlikely species transformed ingeniously into lifesavers. Gila monster saliva, for instance, might seem to be worth less than spit. But a hormone in the saliva has become the model for a drug used to treat type 2 diabetes, an epidemic disease that now afflicts 26 million Americans (with another 79 million considered prediabetic). Cone snails deep in the Indo-Pacific prey on fish by jabbing them with a venom toxic enough to kill a person. But a compound in that venom is now a painkiller that’s 1,000 times more effective than morphine, without being addictive.
At times the list of past discoveries from the natural world can seem like a one-upmanship contest, with each new product even more improbable than the one before. The basis for the entire class of cholesterol-lowering drugs called statins? A fungus from an orange peel. The standard tool for testing the purity of high-tech medical devices? An extract from the blood of horseshoe crabs. The key ingredient in every DNA cloning and sequencing procedure in the world? A bacterium fished out of the mud at a hot spring in Yellowstone National Park (which, like other habitats, has not shared in the profits).
One possible reason the discovery process has stumbled lately is that government agencies (including the U.S. National Park Service) have become far more aggressive about negotiating access and benefit-sharing terms with researchers. Particularly in the developing world, these negotiations tend to be shaped by resentment over past “biopiracy” and by uncertainty about fair market value for access to genetic resources. So each new negotiation starts from scratch and can entail months or even years of “significant legal and travel expense, all before a single collection is made,” says Miller. The uncertainty of these negotiations “may be more of an impediment to pharmaceutical companies,” he suggests, “than the actual commitment to share potential profits.”
Horror stories abound, Miller notes. In the late 1980s, a U.S. National Cancer Institute team was working in the West African nation of Cameroon on a compound that looked like the cure for AIDS. “This was a plant that was still eating research dollars at an enormous rate, it wasn’t making any money, and, man, the Cameroonians were all wanting to buy themselves new Mercedes.” Though the researchers had an access agreement with one government ministry, “about five other ministries stood up and said, ‘Oh you should have signed that with us.’” Then they bickered. Even if the compound had proved to be the cure (it turned out to be too toxic), “I’m not sure we would have been able to work on it,” says Miller, “because the Cameroonians put such tight clamps on it.”
But drug companies also botched their bioprospecting efforts through a combination of financial and technological hubris, critics say. The financial side is a familiar story of senior executives focusing on quarterly growth at the expense of science. Getting a new drug to market, says John C. Vederas, a medicinal chemist at the University of Alberta, “requires a lot of creativity and intellectual input and study and time and money”—on average, ten years and $1 billion worth of research. Boosting revenues by buying up other large drug companies can look like a quicker way to keep Wall Street happy. And with each round of consolidation, company leaders “basically lay off employees, close research and development units that have a long record of being successful, and buy technologies that look promising from smaller companies.”
Beginning in the late 1980s, big drug companies also increasingly diverted their research dollars from natural products to combinatorial chemistry and high-throughput screening. That is, they turned to automated methods to bang out large libraries of closely related synthetic compounds. Then they sorted out the biologically active ones by running these compounds through a device the size of a hardcover book, with 1,536 little plastic wells, each containing a different bioassay. It’s a “brute-force method,” says Vederas, and can take a million tries to produce one promising lead. But the numbers may still seem to work because automation makes those million tries relatively cheap.
Natural products didn’t fit the new technology. A plant sample—even something as basic as coffee or tea—may contain thousands of compounds. In the lab, chemists “fractionated” plant samples, breaking them down into crude extracts. But they still ended up with hundreds of compounds in each of their 1,536 test wells. “This is where the wheels fell off of this thing,” says Paul Armond, a plant cell biologist who spent 30 years in drug development at Pfizer. “High-throughput screeners hated these samples. They didn’t want to have anything to do with them because even if you got a hit in one of these fractionated samples, you didn’t know which of the hundred compounds in the test well was the active one.” A high-throughput screener’s job is to test as many compounds and get as many hits as possible, and natural compounds just seemed to clog the pipeline.
Even if they managed to isolate an active compound from a plant, says Armond, “it would be, from the organic chemist’s point of view, some ugly compound, this big, giant molecule that no chemist could ever possibly synthesize. They’d say, ‘What am I supposed to do with this?’” When a compound seems promising, the usual next step is to “add things to it, take things away, rearrange things, and find where the important parts of the molecule are and where the not-so-important parts are.” Through the magic of combinatorial chemistry, researchers can target the molecule more carefully or weed out unwanted side effects. But if a compound from a natural product is too complex to synthesize in the first place, “then you can’t do any of those things.”
One final obstacle made natural products problematic: getting enough of the desired compound can be difficult because living things normally vary by season or site—and sometimes disappear completely. It happened to another NCI research team in the late 1980s. When they got a promising hit for an anti-HIV compound from a tree in Sarawak, Malaysia, researchers hurried back to collect more samples. But someone had cut down the only known tree. After a frantic search, the only other evidence of the species they could find was a 100-year-old specimen in the Singapore Botanical Garden. Chemists eventually figured out how to synthesize the compound, and Calanolide A is now an experimental treatment for HIV patients.
By contrast, products of combinatorial chemistry are wonderfully simple. That may, however, be their only advantage. The combinatorial compound libraries researchers worked with in the early years were so badly flawed, according to Christopher Lipinski, a drug development guru who spent most of his career at Pfizer, that the industry would have been more productive if it had “stored them in giant dumpsters.” Even now, after tens of billions of dollars and 25 years of research, combinatorial chemistry and high-throughput screening have put only a single completely new FDA-approved compound into the marketplace. The new methodologies can thus seem a bit like the drunk who searches for his keys under a lamp post, not because that’s where he dropped them, but because the light is better there.
So where does all this leave drug research from the natural world? Miller, Vederas, and a few small drug companies remain surprisingly optimistic. That’s partly because the resource, though rapidly dwindling, is still out there waiting to be studied. Miller estimates that medical researchers have tested only about 60,000 of the 400,000 or so plant species on Earth, and most of those against only a handful of diseases. Extrapolating from the past success rate, he estimates that the plant species still waiting to be studied may contain upwards of 500 new botanical drugs.
Moreover, new technologies are making it easier to find them, according to Vederas. Automated fractionation can now rapidly break down botanical specimens, thinning out the natural complexity to just three compounds per test well for high-throughput screening. New techniques are also making it easier for researchers to clone and work with individual genes in a plant. At the University of California at Berkeley, for instance, Jay Keasling’s laboratory has recently overcome obstacles to transferring plant genes into bacteria and fungi for synthetic production of the highly effective antimalarial artemisinin from the sweet wormwood plant.
At the same time, many of the remarkable biochemical functions attributed to plants and animals are turning out to come not from the organism itself but from the bacteria and other microbes around it. Instead of having to plant fields or cut down forests to get medicinal compounds, drug companies may soon be able to have these microbes brew them for us in fermentation vats. Such improvements could lead to what Miller calls a “second renaissance” in natural-products drug development. Ethnobotanist Mark Plotkin, an early proponent of bioprospecting, adds, “Just because capitalism doesn’t get something right, doesn’t mean it’s not there. We know that well these days. You need to look everywhere, but I think the sweet spot lies somewhere between the medicine man and the microchip.”
This is not to say that blockbuster billion-dollar-a-year drugs are ever going to produce a steady flow of cash for habitat preservation. Big drug discoveries “are few and far between,” says agricultural and resource economist George Frisvold at the University of Arizona, “and there’s a long lag” from discovery to marketplace stardom. Banking on that income is like staking your future on your kid’s chances of becoming the most valuable player in the NBA. For instance, taxol, originally discovered in 1961 in the bark of a Pacific yew tree in Washington State, now earns $1.7 billion a year and saves the lives of thousands of women with breast, ovarian, and other cancers. If Washington officials back then had somehow negotiated a one-percent royalty agreement, they might now be cashing a check for $17 million a year. But it took 30 years for the drug to reach the marketplace, and it often looked as if it might never get there at all. Meanwhile, would the distant chance that this might happen at some unknown time in the future have motivated the state to protect a single extra acre of habitat or to shut down part of its lucrative logging industry?
Governments everywhere “are continuously going to face all kinds of current pressures to convert the land,” says Frisvold, and the only thing likely to outweigh those pressures is some other “immediate tangible benefit.” Bioprospecting deals might add up to such a tangible benefit—but only if also combined with ecotourism, sale of green products, and fees for carbon storage, flood control, or other services natural habitats provide. Frisvold believes conservationists would get better results by working to attack the pressures to convert the land—by fighting subsidies that encourage deforestation and by pushing land reform so small farmers have a means to feed their families other than by hacking fields out of the forest.
That is, conservation is always going to be hard, slow work—and, more often than not, with a major headache at the end of the day. You can take two aspirin—or the latest miracle drug—and go to bed. But don’t expect everything to be better in the morning. ❧
–Richard Conniff’s articles have appeared in Time, Smithsonian, The Atlantic, The New York Times Magazine, National Geographic, and other publications. He is the author of many books, including The Natural History of the Rich, Spineless Wonders, and Swimming with Piranhas at Feeding Time. His latest book is The Species Seekers, published by W. W. Norton & Company, Inc. in 2011.
Art by David Cutter