Shaman Loses Its Magic
Shaman Loses Its Magic
Shaman Loses Its Magic
Ethnobotany and Drug Discovery
Date: February 18, 1999
Source: "Shaman Loses Its Magic," The Economist, February 18, 1999.
About the Author: This article, published without attribution or byline, was written by a staff writer for the The Economist, a weekly London newspaper with a circulation of over one million readers worldwide, over half in the United States.
Fossil remains identified in northern Iraq reveal that the use of medicinal plants may date from the middle Paleolithic age some 60,000 years ago. Even today many significant drugs, including morphine, aspirin, and quinine are plant based. Still more come from other natural sources—many cholesterol-lowering drugs and antibiotics, for instance, are extracted from bacteria and fungi. In addition, natural products can often be chemically adapted to produce semisynthetic versions. In total, close to half of all drugs now in use come directly or indirectly from natural sources.
There are an estimated quarter-million plant species on earth, of which only around 6 percent have been investigated scientifically for their medicinal properties. An early approach to drug discovery—extracting useful medicines from plants—was English physician William Withering's extraction of the cardiac drug digitalis from the foxglove plant (Digitalis purpurea) in 1785. The following article describes how Shaman Pharmaceuticals, a company based in San Francisco, tried to bring modern science to ethnobotany, which studies a culture's botanical knowledge and use of local plants for food, medicine, clothing, and in religious ritual.
SHAMAN LOSES ITS MAGIC
IT WAS a tree-hugger's dream. Save the rainforests. Respect and honour the knowledge of the people who live there. And still make money for your shareholders. Unfortunately, it doesn't look as though it is going to work. Earlier this month, Shaman Pharmaceuticals, the leading proponent of the "ethnobotanical" approach to drug discovery—an attempt to identify the active molecules in folk remedies, in order to turn them into modern prescription medicines—threw in the towel.
Shaman's failure to convert old-wives' tales into drugs (though it is still pursuing the idea in the less rigorously regulated field of herbal dietary supplements) probably marks the end of the sort of selective "botanising " that started the pharmaceutical industry, when the pain-killing properties of willow bark led to the invention of aspirin. Merck, one of the world's biggest drug companies, spent ten years trying to extract and develop the active principles from Chinese herbal remedies. It failed too. Other firms are downgrading the role of traditional medicine when screening plants for useful substances. Instead, they prefer the automated mass-screening techniques originally developed to deal with the artificial products created in vast numbers by modern combinatorial chemistry.
It is a popular misconception, probably generated by such pharmaceutical celebrities as quinine, and fed by environmentalists keen to preserve rainforests, that those forests abound with billion-dollar blockbuster drugs just waiting to be discovered. The facts are different. Between 1960 and 1982, America's National Cancer Institute (NCI) and Department of Agriculture (DOA) collected 35,000 samples of roots, fruits, and bark from 12,000 species of plants. Only three significant products were discovered in them.
Taxol, Camptothecin, and homoharringtonine have all proved useful as anticancer drugs, but they do not suggest that the forests are teeming with pharmaceutical opportunities. And more recent collections by the NCI and DOA (gathered between 1986 and 1996 from South America) have been even more disappointing. As yet, not a single drug has emerged from them.
Shaman tried hard. It sent teams of physicians and botanists into the rainforests of more than 30 countries in Asia, Africa, and South America. They collaborated with local healers to identify plants with medicinal properties. And the firm abided by the standards laid down in the Convention on Biological Diversity signed in Rio de Janeiro in 1992. This sought to highlight the economic value of regions rich in species and ensure that local people benefited.
That meant that, in exchange for the knowledge it received, Shaman provided a payment of up to $8,000 (or the equivalent in goods and services) to the healer's community. It also promised long-term benefits if a drug was actually developed from one of the plants concerned.
But although short-circuiting the screening process by starting with medically proven plants may have looked a smart move ten years ago, screening technology has got better and better. It will soon be possible to check molecules for promising biological activity at a rate of 100,000 a day. It may look more elegant to ask the locals, but screening everything, regardless, is now faster and cheaper.
On top of that, the folk healers' concerns are not necessarily those of drug companies. The former are frequently preoccupied with curing parasitic infestations unknown in the rich countries that provide the companies with their markets. They are much less adept at diagnosing and treating diseases such as cancer, where the real money is to be made.
There are some areas of overlap, however. Shaman had seemed to be making good progress on type II diabetes (which is untreatable with insulin). Diabetes is a disease that is recognised in many cultures because sufferers, whose blood-sugar levels are out of control, tend to pass sugar-rich urine. By using ethnobotany to provide the raw materials, Shaman's researchers were able within four years to isolate 30 compounds that lowered blood-sugar levels enough to make them look promising as anti-diabetes drugs.
Whether any of those molecules would have made it through the regulatory process will probably never be known, but it was that process that eventually brought things to a halt. The drug in question, Provir, was actually intended as an antidiarrhoeal treatment (diarrhoea being another problem that the rich and poor worlds share).
Provir was particularly designed for AIDS patients. That did not save it. When the Food and Drug Administration, which approves medicinal drugs in America, told Shaman it would have to conduct a further series of clinical trials on the stuff, it gave up. The trials would have delayed things by 18 months, and cost tens of millions of dollars that the company could not afford.
The end of Shaman's adventure does not, however, mean that the rainforests have lost their allure completely. Merck, for example, has a long-standing arrangement with Costa Rica to prospect for drugs in that country's forests. The firm also collaborates with the New York Botanical Gardens to collect plants from all over the world. But the wisdom of the ages will not be coming with them. Modern technology has won.
In the pharmaceutical industry, failure is more common than success when it comes to finding drugs that actually work in real patients. So the demise of Shaman's business is not surprising. But while their difficulties do not entirely doom the chances that new drugs will be discovered from natural resources, it is a cautionary tale, highlighting some of the issues involved in ethnobotany.
There are two main kinds of drugs, classified according to their chemical structure. Small molecules, like aspirin, can be made either in the laboratory or extracted from plants and other natural resources. Biologics, such as insulin, are generally produced by fermentation or culturing genetically modified cells. These are large-protein molecules, normally given by injection. Advances in genetic technology have put biologics on the ascendant, providing new treatments for cancer, inflammatory disease, and other conditions. Small-molecule drugs still hold an important place in the pharmacological armory, especially as they can often be given in tablet form. But the advent of biologics means the process of drug discovery has changed and approaches to natural products must be revised.
Chemists searching for new small-molecule drugs now have technology that can screen thousands of natural compounds for biological activity in a short time, allowing the myriad compounds in the plant and microbial worlds to be studied with high-throughput methods. Once found, however, obtaining these extracts may prompt legal questions of compensation, intellectual property rights, and environmental protection in the country of origin. The 1992 United Nations Convention on Biological Diversity established guidelines under which such natural resources may be exploited, including protecting delicate biological environments, fair compensation, and minimizing potentially harmful impacts upon indigenous cultures.
Besides the regulatory issues, there are practical ones. Plants often contain hundreds of different compounds and much chemical analysis may be needed to identify the active ingredients. Some such botanical extracts—mixtures of compounds used as medicine—have been evaluated clinically. Saint-John's-wort, for example, has been touted in the treatment of mild to moderate depression; some studies claim it is as effective conventional antidepressant drugs; other claims remain unproven. Many botanical extracts are available and can often be bought without a prescription, but consumer's cannot always be as sure of content or quality as they can with a pharmaceutical drug.
The demise of Shaman Pharmaceuticals does not mean the end of ethnobotany. Taxol, originally produced from the bark of Pacific yew trees (Taxus brevitola), is one of the most effective cancer drugs. A synthetic version allowing for mass production was introduced in 1994. Meanwhile, researchers in Norway and Australia are searching the marine environment for new antibiotics and cancer drugs. Researchers cannot afford to overlook any resource, either natural or synthetic, when it comes to the discovery of new medicines. Adding technology to the search should help speed up the process.
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