November 26, 1999
 

Biological Products Raise Genetic Ownership Issues

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  • Who Owns Genetic Resources?
    • By ANDREW POLLACK
     

     
     
     

    For generations, tribesmen in the Amazon rain forest have used secretions from the skin of a frog to make poison blow darts. Now Abbott Laboratories is developing a painkiller modeled on the active chemical in the frog secretion that seems as effective as morphine but without damaging side effects. 

    This does not sit well with the government of Ecuador and local environmental groups. With the American drug company standing to make millions of dollars if the new drug is successful, they say the country that is the source of the frog and the indigenous people who discovered the secretions should get a share of the proceeds.
    PATENTING LIFE
    A special report.

    Angry that they have not profited from the animal and plant life within their borders, Ecuador and many other developing countries have begun restricting the freedom of scientists to collect biological samples and demanding compensation in exchange for permits. Some scientists warn that scores of research projects that might lead to breakthroughs in medicine and agriculture, as well as to the study and preservation of endangered species, are being impeded or abandoned.

    "Ultimately, things on certain species will never be done because they'll be extinct before the countries can do it themselves," said John Daly, the scientist at the National Institutes of Health who isolated the Ecuadoran frog chemical. He now has great difficulty getting permits. It took him three years to get clearance from Panama to collect frogs with a cardiac stimulant in their skin. He gave up on Venezuela.

    Projects around the world have been caught up in controversy, including a study of genes for longevity in China, a search for cancer fighting chemicals in Southeast Asian marine life, the breeding of new rice strains from South Asian varieties and the development of a powerful sweetener from a West African berry. Earlier this month, the U.S. Patent Office overturned a patent held by an American entrepreneur on a plant from the Amazon rain forest.

    Once considered the common heritage of mankind, wild animals, plants and crops were taken without asking or freely exchanged. Now wildlife is increasingly viewed as a "genetic resource," the raw material of the biotechnology era, just as oil and iron were in the industrial age.

    The Convention on Biological Diversity, forged at the Earth Summit in Rio de Janeiro in 1992, established that nations have sovereignty over their genetic resources and are entitled to "fair and equitable sharing of the benefits."

    Since then, the Philippines, Costa Rica and the Andean Pact countries of Bolivia, Colombia, Ecuador, Peru and Venezuela have adopted laws controlling access to genetic resources and requiring compensation. Dozens of countries, including Brazil and India, are considering legislation or using existing authority to regulate sampling.

    While the Clinton administration supports the biodiversity treaty, the U.S. Senate has never ratified it, in part because of fears it would hurt the biotechnology industry. Nevertheless, the United States has begun seeking compensation for collection of micro-organisms in national parks. While many scientists support compensating source countries, they say unreasonable demands and red tape are threatening research.

    "What's really happening is a tremendous slowdown in the amount of material that's crossing borders," said Geoffrey Hawtin, director general of the International Plant Genetics Resources Institute in Rome, an institute under the auspices of the World Bank. "Genetic resources for agriculture as a public good, freely available, are now becoming suddenly unavailable, locked up for private profit."

    In an effort to preserve the world's food security, the Food and Agriculture Organization of the United Nations is conducting an international negotiation to ensure that seed exchanges continue for important crops.

    Limiting exchanges could imperil agriculture, Hawtin said. Varieties of wheat important to the Green Revolution, which increased crop yields in previous generations, share ancestry with as many as 30 countries.

    Natural products are also vital as pharmaceuticals, although some drug companies are de-emphasizing natural sources in favor of synthetic technology.

    Of the world's 25 top-selling drugs in 1997, seven, with a combined $11.6 billion in sales, were derived from natural products, according to "The Commercial Use of Biodiversity," a new book. These include Merck's Mevacor for lowering cholesterol, derived from a fungus on a Japanese golf course, and Novartis' cyclosporine, for fighting transplant rejection, derived from a Norwegian mountain fungus.

    Plants and animals are not the only focus of tension. Some tribesmen and others are reluctant to give samples of blood and tissues for medical research.

    "We really can no longer get access to some of the most valuable resources because of the issue and the suspicions," said David P. Beck, president of the Coriell Institute for Medical Research in Camden, N.J., the world's largest repository of human cell lines. Such cells have been used to find genes that cause illnesses like Huntington's disease and cystic fibrosis.

    Last year, the government of China halted a project, partly financed by the National Institute of Health, that sought clues to longevity by studying the genes of 10,000 elderly Chinese. The project resumed after organizers promised that the samples would stay in China and local scientists would share in patents and publications.

    Jeremy Rifkin, the biotechnology critic, said efforts by countries to restrict access to wildlife, however understandable, were pushing the world in the same direction as the biotechnology companies -- toward private ownership of genetic resources.

    "You'll have gene wars in the 21st century if we begin to enclose the gene pool," he said.

    HISTORY'S LESSONS: PAYING THE PRICE FOR PAST MISTAKES
    The countries controlling access say that their resources have been used without compensation, acts they call "bio-colonialism" or "bio-piracy."

    They point to two cancer drugs, vincristine and vinblastine, developed by Eli Lilly & Co. in the 1950s and 1960s from the rosy periwinkle of Madagascar. The drugs have helped dramatically reduce deaths from testicular cancer and childhood leukemia and netted Lilly hundreds of millions of dollars.

    Madagascar did not share in the profits.

    Similarly, crossbreeding with barley collected from Ethiopia in the 1950s saved California's crop from the yellow dwarf virus, resulting in hundreds of millions of dollars' worth of increased output, without any return to Ethiopia.

    "I'm not saying it was unfair," said Tewolde Berhan Gebre Egziabher, general manager of the Ethiopia Environmental Protection Authority. "That was before fairness in this line became an issue."

    One factor behind the increased chauvinism about genetic resources is that the advent of genetic engineering is perceived as having increased the value of genes by making them easier to exploit.

    University of Wisconsin scientists, for instance, isolated a protein 2,000 times sweeter than sugar from a West African berry. The gene for that protein can now be inserted into other fruits to make them sweeter. If a table sweetener is developed from the protein, it will probably be produced in genetically modified bacteria, eliminating the need for the berry itself.

    "The West African plant has been replaced on the international market," said Joseph M. Gopo, director of Zimbabwe's national biotechnology laboratory.

    Another factor is the increased patenting of genetically modified plants and animals in the West. Some developing nations say that if a company takes a seed from a farmer's field, adds a gene and patents the resulting seed for sale at a profit, there is no reason the initial seed should be free.

    "It's not until we've had to deal with some of these intellectual property issues in recent years that we've started to have problems," said Henry L. Shands, of the Agriculture Department's research service. It has long collected seeds from abroad for the nation's seed banks and freely dispenses seeds to other countries.

    Patents on living things changed by genetic engineering have been allowed since a 1980 U.S. Supreme Court decision on a microbe genetically enhanced to consume oil spills. U.S. patents are granted for chemicals and genes isolated from plants and animals. They have also been given for many years for plant varieties developed by breeders.

    But many countries do not allow patents on plants and animals of any kind and view natural products as discoveries, not inventions.

    Arguments on patenting of life are being made in the five-year review of a global agreement known as Trade-Related Aspects of Intellectual Property Rights. It requires signatory countries to provide patents on micro-organisms and intellectual property protection for plant varieties.

    Developing countries object that widespread patenting will make them dependent on Western companies for seeds and drugs. They also say patents ignore the contributions by indigenous peoples, who often are the true discoverers of useful plants and animals, or of farmers who improve crops over the generations.

    The negotiation run by the Food and Agriculture Organization is weighing whether to compensate traditional farmers for work in improving crops and maintaining different varieties. Malaysia has proposed an international fund of $3 billion but the United States opposes it.

    Farmers in India last year protested the patenting of a form of basmati rice by Ricetec, a Texas company with annual sales of about $10 million. Ricetec obtained a basmati seed, believed to be from Pakistan, free of charge from an Agriculture Department seed bank. Through crossbreeding, it developed a form of the long-grained, fragrant rice suitable for growing in America.

    In India, the world's largest producer of basmati rice, farmers accused the company of usurping the nation's heritage, threatening its exports and piggybacking on the work of generations of farmers who developed the crop.

    "It's a hijacking of prior innovation," said Vandana Shiva, an activist on these issues in India.

    Ricetec argues that its patent covers only one variety, not all basmati rice, and that it has no intention of trying to ban imports from India.

    Such patents can be challenged. Two years ago, the U.S. Patent Office overturned a patent awarded to two scientists at the University of Mississippi for the use of turmeric, a spice, in healing wounds. The government of India had challenged the patent on the grounds that this was an old Indian folk remedy, not a new invention.

    Earlier this month, the Patent Office issued a preliminary ruling overturning a patent awarded to Loren Miller, an American entrepreneur, on a hallucinogenic plant used in religious ceremonies by Amazon tribes.

    One Amazon group challenged not only Miller's patent but also his life. It declared him "an enemy of indigenous peoples" and warned that if he or his associates returned to the Amazon it would "not be responsible for the consequences to their physical safety."

    Miller, who lives in Newark, Calif., said he was given the plant by a tribe in Ecuador in 1974, and built a school in return. He cultivated the plant in Hawaii, developed a stable variety eligible for patent, and formed a small company to see if the plant's compounds were useful in psychotherapy or cancer treatment. Those efforts, he said, never succeeded and are all but dead.

    "Nobody's going to invest in a company that we could all be killed for," he said.

    BARRING ACCESS: RESTRICTIONS SLOW EXCHANGE OF IDEAS
    One of the premises of the Convention on Biological Diversity was that if countries were compensated for their genetic resources, they would have an incentive to conserve them.

    "If you can't get farmers to recognize that there is a value in a forest other than for cattle, the outlook is really very grim for the tropics," said Joshua P. Rosenthal, biodiversity director at the Fogarty International Center of the National Institutes of Health.

    There have been some successes. In an oft-cited model, Merck & Co. in 1991 paid $1 million to the National Institute of Biodiversity in Costa Rica for the right to collect plants in its search for drugs. Both the Fogarty Center and the National Cancer Institute coordinate collections overseas involving drug companies and academic institutions. Compensation to source countries can include upfront payments of tens of thousands of dollars, product royalties and training of scientists.

    But many experts say countries and companies have reached fewer "bio-prospecting" deals than expected, in part because of mutual suspicions.

    "When the world mentality was that natural resources were common ownership, then there was a fertile utilization of natural resources for drug discovery," said William Fenical, director of the Center for Marine Biotechnology and Biomedicine at the University of California in San Diego. "The Rio convention destroyed it."

    Fenical said it had taken him four years to get further access to an Australian coral that contains what appears to be a potent cancer-fighting chemical.

    He also said he had negotiated for two years for a permit to sample marine organisms in the Philippines, to look for chemicals toxic to cancer cells. While he was on the plane there last year to begin his work, he said, the government revoked his permit and added demands like payments of about $600,000 from Bristol-Myers Squibb, which was to follow up leads produced by the initial screening.

    "They went ballistic about demands and we walked away," he said.

    The Philippines in 1995 became the first country to enact a law in response to the biodiversity convention. It requires compensation and collaboration with local scientists and informed consent from indigenous tribes in areas where the sampling will take place.

    Many scientists say the rules are extremely restrictive. According to a Columbia University study, only two of 37 applications have been approved.

    Althea Lota, a Philippine government environmental manager, said that getting a permit is "not really that hard" but that the government intends to streamline the process. Fenical's permit was revoked, she said, because "they did not go through the whole process."

    Colombia rejected an application filed by Andes Pharmaceuticals four times. The Washington-based company was started in response to the biodiversity convention and formed a joint venture with a local citizen so that some profits would go back to Colombia. But Colombia said the application was not specific enough in stating which species would be sampled and how much cash would be paid.

    Problems may continue after samples are collected. David Spooner, a botanist with the Agriculture Department and the University of Wisconsin, has been unable to bring back samples of wild potatoes he gathered in Peru earlier this year. Britain's Portsmouth University was pressed to return 120 bottles of marine fungi obtained in Thailand several years ago.

    Controversy has dogged the first bio-prospecting agreement in the United States. In 1997, for a $100,000 payment and royalties ranging from a half of 1 percent to 10 percent, the Diversa Corp. of San Diego won the right to collect microbes from Yellowstone National Park's geysers for five years.

    The Park Service entered the profit-sharing agreement because it had already lost out once. In the 1960s, a microbe discovered in a Yellowstone hot spring yielded a heat-resistant enzyme that is now key to a DNA-amplification process. Hoffmann-LaRoche, which owns the patents, gets about $100 million a year from them. Yellowstone gets nothing.

    But some opponents of biotechnology, arguing that these genetic resources should not be commercialized, sued and won a temporary suspension of the Diversa agreement.

    ROUGH TRANSITION: NO GOING BACK TO THE OLD WAYS
    Scientists say a major obstacle to bio-prospecting is that many countries overestimate the value of raw genetic resources. Drug companies may need to invest $500 million to develop a drug over 15 years. How much should a country get merely because a plant happens to live within its borders?

    The chances of finding a big drug are remote. The National Cancer Institute has collected 50,000 plant samples from 30 countries since 1986 and has only one drug in clinical trials.

    Drug companies like Abbott and SmithKline Beecham, have cut back natural drug discovery programs. A new technology called combinatorial chemistry allows them to generate thousands of synthetic compounds quickly. Some companies still doing natural drug research focus on micro-organisms and fungi, which can be found all over the world, not just in the tropics, and can be reproduced in vats.

    Valuing raw genetic resources can be difficult when the link between drug and source is indirect, as with Abbott's painkiller. The company said it owes no compensation to Ecuador because it merely got the inspiration for its drug by reading a scientific paper about the frog chemical.

    "We've never seen the frog," Michael Williams, a vice president, said. "We've never touched the frog."

    In any case, Ecuadoran officials acknowledge that they have no legal right to compensation because no rules were in effect when the frogs were collected by Daly in the 1970s.

    Some experts say the problem is not that payments are too high but too low to encourage conservation.

    "The bio-prospecting stuff is turning out to be just a flimflam," said Ed Hammond of Rural Advancement Foundation International, a Canadian group. "It's not doing anything for developing countries."

    Nations and tribes can be played off against one another, weakening their bargaining positions, when plants grow in more than one area. One NIH project, unable to get into the Philippines, went to Laos and Vietnam instead.

    Some developing countries are becoming more directly involved in the commercialization of their genetic resources. Brazil is reluctant to let plant samples be taken to the United States, so the National Cancer Institute does its drug screening on Brazilian plants there. The Malaysian state of Sarawak has formed a joint venture with an American company to conduct clinical trials of an AIDS drug discovered there.

    Some say rough spots are to be expected as the world moves from free to controlled access of genetic resources.

    "I think the realization is coming that this isn't some sort of 'green gold,' and it's going to take a lot of work and a lot of cooperation to derive the benefits for all parties," Gordon M. Cragg of the National Cancer Institute said. But, he added, "There's not going to be a return to the old days when everyone would just walk in and take things out."