Taxol, first discovered in the bark of the Pacific yew 30 years ago, holds great promise as a treatment for various forms of cancer. The fascinating swings in taxol's fortunes over these 30 years illuminate a surprisingly wide variety of issues concerning the commercial exploitation of a natural substance - issues being explored in a historical project in Manchester.

             Taxol is no ordinary drug. It is a drug of our time. It has become an icon reflecting profound changes in society, economy and culture. At the same time, it has acted as a reference point for conflicts between otherwise desirable social goals, and for the accommodation of seemingly conflicting goals. As an example of innovation, its history reveals how profoundly uncertain, fragile and politically charged that process is. The story of taxol covers an extraordinary breadth of issues - the chemotherapy of ovarian and breast cancer, the protection of the environment and endangered species, the economics of biodiversity, and market forces and public property. These issues are being explored by Dr Jordan Goodman and Dr Vivien Walsh at the University of Manchester Institute of Science and Technology, in a history of medicine project funded by the Wellcome Trust.

             It took 30 years to develop taxol. For much of the time, its existence was known only to a few researchers and administrators. In the late 1980s and early 1990s, however, the public became the spectators to a drama based on taxol. Investigating how taxol, the drug, was made and how taxol, the drama, was performed provides us with a unique insight into the indeterminacy of the politics of science and medicine.

Making the drug taxol
Proclaimed in headlines as a miracle drug, taxol received Food and Drug Administration (FDA) approval in 1992 for the treatment of advanced ovarian cancer, and in 1994 for metastatic breast cancer. Yet taxol began life unceremoniously. In 1962, as part of the plant procurement and screening programme jointly organized by the National Cancer Institute (NCI) and the US Department of Agriculture (USDA), pieces of bark, stem and fruit of the Pacific yew tree were collected in the Gifford Pinchot National Forest in Washington State. Cytotoxic activity was found in the crude extract in 1964. The active compound was isolated in 1966, it was named taxol in 1967, and its molecular structure was published in 1971. In screens, taxol met the criteria of minimal activity, but so did many other natural products.

             As research continued, taxol was found to possess very low solubility in the media normally used for drug delivery. It appeared to be less potent than existing antitumour natural products, and it was thought to work similarly to other well-studied plant products. Securing the necessary supplies of the raw material was also far from straightforward. Larger-scale procurements could not be done at a distance by the USDA, but local knowledge and competence was lacking and no one had ever tried to scale-up methods for extraction and purification. There was no doubt that taxol would be a very expensive compound to develop. Pursuing taxol seemed worthwhile only to one or two people in the NCI who were prepared to associate their careers with it and enrol the interests of others in the organization.

             As was routine practice, taxol was offered to the extramural community for biological and chemical studies. A research team at the Albert Einstein College of Medicine in New York realized that taxol was no ordinary antimitotic poison as the NCI had assumed. In 1979, the team announced that taxol was unique in its mechanism of action. Unlike other mitotic poisons, which inhibited mitosis by inducing the disassembly of microtubules, taxol discouraged microtubule depolymerization, eventually blocking cell growth.

             To the clinically minded cancer community, this was not particularly noteworthy, but it turned out to be an unexpected boon to cell biologists and natural product chemists, both of whom valued its unique structure and activity. The NCI was flooded with requests for taxol. This surge in demand put taxol into the spotlight within the NCI. Few could now afford not to be associated with it.

             Events began to accelerate. By the middle of 1982 taxol passed a number of toxicology tests. In the following year, more than 20 years after the first collection of yew bark, the NCI filed an Investigational New Drug Application. Phase I clinical trials started in 1984 and phase II trials a year later. In 1989 a clinical oncology team at Johns Hopkins University announced that taxol was active against refractory ovarian cancer, and at the end of 1991 a team at the MD Anderson Cancer Center in Houston reported excellent response rates to taxol in metastatic breast cancer patients. Approval for commercial use was granted the following year, in record time.

             Yet taxol might never have made it this far. Because of the problems associated with its synthesis, the NCI gave it low priority as a candidate anticancer drug. The enthusiastic support of one or two 'product champions' ensured that the project was never abandoned. The fate of taxol thus turned as much on the internal politics and inertia of a large organization as on any traditional scientific criteria.

Performing the drama of taxol
Every performance requires actors and a script. While few actors were prepared to speak for taxol during the 1960s and 1970s, events following the publication of taxol's unique structure and mechanism brought many more actors onto the scene, all urging that taxol should be developed as an anticancer drug. Their shared enthusiasm, however, obscured the fact that they had overlooked taxol's real producer, the yew tree. No one had bothered to collect any new information about the yew, including such vital details as their number, their distribution, their habitat, concentration of taxol under different growing conditions and locations, and the average yield of taxol per tree. Only vague details existed. It was known that the Pacific yew grew very slowly and in isolated and randomly distributed stands; it nestled in the shadow of much larger and then more commercially valuable species. Logging companies traditionally considered the yew tree as waste. Apart from a few enthusiasts, nobody had much to say for the yew.

             Another detail was that stripping the bark killed the tree, but this had never been a problem since the total supply of bark between 1962 and 1977 amounted to just over 2,000 pounds - equivalent to the death of 700 trees. The upsurge in demand for taxol from phase II trials caught the NCI off-guard. They reacted by ordering 60,000 pounds of bark in 1987, with a similar quantity estimated for the following year. Yew mortality previously in the hundreds would now reach the tens of thousands.

             The yew now began to acquire voices speaking on its behalf. The NCI soon became aware that its procurement of bark was beginning to provoke a political response from environmental pressure groups with new concerns for endangered species and protecting biodiversity. One of the first was made in 1990 when the Environmental Defense Fund petitioned under the Endangered Species Act to have the yew tree classified as a threatened species. They represented the voices of several leading taxol scientists, the American Cancer Society and the Oregon Natural Resources Council. Though the Department of Interior rejected the petition in January 1991, it was clear that taxol had now become a political issue. The US media quickly seized on the apparent conflicts of interest between those speaking for cancer sufferers and those speaking for the yew. With headlines such as "Save A Life, Kill A Tree?" and "Tree Yields A Cancer Treatment, But Ecological Costs May Be High" in the New York Times and the Wall Street Journal, Americans were treated to a heady, and hitherto unencountered, mixture of medical and environmental ethics.

             Ethical controversy next emerged in a new arena, the privatization of an activity that had previously been the province of the public sector. Throughout its development of taxol the NCI, a government agency, had acted as an innovator. It brought taxol to the point of commercialization, but it would not have been allowed to launch a drug onto the market. The NCI began to make provision for the transfer of responsibilities to the private sector, where there was more direct experience of drugs and a more skilled and extensive marketing machine.

             The mechanism for enlisting a commercial operation was the Cooperative Research and Development Agreement. A tender was announced August 1989 for a drug company to bring taxol to the market. By the end of the year, Bristol-Myers Squibb emerged as the successful applicant. The company was rewarded with a monopoly over the supply of yew bark from public lands and full access to the NCI's development files and exclusive rights to use its intellectual property.

             The formal agreement was signed in January 1991. Then, in addition to the environmentalists and oncologists, central government made its entrance into the drama. A congressional hearing in July, chaired by the Democratic representative from Oregon, questioned the grant of exclusive rights to one firm. The drama of taxol now entwined issues far beyond the forests of the Pacific north-west, raising questions about the fundamental assumptions underlying the relationship between private enterprise and public property rights. In 1993, the same committee returned to a similar theme, the thorny issue of the drug pricing.

             Thus taxol has come to mean many things to many different people. Those meanings developed as our understanding of taxol's biological properties gradually emerged, and were shaped by numerous cultural, political and social factors. Recovering and re-evaluating this history promises to tell us as much about ourselves as it does about taxol, the anticancer drug.

Dr Jordan Goodman and Dr Vivien Walsh are in Manchester School of Management, University of Manchester Institute of Science and Technology. Their work on taxol is funded by a history of medicine project grant.
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NOTE:
Paclitaxel (structure above on p.12) and docetaxel (structure below) are taxoid drugs derived from the bark of the Pacific yew and the needles of the English yew, respectively.

Paclitaxel is sold by Bristol-Myers Squibb as Taxol (produced at their Dublin plant) and docetaxel is sold as Taxotere by Rhone-Poulenc Rorer (produced in France). They have different but related chemical structures and both are effective against cancer by interfering with mitosis, but work in slightly different ways.

Taxol links:
www.21cep.com/9top/story.htm
(The story of paclitaxel from a company which extracts directly from yew bark as a natural product.)
http://biotech.icmb.utexas.edu/botany/tax.html
(Page describing the pharmacology of paclitaxel and docetaxel.)
www.taxol.com
(For the taxol story.)