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1. Cancer Chemotherapy: Plant Knowledge and Practice

To follow and understand taxol's path through the American cancer research and biomedical community, it is necessary to explore, in some detail, two principal contexts: the history and development of cancer chemotherapy and its target; and the structure and strategy of the NCIUSDA plant screening programme.

Cancer Chemotherapy and the Malignant Cell

The years from roughly 1945 to 1970 were formative in the history of cancer chemotherapy in two principal senses.' First, chemotherapy came to achieve status as a therapeutic regimen for the cure or at least the palliation of cancer, towering over surgery and radiotherapy, during this period.' Secondly, chemotherapy became a research regimen in biomedicine that mirrored, incorporated and modified models of large-scale cooperative ventures in other scientific endeavours.

The medical literature abounds with reviews of the historical development of cancer chemotherapy. The generalconsensus of the literature is that 'modern' cancer chemotherapy emerged from research in gas warfare by the Americans and British during World War II.' The landmark papers on nitrogen mustards contributed to a heightened interest and belief in chemical agents rather than radiotherapy and surgery as the techniques of choice in cancer treatment: attacking the 'biochemical soil' in which cancers arose, as a leading advocate of chemotherapy put it. Wartime programmes devoted to the large-scale production of penicillin and antimalarial drugs built on the success of the sulpha drugs of the late 1930s in convincing many people that disease could be eradicated by chemical means.

The bulk of experimental and clinical research on chemotherapeutic agents from roughly 1945 to 1960 focused on two kinds of chemicals and two mechanisms of action: alkylating agents that combine chemically with cellular constituents, and antimetabolites that compete with the substrate of an enzyme system for engagement in metabolism.' Steroid hormones and antibiotics were also examined for chemotherapeutic potential. Cortisone, for example, was studied for its ability to regress tumours long before its more famous effects on arthritis were observed.' Among antibiotics, the only one to be used clinically was actinomycin D.

Cancer chemotherapy was not then the core activity it would become. Research glided between experimental (laboratory) activities, predominantly biological work on animal tumours, and clinical trials on humans. Until the 1940s, experimental cancer chemotherapy was carried out by many different investigators in many different disciplinary specialties - biology, physiology, pharmacology and botany, and in many different sites - pathology laboratories, hospitals, universities, and private biological research institutes." One of the most important of the latter type was the Rockefeller Institute which, for many decades, had been actively engaged in experimental cancer research. James Murphy, who was with the Institute from 1911 to his death in 1950, summed up the achievements of cancer research during his period of activity. According to Murphy, the chief insights included: (i) that tumours could be transplanted, a fact that demonstrated that malignancy was centred in the cells; (11) that genetic factors influenced cancer but that they varied within the population; (iii) that there were certain agents called carcinogens that induced tumours; and (iv) that in the change from normality to malignancy, the cell was altered and that proliferation became automatic and therefore no longer dependent on the causative agent.

With the ending of World War II, the diffracted nature of experimental and clinical cancer chemotherapy gave way to a more standardized practice. As architects of early post-war American chemotherapy, Cornelius Packard 'Dusty' Rhoads and the Sloan-Kettering Institute were instrumental in this change. Rhoads began his professional career in haematology at the Rockefeller Institute in 1928,14 and in 1933 was put in charge of the clinical haematology service where he remained until 1940 when he was made director of the Memorial Hospital for Cancer and Allied Diseases. Within a very short time of the date of this appointment, Rhoads became the Chief of the Medical Division of the Chemical Warfare Service of the United States Army. Rhoads assembled under him an impressive array of medical scientists. Many of them joined him after the war at the Sloan-Kettering Institute and those that did not found their way into other cancer research centres in the United States.

It was during his time as Chief of the Division that experiments were conducted with nitrogen mustards, investigating their pharmacology, toxicology and mechanism of action: according to one commentator, nitrogen mustards became 'a model for the study of antitumor drugs'. Once the war ended and the ban on public statements about this research was lifted, it was Rhoads who made the knowledge public to the American Medical Association." At the close of the war, the work on nitrogen mustards came under the direction of the Committee on Growth of the National Research Council who, in turn assigned the work to three institutions, one of which was the Memorial Hospital."

The Sloan-Kettering Institute was founded in 1945 and rapidly became the largest private cancer research institute in the United States. In tracing the first few years of its history, the historian Robert Bud reminds us that the institute was founded on industrial principles of organization and practice. Not only were its founders and many of the trustees industrialists - Alfred P Sloan and Charles F Kettering of General Motors, Frank Howard of Standard Oil - but it also expressly adopted a programme of research modelled on the industrial laboratories of such companies as Bell, DuPont, General Motors, etc. The press release announcing the founding of the institute contended that its task was to 'concentrate on the organization of industrial techniques for cancer research'.

Precisely what was meant by the 'organization of industrial techniques' would only become apparent as the system of research evolved over the years. What was emphatically clear, however, was that the centrepiece of the entire organization was the cell. Rhoads had a deep conviction of the truth of the central tenet of chemotherapy, namely that there were chemical agents that could selectively destroy or control the cancer cell, in contrast to the prevailing focus on surgery and radiotherapy. This was founded on his own experience with nitrogen mustards and laid the foundation of what he called 'an empiric attack on cancer'. The laboratories at the institute began to construct an organization and programme to fulfil the promise. The structure of the organization followed on from the strategy of testing as many substances as possible against a number of experimental tumour models...