Drug Companies Must Adapt to the 'Bioburst' Era

“Bioburst” as the name Richard Noel Re gives to the revolution now taking place in molecular biology. In his book Bioburst: The Impact of Modern Biology on the Affairs of Man (Louisiana State University Press, 1986), Re discusses how that revolution will permeate contemporary life. He uses the discovery of cyclosporin A to illustrate the new flexibility needed in the pharmaceutical industry to deal with this revolution. The excerpt below is taken from the book. Chance favors the prepared mind, and this is nowhere more true than in the arcane world of molecular biology. The need for a staff well versed in all areas of biology has always existed in biomedical research, but the need is all the more acute now that so apparently great an intellectual gulf separates the old and the new biologies. That this schism is real can be readily seen by discussing the issue with the faculty of any medical school, the large majority of whom are not involved in the Bioburst phenomenon and in many ways resent those who are. They feel that the new breed is elitist, devoted to the study of very narrow biochemical issues, and is moreover the undeserving recipient of an unreasonable amount of grant support. The new breed, for its part, too often retreats into its own world. This situation is unfortunate and unnecessary, and it will be counterproductive if permitted to persist. There are some who want to bridge the gap, but clearly a new breed of scientist capable of interfacing with both camps must spring up if a synthesis of the insights of both groupa is to be achieved and the productivity of each is to be maximized. If it is hard to predict what form this interfacing will take in academia, it is even more difficult to speculate about the response of industry. Yet the successful meshing of the molecular biology of Bioburst and the tenets of classical pharmacology is absolutely critical to the very survival of the domestic pharmaceutical industry. It is apparent to many that the American drug industry is rapidly losing its innovative edge to foreign concerns. Failure to lead in the expanding application of Bioburst technology to the design of new pharmacological agents could actually spell the end of the domestic industry. This fact is not lost on the industry’s foreign competition. Conceptually, the worst response of a traditionally organized pharmaceutical firm to this challenge would be a rigid adherence to standard pyramidal structures in management and research. The inflexibility inherent in this approach would almost certainly impede the efficient exchange of ideas and information between modern molecular biologists and traditional pharmacologists. The pharmaceutical industry has always been aware of the value of research cross-fertilization and even of serendipity, but the new era will place even more emphasis on, and test more severely, the flexibility of this industry than anything that has gone before. Cyclosporin A A recent example illustrates this point. Sandoz, like many other pharmaceutical firms, asks its employees to collect, whenever traveling abroad, soil samples from the areas they visit. Jean Borel was the man at Sandoz responsible for evaluating the products of fungi found in these samples for their potential efficacy as chemotherapeutic agents. When a new fungus was isolated from samples obtained from Norway and the United States, Sandoz scientists evaluated a water-soluble substance that it produced for possible antibiotic activity. Based on his past experience regarding the internlation, or lack thereof, of antibiotic and immunoregulatory properties, Borel elected to check this material, now known as cyclosporin A, in assays designed to detect immunological activity. To his surprise, the compound suppressed T-cell-mediated immunity, but unlike other suppressors of cell-mediated immunity, cyclosporin A did not kill T-cells. Rather, it simply arrested their proliferation in response to antigen. Thus, the T-cell effect was reversible, and the drug’s toxicity was therefore substantially less than that of previously used agents. Company management was not initially enthused by the project and wished to cancel it as part of a general reassessment of immunology at Sandoz, but Borel persisted and eventually was persuasive. In recent clinical trials cyclosporin has proved to be the most useful suppressant of transplant rejection yet discovered. It has revolutionized transplant technology to the point where liver transplantation and similar procedures are arguably routine rather than experimental. Indeed, the availability of this drug may so dramatically change the transplantation field that shortages of organs for transplantation will become critical. In addition, the drug may prove useful in the therapy of autoimmune disorders and may even prevent the development of diabetes in some susceptible patients. Although the financial payoff to Sandoz is still unclear, it is likely to be substantial. A Changing Industry In analyzing this story, several points should be noted. First, it was the free flow of knowledge, ideas, and hunches between microbiologists, immunologists and management that saved the project. it is a credit to Sandoz that it did not permit its plans for the redirection of immunology research to prevent continued development of cyclosporin A. But it is most of all a credit to Borel’s persistence and, in the final analysis, to a management that eventually listened to him. No one knows exactly how cyclosporin A works. Its end result—T-cell suppression— is appreciated, but not its mechanism of action. For the purpose of argument (and purely hypothetically), suppose that this drug is taken up by cells and alters DNA structure by converting stretches of the double helix into the so-called Z-form, and further assume that this action somehow accounts for its effects on T-cells by preventing the production ofT-cell growth factors. Then suppose that this action on DNA was known, but the final effect on T-cell-mediated immunity was not. How much harder would it have been to convince management to keep the project alive? Many of the great insights of the future are likely to come in this way—as biochemical observations related to DNA gyrase, or polymerase or what have you. The insights will arise first in a recombinant DNA laboratory and not in a Norwegian field, and the ultimate implications and consequences of the application of these insights will not be immediately obvious at the time of their discovery. This is a radical departure from the way pharmaceutical advances occurred in the past. Heretofore, assays of biological potency were used to screen a vast number of compounds, with efficacious products identified by this random selection process. Thus, many pharmaceuticals were developed by a mechanism much akin to nature’s development scheme, natural selection. At other times, chemists produced analogs of compounds known to be biologically active so as to enhance one or another aspect of the compounds’ actions. But breakthroughs in the future will come from the drawing boards of the molecular engineer, and, although rich in potential, they will arrive in the world in a relatively obscure form. Management and scientists alike will require a new way of looking at things in order to realize the full importance of such observations and to ensure that these findings are transferred to the immunologists, microbiologists, and others who can put them to work. New working relationships between product-seeking management teams and knowledge-seeking academic teams must be developed. Solid education in biology, molecular and otherwise, will be indispensable to the Bioburst industry employee, be he or she a technician or a company president. Students interested in preparing to work in this industry must plan their study accordingly, and schools must respond with courses to meet their needs. This educational process could profitably begin in junior high school. Pharmaceutical managers who have not been schooled in molecular biology should undertake the comprehensive study of the subject by way of the three traditional means open to them: learning from newly recruited scientists, interacting with consultants, and teaching themselves. Business schools would be wise tojoin with their basic science colleagues in offering programs of study designed to aid in this knowledge acquisition by senior management. Because molecular biology is so basic, its ramifications are quintessentially multidisciplinary. Management structure should reflect this characteristic and should be as fluid as possible so as to provide maximum input from all parties and to assure the sharing of information across departmental or division lines. Even then, new and creative modes of interacting freely with academia must be developed. Only in this way will productivity be maximized. Re is vice president of the Alton Ochsner Medical Foundation, 1516 Jefferson Highway, New Orleans, LA 70121. Copyright © 1986 by Louisiana State Univeisity Press. Reprinted with permission of the publisher.

Drug Companies Must Adapt to the 'Bioburst' Era

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Richard Noel Re

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October 1987

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