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4. University of California Technology Transfer [homepage on the Internet]. 2007, August. Available from: URL: www. ucop.edu. 5. Bush V. Science—The endless frontier. A report to the president. Washington, DC: Office of Scientific Research and Development; 1945. 6. Bremer HW. The first two decades of the Bayh–Dole act as public policy. Speech given at: the National Association of State Universities and Land Grant Colleges; November 11, 2001; New York, NY. 7. Henderson JA, Smith JJ. Academic, industry, and the Bayh– Dole act: An implied duty to commercialize. Boston: Center for Integration of Medicine and Innovative Technology; 2002. 8. Bayh-Dole act [monograph on the Internet]. 2007, August. Available from: URL: www.wikipedia.org/wiki/Bayh-Dole_Act. 9. Bremmer HW. Innovation’s golden goose. The Economist. December 12, 2002. 10. The Bayh–Dole act: A guide to the law and implementing regulations. Washington, DC: Council on Governmental Relations; 1999. 11. Schacht W. The Bayh–Dole act: Selected issues in patent policy and the commercialization of technology. Storming Media, Pentagon Reports: Past, Definitive Complete. 2005. Available from: http://www.stormingmedia.us/41/4165/ A416534.html. 12. Thursdy J, Thursby M. University licensing under Bayh– Dole: What are the issues and evidence? Science 2003;301: 1052. 13. Stanford Technology brainstorm [newsletter]. 2006;12(2). 14. Malone MS. Bill & Dave: How Hewlett and Packard built the world’s greatest company. Portfolio 2007. 15. Stanford University Office of Technology Licensing [homepage on the Internet]. 2007, August. Available from: URL: http://otl.stanford.edu. 16. Evans H, Buckland G, Lefer D. They made America: From the steam engine to the search engine: Two centuries of innovators. Boston: Back Bay Books; 2006. 17. Krummel TM, guest editor; Grosfeld JL, editor. Advanced and emerging technologies in pediatric surgery and the process of innovation. Semin Pediatr Surg 2006; 15(4). 18. Entrepreneur [monograph on the Internet]. 2007, August. Available from: URL: http://en.wikipedia.org/wiki/Entre preneur. 19. Drucker P. Innovation and entrepreneurship. New York: Collins; 1993. 20. Kelley T. The art of innovation. New York: Doubleday; 2001. 21. Kelley T. The ten faces of innovation. New York: Doubleday; 2005. 22. Berkum S. The myths of innovation. Sebastopol, CA: O’Reilly Media; 2007. 23. Gillmor CS. Fred Terman at Stanford, building a discipline, a university, and Silicon Valley. Stanford, CA: Stanford University Press; 2004. 24. Davis K. Public libraries open their doors. BIO-IT World [serial online]. 2007, February. Available from: URL: www. bio-itworld.com/archive/111403/plos/. 25. Kawasaki G. The art of the start: The time-tested, battle-hardened guide for anyone starting anything. Portfolio 2004. 26. Wall J, Longaker M, Gurtner G. From idea to bedside: The process of surgical invention and innovation. In: Darzl A, Debas H, Athanasiou T, editors. Key topics in surgical research. In press. 27. Osborn A. Applied imagination. Boston: Charles Scribner’s Sons; 1957.

28. Stanford University Product Realization Lab [homepage on the Internet]. 2007, August/ Available from: URL: www. stanford.edu/group/prl/aboutus. 29. Connor J: Making sense of the FDA as found in Krummel, TM, guest ed: Advanced and emerging technologies in pediatric surgery and the process of innovation, Sem Pediatr Surg, JL Grosfeld, editor, W.B. Saunders Co., Philadelphia, PA, Vol 15(4), November 2006, pp 293-301. 30. Moore FD. Three ethical revolutions: Ancient assumptions remodeled under pressure of transplantation. Transplant Proc 1988;20:S1061-2. 31. Moore FD. The desperate case: CARE (costs, applicability, research, ethics). JAMA 1989;261:1483-4. 32. Guidelines offered for responsible technology licensing. In the public interest: Nine points to consider in licensing university technology. Report from a meeting of research officers, licensing directors, and a representative from the Association of American Medical Colleges; Seattle, WA; Summer 2006. 33. Stossel TP. Regulation of financial conflict of interest in medical practice and medical research: a damaging solution in search of a problem. Perspect Biol Med 2007;50:54-71.

PATENTS AND RESEARCH: FRIENDS OR FOES? David H. Sachs, MD, Boston, Mass From the Department of Surgery, Massachusetts General Hospital, Boston, Mass

HAVING SPENT THE PAST 17 YEARS building and directing a research center devoted to transplantation in the Department of Surgery at Massachusetts General Hospital (MGH), I am pleased to provide my perspective on the interaction between industry and academic research. This article represents my personal views, which are built largely on my experience trying to manage this interaction to the advantage of our research goals without compromising our independence or our academic freedom. There is no question that a relationship with industry can be advantageous to a research endeavor. Once it is clear that collaboration will be of mutual benefit to the laboratory and to the industrial partner, the availability of funding without a lengthy review process provides flexibility in hiring and purchase of equipment and supplies that can make the difference between the timely initiation of a successful project and failure to ever get it started. In my case, I had spent 21 years at the National

Accepted for publication November 5, 2007. Reprint requests: David H. Sachs, MD, Professor of Surgery (Immunology), Harvard Medical School, Director, Transplantation Biology Research Center, Massachusetts General Hospital, MGH East, Building 149-9019, 13th Street, Boston, MA 02129. Surgery 2008;143:191-3. 0039-6060/$ - see front matter Ó 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2007.11.001

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Institutes of Health (NIH) where I was chief of the Immunology Branch of the National Cancer Institute. Before accepting my current position in 1991 as director of the Transplantation Biology Research Center (TBRC) at MGH, I had never applied for a research grant. Several years earlier, however, I had been approached by Mr Wallace Steinberg, then-president of Healthcare Ventures, Inc, about the possibility of helping him start a company in the field of transplantation. Although flattered by his interest, I declined his offer because it would have been inconsistent with the rules governing interactions between government scientists and industry. After leaving the NIH, however, I asked Steinberg if he was still interested in starting the company; his answer was ‘‘more than ever.’’ Within a year of my becoming director of the TBRC, Steinberg had launched a new company called BioTransplant, Inc (BTI), the goals of which were to become a leading biotechnology company in the field of transplantation. The company was built in close proximity to MGH, and a chief executive officer was hired who had a strong interest in transplantation and considerable experience in the biotechnology industry. I was asked to head the company’s Scientific Advisory Board. The MGH and Harvard rules made it clear that I either could have equity in the company or sponsored research from the company, but not both. I chose sponsored research, which enabled the MGH Office of Technology Affairs to reach an agreement with the company allowing it to license TRBC inventions in the field of transplantation in return for considerable funding of the infrastructure of our laboratories. I was able to recruit several investigators and fellows to join me in starting the new research center at MGH. Fortunately, we were very successful in obtaining grants from the NIH for the transplantation studies we intended to perform in our new center. Nevertheless, without the substantial financial resources provided by BTI, it would have been very difficult to launch these studies so quickly or to build the infrastructure, especially the animal care resources, which were critical in enabling us to expand our research efforts. One of the main interests of BTI, and probably the area with the greatest potential for eventual financial return, was that of xenotransplantation, the use of animal organs to overcome the organ shortage presently limiting the field of transplantation. We had produced some special strains of swine with characteristics extremely appropriate as potential donors of organ transplants to humans. Then, in the mid- 1990s, a much larger pharmaceutical company (Novartis) also became highly interested in this area. Together, BTI and Novartis spun off a joint venture in the field of xenotransplantation, which was called Immerge BioTherapeutics (IBT). Much of the research previously sponsored by BTI was taken over by the new company. Novartis brought enormous resources to this field, enabling some of the most exciting developments undertaken by IBT, including the production of new, genetically modified pigs from our most inbred line of miniature

Surgery February 2008

swine. These pigs, called Gal knock-out (GalT-KO) pigs, were engineered using new nuclear transfer cloning technology so that their cells would not express the Gal antigen, which is the most important cause of rejection of pig xenografts by primates. Nevertheless, Novartis made a high-level corporate decision in 2002 to leave the field of xenotransplantation. The full reasons for this change in interest were never made entirely clear to me. However, it is likely that, in addition to the high cost and slow progress of this area of research up to that time, potential liability issues were of importance to the decision. After this loss of funding, IBT as well as other companies in this field that were also supported directly or indirectly by Novartis were unable to obtain sufficient funding to continue operations and went out of business. Fortunately, much of the research in xenotransplantation being carried out in the TBRC was funded by NIH grant support rather than through industry-sponsored research. We were therefore able to continue our work. The loss of infrastructure support, however, was enormous, requiring us to seek additional grant funding to maintain our animal colony and curtailing some of the expensive projects in genetic engineering of our pigs, that were previously financed by IBT. I think there are several lessons to be learned from this experience that could be of general interest with regard to the overall subject of interactions between industry and academic research endeavors. First, let’s look at the advantages. Our relationship with BTI and then with IBT made it possible for us to share the expense of many of the infrastructure requirements that this type of expensive, large animal research entails. Both of these small companies also paid great attention to maintaining an excellent relationship with MGH. In return for licensing rights to advances made in our laboratory, they were willing to contribute to the building of new large animal facilities, the support of administrative and technical personnel, and the educational needs of the TBRC. They also tried to ensure that the licensing agreements would not impede our progress, frequently allowing exceptions to the agreement requirements so that our investigators could sign material transfer agreements with other corporate entities, or filing patent applications on short notice in order not to inhibit oral or written communications. Without the support of these companies, it is unlikely that we could have achieved the GalT-KO--engineered animals in such a short time after nuclear transfer technology first became available or progressed as quickly in our studies or induction of tolerance to xenografts. In general, then, if the agreement between industry and the laboratory is effective and maintained in good faith, the relationship can have enormous benefit to the research endeavor. Now let’s examine some of the disadvantages of this kind of relationship, the first of which is the potential loss of academic freedom. To protect patent rights, agreements between industry and academic institutions almost always contain language restricting disclosure and distribution of intellectual property. I have found

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that the small companies with which I have worked have been willing to make exceptions to these rules when necessary; large companies, however, are frequently less willing to do so. Generally, this reluctance is blamed on the lawyers of those companies that are intent on protecting intellectual property, but often there is no real attempt by corporate management to convince the lawyers otherwise. A good working relationship based on mutual trust is essential to keep this issue from becoming a problem. The second major disadvantage is the speed with which industry support can be withdrawn. Just as the flexibility offered by quick decisions on project funding can be of great advantage at the outset of these relationships, an abrupt loss of funding, can occur just as quickly, leading to loss of stability for both projects and personnel. Because the scientist generally has very little to say about whether the small company with which he or she is working will enter into an agreement with a larger company, this loss of security of funding is largely out of the scientist’s control. It is also clear that, once a large company decides to stop funding a small company, it is very difficult for the small company to recover. Other investors and other larger companies are wary of putting money into a company after learning that a competitor has lost interest (and/or lost money). There is another general problem related to industrial-academic collaborations that involves the area of conflict of interest. Most institutions, like MGH, have created effective guidelines with regard to compensation of scientists for their industrial interactions that provide safeguards against undue influence of such compensation on research. Such regulations are mandated by the NIH for all institutions receiving federal research funding. However, I consider the conflict of interest posed by requirements for secrecy to be at least as important as those related to compensation, but to be much less wellregulated to date. Many companies refuse to enter into collaboration with an academic scientist without a written agreement that results will be kept secret for a specified period of time. Generally, companies will not provide their product or their assistance without such an agreement, despite the likelihood that both parties will lose the benefit that might arise from collaboration. This situation is particularly unfortunate when it involves research that might lead to the cure for a disease. I believe that most such requirements for secrecy are ill-founded, because scientists generally respect and appreciate the benefit of industrial support and are not interested in undermining the legitimate rights of a sponsor to profit from patents on the work they have sponsored. Scientists are willing to provide the results to the sponsor for a decision on patenting before publication, giving the company a specified time (eg, 30 days) to decide. Because it usually takes more than 30 days for a paper to be accepted by a journal, and because the information is considered confidential until it is published, this requirement should rarely cause concern. As mentioned above, I have frequently found companies, especially small companies, willing to accept

the alternative of receiving the manuscript as a privileged communication at the same time it is submitted to a journal. Therefore, a good working relationship can again help to keep this problem under control. What, then, are my recommendations for academic scientists seeking to enter into agreements with industry? (1) Be sure that the work on which you intend to collaborate is of a high level of interest to both you and the industrial sponsor, and that you agree on the research goals and priorities; (2) try to get to know the people in the company with whom you will be interacting and assess their longevity in the company and the company’s longevity of interest in your area of work; (3) work closely with your institution’s corporate licensing office and make sure that you understand all the obligations in any written contract and that they do not unreasonably compromise your own academic freedom; and (4) be sure that your research is not so heavily dependent on funding from the corporate sponsor that you cannot continue without it. There is no substitute for public grant funding. It ensures stability of funding for a defined period and the quality control inherent in periodic peer review. With attention to these recommendations, I believe that the relationship between industry and research can be mutually beneficial, leading to advances that would not be possible by public funding alone. The author gratefully acknowledges Drs Elliot Lebowitz and Megan Sykes for helpful comments and Ms Michelle Willis for expert secretarial assistance.

A BIOPSY OF FINANCIAL CONFLICTS OF INTEREST IN MEDICINE Thomas P. Stossel, MD, Boston, Mass From the Divisions of Translational Medicine and Hematology, Brigham & Women’s Hospital, Boston, Mass

I GREW UP WITH THE IMAGE of the masked, gowned, and gloved surgeon as the superhero of medicine and entered medical school with aspirations to be one. However, my first surgery instructor, Dr Judah Folkman, judged my knot-tying skills sufficiently clumsy to disabuse me of this ambition, and I adopted the more prosaic uniform of an internist by default. I therefore Accepted for publication November 27, 2007. Reprint requests: Thomas P. Stossel, MD, Translational Medicine & Hematology Divisions, Brigham & Women’s Hospital, 1 Blackfan Circle, Karp 6, Boston, MA 02115; E-mail: [email protected]. Surgery 2008;143:193-8. 0039-6060/$ - see front matter Ó 2008 Mosby, Inc. All rights reserved. doi:10.1016/j.surg.2007.11.013