Obviously, this project could not have been undertaken without access to the people and events described in the narrative. As a condition of my having nearly complete freedom to come and go at Vertex for almost four years while I researched and wrote this book, I agreed to let the company review my manuscript for factual accuracy and proprietary disclosures. Also, all those individuals quoted directly in connection with Vertex (including Stu Schreiber) were allowed to review their quotations, again to ensure accuracy and confidentiality on scientific matters. For scenes involving discussions with individuals outside the company from which I was excluded, I was able to reconstruct dialogue extensively due to the cooperation of the participants. In many cases, that meant talking with everyone who was there. Only in a few cases were people unwilling to talk with me. In those instances, in addition to corroboration from Vertex, I confirmed with at least one person who was present at the discussion on behalf of the other party.

•  •  •

For sections of the book that fall outside of the narrative, I relied on a variety of sources. I am indebted to Mary Snead Boger for helping me to reconstruct her son’s family background and Ken Boger and Amy Boger for their thoughtful perspectives. Director Don Cummings of the Stonewall Jackson Training School helped me with Boger family history. Bill Holder of the Wesleyan University News Office facilitated my search through back issues of the Argus, the student newspaper. Other helpful sources regarding the Bogers and life in Concord were the Concord Tribune, on microfilm at the Concord Memorial Library, and North Carolina: Through Four Centuries by William S. Powell (1989, Chapel Hill, NC: University of North Carolina Press).

•  •  •

I relied heavily on the scientists whom I interviewed to tutor me in their fields. I owe a particular debt of gratitude to Jim Mullins of Stanford University and Mark Feinberg of the University of California at San Francisco, neither of whom I’ve written about here, for their patient explanations of molecular biology and of the world and culture of high-stakes biomedical research. Among print sources, there are two that tower as the most comprehensive: The Molecular Biology of the Cell by Alberts et al. (1989, New York: Garland Publishing), the standard undergraduate text; and The Eighth Day of Creation by Horace Freeland Judson (1979, New York: Simon and Schuster), which chronicles the revolution in biology. I also relied on the following articles and books:

Angier, N. 1988. Natural Obsessions: Striving to Unlock the Deepest Secrets of the Cancer Cell. Boston: Houghton Mifflin.

Bishop, J. E., and M. Waldholz. 1990. Genome: The Story of the Most Astonishing Scientific Adventure of Our Time—The Attempt to Map All the Genes in the Human Body. New York: Simon and Schuster.

Borek, E. 1961. The Atoms Within Us. New York: Columbia University Press.

Doolittle, R. F. 1985. Proteins. Scientific American, October.

Fruton, J. 1950. Proteins. Scientific American 182, 33-41.

Gold, M. 1986. A Conspiracy of Cells. Albany, NY: State University of New York Press.

Goldberg, J. 1988. Anatomy of a Scientific Discovery. New York: Bantam Books.

Gund, P., J. D. Andose, J. B. Rhodes, and G. M. Smith. 1980. Three-Dimensional Molecular Modeling and Drug Design. Science 208, 1425-31.

Hall, S. S. 1987. Invisible Frontiers: The Race to Synthecize a Human Gene. Boston: The Atlantic Monthly Press.

Hilts, P. J. 1982. Scientific Temperaments: Three Lives in Contemporary Science. New York: Simon and Schuster.

The Howard Hughes Medical Institute. 1990. Finding the Critical Shapes. Bethesda, MD.

Jevons, F. R. 1968. The Biochemical Approach to Life. New York: Basic Books.

Kendrew, J. C. 1961. The Three-dimensional Structure of a Protein Molecule. Scientific American 205, 96-110.

Lessing, L. 1969. The Life-Saving Promise of Enzymes. Fortune, March.

Marx, J. L. 1980. NMR Opens a New Window into the Body. Science, October.

Monod, J. 1971. Change and Necessity: An Essay on the Natural Philosophy of Modern Biology. New York: Alfred A. Knopf.

Perutz, M. F. 1964. The Hemoglobin Molecule. Scientific American 211, 64-76.

Salem, L. 1987. Marvels of the Molecule. New York: VCH Publishers.

Spilker, B., and P. Cuatrecasas. 1990. Inside the Drug Industry. Barcelona: Prous Science Publishers.

Stein, W. H., and S. Moore. 1961. The Chemical Structure of Proteins. Scientific American 205, February, 81-92.

Thomas, L. 1974. The Lives of a Cell: Notes of a Biology Watcher. New York: The Viking Press.

Watson, J. D. 1968. The Double Helix. New York: W. W. Norton and Co.

Weinberg, R. A. 1985. The Molecules of Life. Scientific American, October.

•  •  •

A great advantage in writing about science is that all work is painstakingly catalogued. When confusion reigned, I relied for clarification on the scientific literature. The following publications, either cited or referred to in the non-Starzl portions of the text, were of particular assistance:

Bierer, B. E., P. K. Somers, T. J. Wandless, S. J. Burakoff, and S. L. Schreiber. 1990. Probing Immunosuppressant Action with Nonnatural Immunophilin Ligand. Science 250, 556-59.

Boger, Joshua, et al. 1983. Novel renin inhibitors containing the amino acid statine. Nature 303, 81-84.

Handshumacher, R. E., M. W. Harding, J. Rice, and R. Drugge. 1984. Cyclophilin: a specific cytosolic binding protein for Cyclosporine A. Science 226, 544-47.

Fischer, G., B. Wittmann-Liebold, K. Lang, T. Kiefhaber, and F. X. Schmid. 1989. Cyclophilin and peptidyl-prolyl cis-trans sis-trans isomerase are probably identical proteins. Nature 337, 476-78.

Friedman, J., and I. Weissman. 1991. Two Cytoplasmic Candidates for Immunophilin Action Are Revealed by Affinity for a New Cyclophilin: One in the Presence and One in the Absence of CsA. Cell 66, 799-806.

Fretz, H., M. W. Albers, A. Galat, R. F. Standaert, W. S. Lane, S. J. Burakoff, B. E. Bierer, and S. L. Schreiber. 1991. Rapamycin and FK506 Binding Proteins (Immunophilins). J.Am.Chem.Soc. 113, 1409-11.

Harding, M. W., A. Galat, D. E. Uehling, and S. L. Schreiber. 1989. A receptor for the immunosuppressant FK506 is a cis-trans peptidyl-prolyl isomerase. Nature 341, 758-60.

Lepre, C. A., J. A. Thomson, and J. M. Moore. 1992. Solution structure of FK506 bound to FKBP-12. FEBS Letters, May 4.

Liu, J., J. D. Farmer, Jr., W. S. Lane, J. Friedman, I. Weissman, and S. L. Schreiber. 1991. Calcineurin Is a Common Target of Cyclophilin-Cyclosporin A and FKBP-FK506 Complexes. Cell 66, 807–15.

Michnick, S. W., M. K. Rosen, T. J. Wandless, M. Karplus, and S. L. Schreiber. 1991. Solution Structure of FKBP, a Rotamase Enzyme and Receptor for FK506 and Rapamycin. Science 252, 836-39

Moore, J. M., D. A. Peattie, M. J. Fitzgibbon, J. A. Thomson, et al. 1991. Solution structure of the major binding protein for the immunosuppressant FK506. Nature 351, 248-50.

Navia, M. A., P. M. D. Fitzgerald, B. M. McKeever, C.-T. Leu, J. C. Heimbach, W. K. Herber, I. S. Sigal, P. L. Darke, and J. P. Springer. 1989. Three-dimensional structure of aspartyl protease from immunodeficiency virus HIV-1. Nature 337, 615-20.

Pauwels, R., K. Andries, J. Desmyter, D. Schols, M. J. Kukla, H. J. Breslin, A. Raeymaeckers, J. Van Gelder, R. Woestenborghs, J. Heykants, K. Schellekens, M. A. C. Janssen, E. De Clercq, and P. A. J. Janssen. 1990. Potent and selective inhibition of HIV-1 replication in vitro by a novel series of TIBO derivatives. Nature 343, 470-74.

Schreiber, S. L. 1991. Chemistry and Biology of the Immunophilins and Their Immunosuppressive Ligands. Science 251, 283-87.

———. 1992. Using the Principles of Organic Chemistry to Explore Cell Biology. Chemical and Engineering News, Oct. 26.

Siekierka, J. J., S. H. Y. Hung, M. Poe, C. S. Lin, and N. H. Sigal. 1989. A cytosolic binding protein for the immunosuppressant FK506 has peptidyl-prolyl isomerase activity but is distinct from cyclophilin. Nature 341, 755-57.

Takahashi, N., T. Hayano, and M. Suzuki. 1989. Peptidyl-prolyl cistrans isomerase is the cyclosporin A-binding protein cyclophilin. Nature 337, 473-75.

Van Duyne, G. D., R. F. Standaert, P. A. Karplus, S. L. Schreiber, and J. Clardy. 1991. Atomic Structure of FKBP-FK506, an Immunophilin-Immunosuppressant Complex. Science 252, 839-42.

•  •  •

For the sections on Tom Starzl and transplantation immunology, I relied on many sources. Much of the work originally appeared as an article in The New York Times Magazine (“The Drug That Works in Pittsburgh,” September 30, 1990), and though I was generally required by the University of Pittsburgh to be accompanied by a member of the staff when speaking with patients on my visits to the medical center, Starzl and all members of the staff were consistently open and receptive. I owe thanks to Cheryl Ackerman, Barbara Banner, Richard Cohen, Benjamin Eidelman, Anthony Demitris, Ashok Jain, Yukio Murase, Jerry McCauley, Mike Nalesnick, Camillo Ricordi, Raman Venkataramanan, and Vijay Warty. I also am indebted to Starzl’s remarkable secretary, Terry Mangan.

Takenori Ochiai, the Japanese surgeon who pioneered the use of FK-506 in animals and whose role is often regrettably obscured by Starzl’s, was extremely helpful in helping me to establish the early history of the drug. I owe him a special thanks.

Starzl’s autobiography, The Puzzle People (1992, Pittsburgh, PA: University of Pittsburgh Press) was invaluable, as was Many Sleepless Nights by Lee Gutkind (1990, Pittsburgh, PA: University of Pittsburgh Press), especially for its descriptions of life on the transplant wards and of the Hardanger Vidda. The following books and articles were also of great use:

Billingham, R. E. 1966. Tissue Transplantation: Scope and Prospect. Science 153, 266-70.

Billingham, R. E., P. L. Krohn, and P. B. Medawar. 1951. Effect of Cortisone on Survival of Skin Homografts in Rabbits. British Medical Journal, May 26, 1158-63.

Foreman, J. 1987. Cracking the secrets of body’s own “army.” Boston Globe, 30-31, Oct. 18.

Medawar, P. 1957. The Uniqueness of the Individual. New York: Basic Books.

Silverstein, A. M. 1989. The History of Immunology. Fundamental Immunology, 21-37. New York: Raven Press.

Starzl, T. E. 1991. My Thirty-five Year View of Organ Transplantation. History of Transplantation: 35 Recollections, ed. P. I. Terasaki. Los Angeles: UCLA Tissue Typing Laboratory.

———. 1990. The Development of Clinical Renal Transplantation. American Journal of Kidney Diseases 16, 548-56.

Starzl, T. E., S. Todo, A. Tzakis, M. Alessiani, A. Casavilla, K. AbuElmagd, and J. J. Fung. 1991. The Many Faces of Multivisceral Transplantation. Surgery, Gynecology and Obstetrics 172, 335-44.

Thomas, E. D., 1987. Bone Marrow Transplantation in Hematologic Malignancies. Hospital Practice, 77-91, Feb. 15.

Thomas, E. D., H. L. Lochte, and J. Ferrebee. 1959. Irradiation of the Entire Body and Marrow Transplantation: Some Observations and Comments. Blood 14, 1-23, January.

Thompson, L. 1988. Jean-François Borel’s Transplanted Dream. Washington Post, Nov. 15.

•  •  •

Four former senior research directors at Merck—Bob Denklewalter, Ralph Hirschmann, Eugene Cordes, and H. Boyd Woodruff—helped me immeasurably in characterizing the Tishler years. Woodruff, a protégé of Selman Waksman, tutored me in microbiology and soil screening. I also am grateful to Leon Gortler, who, along with John Heitmann, conducted a comprehensive interview of Tishler for the American Chemical Society’s Eminent Chemists series, and to Peter Jacobi, chairman of the Chemistry Department at Wesleyan University, who directed me toward material about both Tishler and R. B. Woodward. Mary Feiser, a member of the chemistry faculty of Harvard for more than fifty years, also enriched my understanding, as did Don Ciappanelli, former director of Harvard’s chemistry labs, who provided me with videotape of several of Woodward’s lectures from the university archives.

I relied principally on two sets of archival material for information about medical research during World War II: the papers of A. N. Richards, which are at the University of Pennsylvania and which include the minutes of the Committee for Medical Research, and the personal papers of Vannevar Bush, which are at the Library of Congress.

The books and articles I found most useful for information about the history of drug research, especially regarding Tishler, Merck, Woodward, and Harvard, are:

Barber, B. 1952. Science and the Social Order. Glencoe, IL: The Free Press.

Baxter, J. P., III. 1946. Scientists Against Time. Boston: Little, Brown.

Borkin, J. 1978. The Crime and Punishment of I. G. Farben. New York: The Free Press.

Braithwaite, J. 1984. Corporate Crime in the Pharmaceutical Industry. London: Routledge & Kegan Paul.

Browning, C. H. 1955. Emil Behring and Paul Ehrlich: Their Contributions to Science. Nature 175, 570-75.

Conant, J. B. 1970. My Several Lives: Memoirs of a Social Inventor. New York: Harper and Row.

Crosby, A. W., Jr. 1976. Epidemic and Peace, 1918. Westport, CT: Greenwood Press.

Dolphin, D. 1977. Robert Burns Woodward: Three Score Years and Then? Aldrichimica Acta 10, No. 1, 3-9.

DuBos, R. J. 1950. Louis Pasteur: Free Lance of Science. Boston: Little, Brown.

Engle, L. 1951. Cortisone and Plenty of It. Harper’s 203, 56-62.

Epstein, S., and B. Williams. 1956. Miracles from Microbes: The Road to Streptomycin. New Brunswick, NJ: Rutgers University Press.

Galdston, I. 1943. Behind the Sulfa Drugs: A Short History of Chemotherapy. New York: D. Appleton Century.

Gallese, L. 1990. Venture Capital Strays Far from Its Roots. New York Times Magazine (The Business World), 24-39, April 1.

Garland, J. E. 1961. Every Man Our Neighbor: A Brief History of the Massachusetts General Hospital. Boston: Little, Brown.

Harris, R. 1964. The Real Voice. New York: Macmillan.

Hayes, P. 1987. Industry and Ideology: IG Farben in the Nazi Era. London: Cambridge University Press.

Hixson, J. 1976. The Patchwork Mouse. Garden City: NY: Anchor Press.

Hobby, G. L. 1985. Penicillin: Meeting the Challenge. New Haven: Yale University Press.

Kahn, E. J. 1981. Jock: The Life and Times of John Hay Whitney. Garden City: NY, Doubleday and Co.

Liebenau, J. 1987. Medical Science and Medical Industry: The Formation of the American Pharmaceutical Industry. Baltimore, MD: Johns Hopkins University Press.

Mahoney, T. 1959. The Merchants of Life: An Account of the American Pharmaceutical Industry. New York: Harper Brothers.

Merck and Co. 1992. Values and Visions: A Merck Century.

Merck, Sharp and Dohme. 1977. Profiles in Discovery.

Merck, Sharp and Dohme Research Laboratories. 1962. By Their Fruits.

Noble, D. F. 1977. America by Design: Science, Technology and the Rise of Corporate Capitalism. New York: Alfred A. Knopf.

Pearson, M. 1969. The Million Dollar Bugs. New York: G. P. Putnam’s Sons.

Pfeiffer, J. 1939. Sulfanilamide: The Story of a Great Medical Discovery. Harper’s, March.

Rettig, R. A. 1977. Cancer Crusade: The Story of the National Cancer Act of 1971. Princeton, NJ: Princeton University Press.

Richards, A. N. 1964. Production of Penicillin in the United States (1941-1946). Nature 201, 441-45.

Roberts, J. D. 1990. The Right Place at the Right Time. Washington, DC: American Chemical Society.

Roberts, R. 1989. Serendipity: Accidental Discoveries in Science. New York: John Wiley and Sons.

Roueché, B. 1955. Annals of Medicine: Ten Feet Tall. The New Yorker, Sept. 10.

Russell, F. 1957. A Journal of the Plague: The 1918 Influenza. Yale Review, December.

Sheehan, John C. 1982. The Enchanted Ring: The Untold Story of Penicillin. Cambridge, MA: The MIT Press.

Sheehan, J. C, and R. N. Ross. 1982. The Fire That Made Penicillin Famous. Yankee, 125-27, November.

Smith, F. R. 1947. Good Microbes Fight Bad Ones. The New York Times Magazine, 17-19, Aug. 10.

Soper, G. A. 1919. The Lessons of the Pandemic. Science 49, 501-5.

Sneader, W. 1985. Drug Discovery: The Evolution of Modern Medicines. Chichester: Wiley and Sons.

Sturchio, J. L. 1981. Chemists and Industry in Modern America: Studies in the Historical Application of Science Indicators. Graduate dissertation. University of Pennsylvania.

Swann, J. P. 1988. Academic Scientists and the Pharmaceutical Industry: Cooperative Research in Twentieth Century America. Baltimore, MD: Johns Hopkins University Press.

Talalay, P. (ed.) 1964. Drugs in Our Society. Baltimore, MD: Johns Hopkins University Press.

Temin, P. 1980. Taking Your Medicine. Cambridge, MA: Harvard University Press.

Tishler, M. 1974. Is Science Dead? New Brunswick Lecture, May 15.

———. 1969. The Siege of the House of Reason. Science 166, 192-95.

Todd, A. 1983. A Time to Remember: The Autobiography of a Chemist. London: Cambridge University Press.

Tuchman, B. W. 1978. A Distant Mirror: The Calamitous 14th Century. New York: Alfred A. Knopf.

Vogel, M. 1980. The Invention of the Modern Hospital. Chicago: University of Chicago Press.

Waksman, S. A. 1954. My Life with the Microbes. New York: Simon and Schuster.

———. 1949. Streptomycin: Nature and Practical Applications. Baltimore, MD: Williams and Wilkins.

Wilson, D. 1976. In Search of Penicillin. New York: Alfred A. Knopf.

Woodruff, H. B. 1981. A Soil Microbiologist’s Odyssey. Annual Review of Microbiology 35, 1-28.

•  •  •

For historical information about Harvard, I relied primarily on Richard Norton Smith’s The Harvard Century: The Making of a University to a Nation (1986, New York: Simon and Schuster) and Carl Vigeland’s Great Good Fortune: How Harvard Makes Its Money (1986, Boston: Houghton Mifflin).

•  •  •

Management consultants Jim Feeney and Harutoshi Mayazumi taught me about the Japanese pharmaceutical industry and the ways of Japanese business. I found especially useful The Samurai Factor: Japanese strategic thinking in industry, a monograph coauthored by Mayazumi and Joseph Rudzinski. Other books and articles about Japan that I found useful were:

Christopher, R. C. 1983. The Japanese Mind: The Goliath Explained. New York: Linden Press.

Gibney, F. 1982. Miracle by Design: The Real Reasons Behind Japan’s Economic Success. New York: Times Books.

Prestowitz, C. V., Jr. 1988. Trading Places: How We Allowed Japan to Take the Lead. New York: Basic Books.

Reich, R. 1983. The Next American Frontier. New York: Times Books.

Toland, J. 1970. The Rising Sun. New York: Random House.

•  •  •

The biotechnology industry is still too young to be the subject of many long-term histories. The best primer I found is Robert Teitleman’s Gene Dreams (1989, New York: Basic Books). To understand the early scientific, legal, and financial precepts behind the industry, I turned to the following articles:

Biddle, W. 1981. A Patent on Knowledge: Harvard goes public. Harper’s, June.

Culliton, B. 1977. Harvard and Monsanto: The $23 Million Alliance. Science 195, 759-63.

Gurin, J., and N. Pfund. 1980. Bonanza in the Biolab. The Nation, Nov. 22.

Noble, D., and N. Pfund. 1980. Business Goes Back to College. The Nation, Sept. 20.

Wade, N. 1980. Gene Goldrush Splits Harvard, Worries Brokers. Science 210, 878-79.