The Emperor of All Maladies

by Siddhartha Mukherjee

  354 In their respective papers: David Baltimore, “RNA-Dependent DNA Polymerase in Virions of RNA Tumor Viruses,” Nature 226, no. 5252 (1970): 1209–11; and H. M Temin and S. Mizutani, “RNA-Dependent DNA Polymerase in Virions of Rous Sarcoma Virus,” Nature 226, no. 5252 (1970): 1211–13.

  355 Spiegelman raced off to prove: Weinberg, Racing to the Beginning, 70.

  355 “It became his single-minded preoccupation”: Robert Weinberg, interview with author, January 2009.

  356 “The hoped-for human virus”: Weinberg, Racing to the Beginning, 83.

  “The hunting of the sarc”

  357 For the Snark was a Boojum, you see: Lewis Carroll, The Hunting of the Snark: An Agony in Eight Fits (New York: Macmillan, 1914), 53.

  358 By analyzing the genes altered in these mutant viruses: For a review of Duesberg’s and Vogt’s contributions, see G. Steven Martin, “The Hunting of the Src,” Nature Reviews Molecular Cell Biology 2, no. 6 (2001): 467–75.

  358 A chance discovery in Ray Erikson’s laboratory: J. S. Brugge and R. L. Erikson, “Identification of a Transformation-Specific Antigen Induced by an Avian Sarcoma Virus,” Nature 269, no. 5626 (1977): 346–48.

  360 other scientists nicknamed the project: See, for instance, Martin, “The Hunting of the Src.”

  361 “Src,” Varmus wrote in a letter: Harold Varmus to Dominique Stehelin, February 3, 1976, Harold Varmus papers, National Library of Medicine archives. Also see Stehelin et al., “DNA Related to the Transforming Genes of Avian Sarcoma Viruses Is Present in Normal DNA,” Nature 260, no. 5547 (March 1976): 170–73.

  362 “Nature,” Rous wrote in 1966: Peyton Rous, “The Challenge to Man of the Neoplastic Cell,” Nobel Lectures, Physiology or Medicine, 1963–1970 (Amsterdam: Elsevier Publishing Company, 1972).

  363 “We have not slain our enemy”: Harold Varmus, “Retroviruses and Oncogenes I,” Nobel Lectures, Physiology or Medicine, 1981–1990, ed. Jan Lindsten (Singapore: World Scientific Publishing Co., 1993).

  The Wind in the Trees

  364 The fine, fine wind: D. H. Lawrence, “The Song of a Man Who Has Come Through,” Penguin Book of First World War Poetry, ed. John Silkin (New York: Penguin Classics, 1996), 213.

  365 Rowley’s specialty was studying: Janet Rowley, “Chromosomes in Leukemia and Lymphoma,” Seminars in Hematology 15, no. 3 (1978): 301–19.

  365 In the late 1950s, Peter Nowell: P. C. Nowell and D. Hungerford, Science 142 (1960): 1497.

  366 In 1969, Knudson moved: Al Knudson, interview with author, July 2009.

  367 “The number two,” he recalled: Ibid.

  368 Knudson’s two-hit theory: A. Knudson, “Mutation and Cancer: Statistical Study of Retinoblastoma,” Proceedings of the National Academy of Sciences of the United States of America 68, no. 4 (1971): 820–23.

  368 “Two classes of genes are apparently critical”: A. Knudson, “The Genetics of Childhood Cancer,” Bulletin du Cancer 75, no. 1 (1988): 135–38.

  369 “jammed accelerators” and “missing brakes”: J. Michael Bishop, in Howard M. Temin et al., The DNA Provirus: Howard Temin’s Scientific Legacy (Washington, DC: ASM Press, 1995), 89.

  A Risky Prediction

  370 They see only their: Plato, The Republic of Plato, Benjamin Jowett, trans. (Oxford: Clarendon Press, 1908), 220.

  370 “Isolating such a gene”: Robert Weinberg, interview with author, January 2009.

  371 “The chair of the department”: Ibid.

  371 Clarity came to him one morning: Ibid.

  373 In the summer of 1979, Chiaho Shih: Ibid.

  374 “If we were going to trap a real oncogene”: Ibid. Also, Cliff Tabin, interview with author, December 2009.

  374 In 1982, Weinberg: C. Shih and R. A. Weinberg (1982), “Isolation of a Transforming Sequence from a Human Bladder Carcinoma Cell Line,” Cell 29: 161–169. Also see M. Goldfarb, K. Shimizu, M. Perucho, and M. Wigler, “Isolation and Preliminary Characterization of a Human Transforming Gene from T24 Bladder Carcinoma Cells,” Nature 296 (1982): 404–9. Also see S. Pulciani et al., “Oncogenes in Human Tumor Cell Lines: Molecular Cloning of a Transforming Gene from Human Bladder Carcinoma Cells,” Proceedings of the National Academy of Sciences. USA 79: 2845–49.

  375 “Once we had cloned”: Robert Weinberg, Racing to the Beginning of the Road (New York: Bantam, 1997), 165.

  375 Ray Erikson traveled to Washington: Ray Erikson, interview with author, October 2009.

  375 “I don’t remember any enthusiasm”: Ibid.

  376 “How can one capture genes”: Robert Weinberg, One Renegade Cell (New York: Basic Books, 1999), 74.

  376 “We knew where Rb lived”: Weinberg, interview with author.

  377 Dryja began his hunt for Rb: Thaddeus Dryja, interview with author, November 2008.

  378 “I stored the tumors obsessively”: Ibid.

  378 “It was at that moment”: Ibid.

  380 “We have isolated [a human gene]”: Stephen H. Friend et al., “A Human DNA Segment with Properties of the Gene that Predisposes to Retinoblastoma and Osteosarcoma,” Nature 323, no. 6089 (1986): 643–46.

  380 When scientists tested the gene isolated by Dryja: D. W. Yandell et al., “Oncogenic Point Mutations in the Human Retinoblastoma Gene: Their Application to Genetic Counseling,” New England Journal of Medicine 321, no. 25 (1989): 1689–95.

  380 Its chief function is to bind to several other proteins: See for instance James A. DeCaprio, “How the Rb Tumor Suppressor Structure and Function was Revealed by the Study of Adenovirus and SV40,” Virology 384, no. 2 (2009): 274–84.

  380 a horde of other oncogenes and anti-oncogenes: George Klein, “The Approaching Era of the Tumor Suppressor Genes,” Science 238, no. 4833 (1987): 1539–45.

  382 Philip Leder’s team at Harvard engineered: Timothy A. Stewart, Paul K. Pattengale, and Philip Leder, “Spontaneous Mammary Adenocarcinomas in Transgenic Mice That Carry and Express MTV/myc Fusion Genes,” Cell 38 (1984): 627–37.

  382 In 1988, he successfully applied for a patent: Daniel J. Kevles, “Of Mice & Money: The Story of the World’s First Animal Patent,” Daedalus 131, no. 2 (2002): 78.

  382 “The active myc gene does not appear to be sufficient”: Stewart, Pattengale, and Leder, “Spontaneous Mammary Adenocarcinomas,” 627–37.

  383 Leder created a second OncoMouse: E. Sinn et al., “Coexpression of MMTV/v-Ha-ras and MMTV/c-myc Genes in Transgenic Mice: Synergistic Action of Oncogenes in Vivo,” Cell 49, no. 4 (1987): 465–75.

  383 “Cancer genetics,” as the geneticist Cliff Tabin: Tabin, interview with author, November 2009.

  The Hallmarks of Cancer

  384 I do not wish to achieve immortality: Eric Lax, Woody Allen and His Comedy (London: Elm Tree Books, 1976).

  385 “The four molecular alterations accumulated”: B. Vogelstein et al., “Genetic Alterations During Colorectal-Tumor Development,” New England Journal of Medicine 319, no. 9 (1988): 525–32.

  387 A tumor could thus “acquire” its own blood supply: Judah Folkman, “Angiogenesis,” Annual Review of Medicine 57 (2006): 1–18.

  387 Folkman’s Harvard colleague Stan Korsmeyer: W. B. Graninger et al., “Expression of Bcl-2 and Bcl-2-Ig Fusion Transcripts in Normal and Neoplastic Cells,” Journal of Clinical Investigation 80, no. 5 (1987): 1512–15. Also see Stanley J. Korsemeyer, “Regulators of Cell Death,” 11, no. 3 (1995): 101–5.

  390 In the fall of 1999, Robert Weinberg attended: Robert Weinberg, interview with author, January 2009.

  390 In January 2000, a few months after their walk: Douglas Hanahan and Robert A. Weinberg, “The Hallmarks of Cancer,” Cell 100, no. 1 (2000): 57–70.

  390 “We discuss . . . rules that govern”: Ibid.

  392 “With holistic clarity of mechanism”: Ibid. Also see Bruce Chabner, “Biological Basis for Cancer Treatment,” Annals of Internal Medicine 118, no. 8 (1993): 633–37.

  PART SIX:

  THE FRUITS OF LONG ENDEAVORS

  393 We are really reaping the fruits:
Mike Gorman, letter to Mary Lasker, September 6, 1985, Mary Lasker Papers.

  393 The National Cancer Institute, which has overseen: “To Fight Cancer, Know the Enemy,” New York Times, August 5, 2009.

  393 The more perfect a power is: See for instance St. Aquinas, Commentary on the Book of Causes, trans. Vincent Guagliardo et al. (CUA Press, 1996), 9.

  “No one had labored in vain”

  395 Have you met Jimmy?: Jimmy Fund solicitation pamphlet, 1963.

  395 In the summer of 1997: “Einar Gustafson, 65, ‘Jimmy’ of Child Cancer Fund, Dies,” New York Times, January 24, 2001; “Jimmy Found,” People, June 8, 1998.

  395 Only Sidney Farber had known: Phyllis Clauson, interview with author, 2009.

  395 “Jimmy’s story,” she recalled: Ibid.

  396 A few weeks later, in January 1998: Karen Cummings, interview with author, 2009.

  396 And so it was in May 1998: Ibid.

  397 “Everything has changed”: Clauson, interview with author.

  398 “How to overcome him became”: Max Lerner, Wrestling with the Angel: A Memoir of My Triumph over Illness (New York: Touchstone, 1990), 26.

  398 The poet Jason Shinder wrote, “Cancer”: “The Lure of Death,” New York Times, December 24, 2008.

  400 “I’ve made a long voyage”: Maxwell E. Perkins, “The Last Letter of Thomas Wolfe and the Reply to It,” Harvard Library Bulletin, Autumn 1947, 278.

  401 In 2005, an avalanche of papers: See, for example, Peter Boyle and Jacques Ferlay, “Mortality and Survival in Breast and Colorectal Cancer,” Nature Reviews and Clinical Oncology 2 (2005): 424–25; Itsuro Yoshimi and S. Kaneko, “Comparison of Cancer Mortality (All Malignant Neoplasms) in Five Countries: France, Italy, Japan, UK and USA from the WHO Mortality Database (1960–2000),” Japanese Journal of Clinical Oncology 35, no. 1 (2005): 48–51; Alison L. Jones, “Reduction in Mortality from Breast Cancer,” British Medical Journal 330, no. 7485 (2005): 205–6.

  401 The mortality for nearly every major: Eric J. Kort et al., “The Decline in U.S. Cancer Mortality in People Born Since 1925,” Cancer Research 69 (2009): 6500–6505.

  401 mortality had declined by about 1 percent: Ibid. Also see Ahmedin Jemal et al., “Cancer Statistics, 2005,” CA: A Cancer Journal for Clinicians 55 (2005): 10–30; “Annual Report to the Nation on the Status of Cancer, 1975–2002,” Journal of the National Cancer Institute, October 5, 2005.

  401 between 1990 and 2005, the cancer-specific: Ibid.

  401 more than half a million American men and women: American Cancer Society, Cancer Facts & Figures 2008 (Atlanta: American Cancer Society, 2008), 6.

  402 Donald Berry, a statistician in Houston: Donald A. Berry, “Effect of Screening and Adjuvant Therapy on Mortality from Breast Cancer,” New England Journal of Medicine 353, no. 17 (2005): 1784–92.

  402 “No one,” as Berry said: Donald Berry, interview with author, November 2009.

  403 Mary Lasker died of heart failure: “Mary W. Lasker, Philanthropist for Medical Research, Dies at 93,” New York Times, February 23, 1994.

  403 the cancer geneticist Ed Harlow captured: Ed Harlow, “An Introduction to the Puzzle,” Cold Spring Harbor Symposia on Quantitative Biology 59 (1994): 709–23.

  404 In the winter of 1945, Vannevar Bush: Vannevar Bush, Science the Endless Frontier: A Report to the President by Vannevar Bush, Director of the Office of Scientific Research and Development, July 1945 (Washington, D.C.: U.S. Government Printing Office, 1945).

  New Drugs for Old Cancers

  405 In the story of Patroclus: Louise Gluck, The Triumph of Achilles (New York: Ecco Press, 1985), 16.

  405 The perfect therapy has not been developed: Bruce Chabner letter to Rose Kushner, Rose Kushner Papers, Box 50.

  408 In the summer of 1985: Laurent Degos, “The History of Acute Promyelocytic Leukaemia,” British Journal of Haematology 122, no. 4 (2003): 539–53; Raymond P. Warrell et al., “Acute Promyelocytic Leukemia,” New England Journal of Medicine 329, no. 3 (1993): 177–89; Huang Meng-er et al., “Use of All-Trans Retinoic Acid in the Treatment of Acute Promyelocytic Leukemia,” Blood 72 (1988): 567–72.

  409 “The nucleus became larger”: Meng-er et al., “Use of All-Trans Retinoic Acid.”

  410 In 1982, a postdoctoral scientist: Robert Bazell, Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer (New York: Random House, 1998), 17.

  411 “It would have been an overnight test”: Ibid.

  411 although Padhy’s discovery was published: Lakshmi Charon Padhy et al., “Identification of a Phosphoprotein Specifically Induced by the Transforming DNA of Rat Neuroblastomas,” Cell 28, no. 4 (1982): 865–71.

  A City of Strings

  412 In Ersilia, to establish the relationships: Italo Calvino, Invisible Cities (Boston: Houghton Mifflin Harcourt, 1978), 76.

  412 In his book Invisible Cities: Ibid.

  413 In the summer of 1984: Robert Bazell, Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer (New York: Random House, 1998).

  414 In 1982, Genentech unveiled the first: “A New Insulin Given Approval for Use in U.S.,” New York Times, October 30, 1982.

  414 in 1984, it produced a clotting factor: “Genentech Corporate Chronology,” http://www .gene.com/gene/about/corporate/history/timeline.html (accessed January 30, 2010).

  414 in 1985, it created a recombinant version: Ibid.

  414 It was under the aegis: L. Coussens et al., “3 Groups Discovered the Neu Homolog (Her-2, Also Called Erb-b2),” Science 230 (1985): 1132–39. Also see T. Yamamoto et al., Nature 319 (1986): 230–34, and C. King et al., Science 229 (1985): 974–76.

  415 In the summer of 1986: Bazell, Her-2, and Dennis Slamon, interview with author, April 2010.

  415 Dennis Slamon, a UCLA oncologist: Ibid.

  415 a “velvet jackhammer”: Eli Dansky, “Dennis Slamon: From New Castle to New Science,” SU2C Mag, http://www.standup2cancer.org/node/194 (accessed January 24, 2010).

  415 “a murderous resolve”: Ibid.

  415 In Chicago, Slamon had performed a series: See, for example, I. S. Chen et al., “The x Gene Is Essential for HTLV Replication,” Science 229, no. 4708 (1985): 54–58; W. Wachsman et al., “HTLV x Gene Mutants Exhibit Novel Transcription Regulatory Phenotypes,” Science 235, no. 4789 (1987): 647–77; C. T. Fang et al., “Detection of Antibodies to Human T-Lymphotropic Virus Type 1 (HTLV-1),” Transfusion 28, no. 2 (1988): 179–83.

  415 If Ullrich sent him the DNA probes: Details of the Ullrich and Slamon collaboration are outlined in Bazell, Her-2, and from Slamon, interview with author.

  416 In a few months: D. Slamon et al., “Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the Her-2/Neu Oncogene,” Science 235 (1987): 177–82.

  417 In the mid-1970s, two immunologists at Cambridge University: See Nobel Lectures, Physiology or Medicine, 1981–1990, ed. Jan Lindsten (Singapore: World Scientific Publishing, 1993).

  418 “allergic to cancer”: Merrill Goozner, The $800 Million Pill: The Truth Behind the Cost of New Drugs (Berkeley: University of California Press, 2004), 195.

  418 Drained and dejected: Ibid.

  418 “Nobody gave a shit”: Bazell, Her-2, 49.

  419 “When I was finished with all that”: Ibid. Also Barbara Bradfield, interview with author, July 2008.

  419 But there was more river to ford: Ibid.

  420 “His tone changed,” she recalled: Ibid.

  420 “I was at the end of my road”: Ibid

  420 “Survivors look back and see omens”: Joan Didion, The Year of Magical Thinking (New York: Vintage, 2006), 152.

  420 On a warm August morning in 1992: Bradfield, interview with author. Details of the trial and the treatment are from Bradfield’s interview, from Bazell’s Her-2, and from Slamon, interview with author, April 2010.

  Drugs, Bodies, and Proof

  423 Dying people don’t have time or energy: “Dying for Compassion,” Breast Cancer Action Newslette
r 31 (August 1995).

  423 It seemed as if we had: Musa Mayer, Breast Cancer Action Newsletter 80 (February/March 2004).

  423 “True success happens”: Breast Cancer Action Newsletter 32 (October 1995).

  424 The number of women enrolled in these trials: Robert Bazell, Her-2: The Making of Herceptin, a Revolutionary Treatment for Breast Cancer (New York: Random House, 1998), 160–80.

  424 “We do not provide . . . compassionate use”: Ibid., 117.

  424 “If you start making exceptions”: Ibid., 127.

  424 “Why do women dying of breast cancer”: “Dying for Compassion,” Breast Cancer Action Newsletter.

  424 “Scientific uncertainty is no excuse”: Charlotte Brody et al., “Rachel’s Daughters, Searching for the Causes of Breast Cancer: A Light-Saraf-Evans Production Community Action & Resource Guide,” http://www.wmm.com/filmCatalog/study/rachelsdaughters.pdf (accessed January 31, 2010).

  424 Marti Nelson, for one, certainly could not: Marti Nelson’s case and its aftermath are described in Bazell, Her-2.

  427 On Sunday, May 17: Bruce A. Chabner, “ASCO 1998: A Commentary,” Oncologist 3, no. 4 (1998): 263–66; D. J. Slamon et al., “Addition of Herceptin to First-Line Chemotherapy for HER-2 Overexpressing Metastatic Breast Cancer Markedly Increases Anti-Cancer Activity: A Randomized, Multinational Controlled Phase III Trial (abstract 377),” Proceedings of the American Society of Clinical Oncology 16 (1998): 377.

  427 In the pivotal 648 study: Slamon et al., “Addition of Herceptin to First-Line Chemotherapy,” 377.

  428 In 2003, two enormous multinational studies: Romond et al. and Piccart-Gebhart et al., New England Journal of Medicine 353 (2005): 1659–84.

  428 “The results,” one oncologist wrote: Gabriel Hortobagyi, “Trastuzumab in the treatment of breast cancer,” editorial, New England Journal of Medicine, 353, no. 16 (2005): 1734.

  428 “The company,” Robert Bazell, the journalist: Bazell, Her-2, 180–82.

  A Four-Minute Mile

  430 The nontoxic curative compound: James F. Holland, “Hopes for Tomorrow versus Realities of Today: Therapy and Prognosis in Acute Lymphocytic Leukemia of Childhood,” Pediatrics 45:191–93.

  430 Why, it is asked, does the supply of new miracle drugs: Lewis Thomas, The Lives of a Cell (New York: Penguin, 1978), 115.