The Emperor of All Maladies

by Siddhartha Mukherjee

  It was like watching someone locked in a chess game. Every time Germaine’s disease moved, imposing yet another terrifying constraint on her, she made an equally assertive move in return. The illness acted; she reacted. It was a morbid, hypnotic game—a game that had taken over her life. She dodged one blow only to be caught by another. She, too, was like Carroll’s Red Queen, stuck pedaling furiously just to keep still in one place.

  Germaine seemed, that evening, to have captured something essential about our struggle against cancer: that, to keep pace with this malady, you needed to keep inventing and reinventing, learning and unlearning strategies. Germaine fought cancer obsessively, cannily, desperately, fiercely, madly, brilliantly, and zealously—as if channeling all the fierce, inventive energy of generations of men and women who had fought cancer in the past and would fight it in the future. Her quest for a cure had taken her on a strange and limitless journey, through Internet blogs and teaching hospitals, chemotherapy and clinical trials halfway across the country, through a landscape more desolate, desperate, and disquieting than she had ever imagined. She had deployed every morsel of energy to the quest, mobilizing and remobilizing the last dregs of her courage, summoning her will and wit and imagination, until, that final evening, she had stared into the vault of her resourcefulness and resilience and found it empty. In that haunted last night, hanging on to her life by no more than a tenuous thread, summoning all her strength and dignity as she wheeled herself to the privacy of her bathroom, it was as if she had encapsulated the essence of a four-thousand-year-old war.

  —S.M., June 2010

  The first medical description of cancer was found in an Egyptian text originally written in 2500 BC: “a bulging tumor in [the] breast . . . like touching a ball of wrappings.” Discussing treatment, the ancient scribe noted: “[There] is none.”

  The anatomist Andreas Vesalius (1514–1564) tried to discover the source for black bile, the fluid thought to be responsible for cancer. Unable to find it, Vesalius launched a new search for cancer’s real cause and cure.

  Medieval surgeons attacked cancer using primitive surgical methods. Johannes Scultetus (1595–1645) describes a mastectomy, the surgical removal of breast cancer, using fire, acid and leather bindings.

  Between 1800 and 1900, surgeons devised increasingly aggressive operations to attack the roots of cancer in the body. In the 1890s, William Stewart Halsted at Johns Hopkins University devised the radical mastectomy—an operation to extirpate the breast, the muscles beneath the breast and the associated lymph nodes.

  “The patient was a young lady whom I was loath to disfigure,” Halsted wrote. In this etching, Halsted presented an idealized patient. Real cancer patients tended to be older women with larger tumors, far less able to withstand this radical attack.

  When radium was discovered by Marie and Pierre Curie, oncologists and surgeons began to deliver high doses of radiation to tumors. Yet radiation was itself carcinogenic: Marie Curie died from a leukemia caused by decades of X-ray exposure.

  During World War Two, hundreds of tons of mustard gas were released on the Bari harbor in Italy during an air raid. The gas decimated normal white blood cells in the body, leading pharmacologists to fantasize about using a similar chemical to kill cancers of white blood cells. Chemotherapy—chemical warfare on cancer cells—was inspired, literally, by war.

  In 1947, Sidney Farber discovered a folic acid analog called aminopterin that killed rapidly dividing cells in the bone marrow. Using aminopterin, Farber obtained brief, tantalizing remissions in acute lymphoblastic leukemia. One of Farber’s first patients was two-year-old Robert Sandler.

  From her all-white apartment in New York City, Mary Lasker, a legendary entrepreneur, socialite, lobbyist and advocate, helped launch a national battle against cancer. Lasker would become the “fairy godmother” of cancer research; she would coax and strong-arm the nation to initiate a War on Cancer.

  Farber’s patient, Einar Gustafson—known as “Jimmy”—a baseball fan, became the unofficial mascot for children’s cancer. The Jimmy Fund, founded in 1948, was one of the most powerful cancer advocacy organizations, with Ted Williams a vocal supporter.

  Sidney Farber, Lasker’s confidant, mentor and co-conspirator, provided medical legitimacy to the War on Cancer and oversaw the building of a new cancer ward in Boston.

  At the National Cancer Institute (NCI) in the 1960s physicians Emil Frei

  Emil Freireich forged a strategy to cure acute lymphoblastic leukemia using highly toxic drugs.

  Henry Kaplan, a physician-scientist, used radiation therapy to cure Hodgkin’s lymphoma. The cures of lymphoblastic leukemia and Hodgkin’s lymphoma invigorated the War on Cancer, raising the possibility of Farber’s “universal cure.”

  Inspired by the early victories of chemotherapy, cancer advocates, led by Lasker and Farber, urged the nation to launch a War on Cancer. In 1970, the Laskerites published a full-page advertisement in the New York Times, coaxing Nixon to support their war.

  Many scientists criticized the War on Cancer as premature, arguing that a political cure would not lead to a medical cure.

  Lasker’s use of canny advertising and potent imagery still inspires generations of advocates, including Greenpeace.

  In 1775, the London surgeon Percivall Pott observed that scrotal cancer occurred disproportionately in adolescent chimney sweeps, and proposed a link between soot and scrotal cancer, launching the hunt for preventable carcinogens in the environment.

  Innovative studies in the 1950s established the link between cigarette smoking and lung cancer. Yet early warning labels affixed on packages in the 1960s avoided the word “cancer.” Explicit warning labels were not required until decades later.

  Although smoking rates have fallen in most developed nations, active marketing and bold political lobbying allows the tobacco industry to flourish in others, creating a new generation of smokers (and of future cancer victims).

  Harold Varmus and J. Michael Bishop discovered that cancer is caused not by exogenous viruses, but by the activation of endogenous precursor genes that exist in all normal cells. Cancer, Varmus wrote, is a “distorted version” of our normal selves.

  Working with collaborators across the globe, Robert Weinberg, of MIT, discovered distorted genes in mouse and human cancer cells.

  Scientists have sequenced the entire genome (all 23,000 genes), making it possible to document every genetic change (relative to normal genes). Dots represent mutations in genes found in colon cancer, with commonly mutated genes becoming “hills” and then “mountains.”

  In the 1990s, Barbara Bradfield was among the first women to be treated with a drug, Herceptin, that specifically attacks breast cancer cells. She is the longest survivor of that treatment, with no hint of her cancer remaining.

  Acknowledgments

  I have many people to thank. My wife, Sarah Sze, whose unfailing faith, love, and patience sustained this book. My daughters Leela and Aria, for whom this book was often a rival sibling; who fell asleep on many nights to the mechanical lullaby of my furious typing and then woke the next morning to find me typing again. My agent Sarah Chalfant, who read and annotated draft upon draft of my proposals; my editor Nan Graham, with whom I began to communicate with “mental telepathy” and whose thoughts are stitched into every page. My early readers: Nell Breyer, Amy Waldman, Neel Mukherjee, Ashok Rai, Kim Gutschow, David Seo, Robert Brustein, Prasant Atluri, Erez Kalir, Yariv Houvras, Mitzi Angel, Diana Beinart, Daniel Menaker, and many mentors and interviewees, particularly Robert Mayer, who were crucial in the development of this book. My parents, Sibeswar and Chandana Mukherjee and my sister, Ranu Bhattacharyya and her family, who found vacations and family gatherings swallowed up by an interminable manuscript and Chia-Ming and Judy Sze who provided sustenance and help during my frequent visits to Boston.

  As with any such book, this work also rests on the prior work of others: Susan Sontag’s masterful and moving Illness as Metaphor, Richard Rhodes’s The Makin
g of the Atomic Bomb, Richard Rettig’s Cancer Crusade, Barron Lerner’s The Breast Cancer Wars, Natalie Angier’s Natural Obsessions, Lewis Thomas’s The Lives of a Cell, George Crile’s The Way It Was, Adam Wishart’s One in Three, Aleksandr Solzhenitsyn’s Cancer Ward, David Rieff’s devastating memoir Swimming in a Sea of Death, Robert Bazell’s Her-2, Robert Weinberg’s Racing to the Beginning of the Road, Harold Varmus’s The Art and Politics of Science, Michael Bishop’s How to Win the Nobel Prize, David Nathan’s The Cancer Treatment Revolution, James Patterson’s The Dread Disease, and Tony Judt’s Postwar. Many archives and libraries were accessed as primary sources for the book: Mary Lasker’s papers, Benno Schmidt’s papers, George Papanicolaou’s papers, Arthur Aufderheide’s papers and specimen collection, William Halsted’s papers, Rose Kushner’s papers, the tobacco documents at UCSF, Evarts Graham’s papers, Richard Doll’s papers, Joshua Lederberg’s papers, Harold Varmus’s papers, the Boston Public Library, the Countway Library of Medicine, Columbia University libraries, and Sidney Farber’s personal photographs and correspondence, shared by several sources, including Thomas Farber, his son. The manuscript was also read by Robert Mayer, George Canellos, Donald Berry, Emil Freireich, Al Knudson, Harold Varmus, Dennis Slamon, Brian Druker, Thomas Lynch, Charles Sawyers, Bert Vogelstein, Robert Weinberg, and Ed Gelmann, who provided corrections and alterations to the text.

  Harold Varmus, in particular, provided astonishingly detailed and insightful commentary and annotations—emblematic of the extraordinary generosity that I received from scientists, writers, and doctors.

  David Scadden and Gary Gilliland provided a fostering laboratory environment at Harvard. Ed Gelmann, Riccardo Dalla-Favera, and Cory and Michael Shen gave me a new academic “home” at Columbia University, where this book was finished. Tony Judt’s Remarque Institute Forum (where I was a fellow) provided an inimitable environment for historical discussions; indeed, this book was conceived in its current form on a crystalline lake in Sweden during one such forum. Jason Rothauser, Paul Whitlatch, and Jaime Wolf read, edited, and checked the facts and figures in the manuscript. Alexandra Truitt and Jerry Marshall researched and cleared copyrights for the pictures.

  Notes

  vii Susan Sontag, Illness as Metaphor and AIDS and Its Metaphors (New York: Picador, 1990), 3.

  PROLOGUE

  1 Diseases desperate grown: William Shakespeare, Hamlet, Act IV, Scene III.

  1 Cancer begins and ends with people: June Goodfield, The Siege of Cancer (New York: Random House, 1975), 219.

  4 In Aleksandr Solzhenitsyn’s novel: Aleksandr Solzhenitsyn, Cancer Ward (New York: Farrar, Straus and Giroux, 1968).

  5 Atossa, the Persian queen: Herodotus, The Histories (Oxford: Oxford University Press, 1998), 223.

  6 “The universe,” the twentieth-century biologist: John Burdon Sanderson Haldane, Possible Worlds and Other Papers (New York: Harper & Brothers, 1928), 286.

  PART ONE:

  “OF BLACKE CHOLOR, WITHOUT BOYLING”

  9 In solving a problem of this sort: Arthur Conan Doyle, A Study in Scarlet (Whitefish, MT: Kessinger Publishing, 2004), 107.

  “A suppuration of blood”

  11 Physicians of the Utmost Fame: Hilaire Belloc, Cautionary Tales for Children (New York: Alfred A. Knopf, 1922), 18–19.

  11 Its palliation is a daily task: William B. Castle, “Advances in Knowledge concerning Diseases of the Blood, 1949–1950,” in The 1950 Year Book of Medicine: May 1949–May 1950 (Chicago: Year Book Publishers, 1950), 313–26.

  11 In a damp: Details concerning aminopterin and its arrival in Farber’s clinic are from several sources. Sidney Farber et al., “The Action of Pteroylglutamic Conjugates on Man,” Science, 106, no. 2764 (1947): 619–21; S. P. Gupta, interview with author, January 2006; and S. P. Gupta, “An Indian Scientist in America: The Story of Dr. Yellapragada Subbarao,” Bulletin of the Institute of Medicine (Hyderabad) 6, no. 2 (1976): 128–43; S. P. Gupta, In Quest of Panacea (New Delhi: Evelyn Publishers, 1987).

  11 Farber’s specialty was pediatric pathology: John Craig, “Sidney Farber (1903–1973),” Journal of Pediatrics 128, no. 1 (1996): 160–62. Also see “Looking Back: Sidney Farber and the First Remission of Acute Pediatric Leukemia,” Children’s Hospital, Boston, http://www.childrenshospital.org/gallery/index.cfm?G=49&page=2 (accessed January 4, 2010); H. R. Wiedemann, “Sidney Farber (1903–1973),” European Journal of Pediatrics, 153 (1994): 223.

  12 “It gave physicians plenty to wrangle over”: John Laszlo, The Cure of Childhood Leukemia: Into the Age of Miracles (New Brunswick, NJ: Rutgers University Press, 1995), 19.

  12 “diagnosed, transfused—and sent home to die”: Medical World News, November 11, 1966.

  13 “He is of dark complexion”: John Hughes Bennett, “Case of Hypertrophy of the Spleen and Liver in Which Death Took Place from Suppuration of the Blood,” Edinburgh Medical and Surgical Journal 64 (October 1, 1845): 413–23. Also see John Hughes Bennett, Clinical Lectures on the Principles and Practice of Medicine, 3rd ed. (New York: William Wood & Company, 1866), 620.

  13 “A suppuration of blood”: Bennett, “Case of Hypertrophy of the Spleen.” Also see Bennett, Clinical Lectures, 896.

  13 Rudolf Virchow, independently published: Rudolf Ludwig Karl Virchow, Cellular Pathology: As Based upon Physiological and Pathological Histology, trans. Frank Chance (London: John Churchill, 1860), 169–71, 220. Also see Bennett, Clinical Lectures, 896.

  14 seeking a name for this condition: Charles J. Grant, “Weisses Blut,” Radiologic Technology 73, no. 4 (2003): 373–76.

  14 in the early 1980s, another change in name: Randy Shilts, And the Band Played On (New York: St. Martin’s), 171.

  14 Virchow’s approach to medicine: “Virchow,” British Medical Journal, 2, no. 3171 (1921): 573–74. Also see Virchow, Cellular Pathology.

  16 Bennett’s earlier fantasy: William Seaman Bainbridge, The Cancer Problem (New York: Macmillan Company, 1914), 117.

  17 Michael Anton Biermer, described: Laszlo, Cure of Childhood Leukemia, 7–9, 15.

  17 From its first symptom to diagnosis to death: Biermer, “Ein Fall von Leukämie,” Virchow’s Archives, 1861, S. 552, cited in Suchannek, “Case of Leukaemia,” 255–69.

  19 Farber completed his advanced training: Denis R. Miller, “A Tribute to Sidney Farber—the Father of Modern Chemotherapy,” British Journal of Haematology 134 (2006): 4, 20–26.

  20 What is true for E. coli: This remark, attributed to Monod (perhaps apocryphally), appears several times in the history of molecular biology, although its precise origins remain unknown. See, for instance, Theresa M. Wizemann and Mary-Lou Pardue, eds., Exploring the Biological Contributions to Human Health: Does Sex Matter? (Washington, DC: National Academy Press, 2001), 32; Herbert Claus Friedmann, “From Butyribacterium to E. coli: An Essay on Unity in Biochemistry,” Perspectives in Biology and Medicine 47, no. 1 (2004): 47–66.

  “A monster more insatiable than the guillotine”

  21 The medical importance of leukemia: Jonathan B. Tucker, Ellie: A Child’s Fight Against Leukemia (New York: Holt, Rinehart, and Winston, 1982), 46.

  21 There were few successes in the treatment: John Laszlo, The Cure of Childhood Leukemia: Into the Age of Miracles (New Brunswick, NJ: Rutgers University Press, 1995), 162.

  21 a cornucopia of pharmaceutical discoveries: Michael B. Shimkin, “As Memory Serves—an Informal History of the National Cancer Institute, 1937–57,” Journal of the National Cancer Institute 59 (suppl. 2) (1977): 559–600.

  21 the drug was reextracted: Eric Lax, The Mold in Dr. Florey’s Coat: The Story of the Penicillin Miracle (New York: Henry Holt and Co., 2004), 67.

  21 In 1942, when Merck had shipped: “Milestone Moments in Merck History,” http://www.merck.com/about/feature_story/01062003_penicillin.html (site is no longer available but can be accessed through http://www.archive.org/web/web.php).

  21 A decade later, penicillin: E. K. Marshall, “Historical Perspectives in Chemotherapy,” Advances
in Chemotherapy 13 (1974): 1–8. Also see Science News Letter 41 (1942).

  22 chloramphenicol in 1947: John Ehrlich et al., “Chloromycetin, a New Antibiotic from a Soil Actinomycete,” Science 106, no. 2757 (1947): 417.

  22 tetracycline in 1948: B. M. Duggar, “Aureomycin: A Product of the Continuing Search for New Antibiotics,” Annals of the New York Academy of Science 51 (1948): 177–81.

  22 “The remedies are in our own backyard”: Time, November 7, 1949.

  22 In a brick building on the far corner: John F. Enders, Thomas H. Weller, and Frederick C. Robbins, “Cultivation of the Lansing Strain of Poliomyelitis Virus in Cultures of Various Human Embryonic Tissues,” Science 49 (1949): 85–87; Fred S. Rosen, “Isolation of Poliovirus—John Enders and the Nobel Prize,” New England Journal of Medicine 351 (2004): 1481–83.

  22 by 1950, more than half the medicines: A. N. Richards, “The Production of Penicillin in the United States: Extracts and Editorial Comment,” Annals of Internal Medicine, suppl. 8 (1969): 71–73. Also see Austin Smith and Arthur Herrick, Drug Research and Development (New York: Revere Publishing Co., 1948).

  22 Typhoid fever: Anand Karnad, Intrinsic Factors: William Bosworth Castle and the Development of Hematology and Clinical Investigation at Boston City Hospital (Boston: Harvard Medical School, 1997).