"The Emperor Of All Maladies", I

[fiefoe]

Among its many merits, Siddhartha Mukherjee's comprehensive review of the history of this disease also lifts several non-male, non-Caucasian medical researchers out of obscurity.

• Two characters stand at the epicenter of this story—both contemporaries, both idealists, both children of the boom in postwar science and technology in America, and both caught in the swirl of a hypnotic, obsessive quest to launch a national “War on Cancer.” The first is Sidney Farber, the father of modern chemotherapy, who accidentally discovers a powerful anti-cancer chemical in a vitamin analogue and begins to dream of a universal cure for cancer. The second is Mary Lasker, the Manhattan socialite of legendary social and political energy


• In a sense, this is a military history—one in which the adversary is formless, timeless, and pervasive. Here, too, there are victories and losses, campaigns upon campaigns, heroes and hubris, survival and resilience—and inevitably, the wounded, the condemned, the forgotten, the dead. In the end, cancer truly emerges, as a nineteenth-century surgeon once wrote in a book’s frontispiece, as “the emperor of all maladies, the king of terrors.”


• In the end, commonplace particulars make up Carla’s memories of illness: the clock, the car pool, the children, a tube of pale blood, a missed shower, the fish in the sun, the tightening tone of a voice on the phone. Carla cannot recall much of what the nurse said, only a general sense of urgency.


• The sentence that flickered on my beeper had the staccato and deadpan force of a true medical emergency: Carla Reed/New patient with leukemia/14th Floor/Please see as soon as you arrive.


• Medical school, internship, and residency had been physically and emotionally grueling, but the first months of the fellowship flicked away those memories as if all of that had been child’s play, the kindergarten of medical training. <> Cancer was an all-consuming presence in our lives. It invaded our imaginations; it occupied our memories; it infiltrated every conversation, every thought. And if we, as physicians, found ourselves immersed in cancer, then our patients found their lives virtually obliterated by the disease.


• (Solzhenitsyn may have intended his absurdly totalitarian cancer hospital to parallel the absurdly totalitarian state outside it, yet when I once asked a woman with invasive cervical cancer about the parallel, she said sardonically, “Unfortunately, I did not need any metaphors to read the book. The cancer ward was my confining state, my prison.”)


• Immersed in the day-to-day management of cancer, I could only see the lives and fates of my patients played out in color-saturated detail, like a television with the contrast turned too high. I could not pan back from the screen.


• Immersed in the day-to-day management of cancer, I could only see the lives and fates of my patients played out in color-saturated detail, like a television with the contrast turned too high. I could not pan back from the screen.


• * And cancer is imprinted in our society: as we extend our life span as a species, we inevitably unleash malignant growth (mutations in cancer genes accumulate with aging; cancer is thus intrinsically related to age).


• Anderson’s Pathology or Boyd’s Pathology of Internal Diseases—page upon page was plastered with images of leukemia cells and appended with elaborate taxonomies to describe the cells. Yet all this knowledge only amplified the sense of medical helplessness. The disease had turned into an object of empty fascination—a wax-museum doll—studied and photographed in exquisite detail but without any therapeutic or practical advances.


• But no other stigmata of infection were to be found. The blood had apparently spoiled—suppurated—of its own will, combusted spontaneously into true pus. “A suppuration of blood,” Bennett called his case. And he left it at that.


• * Virchow ultimately settled for weisses Blut—white blood—no more than a literal description of the millions of white cells he had seen under his microscope. In 1847, he changed the name to the more academic-sounding “leukemia”—from leukos, the Greek word for “white.”


• * Renaming the disease—from the florid “suppuration of blood” to the flat weisses Blut—hardly seems like an act of scientific genius, but it had a profound impact on the understanding of leukemia. An illness, at the moment of its discovery, is a fragile idea, a hothouse flower—deeply, disproportionately influenced by names and classifications... His insight lay entirely in the negative. By wiping the slate clean of all preconceptions, he cleared the field for thought.


• Virchow set out to create a “cellular theory” of human biology, basing it on two fundamental tenets. First, that human bodies (like the bodies of all animals and plants) were made up of cells. Second, that cells only arose from other cells—omnis cellula e cellula, as he put it... growth could occur in only two ways: either by increasing cell numbers or by increasing cell size... Every growing human tissue could be described in terms of hypertrophy and hyperplasia. In adult animals, fat and muscle usually grow by hypertrophy. In contrast, the liver, blood, the gut, and the skin all grow through hyperplasia


• When the heart muscle is forced to push against a blocked aortic outlet, it often adapts by making every muscle cell bigger to generate more force, eventually resulting in a heart so overgrown that it may be unable to function normally—pathological hypertrophy.


• Virchow soon stumbled upon the quintessential disease of pathological hyperplasia—cancer. Looking at cancerous growths through his microscope, Virchow discovered an uncontrolled growth of cells—hyperplasia in its extreme form.


• Normal white cells in the blood can be broadly divided into two types of cells—myeloid cells or lymphoid cells. Acute myeloid leukemia (AML) was a cancer of the myeloid cells. Acute lymphoblastic leukemia (ALL) was cancer of immature lymphoid cells. (Cancers of more mature lymphoid cells are called lymphomas.)


• The elder Farber often brought home textbooks and scattered them across the dinner table, expecting each child to select and master one book, then provide a detailed report for him.


• * he chose, among all cancers, to focus his attention on one of its oddest and most hopeless variants—childhood leukemia. To understand cancer as a whole, he reasoned, you needed to start at the bottom of its complexity, in its basement. And despite its many idiosyncrasies, leukemia possessed a singularly attractive feature: it could be measured.


• Penicillin, that precious chemical that had to be milked to its last droplet during World War II (in 1939, the drug was reextracted from the urine of patients who had been treated with it to conserve every last molecule),


• * When English physicians tested these mill workers in the 1920s to study the effects of this chronic malnutrition, they discovered that many of them, particularly women after childbirth, were severely anemic. (This was yet another colonial fascination: to create the conditions of misery in a population, then subject it to social or medical experimentation.) <> In 1928, a young English physician named Lucy Wills, freshly out of the London School of Medicine for Women, traveled on a grant to Bombay to study this anemia... Wills could not determine the key chemical nutrient of Marmite... Wills factor turned out to be folic acid, or folate, a vitamin-like substance


• The observations of Minot and Wills began to fit into a foggy picture. If the bone marrow was a busy cellular factory to begin with, then a marrow occupied with leukemia was that factory in overdrive, a deranged manufacturing unit for cancer cells... could the malignant marrow be shut off by choking the supply of nutrients?


• * Yellapragada Subbarao: Subbarao purified a molecule called ATP, the source of energy in all living beings (ATP carries chemical “energy” in the cell), and another molecule called creatine, the energy carrier in muscle cells. Any one of these achievements should have been enough to guarantee him a professorship at Harvard. But Subbarao was a foreigner, a reclusive, nocturnal, heavily accented vegetarian


• These variants of folic acid—closely related molecular mimics—possessed counterintuitive properties. Enzymes and receptors in cells typically work by recognizing molecules using their chemical structure. But a “decoy” molecular structure—one that nearly mimics the natural molecule—can bind to the receptor or enzyme and block its action, like a false key jamming a lock. Some of Yella’s molecular mimics could thus behave like antagonists to folic acid.


• * We tend to think of cancer as a “modern” illness because its metaphors are so modern. It is a disease of overproduction, of fulminant growth—growth unstoppable, growth tipped into the abyss of no control.


• TB (or consumption) was Victorian romanticism brought to its pathological extreme—febrile, unrelenting, breathless, and obsessive. It was a disease of poets... The cancer cell is a desperate individualist, “in every possible sense, a nonconformist,” as the surgeon-writer Sherwin Nuland wrote... a curious mix of meta and stasis—“beyond stillness” in Latin—an unmoored, partially unstable state that captures the peculiar instability of modernity... cancer asphyxiates us by filling bodies with too many cells; it is consumption in its alternate meaning—the pathology of excess. Cancer is an expansionist disease;


• * collected teachings of Imhotep, a great Egyptian physician who lived around 2625 BC. Imhotep, among the few nonroyal Egyptians known to us from the Old Kingdom, was a Renaissance man at the center of a sweeping Egyptian renaissance. As a vizier in the court of King Djozer, he dabbled in neurosurgery,.. Even the Greeks, encountering the fierce, hot blast of his intellect as they marched through Egypt centuries later, cast him as an ancient magician and fused him to their own medical god, Asclepius... it is under these clarifying headlamps of an ancient surgeon that cancer first emerges as a distinct disease.


• Histories, written around 440 BC, the Greek historian Herodotus records the story of Atossa, the queen of Persia, who was suddenly struck by an unusual illness. Atossa was the daughter of Cyrus, and the wife of Darius, successive Achaemenid emperors of legendary brutality... Atossa lived, and she had Democedes to thank for it. And that reprieve from pain and illness whipped her into a frenzy of gratitude and territorial ambition. Darius had been planning a campaign against Scythia, on the eastern border of his empire. Goaded by Democedes, who wanted to return to his native Greece, Atossa pleaded with her husband to turn his campaign westward—to invade Greece. That turn of the Persian empire from east to west, and the series of Greco-Persian wars that followed, would mark one of the definitive moments in the early history of the West. It was Atossa’s tumor, then, that quietly launched a thousand ships.


• Aufderheide isn’t the only paleopathologist to have found cancers in mummified specimens. (Bone tumors, because they form hardened and calcified tissue, are vastly more likely to survive over centuries and are best preserved.)


• *  To name an illness is to describe a certain condition of suffering—a literary act before it becomes a medical one. A patient, long before he becomes the subject of medical scrutiny, is, at first, simply a storyteller, a narrator of suffering—a traveler who has visited the kingdom of the ill.


• * a burden; cancer was imagined as a burden carried by the body. In Greek theater, the same word, onkos, would be used to denote a tragic mask that was often “burdened” with an unwieldy conical weight on its head to denote the psychic load carried by its wearer.


• culminating with Archaemedes discovering his eponymous laws in his bathtub. This preoccupation with hydraulics also flowed into Greek medicine and pathology. To explain illness—all illness—Hippocrates fashioned an elaborate doctrine based on fluids and volumes.. Indeed, melancholia, the medieval name for “depression,” would draw its name from the Greek melas, “black,” and khole, “bile.” Depression and cancer, the psychic and physical diseases of black bile, were thus intrinsically intertwined.)


• The gibbet and the graveyard—the convenience stores for the medieval anatomist—yielded specimen after specimen for Vesalius, .. he could not find Galen’s black bile. The word autopsy comes from the Greek “to see for oneself”; as Vesalius learned to see for himself, he could no longer force Galen’s mystical visions to fit his own... Guiltily, he heaped even more praise on the long-dead Galen. But, an empiricist to the core, Vesalius left his drawings just as he saw things, leaving others to draw their own conclusions.


• The first of these discoveries, anesthesia, was publicly demonstrated in 1846 in a packed surgical amphitheater at Massachusetts General Hospital


• * In the postsurgical wards of the Glasgow infirmary, Lister had again and again seen an angry red margin begin to spread out from the wound and then the skin seemed to rot from inside out, often followed by fever, pus, and a swift death... Pasteur had made a bold claim: the turbidity was caused by the growth of invisible microorganisms—bacteria—that had fallen out of the air into the broth. Lister took Pasteur’s reasoning further. An open wound—a mixture of clotted blood and denuded flesh—was, after all, a human variant of Pasteur’s meat broth.. In the neighboring town of Carlisle, Lister had observed sewage disposers cleanse their waste with a cheap, sweet-smelling liquid containing carbolic acid.


• Antisepsis and anesthesia were twin technological breakthroughs that released surgery from its constraining medieval chrysalis. Armed with ether and carbolic soap, a new generation of surgeons lunged toward the forbiddingly complex anatomical procedures


• Billroth’s approach to the problem was meticulous and formal: for nearly a decade, he spent surgery after surgery simply opening and closing abdomens of animals and human cadavers, defining clear and safe routes to the inside. By the early 1880s, he had established the routes: ... this task, Billroth soon discovered, demanded a nearly godlike creative spirit. <> Since the time of Vesalius, surgery had been immersed in the study of natural anatomy. But cancer so often disobeyed and distorted natural anatomical boundaries that unnatural boundaries had to be invented to constrain it. To remove the distal end of a stomach filled with cancer, for instance, Billroth had to hook up the pouch remaining after surgery to a nearby piece of the small intestine.


• * He had, it would seem, conquered all his mortal imperfections: the need to sleep, exhaustion, and nihilism. His restive personality had met its perfect pharmacological match. <> For the next five years, Halsted sustained an incredible career as a young surgeon in New York despite a fierce and growing addiction to cocaine.


• Moore had begun to record the anatomy of each relapse, denoting the area of the original tumor, the precise margin of the surgery, and the site of cancer recurrence by drawing tiny black dots on a diagram of a breast—creating a sort of historical dartboard of cancer recurrence. And to Moore’s surprise, dot by dot, a pattern had emerged. The recurrences had accumulated precisely around the margins of the original surgery, as if minute remnants of cancer had been left behind by incomplete surgery and grown back. “Mammary cancer requires the careful extirpation of the entire organ,” Moore concluded... Halsted decided to dig even deeper into the breast cavity, cutting through the pectoralis major, the large, prominent muscle responsible for moving the shoulder and the hand.


• * Halsted’s mastectomy is thus a peculiar misfit in both cases; it underestimates its target in the first case and overestimates it in the second. In both cases, women are forced to undergo indiscriminate, disfiguring, and morbid operations—too much, too early for the woman with local breast cancer, and too little, too late, for the woman with metastatic cancer... he never wrote another scholarly analysis of the majestic and flawed operation that bore his name.


• To arrive at that sort of logic—the Hippocratic oath turned upside down—demands either a terminal desperation or a terminal optimism. In the 1930s, the pendulum of cancer surgery swung desperately between those two points.  Halsted, Brunschwig, and Pack... lacked formal proof, and as they went further up the isolated promontories of their own beliefs, proof became irrelevant and trials impossible to run. The more fervently surgeons believed in the inherent good of their operations, the more untenable it became to put these to a formal scientific trial. Radical surgery thus drew the blinds of circular logic around itself for nearly a century.


• The metal lay on the far edge of the periodic table, emitting X-rays with such feverish intensity that it glowered with a hypnotic blue light in the dark, consuming itself. Unstable, it was a strange chimera between matter and energy—matter decomposing into energy. Marie Curie called the new element radium, from the Greek word for “light.”.. X-rays: they could not only carry radiant energy through human tissues, but also deposit energy deep inside tissues.


• * the spectrum of damaged tissues—skin, lips, blood, gums, and nails—already provided an important clue: radium was attacking DNA. DNA is an inert molecule, exquisitely resistant to most chemical reactions, for its job is to maintain the stability of genetic information. But X-rays can shatter strands of DNA or generate toxic chemicals that corrode DNA. Cells respond to this damage by dying or, more often, by ceasing to divide. X-rays thus preferentially kill the most rapidly proliferating cells in the body, cells in the skin, nails, gums, and blood.


• Grubbe had stumbled on another important observation: X-rays could only be used to treat cancer locally, with little effect on tumors that had already metastasized... The second limit was far more insidious: radiation produced cancers. The very effect of X-rays killing rapidly dividing cells—DNA damage—also created cancer-causing mutations in genes.


• U.S. Radium promoted Undark for clock dials, boasting of glow-in-the-dark watches. Watch painting was a precise and artisanal craft, and young women with nimble, steady hands were commonly employed. These women were encouraged to use the paint without precautions, and to frequently lick the brushes with their tongues to produce sharp lettering on watches.


• spilled into the body exactly like the black bile that Galen had envisioned so vividly nearly two thousand years ago. <> In fact, Galen seemed to have been right after all—in the accidental, aphoristic way that Democritus had been right about the atom or Erasmus had made a conjecture about the Big Bang centuries before the discovery of galaxies.


• By the mid-1880s, Germany had emerged as the champion of the chemical arms race (which presaged a much uglier military one) to become the “dye basket” of Europe.


• Early interactions between synthetic chemistry and medicine had largely been disappointing. Gideon Harvey, a seventeenth-century physician, had once called chemists the “most impudent, ignorant, flatulent, fleshy, and vainly boasting sort of mankind.”


• In 1828, a Berlin scientist named Friedrich Wöhler had sparked a metaphysical storm in science by boiling ammonium cyanate, a plain, inorganic salt, and creating urea, a chemical typically produced by the kidneys. The Wöhler experiment... demolished vitalism. Organic and inorganic chemicals, he proved, were interchangeable.


• This molecular specificity, encapsulated so vividly in that reaction between a dye and a cell, began to haunt Ehrlich. In 1882, working with Robert Koch, he discovered yet another novel chemical stain, this time for mycobacteria, the organisms that Koch had discovered as the cause of tuberculosis. A few years later, Ehrlich found that certain toxins, injected into animals, could generate “antitoxins,” which bound and inactivated poisons with extraordinary specificity (these antitoxins would later be identified as antibodies)... If biology was an elaborate mix-and-match game of chemicals, Ehrlich reasoned, what if some chemical could discriminate bacterial cells from animal cells—and kill the former without touching the host?... Ehrlich’s chemicals had successfully targeted bacteria because bacterial enzymes were so radically dissimilar to human enzymes. With cancer, it was the similarity of the cancer cell to the normal human cell that made it nearly impossible to target.


• * Mustard gas: In a world less preoccupied with other horrors, this news might have caused a small sensation among cancer doctors. Although evidently poisonous, this chemical had, after all, targeted the bone marrow and wiped out only certain populations of cells—a chemical with specific affinity. But Europe was full of horror stories in 1919, and this seemed no more remarkable than any other.


• * When Hitchings found Trudy Elion, who would soon become one of the most innovative synthetic chemists of her generation (and a future Nobel laureate), she was working for a food lab in New York, testing the acidity of pickles... Elion focused on one class of compounds, called purines. Purines were ringlike molecules with a central core of six carbon atoms that were known to be involved in the building of DNA. She thought she would add various chemical side chains to each of the six carbon atoms, producing dozens of new variants of purine.


• In 1948, Cornelius “Dusty” Rhoads, a former army officer, left his position as chief of the army’s Chemical Warfare Unit to become the director of the Memorial Hospital (and its attached research institute), thus sealing the connection between the chemical warfare of the battlefields and chemical warfare in the body.


• Cancer research, they felt, needed a more effective message, a strategy to catapult it into public fame. Sometime that spring, Koster, remembering the success with Sheridan, had the inspired idea of finding a “mascot” for Farber’s research fund—a Catherine Sheridan for cancer. Koster and Farber searched Children’s wards and Farber’s clinic for a poster child to pitch the fund to the public.


• in 1944, the Manhattan Project spent $100 million every month at the Oak Ridge site. In 1948, Americans spent more than $126 million on Coca-Cola alone... The campaign against cancer, Farber learned, was much like a political campaign: it needed icons, mascots, images, slogans—the strategies of advertising as much as the tools of science. For any illness to rise to political prominence, it needed to be marketed, just as a political campaign needed marketing.


• * The Laskers: In time, a variant of this idea, of advertising as a lubricant of information and of the need to distill information into elemental iconography would leave a deep and lasting impact on the cancer campaign. <> Mary and Albert had a brisk romance.. The Laskers were professional socialites, in the same way that one can be a professional scientist or a professional athlete; they were extraordinary networkers, lobbyists, minglers, conversers, persuaders, letter writers, cocktail party–throwers, negotiators, name-droppers, deal makers. Fund-raising—and, more important, friend-raising—was instilled in their blood... the new rules, arguably among the more unusual set of stipulations to be adopted by a scientific organization: “The Committee should not include more than four professional and scientific members. The Chief Executive should be a layman.” <> In those two sentences, Adams epitomized the extraordinary change that had swept through the ACS.


• When I went through the avalanche of chemotherapy drugs that would be used over the next two years to treat her, she repeated the names softly after me under her breath, like a child discovering a new tongue twister:


• When Freireich entered the office, he confronted a tall, thin young man who identified himself as Emil Frei... “Zubrod’s cooperative group model galvanized cancer medicine,” Robert Mayer (who would later become the chair of one of these groups) recalls. “For the first time, an academic oncologist felt as if he had a community. The cancer doctor was not the outcast anymore


• Hill’s proposed solution was to remove such biases by randomly assigning patients to treatment with streptomycin versus a placebo. By “randomizing” patients to each arm,


• The situation was reminiscent of TB. Like cancer cells, mycobacteria—the germs that cause tuberculosis—also became resistant to antibiotics if the drugs were used singly... In just six pivotal years, the leukemia study group had slowly worked itself to giving patients not one or two, but four chemotherapy drugs, often in succession. By the winter of 1962, the compass of leukemia medicine pointed unfailingly in one direction. If two drugs were better than one, and if three better than two, then what if four antileukemia drugs could be given together—in combination, as with TB?


• * in the 1950s, then Min Chiu Li was an outsider even among outsiders. He had come to the United States from Mukden University in China, then spent a brief stint at the Memorial Hospital in New York. In a scramble to dodge the draft during the Korean War, he had finagled a two-year position in Hertz’s service as an assistant obstetrician... “She was bleeding so rapidly,” a hematologist recalled, “that we thought we might transfuse her back with her own blood... Li reasoned that his patients had not been fully cured. In the end, he seemed almost to be treating a number rather than a patient; ignoring the added toxicity of additional rounds of the drug, Li doggedly administered dose upon dose until, at last, the hcg level sank to zero...  the patients treated on Li’s protocol remained free of disease—even months after the methotrexate had been stopped. <> Li had stumbled on a deep and fundamental principle of oncology: cancer needed to be systemically treated long after every visible sign of it had vanished...  This strategy—which cost Min Chiu Li his job—resulted in the first chemotherapeutic cure of cancer in adults.


• “Frei and Freireich were simply taking drugs that were available and adding them together in combinations. . . . The possible combinations, doses, and schedules of four or five drugs were infinite. Researchers could work for years on finding the right combination of drugs and schedules.” Zubrod’s sequential, systematic, objective trials had reached an impasse. What was needed was quite the opposite of a systematic approach—an intuitive and inspired leap of faith into the deadly abyss of deadly drugs.


• Skipper emerged with two pivotal findings. First, he found that chemotherapy typically killed a fixed percentage of cells at any given instance no matter what the total number of cancer cells was... Second, Skipper found that by adding drugs in combination, he could often get synergistic effects on killing.


• * In the folklore of science, there is the often-told story of the moment of discovery: the quickening of the pulse, the spectral luminosity of ordinary facts, the overheated, standstill second when observations crystallize and fall together into patterns,.. But there is another moment of discovery—its antithesis—that is rarely recorded: the discovery of failure. It is a moment that a scientist often encounters alone.


• It was a consequence of the body’s own defense system subverting cancer treatment. The brain and spinal cord are insulated by a tight cellular seal called the blood-brain barrier that prevents foreign chemicals from easily getting into the brain... But the same system had likely also kept VAMP out of the nervous system, creating a natural “sanctuary” for cancer within the body... To watch this sort of intense, intimate enterprise fold up and die is to suffer the loss of a child.


• * But the story of leukemia—the story of cancer—isn’t the story of doctors who struggle and survive, moving from one institution to another. It is the story of patients who struggle and survive, moving from one embankment of illness to another. Resilience, inventiveness, and survivorship—qualities often ascribed to great physicians—are reflected qualities, emanating first from those who struggle with illness and only then mirrored by those who treat them.


• Even referring to them by the same name, cancer, felt like some sort of medical anachronism, like the medieval habit of using apoplexy to describe anything from a stroke to a hemorrhage to a seizure. Like Hippocrates, it was as if we, too, had naively lumped the lumps. <> But naive or not, it was this lumping—this emphatic, unshakable faith in the underlying singularity of cancer more than its pluralities—that galvanized the Laskerites in the 1960s.


• Hodgkin: The story of a compulsive young doctor putting old swellings into new pathological bottles was received without much enthusiasm... It was this propensity to spread locally from one node to the next that poised Hodgkin’s uniquely in the history of cancer... Hodgkin’s disease inhabited yet another strange borderland: a local disease on the verge of transforming into a systemic one—Halsted’s vision of cancer on its way to becoming Galen’s.


• X-rays: The characteristics that Kaplan sought in his target were relatively well defined. Since the linac could only focus its killer beam on local sites, it would have to be a local, not a systemic, cancer... The powerful oculus of Kaplan’s intellect, swiveling about through the malignant world, ultimately landed on the most natural target for his investigation: Hodgkin’s disease.


• The trials that Kaplan designed still rank among the classics of study design... Kaplan meticulously restricted radiotherapy to patients with early-stage disease. He went to exhaustive lengths to stage patients before unleashing radiation on them... This simple principle—the meticulous matching of a particular therapy to a particular form and stage of cancer—would eventually be given its due merit in cancer therapy.


• Chemotherapy caused permanent sterility in men and some women. The annihilation of the immune system by the cytotoxic drugs allowed peculiar infections to sprout up:


• Pinkel reasoned that while combinations of drugs were necessary to induce remissions, combinations were insufficient in themselves. Perhaps one needed combinations of combinations—six, seven, or even eight different chemical poisons mixed and matched together for maximum effect... perhaps one needed to instill chemotherapy directly into the nervous system by injecting it into the fluid that bathes the spinal cord...


• * Walking across the hospital in the morning to draw yet another bone marrow biopsy, with the wintry light crosshatching the rooms, I felt a certain dread descend on me, a heaviness that bordered on sympathy but never quite achieved it.


• * Wars also demand a clear definition of an enemy. They imbue even formless adversaries with forms. So cancer, a shape-shifting disease of colossal diversity, was recast as a single, monolithic entity. It was one disease... cancer scientists had their own theory to advance for its unifying cause: viruses.


• In the late eighteenth century, an English surgeon named Percivall Pott had argued that cancer of the scrotum, endemic among chimney sweeps, was caused by chronic exposure to chimney soot and smoke. .. These observations had led to a theory called the somatic mutation hypothesis of cancer. The somatic theory of cancer argued that environmental carcinogens such as soot or radium somehow permanently altered the structure of the cell and thus caused cancer.


• until the cells had been eliminated from the mix and all that was left was the filtrate derived from the cells. Rous expected the tumor transmission to stop, but instead, the tumors continued propagating with a ghostly efficacy—at times even increasing in transmissibility as the cells had progressively vanished. <> The agent responsible for carrying the cancer, Rous concluded, was not a cell or an environmental carcinogen, but some tiny particle lurking within a cell... The only biological particle that had these properties was a virus. His virus was later called Rous sarcoma virus, or RSV for short... Rous lambasted the idea that cancer could be caused by something inherent to the cells, such as a genetic mutation.


• In her letters, Mary Lasker began to refer to a programmatic War on Cancer as the conquest of “inner space” (as opposed to “outer space”), instantly unifying the two projects.


• When a disease insinuates itself so potently into the imagination of an era, it is often because it impinges on an anxiety latent within that imagination.. Every era casts illness in its own image. Society, like the ultimate psychosomatic patient, matches its medical afflictions to its psychological crises;


• 70s: This thing, The Bomb, belonged to a generation of war babies. . . . But we are fickle even about fear. We seem to have dropped our bombphobia now without, in any way, reducing the reasons for it. Cancer now leads this macabre hit parade.


• The notion of science as an open-ended search for obscure truths bothered and befuddled him. Nixon often groused that scientists didn’t “know a goddamn thing” about the management of science.


• Halsted, meanwhile, had become the patron saint of cancer surgery, a deity presiding over his comprehensive “theory” of cancer. He had called it, with his Shakespearean ear for phrasemaking, the “centrifugal theory”—the idea that cancer, like a malevolent pinwheel, tended to spread in ever-growing arcs from a single central focus in the body... Even for patients, that manic diligence had become a form of therapy. Women wrote to their surgeons in admiration and awe, begging them not to spare their surgical extirpations


• * Political revolutions, the writer Amitav Ghosh writes, often occur in the courtyards of palaces, in spaces on the cusp of power, located neither outside nor inside. Scientific revolutions, in contrast, typically occur in basements, in buried-away places removed from mainstream corridors of thought. But a surgical revolution must emanate from within surgery’s inner sanctum—for surgery is a profession intrinsically sealed to outsiders.


• In 1928, four years after Keynes had begun his lumpectomies in London, two statisticians, Jerzy Neyman and Egon Pearson, provided a systematic method to evaluate a negative statistical claim. To measure the confidence in a negative claim, Neyman and Pearson invoked a statistical concept called power. “Power” in simplistic terms, is a measure of the ability of a test or trial to reject a hypothesis. Intuitively, Neyman and Pearson reasoned that a scientist’s capacity to reject a hypothesis depends most critically on how intensively he has tested the hypothesis—and thus, on the number of samples that have independently been tested.


• even Crile—a full forty years after Keynes’s discovery—couldn’t run a trial to dispute Halsted’s mastectomy. The hierarchical practice of medicine, its internal culture, its rituals of practice (“The Gospel[s] of the Surgical Profession,” as Crile mockingly called it),


• * By the late 1960s, the relationship between doctors and patients had begun to shift dramatically. Medicine, once considered virtually infallible in its judgment, was turning out to have deep fallibilities—flaws that appeared to cluster pointedly around issues of women’s health. Thalidomide, prescribed widely to control pregnancy-associated “hysteria” and “anxiety,”... Political feminism, in short, was birthing medical feminism—and the fact that one of the most common and most disfiguring operations performed on women’s bodies had never been formally tested in a trial stood out as even more starkly disturbing to a new generation of women...  Rachel Carson, the author of Silent Spring and a close friend of Crile’s, refused a radical mastectomy.. Rollin and Kushner appeared (often uninvited) at medical and surgical conferences, where they fearlessly heckled surgeons about their data


• Immersed in the traditions of radical surgery, many American surgeons put up such formidable barriers to patient recruitment that Canadian surgeons and their patients were added to complete the study.


• Cisplatin was unforgettable in more than one sense. The drug provoked an unremitting nausea, a queasiness of such penetrating force and quality that had rarely been encountered in the history of medicine: on average, patients treated with the drug vomited twelve times a day.


• In the early 1970s, young doctors who opposed the Vietnam War flooded to the NCI. (Due to an obscure legal clause, enrollment in a federal research program, such as the NIH, exempted someone from the draft.) The undrafted soldiers of one battle were thus channeled into another.


• his pattern was repeated with tiresome regularity for many forms of cancer. In metastatic lung cancer, for instance, combination chemotherapy was found to increase survival by three or four months;.. “When doctors say that the side effects are tolerable or acceptable, they are talking about life-threatening things,” she wrote. “But if you just vomit so hard that you break the blood vessels in your eyes . . . they don’t consider that even mentionable.


• He found that if he surgically removed the testicles of his dogs—and thereby depleted the dogs of the hormone testosterone—the prostate gland involuted and shriveled and the fluid secretion dried up precipitously. If he injected the castrated dogs with purified testosterone, the exogenous hormone saved the prostate from shriveling. Prostate cells were thus acutely dependent on the hormone testosterone for their growth and function... Dogs, humans, and lions are the only animals known to develop prostate cancer


• what remained was a cell driven to divide with such pathological and autonomous fecundity that it had erased all memory of normalcy. <> But Huggins knew that certain forms of cancer did not obey this principle. Variants of thyroid cancer, for instance, continued to make thyroid hormone


• malignant prostate cells were nearly addicted to the hormone—so much so that the acute withdrawal acted like the most powerful therapeutic drug conceivable.


• intrigued by the inexplicable link between ovaries and breasts, Beatson had surgically removed the ovaries of three women with breast cancer. <> In an age before the hormonal circuits between the ovary and the breast were even remotely established, this was unorthodox beyond description—like removing the lung to cure a brain lesion. But to Beatson’s astonishment, his three cases revealed marked responses to the ovarian removal


• Using a radioactively labeled version of the hormone as bait, in 1968 Jensen found the estrogen receptor—the molecule responsible for binding estrogen and relaying its signal to the cell. <> Jensen now asked whether breast cancer cells also uniformly possessed this receptor. Unexpectedly, some did and some did not. Indeed, breast cancer cases could be neatly divided into two types—ones with cancer cells that expressed high levels of this receptor and those that expressed low levels, “ER-positive” and “ER-negative” tumors.


• But Jensen had no such drug. Testosterone did not work, and no synthetic “antiestrogen” was in development. In their dogged pursuit of cures for menopause and for new contraceptive agents (using synthetic estrogens), pharmaceutical companies had long abandoned the development of an antiestrogen.. The antiestrogenic properties of his new drug raised an intriguing possibility. ICI 46474 may be a useless contraceptive, but perhaps, he reasoned, it might be useful against estrogen-sensitive breast cancer.. the success of the trial was incontrovertible—and the proof of principle historic. A drug designed to target a specific pathway in a cancer cell—not a cellular poison discovered empirically by trial and error—had successfully driven metastatic tumors into remission.


• Cole now wondered whether Halsted had tried to cleanse the Augean stables of cancer with all the right intentions, but with the wrong tools. Surgery could not eliminate invisible reservoirs of cancer. But perhaps what was needed was a potent chemical—a systemic therapy,... Li had been packed off in ignominy, but the strategy that had undone him—using chemotherapy to “cleanse” the body of residual tumor—had gained increasing respectability at the institute.


• * By the mid-1960s, as radical surgery became increasingly embattled, most breast surgeons had begun to view chemotherapists as estranged rivals that could not be trusted with anything, least of all improving surgical outcomes... Bonadonna and Veronesi, the only surgeon-chemotherapist pair seemingly on talking terms with each other, proposed a large randomized trial to study chemotherapy after breast surgery for early-stage breast cancer... In America, the landscape of cancer medicine had become so deeply gashed by internal rifts that the most important NCI-sponsored trial of cytotoxic chemotherapy to be launched after the announcement of the War on Cancer had to be relocated to a foreign country.


• in 1967, she created a hospice in London to care specifically for the terminally ill and dying, evocatively naming it St. Christopher’s—not after the patron saint of death, but after the patron saint of travelers. <> It would take a full decade for Saunders’s movement to travel to America and penetrate its optimism-fortified oncology wards.


• Counting is the religion of this generation. It is its hope and its salvation. —Gertrude Stein


• But here, too, there are profound methodological glitches. “Cancer-related death” is a raw number in a cancer registry, a statistic that arises from the diagnosis entered by a physician when pronouncing a patient dead. The problem with comparing that raw number over long stretches of time is that the American population (like any) is gradually aging overall,