## Metadata - Author: [[Siddhartha Mukherjee]] - Full Title: The Emperor of All Maladies - Category: #books ## Highlights - the arrival of a patient with acute leukemia still sends a shiver down the hospital’s spine—all the way from the cancer wards on its upper floors to the clinical laboratories buried deep in the basement. Leukemia is cancer of the white blood cells—cancer in one of its most explosive, violent incarnations. ([Location 219](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=219)) - leukemia represents a special incarnation of cancer. Its pace, its acuity, its breathtaking, inexorable arc of growth forces rapid, often drastic decisions; it is terrifying to experience, terrifying to observe, and terrifying to treat. The body invaded by leukemia is pushed to its brittle physiological limit—every system, heart, lung, blood, working at the knife-edge of its performance. ([Location 222](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=222)) - Cell division allows us as organisms to grow, to adapt, to recover, to repair—to live. And distorted and unleashed, it allows cancer cells to grow, to flourish, to adapt, to recover, and to repair—to live at the cost of our living. Cancer cells can grow faster, adapt better. They are more perfect versions of ourselves. ([Location 278](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=278)) - Malignant growth and normal growth are so genetically intertwined that unbraiding the two might be one of the most significant scientific challenges faced by our species. ([Location 282](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=282)) - 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. (More than a century later, in the early 1980s, another change in name—from gay related immune disease (GRID) to acquired immuno deficiency syndrome (AIDS)—would signal an epic shift in the understanding of that disease.*) ([Location 374](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=374)) - Virchow entered medicine in the early 1840s, when nearly every disease was attributed to the workings of some invisible force: miasmas, neuroses, bad humors, and hysterias. Perplexed by what he couldn’t see, Virchow turned with revolutionary zeal to what he could see: cells under the microscope. In 1838, Matthias Schleiden, a botanist, and Theodor Schwann, a physiologist, both working in Germany, had claimed that all living organisms were built out of fundamental building blocks called cells. Borrowing and extending this idea, 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. ([Location 384](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=384)) - sitting in his basement laboratory in the summer of 1947, Farber had a single inspired idea: 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. ([Location 466](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=466)) - Leukemia was an orphan disease, abandoned by internists, who had no drugs to offer for it, and by surgeons, who could not possibly operate on blood. “Leukemia,” as one physician put it, “in some senses, had not [even] been cancer before World War II.” The illness lived on the borderlands of illnesses, a pariah lurking between disciplines and departments—not unlike Farber himself. ([Location 614](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=614)) - the disease that doesn’t knock before it enters ([Location 806](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=806)) - The notion of cancer as an affliction that belongs paradigmatically to the twentieth century is reminiscent, as Susan Sontag argued so powerfully in her book Illness as Metaphor, of another disease once considered emblematic of another era: tuberculosis in the nineteenth century. Both diseases, as Sontag pointedly noted, were similarly “obscene—in the original meaning of that word: ill-omened, abominable, repugnant to the senses.” Both drain vitality; both stretch out the encounter with death; in both cases, dying, even more than death, defines the illness. ([Location 811](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=811)) - The cancer cell is a desperate individualist, “in every possible sense, a nonconformist,” as the surgeon-writer Sherwin Nuland wrote. The word metastasis, used to describe the migration of cancer from one site to another, is a curious mix of meta and stasis—“beyond stillness” in Latin—an unmoored, partially unstable state that captures the peculiar instability of modernity. If consumption once killed its victims by pathological evisceration (the tuberculosis bacillus gradually hollows out the lung), then 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; it invades through tissues, sets up colonies in hostile landscapes, seeking “sanctuary” in one organ and then immigrating to another. It lives desperately, inventively, fiercely, territorially, cannily, and defensively—at times, as if teaching us how to survive. To confront cancer is to encounter a parallel species, one perhaps more adapted to survival than even we are. ([Location 821](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=821)) - 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. ([Location 974](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=974)) - The gibbet and the graveyard—the convenience stores for the medieval anatomist—yielded specimen after specimen for Vesalius, and he compulsively raided them, often returning twice a day to cut pieces dangling from the chains and smuggle them off to his dissection chamber. Anatomy came alive for him in this grisly world of the dead. In 1538, collaborating with artists in Titian’s studio, Vesalius began to publish his detailed drawings in plates and books—elaborate and delicate etchings charting the courses of arteries and veins, mapping nerves and lymph nodes. ([Location 1063](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=1063)) - 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 that Hunter and his colleagues had once concocted on cadavers. An incandescent century of cancer surgery emerged; between 1850 to 1950, surgeons brazenly attacked cancer by cutting open the body and removing tumors. ([Location 1171](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=1171)) - Halsted, Brunschwig, and Pack persisted with their mammoth operations because they genuinely believed that they could relieve the dreaded symptoms of cancer. But they 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. ([Location 1413](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=1413)) - 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. ([Location 1482](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=1482)) - Dye making in England had rapidly become an intricate chemical business. In Germany—goaded by the textile industry, cosseted by national subsidies, and driven by expansive economic growth—synthetic chemistry underwent an even more colossal boom. In 1883, the German output of alizarin, the brilliant red chemical that imitated natural carmine, reached twelve thousand tons, dwarfing the amount being produced by Perkin’s factory in London. German chemists rushed to produce brighter, stronger, cheaper chemicals and muscled their way into textile factories all around Europe. 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. Initially, the German textile chemists lived entirely in the shadow of the dye industry. But emboldened by their successes, the chemists began to synthesize not just dyes and solvents, but an entire universe of new molecules: phenols, alcohols, bromides, alkaloids, alizarins, and amides, chemicals never encountered in nature. By the late 1870s, synthetic chemists in Germany had created more molecules than they knew what to do with. “Practical chemistry” had become almost a caricature of itself: an industry seeking a practical purpose for the products that it had so frantically raced to invent. ([Location 1608](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=1608)) - 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—seemingly trivial—had enormous implications. Urea was a “natural” chemical, while its precursor was an inorganic salt. That a chemical produced by natural organisms could be derived so easily in a flask threatened to overturn the entire conception of living organisms: for centuries, the chemistry of living organisms was thought to be imbued with some mystical property, a vital essence that could not be duplicated in a laboratory—a theory called vitalism. Wöhler’s experiment demolished vitalism. Organic and inorganic chemicals, he proved, were interchangeable. Biology was chemistry: perhaps even a human body was no different from a bag of busily reacting chemicals—a beaker with arms, legs, eyes, brain, and soul. ([Location 1625](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=1625)) - In 1878, in Leipzig, a twenty-four-year-old medical student, Paul Ehrlich, hunting for a thesis project, proposed using cloth dyes—aniline and its colored derivatives—to stain animal tissues. At best, Ehrlich hoped that the dyes might stain the tissues to make microscopy easier. But to his astonishment, the dyes were far from indiscriminate darkening agents. Aniline derivatives stained only parts of the cell, silhouetting certain structures and leaving others untouched. The dyes seemed able to discriminate among chemicals hidden inside cells—binding some and sparing others. ([Location 1642](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=1642)) - Scientists often study the past as obsessively as historians because few other professions depend so acutely on it. Every experiment is a conversation with a prior experiment, every new theory a refutation of the old. ([Location 1816](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=1816)) - A model is a lie that helps you see the truth ([Location 2590](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=2590)) - “It is the dose that makes a poison,” runs the old adage in medicine: all medicines were poisons in one form or another merely diluted to an appropriate dose. But chemotherapy was poison even at the correct dose. ([Location 2658](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=2658)) - Cancers possessed temperaments, personalities—behaviors. And biological heterogeneity demanded therapeutic heterogeneity; the same treatment could not indiscriminately be applied to all. But even if Kaplan understood it fully in 1963 and made an example of it in treating Hodgkin’s disease, it would take decades for a generation of oncologists to come to the same realization. ([Location 2993](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=2993)) - In the 1920s, the only known causes of human cancer were environmental carcinogens such as radium (recall Marie Curie’s leukemia) or organic chemicals, such as paraffin and dye by-products, that were known to cause solid tumors. ([Location 3208](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3208)) - 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. But the precise nature of the alteration was unknown. ([Location 3212](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3212)) - In 1910, unwittingly, Rous threw the somatic theory into grave doubt. Experimenting with the spindle-cell sarcoma, Rous injected the tumor in one chicken into another chicken and found that the cancer could be transmitted from one bird to another. “I have propagated a spindle-cell sarcoma of the common fowl into its fourth generation,” he wrote. “The neoplasm grows rapidly, infiltrates, metastasizes, and remains true to type.” This was curious, but nonetheless still understandable—cancer was a disease of cellular origin, and transferring cells from one organism to another might have been expected to transmit the cancer. But then Rous stumbled on an even more peculiar result. Shuttling tumors from one bird to another, he began to pass the cells through a set of filters, a series of finer and finer cellular sieves, 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. ([Location 3216](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3216)) - Two superficial theories were thus stitched audaciously—and prematurely—into one comprehensive whole. One offered a cause: viruses caused cancer (although a vast majority of them were yet undiscovered). The second offered a cure: particular combinations of cytotoxic poisons would cure cancer (although specific combinations for the vast majority of cancers were yet undiscovered). ([Location 3267](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3267)) - 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. AIDS loomed so large on the 1980s in part because this was a generation inherently haunted by its sexuality and freedom; SARS set off a panic about global spread and contagion at a time when globalism and social contagion were issues simmering nervously in the West. Every era casts illness in its own image. Society, like the ultimate psychosomatic patient, matches its medical afflictions to its psychological crises; when a disease touches such a visceral chord, it is often because that chord is already resonating. ([Location 3373](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3373)) - The Apollo mission and the Manhattan Project, the two models driving this War on Cancer were both technological achievements that stood on the shoulders of long and deep scientific discoveries (atomic physics, fluid mechanics, and thermodynamics). In contrast, even a cursory understanding of the process that made cells become malignant was missing. Seizing on the Laskerites’ favorite metaphor, Sol Spiegelman, the Columbia University cancer scientist, argued, “An all-out effort at this time would be like trying to land a man on the moon without knowing Newton’s laws of gravity.” ([Location 3467](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3467)) - For any trial to be adequately “powered,” it needs to recruit an adequate number of patients. But to recruit patients, a trialist has to convince doctors to participate in the trial—and yet these doctors are often precisely those who have the least interest in having a theory rejected or disproved. ([Location 3660](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3660)) - Between 1891 and 1981, in the nearly one hundred years of the radical mastectomy, an estimated five hundred thousand women underwent the procedure to “extirpate” cancer. Many chose the procedure. Many were forced into it. Many others did not even realize that it was a choice. Many were permanently disfigured; many perceived the surgery as a benediction; many suffered its punishing penalties bravely, hoping that they had treated their cancer as aggressively and as definitively as possible. Halsted’s “cancer storehouse” grew far beyond its original walls at Hopkins. His ideas entered oncology, then permeated its vocabulary, then its psychology, its ethos, and its self-image. When radical surgery fell, an entire culture of surgery thus collapsed with it. The radical mastectomy is rarely, if ever, performed by surgeons today. ([Location 3722](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3722)) - Estrogen is the principal hormone secreted by the ovaries. As with testosterone for the normal prostate, estrogen was soon demonstrated to be a vital hormone for the maintenance and growth of normal breast tissue. ([Location 3964](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=3964)) - In the history of medicine, no significant disease had ever been eradicated by a treatment-related program alone. If one plotted the decline in deaths from tuberculosis, for instance, the decline predated the arrival of new antibiotics by several decades. Far more potently than any miracle medicine, relatively uncelebrated shifts in civic arrangements—better nutrition, housing, and sanitation, improved sewage systems and ventilation—had driven TB mortality down in Europe and America. Polio and smallpox had also dwindled as a result of vaccinations. Cairns wrote, “The death rates from malaria, cholera, typhus, tuberculosis, scurvy, pellagra and other scourges of the past have dwindled in the US because humankind has learned how to prevent these diseases.… To put most of the effort into treatment is to deny all precedent.” ([Location 4217](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=4217)) - In the turbulent century between 1850 and 1950, the world offered conflict, atomization, and disorientation. The cigarette offered its equal and opposite salve: camaraderie, a sense of belonging, and the familiarity of habits. If cancer is the quintessential product of modernity, then so, too, is its principal preventable cause: tobacco. ([Location 4428](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=4428)) - In 1884, the microbiologist Robert Koch had stipulated that for an agent to be defined as the “cause” of a disease, it would need to fulfill at least three criteria. The causal agent had to be present in diseased animals; it had to be isolated from diseased animals; and it had to be capable of transmitting the disease when introduced into a secondary host. But Koch’s postulates had arisen, crucially, from the study of infectious diseases and infectious agents; they could not simply be “repurposed” for many noninfectious diseases. ([Location 4658](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=4658)) - Hill acknowledged epidemiology’s infernal methodological struggle with causation—this was not an experimental discipline at its core—but he rose beyond it. At least in the case of lung cancer and smoking, he argued, the association possessed several additional features: It was strong: the increased risk of cancer was nearly five- or tenfold in smokers. It was consistent: Doll and Hill’s study, and Wynder and Graham’s study, performed in vastly different contexts on vastly different populations, had come up with the same link. It was specific: tobacco was linked to lung cancer—precisely the site where tobacco smoke enters the body. It was temporal: Doll and Hill had found that the longer one smoked, the greater the increase in risk. It possessed a “biological gradient”: the more one smoked in quantity, the greater the risk for lung cancer. It was plausible: a mechanistic link between an inhaled carcinogen and a malignant change in the lung was not implausible. It was coherent; it was backed by experimental evidence: the epidemiological findings and the laboratory findings, such as Graham’s tar-painting experiments in mice, were concordant. It behaved similarly in analogous situations: smoking had been correlated with lung cancer, and also with lip, throat, tongue, and esophageal cancer. Hill used these criteria to advance a radical proposition. Epidemiologists, he argued, could infer causality by using that list of nine criteria. No single item in that list proved a causal relationship. Rather, Hill’s list functioned as a sort of à la carte menu, from which scientists could pick and choose criteria to strengthen (or weaken) the notion of a causal relationship. For scientific purists, this seemed rococo—and, like all things rococo, all too easy to mock: imagine a mathematician or physicist choosing from a “menu” of nine criteria to infer causality. Yet Hill’s list would charge epidemiological research with pragmatic clarity. Rather than fussing about the metaphysical idea about causality (what, in the purest sense, constitutes “cause”?), Hill changed its emphasis to a functional or operational idea. Cause is what cause does, Hill claimed. Often, like the weight of proof in a detective case, the preponderance of small bits of evidence, rather than a single definitive experiment, clinched cause. ([Location 4680](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=4680)) - It remains an astonishing, disturbing fact that in America—a nation where nearly every new drug is subjected to rigorous scrutiny as a potential carcinogen, and even the bare hint of a substance’s link to cancer ignites a firestorm of public hysteria and media anxiety—one of the most potent and common carcinogens known to humans can be freely bought and sold at every corner store for a few dollars. ([Location 5055](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=5055)) - chemicals that scored as mutagens in his test tended to be carcinogens as well. Dye derivatives, known to be potent human carcinogens, scored floridly, causing hundreds of colonies of bacteria. So did X-rays, benzene compounds, and nitrosoguanidine derivatives—all known to cause cancers in rats and mice. In the tradition of all good tests, Ames’s test transformed the unobservable and immeasurable into the observable and measurable. ([Location 5094](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=5094)) - Carcinogens, Ames suggested, had a common, distinctive functional property: they altered genes. Ames ([Location 5103](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=5103)) - There was little precedent in other diseases for such an astonishing diversity of causes. Diabetes, a complex illness with complex manifestations, is still fundamentally a disease of abnormal insulin signaling. Coronary heart disease occurs when a clot, arising from a ruptured and inflamed atherosclerotic plaque, occludes a blood vessel of the heart. But the search for a unifying mechanistic description of cancer seemed to be sorely missing. What, beyond abnormal, dysregulated cell division, was the common pathophysiological mechanism underlying cancer? ([Location 5227](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=5227)) - The Pap smear had, in effect, pushed the clock of cancer detection forward by nearly two decades, and changed the spectrum of cervical cancer from predominantly incurable to predominantly curable. ([Location 5314](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=5314)) - Epidemiologists think about prevention in two forms. In primary prevention, a disease is prevented by attacking its cause—smoking cessation for lung cancer or a vaccine against hepatitis B for liver cancer. In secondary prevention (also called screening), a disease is prevented by screening for its early, presymptomatic stage. ([Location 5317](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=5317)) - Death possessed the imagination of my patients that month, and my task was to repossess imagination from death. It is a task almost impossibly difficult to describe, an operation far more delicate and complex than the administration of a medicine or the performance of surgery. It was easy to repossess imagination with false promises; much harder to do so with nuanced truths. ([Location 5608](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=5608)) - In an essay titled A View from the Front Line, Jencks described her experience with cancer as like being woken up midflight on a jumbo jet and then thrown out with a parachute into a foreign landscape without a map: “There you are, the future patient, quietly progressing with other passengers toward a distant destination when, astonishingly (Why me?) a large hole opens in the floor next to you. People in white coats appear, help you into a parachute and—no time to think—out you go. “You descend. You hit the ground.… But where is the enemy? What is the enemy? What is it up to?… No road. No compass. No map. No training. Is there something you should know and don’t? “The white coats are far, far away, strapping others into their parachutes. Occasionally they wave but, even if you ask them, they don’t know the answers. They are up there in the Jumbo, involved with parachutes, not map-making.” ([Location 6053](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6053)) - Postdocs and graduate students hover around the microscopes and centrifuges. Medical words and phrases are occasionally recognizable here, but the dialect of the lab bears little resemblance to the dialect of medicine. It is like traveling to a neighboring country—one that has similar mannerisms but speaks a different language: ([Location 6176](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6176)) - Viruses, initially isolated in 1898 as minuscule infectious microbes that caused plant diseases, were becoming increasingly recognized as causes for a variety of animal and human diseases. In 1909, a year before Rous isolated his cancer-causing virus, Karl Landsteiner implicated a virus as the cause for polio. By the early 1920s, viruses that caused cowpox and human herpes infections had been isolated and grown in laboratories, further cementing the connection between viruses and human and animal diseases. ([Location 6245](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6245)) - Mendel had found that genes could move from one generation to the next; Morgan had proved that they did so by being carried on chromosomes. In 1926, Avery found that in certain species of bacteria, genes could also be transmitted laterally between two organisms—from one bacterium to its neighbor. ([Location 6282](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6282)) - Even dead, inert bacteria—no more than a conglomeration of chemicals—could transmit genetic information to live bacteria. This implied that an inert chemical was responsible for carrying genes. Avery separated heat-killed bacteria into their chemical components. And by testing each chemical component for its capacity to transmit genes, Avery and his colleagues reported in 1944 that genes were carried by one chemical, deoxyribonucleic acid, or DNA. What scientists had formerly disregarded as a form of cellular stuffing with no real function—a “stupid molecule,” as the biologist Max Delbruck once called it dismissively—turned out to be the central conveyor of genetic information between cells, the least stupid of all molecules in the chemical world. ([Location 6285](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6285)) - A protein is a gene realized—the machine built from a gene’s instructions. But proteins are not created directly out of genes. In the late 1950s, Jacques Monod and François Jacob, working in Paris, Sydney Brenner and Matthew Meselson at Caltech, and Francis Crick in Cambridge, discovered that the genesis of proteins from genes requires an intermediary step—a molecule called ribonucleic acid, or RNA. ([Location 6303](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6303)) - An incandescent century of biological discovery—spanning from Mendel’s discovery of genes in 1860 to Monod’s identification of the RNA copy of genes in the late 1950s—illuminated the inner workings of a normal cell. But it did little to illuminate the workings of a cancer cell or the cause of cancer—except in two tantalizing instances. ([Location 6319](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6319)) - The link between X-rays and mutations nearly led Morgan and Muller to the brink of a crucial realization about cancer. Radiation was known to cause cancer. (Recall Marie Curie’s leukemia, and the tongue cancers of the radium-watch makers.) Since X-rays also caused mutations in fruit fly genes, could cancer be a disease of mutations? And since mutations were changes in genes, could genetic alterations be the “unitary cause” of cancer? ([Location 6341](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6341)) - The hunt for an internal, genetic cause of cancer had stalled since Boveri. Pathological mitosis was visible in cancerous tissue. But both geneticists and embryologists failed to answer the key question: what caused mitosis to turn so abruptly from such an exquisitely regulated process to chaos? ([Location 6355](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6355)) - More deeply, what had failed was a kind of biological imagination. Boveri’s mind had so acrobatically leapt from sea urchins to carcinomas, or Morgan’s from pea plants to fruit flies, in part because biology itself was leaping from organism to organism, finding systematic cellular blueprints that ran deeply through all the living world. But extending that same blueprint to human diseases had turned out to be a much more challenging task. At Columbia, Morgan had assembled a fair collection of fruit fly monsters, but none that even remotely resembled a real human affliction. The notion that the cancer doctor might call in a “genetic friend” to help understand the pathophysiology of cancer seemed laughable. ([Location 6357](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6357)) - By the early 1950s, cancer researchers had thus split into three feuding camps. The virologists, led by Rous, claimed that viruses caused cancer, although no such virus had been found in human studies. Epidemiologists, such as Doll and Hill, argued that exogenous chemicals caused cancer, although they could not offer a mechanistic explanation for their theory or results. The third camp, of Theodor Boveri’s successors, stood at the farthest periphery. They possessed weak, circumstantial evidence that genes internal to the cell might cause cancer, but had neither the powerful human data of the epidemiologists nor the exquisite experimental insights of the chicken virologists. ([Location 6384](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6384)) - Great science emerges out of great contradiction, and here was a gaping rift slicing its way through the center of cancer biology. Was human cancer caused by an infectious agent? Was it caused by an exogenous chemical? Was it caused by an internal gene? ([Location 6389](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6389)) - RNA into DNA. Even the thought made him shiver: a molecule that could write history backward, turn back the relentless forward flow of biological information. ([Location 6432](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6432)) - The developments of the summer of 1976 drastically reorganized the universe of cancer biology, returning genes, again, to its center. Harold Varmus and Michael Bishop’s proto-oncogene theory provided the first cogent and comprehensive theory of carcinogenesis. The theory explained how radiation, soot, and cigarette smoke, diverse and seemingly unrelated insults, could all initiate cancer—by mutating and thus activating precursor oncogenes within the cell. ([Location 6641](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6641)) - The cloning of ras and retinoblastoma—oncogene and anti-oncogene—was a transformative moment in cancer genetics. In the decade between 1983 and 1993, a horde of other oncogenes and anti-oncogenes (tumor suppressor genes) were swiftly identified in human cancers: myc, neu, fos, ret, akt (all oncogenes), and p53, VHL, APC (all tumor suppressors). ([Location 6947](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=6947)) - By the early 1990s, cancer biologists could begin to model the genesis of cancer in terms of molecular changes in genes. To understand that model, let us begin with a normal cell, say a lung cell that resides in the left lung of a forty-year-old fire-safety-equipment installer. One morning in 1968, a minute sliver of asbestos from his equipment wafts through the air and lodges in the vicinity of that cell. His body reacts to the sliver with an inflammation. The cells around the sliver begin to divide furiously, like a minuscule wound trying to heal, and a small clump of cells derived from the original cell arises at the site. In one cell in that clump an accidental mutation occurs in the ras gene. The mutation creates an activated version of ras. The cell containing the mutant gene is driven to grow more swiftly than its neighbors and creates a clump within the original clump of cells. It is not yet a cancer cell, but a cell in which uncontrolled cell division has partly been unleashed—cancer’s primordial ancestor. A decade passes. The small collection of ras-mutant cells continues to proliferate, unnoticed, in the far periphery of the lung. The man smokes cigarettes, and a carcinogenic chemical in tar reaches the periphery of the lung and collides with the clump of ras-mutated cells. A cell in this clump acquires a second mutation in its genes, activating a second oncogene. Another decade passes. Yet another cell in that secondary mass of cells is caught in the path of an errant X-ray and acquires yet another mutation, this time inactivating a tumor suppressor gene. This mutation has little effect since the cell possesses a second copy of that gene. But in the next year, another mutation inactivates the second copy of the tumor suppressor gene, creating a cell that possesses two activated oncogenes and an inactive tumor suppressor gene. Now a fatal march is on; an unraveling begins. The cells, now with four mutations, begin to outgrow their brethren. As the cells grow, they acquire additional mutations and they activate pathways, resulting in cells even further adapted for growth and survival. One mutation in the tumor allows it to incite blood vessels to grow; another mutation within this blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen. Mutant cells beget cells beget cells. A gene that increases the mobility of the cells is activated in a cell. This cell, having acquired motility, can migrate through the lung tissue and enter the bloodstream. A descendant of this mobile cancer cell acquires the capacity to survive in the bone. This cell, having migrated through the blood, reaches the outer edge of the pelvis, where it begins yet another cycle of survival, selection, and colonization. It represents the first metastasis of a tumor that originated in the lung. The man is occasionally short of breath. He feels a tingle of pain in the periphery of his lung. Occasionally, he senses something moving under… ([Location 7091](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7091)) - As a medical procedure, childbirth is least likely to involve infectious complications and is thus the safest neighbor to a chemotherapy ward, where any infection can turn into a lethal rampage. As in so much in medicine, the juxtaposition between the two wards is purely functional and yet just as purely profound.) ([Location 7241](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7241)) - In a bewildering spurt over just two decades, scientists had unveiled a fantastical new world—of errant oncogenes and tumor suppressor genes that accelerated and decelerated growth to unleash cancer; of chromosomes that could be decapitated and translocated to create new genetic chimeras, of cellular pathways corrupted to subvert the death of cancer. But the therapeutic advances that had led to the slow attrition of cancer mortality made no use of this novel biology of cancer. There was new science on one hand and old medicine on the other. ([Location 7318](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7318)) - For nearly a decade, practicing cancer medicine had become like living inside a pressurized can—pushed, on one hand, by the increasing force of biological clarity about cancer, but then pressed against the wall of medical stagnation that seemed to have produced no real medicines out of this biological clarity. ([Location 7345](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7345)) - Surgery and radiation are intrinsically localized strategies, and they fail when cancer cells have spread beyond the limits of what can be surgically removed or irradiated. More surgery thus does not lead to more cures, as the radical surgeons discovered to their despair in the 1950s. Targeting cellular growth also hits a biological ceiling because normal cells must grow as well. Growth may be the hallmark of cancer, but it is equally the hallmark of life. A poison directed at cellular growth, such as vincristine or cisplatin, eventually attacks normal growth, and cells that grow most rapidly in the body begin to bear the collateral cost of chemotherapy. Hair falls out. Blood involutes. The lining of the skin and gut sloughs off. More drugs produce more toxicity without producing cures, as the radical chemotherapists discovered to their despair in the 1980s. ([Location 7376](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7376)) - The central therapeutic challenge of the newest cancer medicine, then, was to find, among the vast numbers of similarities in normal cells and cancer cells, subtle differences in genes, pathways, and acquired capabilities—and to drive a poisoned stake into that new heel. ([Location 7394](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7394)) - Proto-oncogenes and tumor suppressors are the molecular pivots of the cell. They are the gatekeepers of cell division, and the division of cells is so central to our physiology that genes and pathways that coordinate this process intersect with nearly every other aspect of our biology. In the laboratory, we call this the six-degrees-of-separation-from-cancer rule: you can ask any biological question, no matter how seemingly distant—what makes the heart fail, or why worms age, or even how birds learn songs—and you will end up, in fewer than six genetic steps, connecting with a proto-oncogene or tumor suppressor. ([Location 7494](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7494)) - kinase—a protein that tagged other proteins with a phosphate group and thus unleashed a cascade of signals in a cell. ([Location 7842](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7842)) - The human genome has about five hundred kinases (of which, about ninety belong to the subclass that contains src and Bcr-abl). Every kinase attaches phosphate tags to a unique set of proteins in the cell. Kinases thus act as molecular master-switches in cells—turning “on” some pathways and turning “off” others—thus providing the cell a coordinated set of internal signals to grow, shrink, move, stop, or die. ([Location 7847](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7847)) - “Cancer is complicated, everyone kept telling me patronizingly—as if I had suggested that it was not complicated.” The growing dogma, he knew, was that CML was perhaps intrinsically a chemotherapy-resistant disease. Even if the leukemia was initiated by that single translocation of the Bcr-abl gene, by the time the disease was identified in full bloom in real patients, it had accumulated a host of additional mutations, creating a genetic tornado so chaotic that even transplantation, the chemotherapist’s bluntest weapon, was of no consequence. The inciting Bcr-abl kinase had likely long been overwhelmed by more powerful driver mutations. Using a kinase inhibitor to try to control the disease, Druker feared, would be like blowing hard on a matchstick long after it had ignited a forest fire. ([Location 7911](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7911)) - Seminal ideas begin in the far peripheries of cancer biology, then ricochet back into more common forms of the disease. And leukemia, of all forms of cancer, is often the seed of new paradigms. This story began with leukemia in Sidney Farber’s clinic in 1948, and it must return to leukemia. If cancer is in our blood, as Varmus reminded us, then it seems only appropriate that we keep returning, in ever-widening circles, to cancer of the blood. ([Location 7985](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=7985)) - I said CML was a “rare” disease, and that was true in the era before Gleevec. The incidence of CML remains unchanged from the past: only a few thousand patients are diagnosed with this form of leukemia every year. But the prevalence of CML—the number of patients presently alive with the disease—has dramatically changed with the introduction of Gleevec. As of 2009, CML patients treated with Gleevec are expected to survive an average of thirty years after their diagnosis. Based on that survival figure, Hagop Kantarjian estimates that within the next decade, 250,000 people will be living with CML in America, all of them on targeted therapy. Druker’s drug will alter the national physiognomy of cancer, converting a once-rare disease into a relatively common one. (Druker jokes that he has achieved the perfect inversion of the goals of cancer medicine: his drug has increased the prevalence of cancer in the world.) Given that most of our social networks typically extend to about one thousand individuals, each of us, on average, will know one person with this leukemia who is being kept alive by a targeted anticancer drug. ([Location 8001](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=8001)) - A small, nondescript Northeastern town bound by a chain of frozen lakes in midwinter, Framingham is nonetheless an iconic place writ large in the history of medicine. In 1948, epidemiologists identified a cohort of about five thousand men and women living in Framingham. The behavior of this cohort, its habits, its interrelationships, and its illnesses, has been documented year after year in exquisite detail, creating an invaluable longitudinal corpus of data for hundreds of epidemiological studies. The English mystery writer Agatha Christie often used a fictional village, St. Mary Mead, as a microcosm of all mankind. Framingham is the American epidemiologist’s English village. Under sharp statistical lenses, its captive cohort has lived, reproduced, aged, and died, affording a rare glimpse of the natural history of life, disease, and death. The Framingham data set has spawned a host of studies on risk and illness. The link between cholesterol and heart attacks was formally established here, as was the association of stroke and high blood pressure. ([Location 8077](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=8077)) - The cigarette epidemic, we might recall, originated as a form of metastatic behavior—one site seeding another site seeding another. Soldiers brought smoking back to postwar Europe; women persuaded women to smoke; the tobacco industry, sensing opportunity, advertised cigarettes as a form of social glue that would “stick” individuals into cohesive groups. The capacity of metastasis is thus built into smoking. If entire networks of smokers can flicker off with catalytic speed, then they can also flicker on with catalytic speed. Sever the ties that bind the nonsmokers of Framingham (or worse, nucleate a large social network with a proselytizing smoker), and then, cataclysmically, the network might alter as a whole. ([Location 8100](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=8100)) - We are chemical apes: having discovered the capacity to extract, purify, and react molecules to produce new and wondrous molecules, we have begun to spin a new chemical universe around ourselves. Our bodies, our cells, our genes are thus being immersed and reimmersed in a changing flux of molecules—pesticides, pharmaceutical drugs, plastics, cosmetics, estrogens, food products, hormones, even novel forms of physical impulses, such as radiation and magnetism. Some of these, inevitably, will be carcinogenic. We cannot wish this world away; our task, then, is to sift through it vigilantly to discriminate bona fide carcinogens from innocent and useful bystanders. ([Location 8110](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=8110)) - The bedlam of the cancer genome, in short, is deceptive. If one listens closely, there are organizational principles. The language of cancer is grammatical, methodical, and even—I hesitate to write—quite beautiful. Genes talk to genes and pathways to pathways in perfect pitch, producing a familiar yet foreign music that rolls faster and faster into a lethal rhythm. Underneath what might seem like overwhelming diversity is a deep genetic unity. Cancers that look vastly unlike each other superficially often have the same or similar pathways unhinged. “Cancer,” as one scientist recently put it, “really is a pathway disease.” ([Location 8248](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=8248)) - The human embryo and many of our adult organs possess a tiny population of stem cells that are capable of immortal regeneration. Stem cells are the body’s reservoir of renewal. The entirety of human blood, for instance, can arise from a single, highly potent blood-forming stem cell (called a hematopoietic stem cell), which typically lives buried inside the bone marrow. Under normal conditions, only a fraction of these blood-forming stem cells are active; the rest are deeply quiescent—asleep. But if blood is suddenly depleted, by injury or chemotherapy, say, then the stem cells awaken and begin to divide with awe-inspiring fecundity, generating cells that generate thousands upon thousands of blood cells. In weeks, a single hematopoietic stem cell can replenish the entire human organism with new blood—and then, through yet unknown mechanisms, lull itself back to sleep. ([Location 8334](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=8334)) - The Greeks used an evocative word to describe tumors, onkos, meaning “mass” or “burden.” The word was more prescient than they might have imagined. Cancer is indeed the load built into our genome, the leaden counterweight to our aspirations for immortality. But if one looks back even further behind the Greek to the ancestral Indo-European language, the etymology of the word onkos changes. Onkos arises from the ancient word nek. And nek, unlike the static onkos, is the active form of the word load. It means to carry, to move the burden from one place to the next, to bear something across a long distance and bring it to a new place. It is an image that captures not just the cancer cell’s capacity to travel—metastasis—but also Atossa’s journey, the long arc of scientific discovery—and embedded in that journey, the animus, so inextricably human, to outwit, to outlive and survive. ([Location 8466](https://readwise.io/to_kindle?action=open&asin=B003UYUP58&location=8466))