"The Emperor Of All Maladies", II

[fiefoe]

The second half of the book takes us more into the cell and recalls his later acrynom laden "The Song of the Cell".

• A vast majority of the institute’s grants, 80 percent, were directed toward treatment strategies for cancer; prevention research received about 20 percent... the notion of the “cure” as the singular solution to cancer had degenerated into a sclerotic dogma.


• Sifting through these observations, Pott eventually pinned his suspicion on chimney soot lodged chronically in the skin as the most likely cause of scrotal cancer.


• * It was precisely this rapid, viral ascendancy of tobacco that made its medical hazards virtually invisible. Our intuitive acuity about statistical correlations, like the acuity of the human eye, performs best at the margins. When rare events are superposed against rare events, the association between them can be striking. Pott, for instance, had discovered the link between scrotal cancer and chimney sweeping because chimney sweeping (the profession) and scrotal cancer (the disease) were both uncommon enough that the juxtaposition of the two stood out starkly like a lunar eclipse—two unusual occurrences in precise overlap... Tobacco, like the nylon stockings of cancer epidemiology, thus vanished from the view of preventive medicine.


• The only formal method to prove the fact that populations undergo defined genetic changes over time involves capturing that change in the real world in real time—prospectively.


• cigarette makers began to proactively tout the benefits of filters added to the tips of their cigarettes as a “safety” measure. (The iconic Marlboro Man, with his hypermasculine getup of lassos and tattoos, was an elaborate decoy set up to prove that there was nothing effeminate or sissy about smoking filter-tipped cigarettes.


• Obfuscation of facts, though, was only the first line of defense. The more ingenious form of manipulation was to gnaw at science’s own self-doubt: “The statistics purporting to link cigarette smoking with the disease could apply with equal force to any one of many other aspects of modern life... The implication was that if more research was needed, then the issue was still mired in doubt—and thus unresolved.


• So, in an inspired experiment performed in his lab in St. Louis, Graham had invented a “smoking machine,” a contraption that would puff the equivalent of hundreds of cigarettes all day (Lucky Strikes were chosen) and deposit the tarry black residue, through a maze of suction chambers, into a distilling flask of acetone. By serially painting the tar on the skins of mice,


• 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 / It was consistent: /It was specific:/ It was temporal: / It possessed a “biological gradient”: /It was plausible: /It was coherent; it was backed by experimental evidence:


• * 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.


• * In medical circles, the link between tobacco and cancer was such stale news that most investigators had begun to focus on secondhand smoke as a risk factor for cancer. But by “revisiting” the evidence, Terry’s commission would vivify it. It would intentionally create a show trial out of real trials, thus bringing the tragedy of tobacco back into the public eye.


• by lightening its blow to tobacco. The effect would be a double boon. By voluntarily pushing for congressional control, the tobacco industry would perform a feat of political acrobatics—a leap from the commission’s hostile fire to the much milder frying pan of Congress.


• “Statistics,” the journalist Paul Brodeur once wrote, “are human beings with the tears wiped off,” and thus far the antitobacco campaign had offered plenty of statistics, but with the human victims of tobacco somehow effaced.


• while his wife at home calmed her stormy nerves with a cigarette. “[It’s] a game only for steady nerves,” the copy ran. “But, then, what isn’t in these days—with all of us fighting, working, living at the highest tempo in years.” Rosie the Riveter, the quintessential symbol of wartime womanhood, was now recast as Rosie the Smoker, depicted in Chesterfield’s advertisements with a cigarette in hand.


• Edell’s insistence that he needed to know what cigarette makers knew about smoking risks allowed him to ask the courts for unprecedented access to the internal files of Philip Morris, Liggett, and Lorillard. Armed with powerful legal injunctions to investigate these private files, Edell unearthed a saga of epic perversity.


• Edell: What was the purpose of this [experiment]?
  Dey: To try to reduce tumors on the backs of mice.
  Edell: It had nothing to do with the health and welfare of human beings? Is that correct?


• Yet the real legacy of the Cipollone case had little to do with legal victories or losses. Lampooned in court as a weak-willed, ill-informed, and dim-witted addict unaware of the “obvious” dangers of tobacco, Rose Cipollone nonetheless turned into a heroic icon of a cancer victim battling her disease—even from her grave.


• By 1994, the per capita consumption of cigarettes in America had dropped for twenty straight years (from 4,141 in 1974 to 2,500 in 1994), representing the most dramatic downturn in smoking rates in history. It had been a long and slow battle of attrition. No intervention had single-handedly decimated tobacco, but the cumulative force of scientific evidence, political pressure, and legal inventiveness had worn the industry down over a decade. <> Yet, old sins have long shadows, and carcinogenic sins especially so.


• leaving big tobacco to become even bigger tobacco. The influx of annual settlement payments from cigarette makers creates “client-states” that depend on this money to fund escalating medical costs. Indeed, the real cost of the agreement is borne by addicted smokers who now pay more for cigarettes, and then pay with their lives.


• he populated his catalog, he made a seminal observation: 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.


• hepatitis B virus, or HBV. The virus was structurally simple—“roughly circular . . . about forty-two nanometers in diameter, one of the smallest DNA viruses that infect humans”


• the mere existence of the bacteria, or even its association with ulcers, was not proof enough that it caused gastritis... I drank it down in one gulp then fasted for the rest of the day. A few stomach gurgles occurred. Was it the bacteria or was I just hungry?” <> Marshall was not “just hungry.” Within a few days of swallowing the turbid bacterial culture, he was violently ill


• (His wife, Maria, in surely one of the more grisly displays of conjugal fortitude, reportedly allowed herself to be tested by cervical smears every day.) As with guinea pigs, he found that cells sloughed off by the human cervix could also foretell the stages of the menstrual cycle in women... The Pap smear, as he called the technique, was neither accurate nor particularly sensitive... At academic conferences, experts scoffed at the crude alternative.


• * A decades-old thought returned to haunt him: if normal cells of the cervix changed morphologically in graded, stepwise fashion over time, might cancer cells also change morphologically in time, in a slow, stepwise dance from normal to malignant?... The thought almost convulsed out of him. The real use of the Pap smear was not to find cancer, but rather to detect its antecedent, its precursor—the portent of cancer. <> “It was a revelation,” one of his students recalled. “A Pap smear would give a woman a chance to receive preventive care... 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.


• Increasing the density of that web, she finds, certainly increases the chances of catching real flies (true positives) but it also increases the chances of capturing junk and debris floating through the air (false positives). Making the web less dense, in contrast, decreases the chances of catching real prey, but every time something is captured, chances are higher that it is a fly.


• Only a test capable of meeting all these criteria—proving mortality benefit in a genuinely randomized setting with an acceptable over- and underdiagnosis rate—can be judged a success. With the odds stacked so steeply, few tests are powerful enough to withstand this level of scrutiny and truly provide benefit in cancer.


• The trial was kept deliberately simple: women enrollees in the HIP between the ages of forty and sixty-four were divided into two groups. One group was screened with mammography while the other was left unscreened. The ethical standards for screening trials in the 1960s made the identification of the groups even simpler. The unscreened group—i.e., the one not offered mammography—was not even required to give consent;.. In an astonishing span of six years, the trio completed a screening that would ordinarily have taken two decades to complete.


• Strax and Shapiro had faltered by selectively depleting the mammography group of high-risk patients. The CNBSS faltered, skeptics now charged, by succumbing to the opposite sin: by selectively enriching the mammography group with high-risk women.


• Its effects, as the statistician Donald Berry describes it, “are indisputable for a certain segment of women—but also indisputably modest in that segment.” Berry wrote, “Screening is a lottery. Any winnings are shared by the minority of women. . . . The overwhelming proportion of women experience no benefit and they pay with the time involved and the risks associated with screening... the fatal flaw in mammography lies in that these rates are not absolute: they depend on age. For women above fifty-five, the incidence of breast cancer is high enough that even a relatively poor screening tool can detect an early tumor and provide a survival benefit.


• * a mammogram or a Pap smear is a portrait of cancer in its infancy. Like any portrait, it is drawn in the hopes that it might capture something essential about the subject—its psyche, its inner being, its future, its behavior. “All photographs are accurate,” the artist Richard Avedon liked to say, “[but] none of them is the truth.”


• It was easy to repossess imagination with false promises; much harder to do so with nuanced truths. It demanded an act of exquisite measuring and remeasuring, filling and unfilling a psychological respirator with oxygen. Too much “repossession” and imagination might bloat into delusion. Too little and it might asphyxiate hope altogether.


• * I noted that he had said “when,” not “if.” The numbers told a statistical truth, but the sentence implied nuance. “We will tend to it,” he said, not “we will obliterate it.” Care, not cure. The conversation ran for nearly an hour. In his hands, information was something live and molten, ready to freeze into a hard shape at any moment, something crystalline yet negotiable; he nudged and shaped it like glass in the hands of a glassblower.


• For most chemotherapy drugs, that dose limit rested principally on a single organ—the bone marrow, whose whirring cellular mill, as Farber had found, was so exquisitely sensitive to most drugs that patients administered drugs to kill cancer were left with no normal blood-forming cells. For a while, then, it was the bone marrow’s sensitivity to cytotoxic drugs that had defined the outer horizon of chemotherapeutic dosage.


• Since the frozen marrow cells were spared the brunt of chemotherapy, transplantation allowed doctors, theoretically at least, to push doses of chemo to their ultimate end. <> For advocates of megadose chemotherapy, ABMT breached a final and crucial roadblock.


• her earlier Illness as Metaphor, Sontag argued that AIDS, like cancer, was becoming not just a biological disease but something much larger—a social and political category replete with its own punitive metaphors. Like cancer patients, AIDS patients were also paralyzed and shrouded by those metaphors—stripped bare, like the cancer patient in Solzhenitsyn’s Cancer Ward, then forced to don the ghoulish uniform of their disease. The stigmas attached to cancer—guilt, secrecy, shame—were recycled and refitted for AIDS,


• Nurses, many of them gay men, gravitated to Ward 5B to tend their friends (or returned poignantly, as the epidemic bloomed, as patients themselves). Doctors reinvented medicine here, pitting their wits against a hostile, mysterious disease that they couldn’t quite fathom that was plaguing a community that they didn’t quite understand.


• Montagnier soon deduced that this was an RNA virus that could convert its genes into DNA and lodge into the human genome—a retrovirus. He called his virus IDAV, immuno-deficiency associated viruses, arguing that it was likely the cause of AIDS.


• Among the most prominent and successful of the megadose transplanters was Werner Bezwoda, an oncologist at the University of Witwatersrand in Johannesburg, South Africa, who was recruiting dozens of women into his trial every month. Transplant was big business: big medicine, big money, big infrastructure, big risks... they christened the procedure a “minitransplant” or “transplant lite” or even “drive-thru transplant.” Transplanters, as one oncologist put it, “became gods at hospitals.”


• Bezwoda left the Atlanta meeting in a hurry, leaving behind a field awash with confusion and tumult. He had underestimated the impact of his data, for it was now the sole fulcrum on which an entire theory of cancer therapy, not to mention a $4 billion industry, rested.


• What if the flat line of cancer mortality represented a dynamic equilibrium of counterbalanced forces pushing and pulling against each other? <> As Bailar and Gornik probed their own data further, they began to discern such forces counterpoised against each other with almost exquisite precision. When cancer mortality between 1970 and 1994 was split into two age groups, the counterbalancing of forces was immediately obvious: in men and women above fifty-five, cancer mortality had increased, while in men and women under fifty-five, cancer mortality had decreased by exactly the same proportion... The national stalemate on cancer was hardly a stalemate, but rather the product of a frantic game of death in progress. Bailar had set out to prove that the War on Cancer had reached terminal stagnancy. Instead, he had chronicled a dynamic, moving battle in midpitch against a dynamic, moving target.


• Lauren, guarded and mature, enlivens her astute assessments with jokes about oncology. Our encounter with cancer has rounded us off; it has smoothed and polished us like river rocks.


• But von Hansemann proposed that the real abnormality lay in the structure of these bodies internal to cancer cells—in chromosomes—and therefore in the cancer cell itself. <> But was it cause or effect?


• The multiple fertilization, Boveri found, precipitated chromosomal chaos. Two sperms fertilizing an egg results in three of each chromosome—a number impossible to divide evenly. The urchin egg, unable to divide the number of chromosomes appropriately among its daughter cells, was thrown into frantic internal disarray... Chromosomes, Boveri concluded, must carry information vital for the proper development and growth of cells... Boveri wrote. Instead, a common feature lurked behind all cancers, a uniform abnormality that emanated from abnormal chromosomes—and was therefore internal to the cancer cell.


• The central problem was this: as causal agents, Rous’s virus and Boveri’s chromosomes were incompatible. A virus is a pathogen, an external agent, an invader exogenous to the cell. A chromosome is an internal entity, an endogenous structure buried deep inside the cell. The two opposites could not both claim to be the “unitary cause” of the same disease. How could an internal structure, a chromosome, and an external infectious agent, a virus, both create cancer?


• Morgan made another observation. He noted that an occasional rare trait, such as white eye color, was intrinsically linked to the gender of the fly: white eyes were found only in male flies. But “maleness”—the inheritance of sex—Morgan knew, was linked to chromosomes. So genes had to be carried on chromosomes—the threadlike structures identified by Flemming three decades earlier.


• 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. 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.


• Had Muller and Morgan, student and mentor, pitched their formidable scientific skills together, they might have answered this question and uncovered this essential link between mutations and malignancy. But once close colleagues, they became pitted and embittered rivals. Cantankerous and rigid with old age, Morgan refused to give Muller full recognition for his theory of mutagenesis, which he regarded as a largely derivative observation.


• Cancer researchers would return to the language of genes and mutations again in the 1970s. But the journey back to this language—and to the true “unitary” cause of cancer—would take a bewildering detour through the terrain of new biology, and a further fifty years.


• The biochemist Arthur Kornberg once joked that the discipline of modern biology in its early days often operated like the man in the proverbial story who is frantically searching for his keys under a streetlamp. When a passerby asks the man whether he lost his keys at that spot, the man says that he actually lost them at home—but he is looking for the keys under the lamp because “the light there is the brightest.”


• By the early 1950s, cancer researchers had thus split into three feuding camps. The virologists, led by Rous, claimed that viruses caused cancer, ..Epidemiologists, such as Doll and Hill, argued that exogenous chemicals caused cancer,.. 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.


• The foci, Temin reasoned, represented cancer distilled into its essential, elemental form: cells growing uncontrollably, unstoppably—pathological mitosis. It was the sheer, driving power of Temin’s imagination that allowed him to look at a tiny heap of cells and reimagine that heap as the essence of the diffuse systemic disease that kills humans. But Temin believed that the cell, and its interaction with the virus, had all the biological components necessary to drive the malignant process. The ghost was out of the organism.


• This observation—that a DNA copy of a virus’s genes could structurally attach itself to a cell’s genes—intrigued Temin and Dulbecco. But it raised an even more intriguing conceptual problem. In viruses, genes are sometimes carried in their intermediary RNA form... How on earth, Temin wondered, could RNA turn around acrobatically and make a DNA copy of itself, driving the wrong way down the one-way street of biological information?... The virus (or the infected cell) therefore had to possess the reverse capacity: reverse transcription. “Temin had an inkling, but his proof was so circumstantial...  When he added RNA to this cellular extract, he could “see” it creating a DNA copy—reversing transcription. Temin had his proof. Rous sarcoma virus was no ordinary virus. It could write genetic information backward: it was a retrovirus.


• In their respective papers, Temin and Baltimore proposed a radical new theory about the life cycle of retroviruses. The genes of retroviruses, they postulated, exist as RNA outside cells. When these RNA viruses infect cells, they make a DNA copy of their genes and attach this copy to the cell’s genes. This DNA copy, called a provirus, makes RNA copies, and the virus is regenerated, phoenixlike, to form new viruses... It is surely a sign of the prevailing schizophrenia of the time that Temin’s work was instantly embraced as a possible mechanistic explanation for cancer by cancer scientists, but largely ignored by clinical oncologists.


• Sol Spiegelman, a Columbia University virologist known for his incendiary enthusiasm and relentless energy, heard Temin’s talk and instantly built a monumental theory out of it—a theory so fiercely logical that Spiegelman could almost conjure it into reality... Spiegelman was convinced that this process, through a yet unknown mechanism, could activate a viral gene. That activated viral gene must induce the infected cell to proliferate—unleashing pathological mitosis, cancer. <> It was a tantalizingly attractive explanation. Rous’s viral theory of the origin of cancer would fuse with Boveri’s internal genetic theory... thus both an internal aberration and an exogenous infection would be responsible for cancer... In the end, though, Spiegelman’s effort turned out to be systematically flawed... Spiegelman’s conjecture about human retroviruses was half-right and half-wrong: he was looking for the right kind of virus but in the wrong kind of cell. Retroviruses would turn out to be the cause of a different disease—not cancer.


• * Temin proposed another bold conjecture—again, standing on the thinnest foundation of evidence. Spiegelman and the retrovirus hunters, Temin argued, had conflated analogy with fact, confused messenger with message. Rous sarcoma virus could cause cancer by inserting a viral gene into cells. This proved that genetic alterations could cause cancer. But the genetic alteration, Temin proposed, need not originate in a virus. The virus had merely brought a message into a cell... By analyzing the genes altered in these mutant viruses, these groups finally pinpointed RSV’s cancer-causing ability to a single gene in the virus. The gene was called src (pronounced “sarc”), a diminutive of sarcoma.


• Src was a prototypical kinase—although a kinase on hyperdrive. The protein made by the viral src gene was so potent and hyperactive that it phosphorylated anything and everything around it, including many crucial proteins in the cell. Src worked by unleashing an indiscriminate volley of phosphorylation—throwing “on” dozens of molecular switches. In src’s case, the activated series of proteins eventually impinged on proteins that controlled cell division. Src thus forcibly induced a cell to change its state from nondividing to dividing, ultimately inducing accelerated mitosis, the hallmark of cancer.


• If one molecule of DNA is tagged with radioactivity, it will seek out its complementary molecule in a mixture and stick to it, thereby imparting radioactivity to the second molecule. The sticking ability can be measured by the amount of radioactivity. <> In the mid-1970s, Bishop and Varmus began to use the viral src gene to hunt for its homologues, using this “sticking” reaction... is everywhere.” But the src gene that existed in normal cells was not identical to the viral src... Viral src carried mutations that dramatically affected its function.


• A theory began to convulse out of these results, a theory so magnificent and powerful that it would explain decades of disparate observations in a single swoop: perhaps src, the precursor to the cancer-causing gene, was endogenous to the cell. Perhaps viral src had evolved out of cellular src.


• Rous’s sarcoma virus had likely picked up an activated src gene from a cancer cell and carried it in the viral genome, creating more cancer. The virus, in effect, was no more than an accidental courier for a gene that had originated in a cancer cell—a parasite parasitized by cancer. Rous had been wrong—but spectacularly wrong. Viruses did cause cancer, but they did so, typically, by tampering with genes that originate in cells.


• Genetics has two distinct ways to “see” genes. The first is structural: genes can be envisioned as physical structures... The second is functional: genes can be imagined, à la Mendel, as the inheritance of traits that move from one generation to the next. In the decade between 1970 and 1980, cancer genetics would begin to “see” cancer-causing genes in these two lights.


• Children with the inherited form of retinoblastoma, in contrast, are born with a defective copy of Rb. In their cells, one gene copy is already defective, and only a single additional genetic mutation is needed before the cell senses the change and begins to divide. ... Knudson’s two-hit theory: Why was a single mutation in src sufficient to provoke cell division, while two were required for Rb? <> The answer lies in the function of the two genes. Src activates a function in cell division... Knudson’s gene, Rb, performs the opposite function. It suppresses cell proliferation, and it is the inactivation of such a gene (by virtue of two hits) that unleashes cell division. Rb, then, is a cancer suppressor gene—the functional opposite of src—an “anti-oncogene,” as Knudson called it... It was an exquisitely astute hypothesis spun, remarkably, out of statistical reasoning alone. Knudson did not know the molecular identity of his phantasmic anti-oncogenes... Like Mendel, Knudson knew his genes only in a statistical sense. He had inferred them, as he put it, “as one might infer the wind from the movement of the trees.”


• A cancer cell, in contrast, has about twenty thousand genes. Searching for a cancer-causing gene in that blizzard of genes was virtually hopeless. <> But an oncogene, by definition, has a special property: it provokes unbridled cellular proliferation in a normal cell... Weinberg pushed Shih to find the precise gene that could convert a normal cell to a cancer cell. Weinberg’s laboratory was now racing to isolate and identify the first native human oncogene.


• * In contrast, the Eyeball, with its proud display of nineteenth-century eyeglasses and lenses in lacquered wooden vitrines, was almost self-indulgently anachronistic. <> Dryja, too, was an unlikely cancer geneticist.


• Since the Rb gene had to be inactivated to unleash retinoblastoma, Dryja reasoned that the mutation responsible was likely a deletion of the gene..  It was the simplest of strategies: to hunt the gene with absent function, Dryja would look for absence in structure... But more than probes, he needed a resource that he uniquely possessed: an enormous bank of frozen tumors. The chances of finding a shared deletion in the Rb gene in both chromosomes were slim, so he would need to test a vast sample set to find one.


• A rather general conceptual framework for carcinogenesis was slowly becoming apparent. The cancer cell was a broken, deranged machine. Oncogenes were its jammed accelerators and inactivated tumor suppressors its missing brakes.


• Even more surprisingly, Leder’s mice typically developed cancers only after pregnancy, suggesting that environmental influences, such as hormones, were strictly required to achieve full transformation of breast cells.


• Vogelstein showed that the genetic progression of cancer was also a multistep process. <> This was a relief. In the decade between 1980 and 1990, proto-oncogenes and tumor suppressor genes had been discovered in such astonishing numbers in the human genome—at last count, about one hundred such genes—that their abundance raised a disturbing question: if the genome was so densely littered with such intemperate genes—genes waiting to push a cell toward cancer as if at the flick of a switch—then why was the human body not exploding with cancer every minute?.. Vogelstein provided the third answer. Activating or inactivating any single gene, he postulated, produced only the first steps toward carcinogenesis.


• Cancer, in short, was not merely genetic in its origin; it was genetic in its entirety. Abnormal genes governed all aspects of cancer’s behavior. Cascades of aberrant signals, originating in mutant genes, fanned out within the cancer cell, promoting survival, accelerating growth, enabling mobility, recruiting blood vessels, enhancing nourishment, drawing oxygen—sustaining cancer’s life. <> These gene cascades, notably, were perversions of signaling pathways used by the body under normal circumstances.


• Jimmy: Old-timers in the town also recalled Gustafson’s trips to Boston for chemotherapy. He had hitchhiked to and from Boston in cars and trucks and delivery vans anytime someone from the town had driven up or down the coast; it had taken a village to save a child.


• Primo Levi: remarked that among the most fatal qualities of the camp was its ability to erase the idea of a life outside and beyond itself. A person’s past and his present were annihilated as a matter of course—to be in the camps was to abnegate history, identity, and personality—but it was the erasure of the future that was the most chilling.


• Nor was there any sign of the woman who had come to the clinic several months earlier, nearly folded over in fear. Tumor out, chemotherapy done, radiation behind her, Fitz’s effervescence poured out of every spigot of her soul. At times, watching her personality emerge as if through a nozzle, it seemed abundantly clear why the Greeks had thought of disease as pathological blockades of humors.


• The second vulnerability is the rapid growth rate of cancer cells. Most chemotherapy drugs discovered before the 1980s target this second vulnerability.


• The discoveries of cancer biology in the 1980s offered a vastly more nuanced view of these vulnerabilities. Three new principles emerged, representing three new Achilles’ heels of cancer. <> First, cancer cells are driven to grow because of the accumulation of mutations in their DNA.. Second, proto-oncogenes and tumor suppressor genes typically lie at the hubs of cellular signaling pathways... Third, the relentless cycle of mutation, selection, and survival creates a cancer cell that has acquired several additional properties besides uncontrolled growth.


• * Of the two forms, cis-retinoic acid had been the most intensively tested, and it had produced the flickering, transient responses. But Wang and Degos wondered if trans-retinoic acid was the true maturation agent. Had the unreliable responses in the old experiments been due to a low and variable amount of the trans-retinoic form present in every batch of retinoic acid? <> Wang, who had studied at a French Jesuit school in Shanghai, spoke a lilting, heavily accented French. Linguistic and geographic barriers breached, the two hematologists outlined an international collaboration.


• Neu, then, was a perfect target, with a large portion, a long molecular “foot,” projected tantalizingly outside the cell membrane. It would have taken Padhy no more than an afternoon’s experiment to add the neu antibody to the neuroblastoma cells to determine the binding’s effect. “It would have been an overnight test,” Weinberg would later recall. “I can flagellate myself. If I had been more studious and more focused and not as monomaniacal about the ideas I had at that time, I would have made that connection.”.. Weinberg, caught in the giddy upswirl of new oncogenes and obsessed with the basic biology of the cancer cell, simply forgot about the neu experiment. Weinberg had an oncogene and possibly an oncogene-blocking drug, but the twain had never met (in human cells or bodies).


• * Invisible Cities, Italo Calvino describes a fictional metropolis in which every relationship between one household and the next is denoted by a piece of colored string stretched between the two houses. As the metropolis grows, the mesh of strings thickens and the individual houses blur away. In the end, Calvino’s city becomes no more than an interwoven network of colored strings. <> If someone were to draw a similar map of relationships among genes in a normal human cell, then proto-oncogenes and tumor suppressors such as ras, myc, neu, and Rb would sit at the hub of this cellular city, radiating webs of colored strings in every direction.


• In the late 1970s, researchers at Stanford and UCSF had invented a technology termed “recombinant DNA.” This technology allowed genes to be manipulated—engineered—in a hitherto unimaginable manner. Genes could be shuttled from one organism to another:


• Insulin, for instance, was produced by grinding up cow and pig innards into a soup and then extracting the protein from the mix—one pound of insulin from every eight thousand pounds of pancreas... Genentech could “engineer” a human gene into a bacterium, say, and use the bacterial cell as a bioreactor to produce vast quantities of that protein.


• * Antibodies are immunological proteins that bind their targets with exquisite affinity and specificity. The immune system synthesizes antibodies to bind and kill specific targets on bacteria and viruses; antibodies are nature’s magic bullets... But to exploit antibodies therapeutically, scientists needed to identify targets unique to cancer cells, and such cancer-specific targets had proved notoriously difficult to identify. Ullrich believed that he had found one such target. Her-2, amplified in some breast tumors but barely visible in normal cells,


• Mouse antibodies, being “foreign” proteins, provoke a potent immune response in humans and make terrible human drugs. To circumvent that response, Genentech’s antibody needed to be converted into a protein that more closely resembled a human antibody. This process, evocatively called “humanizing” an antibody, is a delicate art, somewhat akin to translating a novel; what matters is not just the content, but the ineffable essence of the antibody—its form.


• Such was the halting, traumatic birth of the new drug that it was easy to forget the enormity of what had been achieved. Slamon had identified Her-2 amplification in breast cancer tissue in 1987; Carter and Shepard had produced a humanized antibody against it by 1990. They had moved from cancer to target to drug in an astonishing three years,


• was an ideal candidate for the drug. But the news came too late.... For BCA activists, Nelson’s death was a watershed event. Livid and desperate, a group of women from the BCA stormed through the Genentech campus on December 5, 1994, to hold a fifteen-car “funeral procession” for Nelson with placards showing Nelson in her chemo turban before her death.


• In return, the National Breast Cancer Coalition would act as a go-between for Genentech and its embittered and alienated community of cancer patients. Visco offered to join the planning committee of the phase III trials of Herceptin, and to help recruit patients for the trial using the NBCC’s extensive network. For Genentech, this was a long-overdue education. Rather than running trials on breast cancer patients, the company learned to run trials with breast cancer patients.


• In early 1998, Novartis finally relented. It would synthesize and release a few grams of CGP57148, just about enough to run a trial on about a hundred patients. Druker would have a shot—but only one shot. To Novartis, CGP57148, the product of its most ambitious drug-discovery program to date, was already a failure... Gleevec was evidently a success. This success continues; Gleevec has become the standard of care for patients with CML. Oncologists now use the phrases “pre-Gleevec era” and “post-Gleevec era” when discussing this once-fatal disease... (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.)


• Even targeted therapy, then, was a cat-and-mouse game. One could direct endless arrows at the Achilles’ heel of cancer, but the disease might simply shift its foot, switching one vulnerability for another. We were locked in a perpetual battle with a volatile combatant... In Lewis Carroll’s Through the Looking-Glass, the Red Queen tells Alice that the world keeps shifting so quickly under her feet that she has to keep running just to keep her position. This is our predicament with cancer: we are forced to keep running merely to keep still


• When highly connected “socializers” stopped smoking, the dense social circle circumscribed around them also slowly stopped as a group. As a result, smoking gradually became locked into the far peripheries of all networks, confined to the “loners” with few social contacts, puffing away quietly in the distant and isolated corners of the town. <> The smoking-network study offers, to my mind, a formidable challenge to simplistic models of cancer prevention. Smoking, this model argues, is entwined into our social DNA just as densely and as inextricably as oncogenes are entwined into our genetic material.


• “recall bias”: patients diagnosed with tumors unconsciously exaggerated the use of cell phones on the same side of their head, and selectively forgot the use on the other side. When the authors corrected for this bias, there was no detectable association between gliomas and cell phone use overall.


• Vogelstein’s answer to these questions borrows beautifully from an insight long familiar to classical landscape artists: negative space can be used to convey expanse, while positive space conveys detail. To view the landscape of the cancer genome panoramically, Vogelstein splayed out the entire human genome as if it were a piece of thread zigzagging across a square sheet of paper... Even brain cancers, which often develop at earlier ages and hence may be expected to accumulate fewer mutations, possess about forty to fifty mutated genes... Scientists speculate that genetically simple tumors (i.e., those carrying few mutations) might inherently be more susceptible to drugs, and thus intrinsically more curable. If so, the strange discrepancy between the success of high-dose chemotherapy in curing leukemia and its failure to cure most other cancers has a deep biological explanation.


• In the breast cancer sample from the forty-three-year-old woman with 127 mutations, only about ten might directly be contributing to the actual growth and survival of her tumor, while the rest may have been acquired due to gene-copying errors in cancer cells. But while functionally different, these two forms of mutations cannot easily be distinguished.


• 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.


• Something akin to this process, a few researchers believe, is constantly occurring in cancer—or at least in leukemia. In the mid-1990s, John Dick, a Canadian biologist working in Toronto, postulated that a small population of cells in human leukemias also possess this infinite self-renewing behavior. These “cancer stem cells” act as the persistent reservoir of cancer—generating and regenerating cancer infinitely. When chemotherapy kills the bulk of cancer cells, a small remnant population of these stem cells, thought to be intrinsically more resistant to death, regenerate and renew the cancer, thus precipitating the common relapses of cancer after chemotherapy.


• there is a subtler reason to remember this story: while the content of medicine is constantly changing, its form, I suspect, remains astonishingly the same. History repeats, but science reverberates... much about this battle will remain the same: the relentlessness, the inventiveness, the resilience, the queasy pivoting between defeatism and hope, the hypnotic drive for universal solutions, the disappointment of defeat, the arrogance and the hubris.


• 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.