The Emperor of All Maladies - by Siddhartha Mukherjee
TODO: edit. bookmark at Line 50 It was an eye-opening journey for me. I did not know not all cancers are the same. The book gave me some hope about finding all the cures for all types of cancer.
Here are some text that I highlighted in the book:
One acknowledgment, though, cannot be left to the end. This book is not just a journey into the past of cancer, but also a personal journey of my coming-of-age as an oncologist. That second journey would be impossible without patients, who, above and beyond all contributors, continued to teach and inspire me as I wrote. It is in their debt that I stand forever.
I felt I was slowly becoming inured to the deaths and the desolation—vaccinated against the constant emotional brunt.
As a doctor learning to tend cancer patients, I had only a partial glimpse of this confinement. But even skirting its periphery, I could still feel its power—the dense, insistent gravitational tug that pulls everything and everyone into the orbit of cancer.
The war necessitated a dramatic reordering of priorities.
cancer’s emergence in the world is the product of a double negative: it becomes common only when all other killers themselves have been killed.
Antisepsis and anesthesia were twin technological breakthroughs that released surgery from its constraining medieval chrysalis.
(At night, he reportedly left a sealed vial of cocaine by his bedside, thus testing himself by constantly having the drug within arm’s reach.) But he relapsed often and fiercely, unable to ever fully overcome his habit.
“the measure of operability depends on the question: ‘Is the lesion removable?’ and not on the question: ‘Is the removal of the lesion going to cure the patient?’”
In comparison, 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. But to measure the genius of the Jimmy campaign in dollars and cents is to miss its point. For Farber, the Jimmy Fund campaign was an early experiment—the building of another model. 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. A disease needed to be transformed politically before it could be transformed scientifically.
“I sense an undercurrent of excitement, a feeling (persistent despite repeated frustrations) of being on the verge of discovery, which makes me almost hopeful.
While the patients who had stopped the drug early inevitably relapsed with cancer, 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. The hcg level—the hormone secreted by choriocarcinoma—had turned out to be its real fingerprint, its marker. In the decades that followed, trial after trial would prove this principle. But in 1960, oncology was not yet ready for this proposal. Not until several years later did it strike the board that had fired Li so hastily that the patients he had treated with the prolonged maintenance strategy would never relapse. This strategy—which cost Min Chiu Li his job—resulted in the first chemotherapeutic cure of cancer in adults.
A model is a lie that helps you see the truth.—Howard Skipper
Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing.—Voltaire
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, like pieces of a kaleidoscope. The apple drops from the tree. The man jumps up from a bathtub; the slippery equation balances itself. 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. A patient’s CT scan shows a relapsed lymphoma. A cell once killed by a drug begins to grow back. A child returns to the NCI with a headache.
She may have been crying, but her face was a cipher that I could not read. “She will try anything, anything,” her husband pleaded. “She is stronger than she looks.” But strong or not, there was nothing left to try. I stared down at my feet, unable to confront the obvious questions. The attending physician shifted uncomfortably in his chair. Beatrice finally broke the awkward silence. “I’m sorry.” She shrugged her shoulders and looked vacantly past us. “I know we have reached an end.” We hung our heads, ashamed. It was, I suspected, not the first time that a patient had consoled a doctor about the ineffectuality of his discipline.
Merely describing an illness, without offering any therapeutic suggestions, seemed like an empty academic exercise to him, a form of intellectual frittering.
I am not opposed to optimism, but I am fearful of the kind that comes from self-delusion.
cancer had struck the raw strings of anxiety already vibrating in the public psyche.
“Dear Readers: If you are looking for a laugh today, you’d better skip Ann Landers. If you want to be part of an effort that might save millions of lives—maybe your own—please stay with me.… How many of us have asked the question, ‘If this great country of ours can put a man on the moon why can’t we find a cure for cancer?’”
“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.”
“In particular we must reject the notion that we will be lucky.… Instead we will be witnessing a massive expansion of well-intentioned mediocrity.”
[the act] states that all NIH institutes are equal, but one [the NCI] is more equal than the others.”
The act, then, was an anomaly, designed explicitly to please all of its clients, but unable to satisfy any of them.
“In God we trust. All others [must] have data”
a sanitized vision of hell.
There was the uncertainty of a new combination and the certainty of death.
Female sexual hormones kept breast cells alive; male hormones had a similar effect on prostate cells.
Opiates, used liberally and compassionately on cancer patients, did not cause addiction, deterioration, and suicide; instead, they relieved the punishing cycle of anxiety, pain, and despair.
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.
But what if, recognizing the impossibility of that experiment, one could settle for the next-best option—for a half-perfect experiment? Random assignment aside, the problem with the Doll and Hill study thus far was that it had estimated risk retrospectively. But what if they could set the clocks back and launch their study before any of the subjects developed cancer? Could an epidemiologist watch a disease such as lung cancer develop from its moment of inception, much as an embryologist might observe the hatching of an egg?
Deaths from lung cancer were tabulated for smokers versus nonsmokers. Doll and Hill could now sit back and watch cancer unfold in real time. In the twenty-nine months between October 1951 and March 1954, 789 deaths were reported in Doll and Hill’s original cohort. Thirty-six of these were attributed to lung cancer. When these lung cancer deaths were counted in smokers versus nonsmokers, the correlation virtually sprang out: all thirty-six of the deaths had occurred in smokers. The difference between the two groups was so significant that Doll and Hill did not even need to apply complex statistical metrics to discern it. The trial designed to bring the most rigorous statistical analysis to the cause of lung cancer barely required elementary mathematics to prove its point.
Richard Doll and Bradford Hill published their prospective study on lung cancer in 1956—the very year that the fraction of smokers in the adult American population reached its all-time peak at 45 percent.
But since the FTC’s role was to regulate tobacco advertisements, it could certainly investigate whether “filtered” cigarettes were truly as safe as advertised.
Politicians were far more protective of the narrow interests of tobacco than of the broad interest of public health. Tobacco makers need not have bothered inventing protective filters, Drew wrote drily: Congress had turned out to be “the best filter yet.”
But Banzhaf’s letter had landed, surprisingly, on sympathetic ears.
“If you do smoke—quit. Don’t be a loser.”
Many of the cigarette makers had not only known about the cancer risks of tobacco and the potent addictive properties of nicotine, but had also actively tried to quash internal research that proved it. Document after document revealed frantic struggles within the industry to conceal risks, often leaving even its own employees feeling morally queasy.
to explain the industry’s three-pronged marketing strategy—“ creating doubt about the health charge without actually denying it, advocating the public’s right to smoke without actually urging them to take up the practice [and] encouraging objective scientific research as the only way to resolve the question of health hazard.”
Pyrrhic victory. (of a victory) won at too great a cost to have been worthwhile for the victor.
the real cost of the agreement is borne by addicted smokers who now pay more for cigarettes, and then pay with their lives.
In China, lung cancer is already a leading cause of death attributable to smoking in men.
Carcinogens, Ames suggested, had a common, distinctive functional property: they altered genes.
carcinogens could be found experimentally—not retrospectively (by investigating cases and controls in human subjects) but by prospectively identifying chemicals that could cause mutations in a rather simple and elegant biological assay.
It was a ‘known fact,’ like ‘everyone knows that the earth is flat.’”
“randomization in clinical trials should be managed in a manner that makes subversion impossible.”
“All photographs are accurate,” the artist Richard Avedon liked to say, “[ but] none of them is the truth.”
He looked away with a flicker of irritation. “I know what the statistics are.” His voice was strained, as if tightening against a harness. “Left to myself, I would not even try. I’m doing this because of the kids.”
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. 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.
they survived the operation, but not the disease.
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.
stale wine being sold in a new bottle.
Obsessed with radical and aggressive therapies, oncologists were devising newer and newer parachutes, but with no systematic maps of the quagmire to guide patients and doctors. The War on Cancer was “lost”—in both senses of the word.
[刻舟求剑] 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.”
They had parted ways for nearly a decade, yet their intellectual paths had kept crisscrossing.
Both abnormalities, activated proto-oncogenes and inactivated tumor suppressors (“ jammed accelerators” and “missing brakes”), represent the core molecular defects in the cancer cell.
I do not wish to achieve immortality through my works. I wish to achieve immortality by not dying.—Woody Allen
Cummings and Jimmy’s wife sat in the car, their eyes also welling with silent tears.
Cancer is not a concentration camp, but it shares the quality of annihilation: it negates the possibility of life outside and beyond itself; it subsumes all living. The daily life of a patient becomes so intensely preoccupied with his or her illness that the world fades away. Every last morsel of energy is spent tending the disease. “How to overcome him became my obsession,” the journalist Max Lerner wrote of the lymphoma in his spleen. “If it was to be a combat then I had to engage it with everything I had—knowledge and guile, ways covert as well as overt.”
“All of us knew that we were living on borrowed time,” Bradfield said, “and so we felt twice as alive and lived twice as fiercely.”
notions about intrinsic boundaries are mythical. What he broke permanently was not a limit, but the idea of limits.
[Red Queen hypothesis Red Queen syndrome—moving incessantly just to keep in place.
circles of relationships were found to be more powerful predictors of the dynamics of smoking than nearly any other factor. Entire networks stopped smoking concordantly, like whole circuits flickering off. A family that dined together was also a family that quit together. 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.
a puzzling pattern emerged: right-sided cell phone use reduced the risk of left-sided brain cancer. The simplest logical explanation for this phenomenon was “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.
She had heard from a nurse that the results were in, and my delay had sent her into a terrifying spiral of depression: in twenty-four hours she had convinced herself that the leukemia had crept back and my hesitation was a signal of impending doom.
In individual specimens of breast and colon cancer, between fifty to eighty genes are mutated; in pancreatic cancers, about fifty to sixty. 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.
One of these is an old culprit, acute lymphoblastic leukemia: only five or ten genetic alterations cross its otherwise pristine genomic landscape.
Every patient’s cancer is unique because every cancer genome is unique. Physiological heterogeneity is genetic heterogeneity.” Normal cells are identically normal; malignant cells become unhappily malignant in unique ways.
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.”
estrogen and progesterone, prescribed in hormone-replacement therapy to women to ease menopausal symptoms, as major risk factors for the incidence and fatality from estrogen-positive breast cancer.
“My breasts had become no more to me than a site for my cancer. They were of no more use to me. They harmed my body, my survival. I went to the surgeon and asked him to remove them.”
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.
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.
Science embodies the human desire to understand nature; technology couples that desire with the ambition to control nature.
“There are far more good historians than there are good prophets,” Klausner wrote. “It is extraordinarily difficult to predict scientific discovery, which is often propelled by seminal insights coming from unexpected directions.
Her illness had tried to humiliate her. It had made her anonymous and seemingly humorless; it had sentenced her to die an unsightly death in a freezing hospital room thousands of miles away from home. She had responded with vengeance, moving to be always one step ahead, trying to outwit it. It was like watching someone locked in a chess game. Every time Germaine’s disease moved, imposing yet another terrifying constraint on her, she made an equally assertive move in return. The illness acted; she reacted. It was a morbid, hypnotic game—a game that had taken over her life. She dodged one blow only to be caught by another. She, too, was like Carroll’s Red Queen, stuck pedaling furiously just to keep still in one place.
To take care of cancer patients is an enormous privilege, but it also involves deploying everything in your toolbox: the emotional, the psychological, the scientific, the epidemiologic.
You’re present at the most moving and terrifying times of a person’s life, and the ability to help at that time is a powerful experience.
When you have to deliver bad news, how do you prepare for that? What really helps is to listen to the person you’re delivering bad news to. That’s the first thing I’ve learned from my teachers. And by that, I mean that often bad news involves a crushing or a deflation of aspirations.
There is a difference between the “cost” of a drug and the “price” of a drug. A pill of Gleevec—I mean, the chemical that we call Gleevec—can be synthesized for pennies. That is its real “cost.” But the “price” of Gleevec is something else. It is set by a series of social arrangements, by our willingness or ability to pay this set “price” and, of course, by the profit motives of the pharmaceutical industry.
What about alternative medicine? I think all medicine is “alternative” before it becomes mainstream
As a practicing oncologist and a father, where did you find time to write a book so big and so complex? I had to make time. What was important was to have a reason to do it. And the reason to do it was that I was trying to answer my patient’s question. As long as I always kept that in mind, I felt as if the book sort of wrote itself. I would come back in the evening after rounds or from the laboratory and I would write. I kept writing until I had answered the question left over from the night before. For instance, when I was writing about mammography, the previous night’s question might have been, “Where did this leave us in 1986?” And then the next day’s writing would bring us from that period up to 1996, filling out the story in between. I think I was able to write because I was responding to a certain sense of urgency that this story had to be told.