Great Throughts Treasury

This site is dedicated to the memory of Dr. Alan William Smolowe who gave birth to the creation of this database.

Siddhartha Mukherjee

American Physician, Biological Scientist and Author, Awarded Pulitzer Prize for his book, The Emperor Of All Maladies: A Biography of Cancer

"A breast cancer might turn out to have a close resemblance to a gastric cancer. And this kind of reorganization of cancer in terms of its internal genetic anatomy has really changed the way we treat and approach cancer in general."

"A cancer patient today has a team that works around him or her, including nurses, psychiatrists, psychologists, and, in some cases, pain and palliative medicine experts."

"A cancer cell is an astonishing perversion of the normal cell. Cancer is a phenomenally successful invader and colonizer in part because it exploits the very features that make us successful as a species or as an organism."

"A model is a lie that helps you see the truth."

"A numerical measure of intelligence was also particularly suited to the demands of the First and Second World Wars, during which recruits had to be assigned to wartime tasks requiring diverse skills based on rapid, quantitative assessments. When veterans returned to civilian life after the wars, they found their lives dominated by intelligence testing."

"A major hindrance to cancer effort has been a chronic, severe shortage of funds?a situation that is not generally recognized."

"A nation which depends upon others for its new basic scientific knowledge will be slow in its industrial progress and weak in its competitive position in world trade, regardless of its mechanical skill."

"A patient, long before he becomes the subject of medical scrutiny, is, at first, simply a storyteller, a narrator of suffering?"

"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 Francois Jacob, working in Paris, discovered that the genesis of proteins from genes required an intermediary step?a molecule called ribonucleic acid or RNA. RNA is the working copy of the genetic blueprint. And it is RNA, not the gene, that is translated into a protein. This intermediary RNA copy of a gene is called a gene?s message. Genetic information is transmitted from a cell to its progeny through a series of discrete and coordinated steps. First, genes, located in chromosomes, are duplicated when a cell divides and are transmitted into progeny cells. Next, a gene, in the form of DNA, is converted into its RNA copy. Finally, this RNA messages is translated into a protein. The protein, the ultimate product of genetic information, carries out the function encoded by the gene. This unidirectional flow of genetic information?DNA->RNA->protein?was found to be universal in living organisms, from bacteria to slime molds to fruit flies to humans. In the mid-1950s, biologists termed this unidirectional flow of information the central dogma of molecular biology."

"A Pap smear would give a woman a chance to receive preventive care [and] greatly decrease the likelihood of her ever developing cancer."

"A positive attitude does not cure cancer, any more than a negative one causes it."

"A ward nurse recalls, was so deep that doctors would not even look us in the eye when we recommended that they stop their efforts to save lives and start saving dignity instead?"

"A static picture cannot capture this qualitative growth. Seeing a small tumor and extracting it from the body does not guarantee our freedom from cancer?a fact that we still struggle to believe. In the end, a mammogram or a Pap smear is a portrait of cancer in its infancy. Like any portrait, it is drawn in the hopes that 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."

"After decades of musing, have we reached the conclusion that fate is, well . . . fate? That being happens through . . . be-ing? I find that formulation illuminatingly beautiful."

"Activating or inactivating any single gene, he postulated, produced only the first steps toward carcinogenesis. Cancer?s march was long and slow and proceeded though many mutations in many genes over many iterations. In genetic terms, our cells were not sitting on the edge of the abyss of cancer. They were dragged toward that abyss in graded, discrete steps."

"Allogeneic transplantation (i.e., transplanting foreign marrow into a patient) was temperamental?tricky, mercurial, often deadly. But in some cancers, particularly leukemias, it was potentially curative. Once could, for instance, obliterate a marrow riddled with leukemia using high dose chemo and replace it with fresh, clean marrow from another patient. Once the new marrow had engrafted, the recipient ran the risk of that foreign marrow turning and attacking his or her own body as well as any residual leukemia left in the marrow, a deadly complication termed graft-versus-host disease or GVHD. But in some patients, that trifecta of assaults?obliterative chemotherapy, marrow replacement, and the attack on the tumor by foreign cells?could be fashioned into an exquisitively potent therapeutic weapon against cancer. The procedure carried severe risks. In Thomas?s initial trial at Seattle, only twelve out of a hundred patients had survived. But by the early 1980s, doctors were using the procedure for refractory leukemias, multiple myeloma, and myelodysplastic syndrome?disease inherently resistant to chemotherapy. Success was limited, but at least some patients were eventually cured."

"Although cancer is not universally caused by viruses, certain viruses cause particular cancers, such as the human papilloma virus (HPV), which causes cervical cancer."

"An emerging, though highly controversial, answer to this question is that cancer?s immortality, too, is borrowed from normal physiology. 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 (call 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."

"All cancers are alike but they are alike in a unique way."

"And despite its many idiosyncrasies, leukemia possessed a singularly attractive feature: it could be measured. Science begins with counting. To understand a phenomenon, a scientist must first describe it; to describe it objectively, he must first measure it."

"An Irish surgeon, Denis Burkitt, discovered an aggressive form of lymphoma?now called Burkitt?s lymphoma?"

"And this was to save rats, right? Or mice? You spent all this money to save mice the problem of developing tumors?"

"As the saying ran, was one night with Venus, followed by a thousand nights with mercury."

"As early as the sixth century BC, ayurvedic practitioners in India had recognized the general symptoms of anemia."

"Before the 1980s, the armamentarium of cancer therapy was largely built around two fundamental vulnerabilities of cancer cells. The first is that most cancers originate as local diseases before they spread systematically. Surgery and radiation therapy exploit this vulnerability. By physically excising locally restricted tumors before cancer cells can spread?or by searing cancer cells with localized bursts of powerful energy using X-rays?surgery and radiation attempt to eliminate cancer en bloc from the body. The second vulnerability is the rapid growth rate of cancer cells. Most chemotherapy drugs discovered before the 1980s target this second vulnerability. Anti-folates, such as Farber?s aminopteriin, interrupt the metabolism of folic acid and starve all cells of a crucial nutrient required for cell division. Nitrogen mustard and cisplatin chemically react with DNA, and DNA-damaged cells cannot replicate their genes and thus cannot divide. Vincristine, the periwinkle poison, thwarts the ability of a cell to construct the molecular ?scaffold? required for all cells to divide."

"Both Premarin (its named derived from pregnant mare urine) and DES were initially marketed as elixirs to cure menopause. But for Huggins, the existence of synthetic estrogens suggested a markedly different use; he could inject them to feminize the male body and stop the production of testosterone in patients with prostate cancer. He called the method chemical castration. And once again, he found striking responses. As with surgical castration, patients with aggressive prostate cancer chemically castrated with feminizing hormones responded briskly to the therapy, often with minimal side effects. (The most prominent complaint among men was the occurrence of menopause-like hot flashes.) Prostate cancer was not cured with these steroids; patients inevitably relapsed with cancer that had become resistant to hormone therapy. But the remissions, which often stretched into several months, proved that hormonal manipulations could choke the growth of a hormone-dependent cancer. To produce a cancer remission, one did not need a general cellular poison (such as cisplatin or nitrogen mustard)."

"But another truth should be foremost in mind: that what we call nature today is a kinder, gentler, more depauperate world than at any time since at least the late Paleozoic, some 300 million years ago. Nature is not a temple but a ruin. A beautiful ruin, but a ruin all the same."

"At 4:17 p.m. EDT on July 20, 1969, a fifteen-ton spacecraft moved silently through the cold, thin atmosphere above the moon and landed on a rocky basalt crater on the lunar surface. A vast barren landscape?a magnificent desolation?stretched out around the spacecraft. It suddenly struck me, one of the two astronauts would recall, that that tiny pea, pretty and blue, was the earth. I put up my thumb and shut one eye, and my thumb blotted out the planet."

"But because of the systematic neglect of cancer research: There are not over two dozen funds in the U.S. devoted to fundamental cancer research. They range in capital from about $500 up to about $2,000,000, but their aggregate capitalization is certainly not much more than $5,000,000...The public willingly spends a third of that sum in an afternoon to match a major football game."

"Basic research leads to new knowledge. It provides scientific capital. It creates the fund from which the practical applications of knowledge must be drawn? basic research is the pacemaker of technological progress. In the nineteenth century, Yankee mechanical ingenuity, building largely upon the basic discoveries of European scientists, could greatly advance the technical arts. Now the situation is different. ?A nation which depends upon others for its new basic scientific knowledge will be slow in its industrial progress and weak in its competitive position in world trade, regardless of its mechanical skill.?"

"But cancer is not simply a clonal disease; it is a clonally evolving disease. If growth occured without evolution, cancer cells would not be imbued with their potent capacity to invade, survive, and metastasize. Every generation of cancer cells creates a small number of cells that is genetically different from its parents. When a chemotherapeutic drug of the immune system attacks cancer, mutant clones that can resist the attack grow out. The fittest cancer cell survives. This mirthless, relentless cycle of mutation, selection, and overgrowth generates cells that are more and more adapted to survival and growth. In some cases, the mutations speed up the acquisition of other mutations. This genetic instability, like a perfect madness, only provides more impetus to generate mutant clones. Cancer thus exploits the fundamental logic of evolution unlike any other illness. If we, as a species, are the ultimate product of Darwinian selection, then so, too, is this incredible disease that lurks inside us."

"BRCA-1, a gene that strongly predisposes humans to breast and ovarian cancer."

"But despite such parallel metaphors, tuberculosis belongs to another century. TB (or consumption) was Victorian romanticism brought to its pathological extreme?febrile, unrelenting, breathless, and obsessive, it was a disease of poets: John Keats involuting silently toward death in a small room overlooking the Spanish Steps in Rome, or Byron, an obsessive romantic, who fantasized about dying of the disease to impress his mistresses. Death and disease are often beautiful?like the hectic glow of consumption, Thoreau wrote in 1852. In Thomas Mann?s Magic Mountain, this hectic glow releases feverish creative force in its victims?a clarifying, edifying, cathartic force that, too, appears to be charged with the essence of its era."

"But the activated ras pathway (Ras?>Mek?>Erk) does not merely cause accelerated cell division; the pathway also intersects with other pathways to enable several other ?behaviors? of cancer cells. At Children?s Hospital in Boston in the 1990s, the surgeon-scientist Judah Folkman demonstrated that certain activated signaling pathways within cancer cells, Ras among them, could also induce neighboring blood vessels to grow. A tumor could thus ?acquire? its own blood supply by insidiously inciting a network of blood vessels around itself and then growing, in grapelike clusters, around those vessels, a phenomenon that folkman called tumor angiogenesis."

"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."

"But the story of leukemia--the story of cancer--isn't the story of doctors who struggle and survive, moving from institution to another. It is the story of patients who struggle and survive, moving from on embankment of illness to another. Resilience, inventiveness, and survivorship--qualities often ascribed to great physicians--are reflected qualities, emanating first from those who struggle with illness and only then mirrored by those who treat them. If the history of medicine is told through the stories of doctors, it is because their contributions stand in place of the more substantive heroism of their patients."

"But the heritability of a trait, no matter how strong, may be the result of multiple genes, each exerting a relatively minor effect. If that was the case, identical twins would show strong correlations in g, but parents and children would be far less concordant. IQ followed this pattern. The correlation between parents and children living together, for instance, fell to 0.42. With parents and children living apart, the correlation collapsed to 0.22. Whatever the IQ test was measuring, it was a heritable factor, but one also influenced by many genes and possibly strongly modified by environment ? part nature and part nurture."

"But Vannevar Bush was not convinced. In a deeply influential report to President Truman entitled Science and the Endless Frontier, first published in 1945, Bush had laid out a view of postwar research that had turned his own model of wartime research on its head: ?Basic research,? Bush wrote, ?is performed without thought of practical ends. It results in general knowledge and an understanding of nature and its laws. This general knowledge provides the means of answering a large number of important practical problems, though it may not give a complete specific answer to any one of them?"

"But these two traditional Achilles? heels of cancer?local growth and rapid cell division?can only be targeted to a point. Surgery and radiation are intrinsically localized strategies, and they fail when cancer cells 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."

"But the pigs--seventy pounds of porcine weight that did not take kindly to weekly endoscopies--did not sprout any ulcers. And testing the theory on humans was ethically impossible: how could one justify infecting a human with a new, uncharacterized species of bacteria to prove that it caused gastritis and predisposed to cancer?"

"But the MSA has not signaled the death of the industry in a more global sense; beleaguered in America, the Marlboro Man has simply sought out new Marlboro countries. With their markets and profits dwindling and their legal costs mounting, cigarette manufacturers have increasingly targeted developing countries as new markets, and the number of smokers in many of these nations has risen accordingly. Tobacco smoking is now a major preventable cause of death in both India and China. Richard peto, an epidemiologist at Oxford and a close collaborator of Richard Doll?s (until Doll?s death in 2005), recently estimated that the number of smoking-related deaths among adults in India would rise to 1 million per year in the 2010s and continue to rise in the next decade. In China, lung cancer is already the leading cause of death, attributable to smoking in men."

"But the last part of the answer lies, surely, in how we imagine cancer and screening. We are a visual species. Seeing is believing, and to see cancer in its early, incipient form, we believe, must be the best way to prevent it. As the writer Malcolm Gladwell once described it, ?This is a textbook example of how the battle against cancer is supposed to work. Use a powerful camera. Take a detailed picture. Spot the tumor as early as possible. Treat it immediately and aggressively?. The danger posed by a tumor is represented visually. Large is bad; small is better.? But powerful as the camera might be, cancer confounds this simple rule. Since metastasis is what kills patients with breast cancer, it is, of course, generally true that the ability to detect and remove pre-metastatic tumors saves women?s lives. But it is also true that just because a tumor is small does not mean it is pre-metastatic. Even relatively small tumors barely detectable by mammography can carry genetic programs that make them vastly more likely to metastasize early. Conversely, large tumors may inherently be designed to be genetically benign?unlikely to invade and metastasize. Size matters, in other words?but only to a point. The difference in the behavior of tumors is not just a consequence of quantitative growth, but of qualitative growth."

"But what sort of experiment? An English statistician named Bradford Hill (a former victim of TB himself) proposed an extraordinary solution. Hill began by recognizing that doctors, of all people, could not be entrusted to perform such an experiment without inherent biases. Every biological experiment requires a control arm?untreated subjects against whom the efficacy of a treatment can be judged. But left to their own devices, doctors were inevitably likely (even if unconsciously so) to select certain types of patients upfront, then judge the effects of a drug on this highly skewed population using subjective criteria, piling bias on top of bias. Hill"

"By 1926, cancer had become the nation?s second most common killer, just behind heart disease."

"By now the perpetually changing landscape of breast cancer was beginning to tire him out. Trials, tables, and charts had never been his forte; he was a surgeon, not a bookkeeper."

"By charting the life and death of leukemia cells as they responded to drugs in these mice, Skipper emerged with two pivotal findings. First, he found that chemotherapy typically killed a fixed percentage of cells at any given instance no matter what the total number of cancer cells was. This percentage was a unique, cardinal number particular to every drug. In other words, if you started off with 100,000 leukemia cells in a mouse and administered a drug that killed 99 percent of those cells in a single round, then every round would kill cells in a fractional manner, resulting in fewer and fewer cells after every round of chemotherapy: 100,000?1,000?10?and so forth, until the number finally fell to zero after four rounds. Killing leukemia was an iterative process, like halving a monster?s body, then halving the half, and halving the remnant half. Second, Skipper found that by adding drugs in combination, he could often get synergistic effects on killing. Since different drugs elicited different resistance mechanisms in cancer cells, using drugs in concert dramatically lowered the chance of resistance. Two drugs were therefore typically better than one; three drugs better than two. With several drugs and several iterative rounds of chemotherapy in rapid-fire succession, Skipper cured leukemias in his mouse model."

"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 inactivated 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 the blood-nourished tumor allows the tumor to survive even in areas of the body with low oxygen."

"By the early twentieth century, g had caught the imagination of the public. First, it captivated early eugenicists. In 1916, the Stanford psychologist Lewis Terman, an avid supporter of the American eugenics movement, created a standardized test to rapidly and quantitatively assess general intelligence, hoping to use the test to select more intelligent humans for eugenic breeding. Recognizing that this measurement varied with age during childhood development, Terman advocated a new metric to quantify age-specific intelligence. If a subject?s ?mental age? was the same as his or her physical age, their ?intelligence quotient,? or IQ, was defined as exactly 100. If a subject lagged in mental age compared to physical age, the IQ was less than a hundred; if she was more mentally advanced, she was assigned an IQ above 100."

"By the early 1940s, such tests had become accepted as an inherent part of American culture. IQ tests were used to rank job applicants, place children in school, and recruit agents for the Secret Service. In the 1950s, Americans commonly listed their IQs on their r‚sum‚s, submitted the results of a test for a job application, or even chose their spouses based on the test. IQ scores were pinned on the babies who were on display in Better Babies contests (although how IQ was measured in a two-year-old remained mysterious)."

"By the early 1940s, asking about a connection between tobacco and cancer was like asking about an association between sitting and cancer."