The Emperor of All Maladies: A Biography of Cancer

The preliminaries

• Cancer is a disease caused by the uncontrolled growth of a single cell.
  • In a normal cell, powerful circuits regulate cell division and growth; in a cancer cell, these circuits are broken, unleashing a cell that can’t stop growing.
  • So, the key to battling cancer is to prevent these mutations from occurring, or to eliminate the mutated cells without compromising normal cells.

The beginnings of cancer

• In the collected recorded teachings of Imhotep, an Egyptian physician who lived around 2625 B.C., we find the first mentions of cancer.
  • In his medical notes, he said that he encountered a patient with bulging masses on the breast that spread over the chest, and the masses were cool to the touch, with no liquid discharge. As for “therapy,” he wrote: “There is none.” It is likely that he was describing breast cancer. 
  • And after that admission, cancer virtually disappeared from ancient medical history.
• More than two millennia passed and in 440 B.C., the Greek historian Herodotus recorded the story of Atossa, the queen of Persia.
  • She had a bleeding lump in her breast, and ultimately, a Greek slave named Democedes persuaded her to allow him to cut out the tumor. After that, all we know is that the procedure was a temporary success.
  • At the time, her husband had been planning a campaign against Scythia. At Democedes’s urging–who wanted to return to his native Greece–Atossa pleaded with her husband to invade Greece.
    • This turn of the Persian empire, and the series of Greco-Persian wars that followed, would mark a definitive moment in the early history of the west. 
• Outside of these instances, the only incontrovertible cases of cancer in history are those where the tissue has somehow been preserved.
  • Such tissue was found in a thousand-year-old gravesite in Peru, containing the mummified remains of members of the Chiribaya tribe.
    • There was a mummy of a young woman, found with a hard “bulbous mass” in her left upper arm, which was a malignant bone tumor (these tumors formed from hardened and calcified tissues, and are much more likely to survive over centuries).
  • In other cases, paleopathologists haven’t found actual tumors, but rather signs left by the tumors in the body. (Some skeletons are riddled with tiny holes created by cancer in the skull or the shoulder bones, from metastatic cancer.)
  • There’s also a jawbone from two million years ago that carried a peculiar form of lymphoma in southeastern Africa.
• Around 400 B.C., the Greek physician Hippocrates first coined a word for cancer: karkinos, from the Greek word for “crab.” The tumor, with its clutch of swollen blood vessels around it, reminded him of a crab dug in the sand.
  • (Also, the word “oncology” comes from the Greek word onkos, which was the term of a mass or a load, more commonly a burden.)
• But overall, in ancient history, cancer was rare, most likely because cancer is an age-related disease and people during this period died young. And if cancer existed, it was submerged under the sea of other illnesses.
  • The current risk of breast cancer, for instance, is about 1-in-400 for a 30-year-old and 1-in-9 for a 70-year-old.
  • Structure of modern life has also radically shifted the spectrum of cancers.
    • Stomach cancer, for instance, was likely the result of several carcinogens found in pickling agents. But with modern refrigeration, stomach cancer abated.
• In the 1760s, a Scottish surgeon, John Hunter, began to classify tumors into “stages.” Movable tumors were typically early-stage, local cancers. Immovable tumors were advanced, invasive, and even metastatic. He concluded that only movable cancers were worth removing surgically.
• Then, between 1850 and 1950, after the discoveries of anesthesia and bacteria, surgeons brazenly attacked cancer by cutting open the body and removing tumors.

Significant cancer-related discoveries

• In 1895, Wilhelm Rontgen, a lecturer at a German institute, was working with an electron tube (a vacuum tube that shot electrons from one electrode to another) and he noticed a strange leakage.
  • He placed his wife Anna’s hand between the source of his rays and a photographic plate. The rays penetrated her hand and left a silhouette of her fingers and her ring on a photographic plate.
    • They had discovered a form of energy so powerful that it could pass through most living tissues. Rontgen called these “X-rays.”
• Soon after, Marie and Pierre Curie began to scour for even more powerful chemical sources of X-rays.
  • They discovered radium, which revealed an unexpected property of X-rays: they not only carried radiant energy through human tissues, but also deposited energy deep inside tissues.
• It soon became clear that radium was attacking DNA. In 1896, a 21-year-old Chicago medical student, Emil Grubbe, thought of using X-rays to treat cancer.
  • He tried this on a patient and the tumor shrank (the first documented local response in the history of X-ray therapy). 
  • Grubbe also stumbled on another important observation: X-rays could only be used to treat cancer locally; it had little effect on metastasized tumors.
  • Inspired, Grubbe began using X-ray therapy to treat patients with local tumors, and a new branch of cancer medicine, radiation oncology, was born.
  • However, people soon discovered that radiation also produced cancers.
• In 1878, a 24-year-old medical student, Paul Ehrlich, proposed using cloth dyes to stain animal tissues.
  • To his surprise, the dyes stained only parts of the cell, and were able to discriminate among chemicals hidden inside cells, binding some and sparing others.
  • Returning from a conference late one evening, he described an idea to two fellow scientists: it might be possible to find artificial substances which are specifically curative for certain diseases, which would directly destroy the microbes responsible for the diseases.
    • The idea of “chemotherapy,” the use of specific chemicals to heal the diseased body, was thus born.
• In the 1950s a researcher named Min Chiu Li worked at the National Cancer Institute.
  • Certain cells, called choriocarcinoma, secrete a hormone called choriogonadotropin, which can be measured with a sensitive blood test. Li used that hormone level to track patients’ cancer during treatment. 
  • The trouble was, after the scheduled chemotherapy, the level of that hormone had fallen to an almost negligible value, but didn’t totally disappear. Li became obsessed with the number, and administered doses until the level sank to zero.
  • When the NCI Institutional Board found out about his decision, they were furious, thinking that giving additional chemotherapy was unnecessary and akin to poisoning patients. They fired him.
  • But later, the patients treated on Li’s protocol remained free of disease long after the treatment.
    • He had stumbled on a deep and fundamental principle of oncology: cancer needed to be systematically treated long after every visible sign of it had vanished.
    • That hormone had turned out to be cancer’s real marker. Patients that he had treated would never relapse. This strategy–which cost him his job–resulted in the first chemotherapeutic cure of cancer in adults.

Sidney Farber, childhood leukemia, and the politics of cancer

• In 1947 in New York, a man named Sidney Farber waited for the arrival of a yellow chemical named aminopterin, hoping it might halt the growth of leukemia in children. His specialty was pediatric pathology, the study of children’s diseases.
  • Leukemia was a malignant proliferation of white cells in the blood, and the disease had been mired in confusion since its discovery in 1845. 
  • Adults, on average, have about 5,000 white blood cells per microliter of blood. Someone with leukemia could have 90,000 cells per microliter.
  • Farber focused on the one attractive feature of leukemia–it could be measured, so any intervention could be evaluated for its potency. He could watch cells grow or die in the blood and use that to measure a drug’s success.
  • At one point, Farber also wondered whether administering folic acid to children with leukemia might restore normalcy to their blood. Unfortunately, it accelerated it. But, if folic acid accelerated things, he wondered if he could cut off its supply with an antifolate.
    • He attempted this project in 1947, and the white cell count in a patient suddenly stopped–it hadn’t vanished, but had temporarily abated. In others, it led to total remission.
    • The disappearance of an aggressive systemic cancer via a chemical drug was virtually unprecedented in the history of cancer.
• Farber also created the Jimmy Fund campaign to address his need for cancer research money. 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.
  • The Jimmy Fund became a household name and a household cause. There were advertisements on billboards throughout Boston, thousands of collection canisters outside movie theaters, and thousands of donations. 
• Farber’s partnership with Mary Woodard Lasker would become critical in the ongoing battle against cancer.
  • Lasker was a socialite, wealthy and connected, who launched a search for her own philanthropic cause. Her husband, Albert Lasker, was the president of an advertising firm.
  • Lasker imagined unleashing the power of medical research to combat diseases–a power that she felt was still largely untapped. She targeted cancer.
  • She met with the American Society for the Control of Cancer, but found it underwhelming.
    • The organization had a small budget and didn’t do much. By 1945, Lasker overhauled the organization, edging out former members and renaming the group the American Cancer Society.
    • Under the Laskers, advertising and fundraising began to dominate the group’s agenda.
  • But what Lasker and the group really needed was a bona fide scientific sponsor, and the one man, perhaps the only man, who fit that role was Farber.
    • Their needs aligned: Farber needed a political lobbyist as urgently as Lasker needed a scientific strategist.
    • Farber and Lasker openly broached the possibility of launching an all-out, coordinated attack on cancer.
• During this time, in 1950, the National Science Foundation was founded, explicitly created to encourage scientific autonomy.
  • A new culture of research–long term, basic scientific research rather than sharply focused quests for treatment–rapidly proliferated.
  • This wasn’t exactly what Lasker and Farber wanted; they wanted a Manhattan Project for cancer.
• In 1971, President Nixon signed the National Cancer Act, which authorized money for cancer research and control–$400 million for 1972, $500 million for 1973, and $600 million for 1974. But much of the act’s prior provisions were gutted, which left Lasker and Farber hugely disappointed.
  • Many scientists thought this was a premature attack on cancer. As a result of this ultimately disappointing political swing, Lasker and Farber withdrew from the political world of cancer.

External causes of cancer

• In 1777, a surgeon in London named Percivall Pott noticed a marked rise in cases of scrotal cancer.
  • His patients were almost always chimney sweeps–poor, indentured orphans apprenticed to sweeps and sent up chimneys to clean ash.
  • The correlation startled Pott, and he started to hunt for the cause of this disease.
  • He noted that sweeps spent hours in bodily contact with grime and ash, and recorded that particles of soot could be found under their skin for days. Soot cancer, Pott claimed, was a man-made disease for which the inciting agent could be identified. In other words, he had discovered a carcinogen.
  • This meant that cancer was preventable. Were there other preventable causes of cancer strewn about in the world?
• In the mid-1900s, cigarette consumption in the U.S. escalated into a national addiction. Yet, when a risk factor for a disease becomes so highly prevalent in a population, it paradoxically begins to disappear into the background.
  • If nearly all men smoked, and only some developed cancer, then how could you separate the statistical link between one and the other?
  • Two doctors in the U.S., Ernst Wynder and Evarts Graham, conducted a trial. Lung cancer patients and a group of control patients without cancer were asked about their history of smoking.
    • The ratio of smokers to nonsmokers within the two groups was measured to estimate whether smokers were overrepresented in lung cancer patients compared to other patients.
  • Two London doctors, Richard Doll and Bradford Hill, were conducting a similar test. As Doll and Hill sifted through the preliminary batch of responses, only one solid and indisputable statistical association with lung cancer leapt out: cigarette smoking.
  • By the early 1960s, people in the U.S. were consuming nearly 4,000 cigarettes per year or about 11 cigarettes per day.
    • Cigarette companies set out to muddle the facts, gnawing at holes in the science and emphasizing that there was no real definitive proof. Further, they pledged aid to the research effort into all phases of tobacco use and health, which not only implied that more research was needed, but that they could be involved in the research.
      • Cigarette makers also proactively touted the benefits of filters on their cigarettes, claiming they were “safety” measures.
    • Bradford Hill came to a solution. At least in the case of lung cancer and smoking, even though scientists could not prove traditional “causation,” the causation here had additional features: it was strong (the increased risk was nearly ten-fold in smokers); it was consistent, it was specific, it was temporal, it possessed a biological gradient (the more you smoked the greater your risk); it was plausible; it was coherent, and it behaved similarly in analogous situations.
      • Epidemiologists could infer causality by using that list of nine criteria. 
  • When people began calling on the government to regulate, President John F. Kennedy ultimately assigned it to a small agency called the Federal Trade Commission.
    • Since the FTC’s role was to regulate tobacco advertisements, it could certainly investigate whether filtered cigarettes were as safe as advertised. They recommended that cigarette packages be labeled with “Caution: Cigarette Smoking Is Dangerous to Health. It May Cause Death from Cancer and Other Diseases.” 
    • The tobacco industry moved quickly and powerfully against this, and the language was significantly diluted by congress to be “Caution: Cigarette smoking may be hazardous to your health.”
  • But in 1966, a young attorney, John Banzhaf, thought to use the “fairness doctrine,” which held that public broadcast media had to allow “fair” airtime to opposing viewpoints on controversial issues–he wanted to use this to attack the disproportionality of cigarette media presence.
    • Incredibly, he won against the tobacco lawyers, and a barrage of anti-smoking commercials appeared on television. The last cigarette commercial was broadcast on TV on January 1, 1971.
  • Another legal case involved Rose Cipollone in 1955. She hunted for a “safe cigarette,” bouncing from brand to brand based on the filters. She was eventually diagnosed with metastatic lung cancer.
    • An attorney named Marc Edell heard of Cipollone’s diagnosis, and he filed suit for her against the three cigarette manufacturers. (Generally, for plaintiffs, the record against tobacco companies was dismal. Not a single case resulted in a judgment against a tobacco company.)
    • Edell decided that what mattered wasn’t how much Rose knew about the risks, but what cigarette makers knew, and how much of the cancer risk they had revealed to consumers.
      • This allowed him to ask the courts for unprecedented access to the internal files of tobacco companies. Many of the cigarette makers had not only known about the cancer risks and the potent addictive properties, but had also actively tried to quash research that proved it.
      • The jury awarded Cipollone $400,000 in damages, but the real win was the flurry of cases that followed, and cigarette makers found themselves increasingly beleaguered and liable. By 1994, the per capita consumption of cigarettes in the U.S. had dropped for 20 straight years.

Modern cancer

• There are several directions in which we can now go to address cancer.
  • The first is cancer therapeutics. That is, once the crucial mutations in any given cancer have been identified, we will need to hunt for targeted therapies against these genes.
  • The second is for cancer prevention, especially in identifying preventable carcinogens.
  • The third and most complex direction is to integrate our understanding of aberrant genes and pathways to explain the behavior of cancer as a whole, thereby renewing the cycle of knowledge, discovery, and therapeutic intervention.
• Part of the unpredictability about the trajectory of cancer is that we don’t know the biological basis for this heterogeneity. We cannot yet fathom, for instance, what makes pancreatic cancer so markedly different from Atossa’s breast cancer.
  • What is certain, however, is that even the knowledge of cancer’s biology is unlikely to eradicate cancer fully from our lives.

• Emil Frei, Emil Freireich, and the VAMP regime (vincristine, amethopterin, mercaptopurine, and prednisone)–a high-dose, life-threatening, four-drug combination therapy for leukemia, and how it illustrated the intense highs and lows of cancer research and medicine
• The advent of cisplatin, which chemically attacked DNA and forced cells to stop dividing–a cure for cancer by chemotherapy–and the drug’s provocation of an unremitting nausea (on average, patients treated with the drug vomited 12 times a day)
• The biological genesis of cancer–in the context of smokers and nonsmokers, the landmark understanding of carcinogenesis conducted by Oscar Auerbach
• George Papanicolaou and the pap smear–the revelation of detecting the antecedent of cancer, giving women a chance to receive preventive care and greatly decrease the likelihood of ever developing cancer
• Albert Salomon, how the mammogram lurked about in the far peripheries of medicine, and how it shot forward to become enshrined in the mainstream
• Background on the STAMP regimen–the mega-dose chemotherapy for breast cancer
• Retinoblastoma genes and the discovery of the protein it encodes, Rb, and how it acts as a gatekeeper for cell division, opening a series of key molecular floodgates each time cell division is activated, and how mutations in Rb inactivate this function
• The discovery of RSV, the first cancer-causing virus, set off a frantic search for more cancer viruses
• William Halsted and the radical mastectomy