One of the Best Reads of a Lifetime

Abstract: The Emperor of all Maladies: a biography of cancer

Written by Siddhartha Mukherjee – abstracted by Lynn Gerlach

Published in 2010; given to me by a friend in 2015; abstracted in 2023

Note to my reader: The author, Siddhartha Mukherjee, calls cancer “a lethal shape-shifting entity… the defining plague of our generation.” He refers to his book as “an attempt to enter the mind of this immortal illness” which is, in its many forms, the abnormal growth of cells.

The book is a 4,000-year history of cancer and the “hypnotic, obsessive quest to launch a national ‘War on Cancer’” by two key individuals: Sydney Farber, “the father of modern chemotherapy,” and Mary Lasker, a Manhattan socialite. Mukherjee notes that the book is also “a personal journey of my coming of age as an oncologist.”

For me, the reader who hopes to cull for you an abbreviated but authentic version of this 400+ page history, it is also “a personal journey” that has allowed me to find my own cancer story within the context of the 4000-year war. This is a long book and a long abstract. My hope is that, when you’ve finished reading my abstract, you’ll go directly to Dr. Mukherjee’s book. You may assume that all quoted material is taken verbatim from this wonderful book, and material in brackets is inserted by me. Let’s now enter Dr. Mukherjee’s compelling cancer biography.

 Prologue

The story begins in 2004 with the case of Carla Reed, a 30-year-old kindergarten teacher in Massachusetts, presenting with acute lymphoblastic leukemia, often curable. An oncologist in training, the author describes what he saw: “A body invaded by leukemia is pushed to its brittle physiological limit – every system, heart, lung, blood, working at the knife-edge of its performance… This was the tenth month of my ‘fellowship’ in oncology – a two-year immersive medical program to train cancer specialists.” The author says that he felt “the dense, insistent gravitational tug that pulls everything and everyone into the orbit of cancer.”

As he emerged from “the strange desolation of those two fellowship years,” he writes, he wondered “Where are we in the ‘war’ on cancer? How did we get here? Can this war even be won?” A disease that unleashes a cell that can’t stop growing, cancer is one of the most significant scientific challenges faced by our species. “Cancer is built into our genomes… If we seek immortality, then so, too, in a rather perverse sense, does the cancer cell.” He quotes the twentieth-century biologist, J.B.S. Haldane, who called cancer the most “relentless and insidious enemy among human diseases,” an illness, the author says, that “was just three decades ago widely touted as being ‘curable’ within a few years.”

PART ONE: “OF BLACK CHOLOR, WITHOUT BOYLING”

“A Suppuration of Blood”

We meet Sidney Farber in 1947, a pathologist whose job “involved dissecting specimens, performing autopsies, identifying cells, and diagnosing diseases, but never treating patients.” At that time, the study of leukemia “had been mired in confusion and despair ever since its discovery.” Most leukemia patients were treated with purging and leeches and “sent home to die.”

In 1845, a Scottish physician named Bennett had postulated that leukemia’s principal component was pus or “spoiled blood.” Shortly thereafter, a German researcher named Virchow published a case history of a patient similar to Bennett’s. “Virchow didn’t understand leukemia. But unlike Bennett, he didn’t pretend to understand it. His insight lay entirely in the negative. By wiping the slate clean of all preconceptions, he cleared the field for thought.” Virchow “set out to create a ‘cellular theory’ of human biology, basing it on two fundamental tenets. First, that human bodies (like the bodies of all animals and plants) were made up of cells. Second, that cells only arose from other cells – omnis cellula e cellula, as he put it… growth could occur in only two ways: either by increasing cell numbers or by increasing cell size.” He called these two modes “hyperplasia and hypertrophy” … and he “soon stumbled upon the quintessential disease of pathological hyperplasia – cancer… By the time Virchow died in 1902… cancer was a disease of pathological hyperplasia… uncontrollable pathological cell division.”

One year after Virchow died, Sidney Farber was born in Buffalo, New York, the third of fourteen children. His colleagues in medical school, it is said, “found him arrogant and insufferable… formal, precise, and meticulous.” In the late 1920s, Farber “became the first full-time pathologist at the Children’s Hospital in Boston.” Soon he was considered “a preeminent pathologist – a ‘doctor of the dead.’”

Apparently Farber had a hunger to treat living patients, and he chose to focus his attention on childhood leukemia. Why? It “could be measured.” There were no CT scans or MRIs in 1947, but “leukemia, floating freely in the blood, could be measured.” And then, Farber reasoned, an intervention could be evaluated for its potency. By nature a “quick and often impulsive thinker… he scarcely realized that he was throwing open an entirely new way of thinking about cancer.”

“A Monster More Insatiable than the Guillotine”

That era saw “a cornucopia of pharmaceutical discoveries,” including penicillin, being mass-produced by 1952 and costing four cents per dose. Tetracyline and streptomycin were developed. And public health made huge forward strides, with massive municipal efforts to cleanse water supplies. Sanitation and public hygiene improved, and “the life expectancy of Americans rose from forty-seven to sixty-eight in half a century… between 1945 and 1960, nearly one thousand new hospitals were launched nationwide… a young generation thus dreamed of cures.” America began to perceive itself as “the invincible society.”

Our author reminds us, though, “of all diseases, cancer had refused to fall into step in this march of progress… cancer still remained a black box… doctors had only two strategies: excising the tumor surgically or incinerating it with radiation.” Fortune magazine published the “startling fact” in 1937 that “no new principle of treatment, whether for cure or prevention, had been introduced.” The article conceded that we now had “modern painless surgery” and “radiation with X-ray and radium… But the fact remains that the cancer ‘cure’ still includes only two principles – the removal and destruction of diseased tissue.” The authors suggested this situation was “as much political as medical” and referred to “the systematic neglect of cancer research.”

 “Between 1900 and 1916, cancer-related mortality grew by 29.8 percent… By 1926, cancer had become the nation’s second most common killer, just behind heart disease.” On August 5, 1937, President Roosevelt signed the National Cancer Institute Act, “designed to coordinate cancer research and education.” Soon came “a state-of-the-art laboratory space” in Bethesda, Maryland. With the threat of World War II, however, “scientific research funding stagnated and was shunted into projects directly relevant to the war… the institute’s sparkling campus turned into a scientific ghost town… the social outcry against cancer also drifted into silence.”

So cancer was a “politically silent illness” when Sidney Farber entered its world in 1947. This allowed him to work “insulated from the spotlights of public scrutiny… on a small obscure piece of the puzzle.” He reasoned that leukemia would be cured by the study of blood – hematology. He thought that, “if he could uncover how normal blood cells were generated” he might “confront cancer in reverse.” In the summer of 1946, he discovered important links between vitamins, bone marrow, and normal blood. And then he learned that folic acid, administered to nutrient-deprived patients, could restore the normal growth of blood. So he tried administering folic acid to pediatric leukemia patients with disastrous results: white blood cell count exploded.

And so Farber wondered about “an antifolate. Could a chemical that blocked the growth of white blood cells stop leukemia?” He imagined bone marrow as a “busy cellular factory.” If it were occupied with leukemia, might that be a cellular factory in overdrive? “Could the malignant marrow be shut off by choking the supply of nutrients?” Apparently “the prospect of an anticancer chemical haunted him.” In 1946, working with an old friend, Farber found “molecular mimics” that could “behave like antagonists to folic acid… precisely the antivitamins that Farber had been fantasizing about.”

Farber’s Gauntlet

In August 1947, two-year-old Robert Sandler, twin to a perfectly healthy brother, was brought to Children’s Hospital with a mysterious illness. Farber injected him with “pteroylaspartic acid or PAA,” an “antifolate.” It had little effect. Soon the child was on the verge of death. But, in late December, Farber received a new version of antifolate from his friend. He injected the child, and “the response was marked. The white cell count… suddenly stopped rising.” It soon actually began to drop, within days, to one-sixth of its peak value. The microscope still revealed malignant white cells. Two weeks later, the child was walking on his own for the first time in two months. “His spleen and liver had shrunk… his bleeding had stopped… Farber noted the child’s alertness, nutrition and activity were equal to his twin’s.”

Soon more children were at Farber’s clinic, and he recruited additional doctors to help him. But hospital authorities had been infuriated with Farber’s first, disastrous clinical trial. “Staff voted to take all the pediatric interns off the leukemia chemotherapy unit,” saying children with cancer should be allowed to just “die in peace.” Farber moved his group to a makeshift clinic where they actually “sharpened their own bone marrow needles.” By winter the team had cut its work to three days per week.

News of Farber’s work with childhood leukemia had begun to spread, though, and “a slow train of children began to arrive… an incredible pattern emerged”: The antifolates were reducing leukemia cell counts, and “there were other remissions as dramatic as Sandler’s.” But, “after a few months of remission, the cancer would inevitably relapse…even the most active antifolates would not keep their growth down. Robert Sandler died in 1948, having responded for a few months.” Ultimately, “about one-third of the initial group remained alive for four or even six months after diagnosis.”

On June 3, 1948, Farber published the story of his results. “The paper was received ‘with skepticism, disbelief, and outrage.’” Farber continued to dream “of malignant cells being killed by specific anticancer drugs, and of normal cells regenerating and reclaiming their physiological spaces.”

A Private Plague

“Cancer is an expansionist disease… It lives desperately, inventively, fiercely, territorially… a phenomenally successful invader and colonizer… a clonal disease. Nearly every known cancer originates from one ancestral cell that, having acquired the capacity of limitless cell division and survival, gives rise to limitless numbers of descendants… a clonally evolving disease… Every generation of cancer cells creates a small number of cells that is genetically different from its parents… Cancer thus exploits the fundamental logic of evolution unlike any other illness.” 

Our biographer, Mukherjee, asks the typical questions of his subject: “Where was cancer born? How old is cancer? Who was the first to record it as an illness?” His story begins with a fifteen-foot-long papyrus “filled with cursive Egyptian script,” thought to have been written in the seventeenth century BC – transcribing a manuscript dating back to 2500 BC! It reports “a case of bulging masses… large, spreading and hard.” In the section titled “therapy” is one sentence: “There is none.” And, “with that admission of impotence, cancer virtually disappeared from ancient medical history” with “no easily identifiable trace” in any literature.

Humanity next hears of cancer in about 440 BC in the story of Atossa who “noticed a bleeding lump in her breast.” The tumor was excised by a slave, and Atossa lived. Mukherjee asks, though, whether early stories of “cancers” might have been about “abscesses, ulcers, warts or moles.” To be certain, he says, we must find the malignant tissue somehow preserved. And so he takes us to “a thousand-year-old gravesite in… the southern tip of Peru.” Apparently a large, desiccated gravesite discovered in 1990 came to the attention of a Minnesota paleopathologist, Arthur Aufderheide. He autopsied the mummified remains, discovering the remains of a woman with “a hard, ‘bulbous mass’ in her left upper arm… a malignant bone tumor.”

“In 1914, a team of archaeologists found a two-thousand-year-old Egyptian mummy in the Alexandrian catacombs with a tumor invading the pelvic bone.” Someone also discovered a “jawbone dating from two million years ago… that carried the signs of a peculiar form of lymphoma.” The most striking finding, we are told, is how rare cancer actually was in the distant past. “…even common cancers, such as breast, lung, and prostate, are conspicuously absent.” Why? “In most ancient societies, people didn’t live long enough to get cancer… It becomes common only when all other killers themselves have been killed… civilization did not cause cancer, but by extending human life spans – civilization unveiled it.”

Mukherjee explains that change in the structure of modern life has shifted the spectrum of cancers. For example, until the late nineteenth century, carcinogens in pickling reagents and preservatives made stomach cancer prevalent. Then came modern refrigeration and improved public hygiene, and stomach cancer abated. “Lung cancer incidence in men increased dramatically in the 1950s as a result of an increase in cigarette smoking… In 1900… tuberculosis was by far the most common cause of death.” As of 1900, cancer caused fewer deaths than pneumonia, diarrhea, gastroenteritis and three other common illnesses. By 1940, cancer was the second-leading cause of death, behind only heart disease. In that half-century, American life expectancy had increased by about 26 years.

Onkos

“It was in the time of Hippocrates, around 400 BC, that a word for cancer first appeared in the medical literature: Karkinos, from the Greek word for ‘crab.’ The tumor… reminded Hippocrates of a crab… with its legs spread in a circle.” Later doctors and patients felt the hardened surface of a tumor was like the carapace of a crab’s body. Others considered the disease spreading like a stealthy crab, or the sharp pain like being gripped by a crab’s pincers.

“Onkos,” another Greek word which eventually led us to the term “oncology,” meant mass or load. “Cancer was imagined as a burden carried by the body.”

The karkinos Hippocrates saw were “mostly large, superficial tumors that were easily visible to the eye: cancers of the breast, skin, jaw, neck, and tongue.” His term included all kinds of swellings such as nonmalignant polyps and swollen glands. The Greeks were also preoccupied with fluid mechanics and hydraulics; Hippocrates “fashioned an elaborate doctrine based on fluids and volumes.” Illness was, in short, the lack of balance among fluids, which led to the idea of Galen, who believed in the “four humors.” Cancer was, therefore, an overabundance of “black bile.” Since depression was also thought to be the result of too much black bile, cancer and depression became intertwined.

Tumors came to be perceived as “just local outcroppings of a deep-seated bodily dysfunction.” And Galen suggested that black bile was everywhere; if you cut the cancer out, the bile would flow right back. Thus, surgical removal of a tumor was “a fool’s operation.” It would be “entertained only in the most extreme circumstances.” Therefore “doctors resorted to… an intricate series of bleeding and purging rituals.”

Vanishing Humors

“In the winter of 1533, a nineteen-year-old student from Brussels, Andreas Vesalius, arrived at the University of Paris…” to learn anatomy, pathology and surgery. Back then, “Without a map of human organs to guide them, surgeons were left to hack their way through the body… Vesalius decided to create his own anatomical map.” Where did he start? In the graveyards, searching for bones and bodies. Five years later Vesalius collaborated with the famous artist, Titian, to publish his detailed drawings, “charting the courses of arteries and veins, mapping nerves and lymph nodes.” But Vesalius could not find Galen’s “black bile… [the] oozing carrier of cancer and depression… Vesalius had started his anatomical project to save Galen’s theory, but, in the end, he quietly buried it.”

“In 1793, Matthew Baillie, an anatomist in London… mapped the body in its diseased, abnormal state… Like Vesalius, Baillie drew anatomy and cancer the way he actually saw it. At long last, the vivid channels of black bile, the humors in the tumors… vanished from the picture.”

“Remote Sympathy”

“Matthew Baillie’s Morbid Anatomy laid the intellectual foundation for the surgical extractions of tumors… In the 1760s, a Scottish surgeon, John Hunter… had started to remove tumors from his patients.” He began to classify them into stages – “movable tumors” were early stage, and “immovable tumors” were advanced. Mukherjee calls Hunter “a reckless and restless man with nearly maniacal energy” who had operated on every animal he could catch. He “drugged his patient with alcohol and opium to near oblivion.” In addition to the pain of surgery, the patient ran a significant risk of post-surgery infection.

A span of 21 years made a huge difference. “…anesthesia was publicly demonstrated in 1846.” Ether! However, “the hurdle of postsurgical infection remained.” Then, in 1865, came a Scottish surgeon named Joseph Lister. He remembered Louis Pasteur, “the great French chemist [who] had shown that meat broth left exposed to the air would soon turn turbid and begin to ferment, while meat sealed in a sterilized vacuum jar would remain clear.” Lister saw that an open wound was something like meat, “a natural petri dish for bacterial growth.”

Lister suspected that “an antibacterial process or chemical could curb…infections.” His idea was to apply “as a dressing some material capable of destroying the life of the floating particles” Pasteur had hypothesized as the cause of turbidity. He began to use a carbolic acid paste on wounds.

“In 1869, Lister removed a breast tumor from his sister… using a dining table as his operating table, ether for anesthesia, and carbolic acid as his antiseptic. She survived without an infection… By the mid-1870s, Lister was routinely operating on breast cancer and had extended his surgery to the cancer-afflicted lymph nodes under the breast.”

“Between 1850 and 1950, surgeons brazenly attacked cancer by cutting open the body and removing tumors. Emblematic of this era was the prolific Viennese surgeon Theodor Billroth… for nearly a decade, he spent surgery after surgery simply opening and closing abdomens of animals and human cadavers, defining clear and safe routes to the inside. By the early 1800s he had established routes… to remove tumors from the stomach, colon, ovaries and esophagus… But cancer so often disobeyed and distorted natural anatomical boundaries.” Still, by the mid-1890s Billroth had removed 41 gastric carcinomas, and 19 of the patients survived the surgery.

Despite all these advances, some cancer patients still relapsed after surgery. The surgeons cut them open again and again. Some surgeons wondered whether the whole cancer might be uprooted in its early stage, being permanently surgically removed.

A Radical Idea

The name of William Stewart Halsted would eventually be permanently attached to the concept of “radical surgery,” but not by his choice. As soon as Halsted became a physician, he was fascinated by surgery. He read every book he could get his hands on, and then “he moved on to real patients with an equally insatiable hunger.”

Halstead began his surgical practice when the common cancer treatments were bloodletting, cupping, leaching and purging and “barbaric attempts at surgery.” In October 1877, he took a “whirlwind tour” of Europe for what Mukherjee calls “an intellectual baptism.”  Then, in 1884, he read about “a new surgical anesthetic called cocaine… it was cheap, accessible, and foolproof… Halstead began to inject himself with the drug” to test it. For the next five years, fiercely addicted to cocaine, he had, nevertheless, “an incredible career as a young surgeon in New York.” In the meantime, his cocaine habit was treated with morphine, and his addiction changed to that drug.

He was recruited to the newly built Johns Hopkins Hospital, where he found Dr. Hopkins’ “awe-inspiring training program for young surgical residents.” Still “deeply addicted to morphine,” he married and managed to control his addiction. He and his wife withdrew from the world, and he “now attacked breast cancer with relentless energy.” Halstead had learned, in his tour of European surgeries, that breast cancer seemed to recur “precisely around the margins of the original surgery, as if minute remnants of cancer had been left behind.” So, he reasoned: Why not extend the margins? He began to cut deeper into the breast cavity, “cutting through the pectoralis major, the large, prominent muscle responsible for moving the shoulder and the hand… Halstead called this procedure the ‘radical mastectomy.’”

“At Hopkins, Halstead’s diligent students now raced to outpace their master with their own scalpels.” They cut farther into the neck, and they found the lymph nodes buried inside the chest. Mukherjee calls it “a macabre marathon.” In the U.S. and Europe, women had their ribs and collarbones removed, and one even had her shoulder amputated. Patients were permanently disfigured. “But did the Halstead mastectomy save lives?”

By 1898 surgeons were so self-confident and self-impressed that the concept of the “operating theater” arose, allowing people to watch Halstead and others operate. Halstead had begun to collect longitudinal data on survival rates “to show that his operation [the radical mastectomy] was the superior choice.”

But, Mukherjee says, “there was a deep conceptual error.” If the cancer had metastasized, no surgery, no matter how aggressive, would cure it. “…the woman with the small, confined cancer does benefit from the operation – but for her, a far less aggressive procedure, a local mastectomy, would have done just as well. Halstead’s mastectomy is thus a peculiar misfit in both cases: it underestimates its target in the first case and overestimates it in the second.” Ultimately, survival from breast cancer was not about how extensive the surgery was but about how extensively the cancer had spread before surgery.

At the turn of the twentieth century, “the superiority of radical surgery in ‘curing’ cancer still stood on shaky ground… ‘Radicalism’ became a psychological obsession, burrowing its way deeply into cancer surgery… The best a surgeon could do… was to deliver the most technically perfect operation. Curing cancer was someone else’s problem… a possibility now flung far into the future… Radical surgery thus drew the blinds of circular logic around itself for nearly a century.” Surgeons berated attempts at non-radical surgery and pooh-poohed any “procedure that did not attempt to obliterate cancer from the body.”

The Hard Tube and the Weak Light

A few months after Halstead unveiled his radical mastectomy, Wilhelm Roentgen “was working with an electron tube – a vacuum tube that shot electrons from one electrode to another.” He asked his wife to place her hand between the tube and a photographic plate. There he saw “a silhouette of her finger bones and her metallic wedding ring… as if through a magical lens.” He had found “a form of energy so powerful that it could pass through most living tissues.” He called it the X-ray.

Soon a French chemist discovered that certain natural materials, including uranium, emitted their own invisible rays. He showed his friends, Pierre and Marie Curie. “Marie and Pierre began hunting for new sources of X-rays… in what is now the Czech Republic, the Curies found… an element many times more radioactive than uranium.” They distilled it from pitchblende, a black sludge from the forest, using “several tons of pitchblende and four hundred tons of washing water.” They finally retrieved one-tenth of one gram of this new element in 1902. Marie Curie called it “radium, from the Latin word for ‘light.’”

The Curies thus revealed a new property of X-rays: “they could not only carry radiant energy though human tissues, but also deposit energy deep inside tissues.” It took decades for biologists to understand the damage X-rays caused to tissues – skin, lips, blood, gums, nails: “radium was attacking DNA… Cells respond to this damage by dying or, more often, by ceasing to divide.”

Only one year after Roentgen’s discovery of X-rays, Emil Grubbe, a twenty-one-year-old Chicago medical student, “had the inspired notion of using X-rays to treat cancer.” In 1896, Grubbe treated an elderly woman whose breast cancer had relapsed. “He irradiated her cancer every night for eighteen consecutive days.” Her tumor ulcerated, tightened and shrank: “the first documented local response in the history of X-ray therapy… A new branch of cancer medicine, radiation oncology, was born.” It “catapulted cancer medicine into its atomic age – an age replete with both promise and peril.” 

“Like surgery, radiation was remarkably effective at obliterating locally confined cancers… But, like surgery, radiation also struggled against its inherent limits… radiation produced cancers… killing rapidly dividing cells – DNA damage – also created cancer-causing mutations in genes… Over the next decades, dozens of radium-induced tumors sprouted in these radium-exposed workers… Many… died of leukemia and other cancers… Marie Curie died of leukemia in July 1934. Emil Grubbe… also succumbed.” His fingers had been amputated, one by one. He died at age 85 with multiple forms of cancer. “Cancer, even when it begins locally, is inevitably waiting to explode out of its confinement… It was a ‘systemic’ illness, just as Galen had once made it out to be.”

Dyeing and Dying

“A systemic disease demands a systemic cure… The trouble lies in finding a selective poison – a drug that will kill cancer without annihilating the patient.” Actually, the hunt for such a poison had been precipitated in the mid-nineteenth century with colonial England’s interest in cotton. Fifty percent of the British economy was printed goods made from the cotton brought in from India and Egypt. And that set off a boom in cloth dyeing. Dyes were not made by chemists at that time. They were extracted from vegetable products and treated with thickeners and solvents.

The printed cloth boom gave rise to a new discipline called practical chemistry. An 18-year-old student boiling nitric acid and benzene in a flask smuggled into his makeshift laboratory accidentally made a purple dye that colored cotton. It was “cheap and imperishable,” and its parent compound could produce other dyes. Within ten years synthetic dyes were plentiful. Synthetic chemistry boomed even bigger in Germany. “… emboldened by their successes the chemists began to synthesize… an entire universe of new molecules.” Within another decade, “Germany had created more molecules than they knew what to do with.”

Still, between synthetic chemistry and medicine existed only scorn. As early as 1828, though, a chemist/physician had produced urea, a substance made by the kidneys, by boiling a plain, inorganic salt. Living organisms, it had been thought, were “imbued with some mystical property, a vital essence that could not be duplicated in a laboratory.” This synthetic urea demonstrated that “biology was chemistry.” Therefore, “could a molecule concocted in a flask affect the inner workings of a biological organism?”

Actually, such multifaceted synthetic chemicals already existed in those German dye factories, just a daytrip away from the producer of synthetic urea. But neither the chemist nor his students saw the connection. “The vast panel of molecules sitting idly on the shelves of the German textile chemists, the precursors of a revolution in medicine, may as well have been a continent away.”

It was fifty years later that a young medical student, looking for a thesis project, used some of those synthetic dyes from the cloth industry to stain animal skins – and discovered in them “molecular specificity”: the dyes were “able to discriminate among chemicals hidden inside cells – binding some and sparing others.” A few years later he discovered that “certain toxins, injected into animals, could generate ‘antitoxins’” which would later be called antibodies. From the blood of horses he made a toxin against diphtheria, and then he got serious and set up his own lab.

The scientist’s name was Paul Ehrlich, and he stayed with the mystery of “molecules picking out their partners,” such as dyes highlighting only particular parts of cells. He wondered whether a chemical might accurately discriminate between an animal cell and a bacterial cell. He dreamed of finding a chemical compound that might kill a parasite because it has a special affinity for it. That was the conceptual birth of “chemotherapy.”

And Ehrlich set up his lab very near those chemical dye factories! He used those abundant molecules to test their biological effects on animals. After several hundred chemicals, he finally had a hit, so he continued his efforts and, in 1910, found something he called “compound 606.” It was active against the notorious microbe that caused syphilis, the “secret malady of eighteenth-century Europe.” By the time he announced his success, he had already tried it on humans and was building a factory to produce it for chemical use. Mukherjee says Ehrlich “proved that diseases were just pathological locks waiting to be picked by the right molecules.” Ehrlich called his drugs “magic bullets.”

Now he had solved the problem of the microbial disease, but he still needed a solution to the malignant human cell – cancer; it defied him. Bacterial enzymes were an easier target because they are so radically different from human enzymes. “With cancer, it was the similarity of the cancer cell to the normal human cell that made it nearly impossible to target… to target the abnormal cell, one would need to decipher the biology of the normal cell. He had returned… to specificity again, to the bar codes of biology hidden inside every living cell.”

In 1915, Ehrlich fell ill with tuberculosis. Then World War I started, and the dye factories were converted to producers of war chemicals, including the infamous mustard gas. In 1917, two years after Ehrlich died, mustard gas rained down on English troops. Within one year it had killed thousands. A few men survived, with respiratory complications, burnt skin, blisters and blindness. Researchers found the mustard gas had targeted the bone marrow, drying up the normal blood-forming cells. Surviving victims were anemic and prone to infection. “This chemical had, after all, targeted the bone marrow and wiped out only certain populations of cells – a chemical with a specific affinity.” But World War I was raging, and the discovery got little attention and was then forgotten.

Poisoning the Atmosphere

During World War II, another mustard gas poisoning left nearly a thousand troops and civilians dead or dramatically deprived of white blood cells, their bone marrow scorched and depleted. This accelerated the effort to investigate war gases and their effects. The two scientists contracted to investigate mustard gas, Gilman and Goodman, wondered whether this effect on white blood cells might be used in tiny doses to target malignant white cells. They experimented with rabbits and mice and finally, in 1942, with a 48-year-old silversmith suffering from lymphoma – cancer of the lymph glands. “In men, as in mice, the drug produced miraculous remissions. The swollen glands disappeared.” Clinicians described it as a “softening” of the cancer, reminiscent of the crab carapace connected to cancer two thousand years earlier. But remission was always followed by relapse; the tumors grew and hardened again.

In 1944, a biochemist named George Hitchings found a young assistant, Trudy Elion, who held a master’s degree in chemistry. Together they searched for “chemicals that could block bacterial growth by inhibiting DNA.” Elion focused on purines, “ringlike molecules with a central core of carbon atoms that were known to be involved in the building of DNA.” She finally found one with promise, called 6-MP, although it was strangely toxic to dogs. In 1948, a former army officer, Cornelius “Dusty” Rhoads, left the army’s chemical warfare unit to join Hitchings and Elion. Within months the three were ready to test 6-MP on humans. Such tests began in the early 1950s on children with lymphoblastic leukemia; again speedy remission was followed by relapse.

The Goodness of Show Business

Sidney Farber heard about these “flickering and feeble” remissions, and he was interested. And he began to wonder if cancer might someday be cured by chemicals alone. Like many dedicated scientists, Farber sought to learn from the past. He recalled the polio epidemics of the 1920s, when he was a student, and how futile the study seemed, poorly advertised and generally ignored. Until Franklin Roosevelt, paralyzed from the waist down by polio, came on the scene. In 1936, having been re-elected, he launched the National Foundation for Infantile Paralysis to advance polio research. One year later the March of Dimes campaign was launched. It was hugely successful nationwide. Soon Sabin and Salk were “well on their way to preparing the first polio vaccines.”

Farber imagined a similar campaign for leukemia or for cancer in general. He sought an ally, and he found one in a group of men in show business who had seen the effects of the Great Depression. Their leader was Bill Koster and, stopping by Farber’s office to seek a mission for a new project, “he found an excitable, articulate scientist with a larger-than-life vision… Farber asked the club to help him create a new fund to build a massive research hospital dedicated to children’s cancer.”

The group agreed, and they found a young cancer patient, a “lanky, cherubic, blue-eyed blond” boy, renamed him “Jimmy,” and introduced him on the radio show, Truth or Consequences, as their poster child. Nationally revered baseball players joined the effort. The broadcast lasted eight minutes. “The public response was staggering.” $231,000 rolled in almost instantly, but that was not a truly significant amount. “In 1948, Americans spent more than $126 million on Coca-Cola alone.” But it was “an early experiment – the building of another model.” Farber saw he needed advertising as much as science. “If Farber’s antifolates were his first discovery in oncology, then this critical truth was his second… The emergence of cancer… into the glaring light of publicity would change the trajectory of this story. It is a metamorphosis that lies at the heart of this book.”

The House that Jimmy Built

Sidney Farber’s life to that point could have been measured in single digits: one closet-sized basement room in a huge hospital; one drug that sometimes worked; one remission in five attempts, and never longer than one year. 

By 1951 that had all changed. Thronged by pediatric patients and their parents, he moved to a larger clinic, but that was soon outgrown. And Children’s Hospital just didn’t want him. “Most of the doctors thought him conceited and inflexible…even if there was space for a few of his bodies, there was no more space for his ego.” Farber turned to fundraising for his own facility, winning tremendous support from Hollywood stars and national sports heroes. “The Jimmy Fund became a household name and a household cause.”

One year later, Farber had his new facility, including outside steps steam-heated against the winter snow, a waiting room filled with toys and carousels, and a library of hundreds of books. But his cure for leukemia still eluded him. The playing children soon showed scars, “horrible swellings on different parts of their bodies… shaven heads… limping… coughing… emaciated.” Farber continued searching for another drug to lengthen remission by a few more months. He needed more money. “He had outgrown the house that Jimmy had built.”

PART TWO: AN IMPATIENT WAR

They Form a Society

Farber recognized both the proclivity of Americans to found societies for causes and the need for a powerful lobbyist to build such a society that might gain access to federal coffers through Congress. And he knew who should do the job: Mary Woodard Lasker, born in Watertown, Wisconsin, in 1900, daughter of a small-town banker and an amazingly successful saleswoman, and a graduate of Radcliffe College. The second man Mary Woodard married, Albert Lasker, was a brilliant advertising genius who viewed advertising “as a lubricant of information.”

Mary Lasker brought with her a few haunting childhood memories of illness: her own brush with death from an unknown illness, possibly dysentery or pneumonia; the radical mastectomy of her family’s laundress; and the Spanish Flu of 1918. In 1939, when her mother suffered a heart attack and then a stroke, leaving her paralyzed and incapacitated, Lasker was infuriated with the impotence and “unrealized potential of medicine.”

When her mother died within a year, Lasker said, “I am opposed to heart attacks and cancer the way one is opposed to sin.” She turned to medical “evangelism.” She and her husband decided to transform “the landscape of American medical research using political lobbying and fund-raising at an unprecedented scale.” Professional socialites, the Laskers had fund-raising and friend-raising “instilled in their blood.” Mary Lasker became “the fairy godmother of medical research.”

She met – and was very disappointed in – the American Society for the Control of Cancer (ASCC). “Her first priority was to make a vast public issue out of cancer.” She turned to Readers Digest for her first foray in 1943. Then she and her husband transformed the ASCC from “a moribund social club” to “a highly organized lobbying group.” Membership became less medical, more executive, legal and creative. They rechristened the organization The American Cancer Society. “In a single year it printed 9 million ‘educational’ pieces, 50,000 posters…” Annual donations exceeded $12 million by 1947.

The president of the former ASCC was forced to resign, and the bylaws and constitution were rewritten. Emphasis for membership and leadership was to be on nonprofessional, non-scientific representation. “The society was now a high-stakes juggernaut spearheaded by a band of fiery ‘laymen’ activists to raise money and publicity for a medical campaign. Lasker was the center of this collective… its queen bee.” The media began to refer to the group as the “Laskerites.”

Within five years, the long-range target was Congress. They sought “federal backing for a War on Cancer… But cannily, Lasker grasped an even more essential truth: that the fight had to begin in the lab before being brought to Congress… The one man – and perhaps the only man – who could possibly fit the role was Sidney Farber… Farber needed a political lobbyist as urgently as the Laskerites needed a scientific strategist. It was like the meeting of two stranded travelers, each carrying one-half of the map.”

Lasker became fascinated by the concept of chemotherapy, “a penicillin for cancer.” Farber “unloaded his scientific knowledge on her, but more important, he also unloaded his scientific and political ambition, an ambition he found easily reflected, even magnified, in her eyes.” By the mid-1950s, they were discussing (by letter) “an all-out, coordinated attack on cancer.” The two became regulars on the Hill. They “struck up a synergistic partnership that would stretch over decades.” And they began to use the word “crusade.”

“These New Friends of Chemotherapy”

Then, in 1951, Albert Lasker, Mary’s husband, was diagnosed with colon cancer. The lymph nodes were “widely involved” and within a few months he was awaiting death. “Mary Lasker chose to descend into melancholy alone.”

Mary soon “charged her way back into New York’s society,” again holding fund-raisers, balls and benefits, but she was fundamentally different. She became more urgent and insistent. In the mid-1950s, Sidney Farber had his inflamed colon quietly removed. He never admitted to having cancer, nor did his son in later years, but Mary Lasker later called Farber “a cancer survivor.” Cloaked in secrecy, Farber’s personal battle “altered the tone and urgency of his campaign… ‘Patients with cancer who are going to die this year cannot wait,’ he insisted.”

Following the focused, goal-oriented scientific research of the frenzied war years, culminating in the atomic bomb of the Manhattan Project, the leader of the Office of Research and Scientific Development (ORSD), Vannevar Bush, insisted on a return to autonomous scientific research based on open-ended inquiry, with “no driving mandate to produce anything.” Both the National Science Foundation (NSF) and the National Institutes of Health (NIH) committed to a “new culture of scientific research – ‘long-term, basic scientific research rather than sharply focused quests for treatment and disease prevention.’”

But the Laskerites had been galvanized by the undiluted commitment of wartime scientific research. “… they felt that it was no longer necessary to wait for fundamental questions about cancer to be solved before launching an all-out attack on the problem… Other scientists echoed this frustration.” They believed scientists must drive toward a solution to the cancer problem, not just because it’s “interesting.” By 1955, through “a furious bout of political lobbying by the Laskerites,” the Cancer Chemotherapy National Service Center (CCNSC) was in full swing. In the next ten years they tested 82,700 synthetic chemicals, 115,000 fermentation products, and 17,200 plant derivatives and treated nearly a million mice each year in search of an ideal drug. 

In the meantime, Farber was still in Boston, driving his own drug discovery program. He had heard about a cellular poison, actinomycin D, taken from soil, that damaged DNA cells – although it also killed human cells. He tested it and related soil molecules on mice with excellent success in killing various malignant tumors. So he tried it on human children with a diverse range of tumors, injected intravenously – and a rare form of kidney cancer did respond. He found it could prevent metastasis of Wilm’s tumor. Soon his team discovered that actinomycin D and radiation together achieved excellent results: Metastases in the lungs cleared completely. “Farber had achieved his long-sought leap from the world of liquid cancers to solid tumors.” 

By the late 1950s, the Jimmy Fund clinic seemed on the verge of discovery. Still, it was described by a parent as both “wonderful and tragic… a snake-pit… of cancer, a seething, immersed box coiled with illness, hope, and desperation.” Visitors saw children with horrible discoloring on their faces and “obliterated” features. Farber made playthings available, but most children “were usually too exhausted to walk.”

Farber believed cancer was “a total disease – an illness that gripped patients not just physically, but psychically, socially, and emotionally. Only a multipronged, multidisciplinary attack would stand any chance.” Still, “death stalked the wards relentlessly… But Farber was unfazed.” He saw amazing possibilities, including “permutations and combinations of medicines, variations in doses and schedules, trials containing two-, three-, and four-drug regimens… This was just the beginning of an all-out attack.” 

An adult lymphoblastic leukemia patient understood she had a 30% chance of survival after months of chemotherapy, which would “come in three phases. The first phase would last about a month.” After that, for a few days, the patient lived in a “body with no immune system, defenseless against the world around it.” If the leukemia went into remission, the next round would last several months, eventually as an outpatient. But, if it metastasized to the brain, the doctors had no choice but to send the chemicals directly to her brain through her spinal fluid and provide whole-brain radiation. If she achieved remission, maintenance chemotherapy would last two years.

“The Butcher Shop”

Bethesda, April 1955: Two men fresh from their residencies, both named Emil, arrived on the scene. Emil Freirich, age 35, “flamboyant, hot-tempered and adventurous… Antibiotics, folic acid, vitamins and antifolates were stitched into Freirich’s soul.” Emil Frei, 40+: “was cool, composed and cautious… charming, soft-spoken, and careful.” The two had been summoned by Gordon Zubrod, the new director of the NCI’s Clinical Center. “Zubrod knew… drugs could be tested, but first the children needed to be kept alive.” He brought the two Emil’s in, sure “Their collaboration was symbolic of a deep intellectual divide that ran through the front lines of oncology: the rift between overmoderated caution and bold experimentation.” 

To “keep leukemia out of trouble… Zubrod proposed that a ‘consortium’ of researchers be created to share patients, trials, data and knowledge.” It was said that his cooperative group model galvanized cancer medicine. “The cancer doctor was not the outcast anymore, not the man who prescribed poisons from some underground chamber in the hospital.” Zubrod was determined oncologists, “to learn how to run objective, unbiased, state-of-the-art clinical trials, would need to study the history of the development of antibiotics.”  

From an English statistician who had been a victim of TB, the oncologists learned the “solution was to remove such biases by randomly assigning patients to treatment with streptomycin versus a placebo.” In that way, “any doctors’ biases in patient assignment would be dispelled… The randomized trial became the most stringent means to evaluate the efficacy of any intervention in the most unbiased manner.”

Based on earlier work against tuberculosis, in which the cancer cells became resistant to a single antibiotic, the team wondered whether they might try two or three drugs simultaneously against cancer – “or would the toxicities be so forbidding that they would instantly kill patients?” In partnership with three hospitals, they launched the first pilot, using random assignment of 84 patients. “The intensive group fared better…” but “even the intensively treated children soon relapsed and died by the end of one year.” But the model of a cancer cooperative group had been launched. Dozens of doctors at three sites had “followed the instructions perfectly… In a world of ad hoc, often desperate strategies, conformity had finally come to cancer.” 

In 1957 the leukemia group tried a new approach, using three patient groups: one group received both drugs (intensive therapy), while the other two groups each received a different one of the single drugs. Neither drug, used alone, succeeded beyond 15-20 percent, but the two drugs (methotrexate and 6-MP) used together achieved a 45-percent remission rate.

Another two years later, the group took an even bigger risk: “Patients were treated with two drugs to send them into complete remission. Then half the group received several months of additional drugs, while the other group was given a placebo. Once again, the pattern was consistent. The more aggressively treated group had longer and more durable responses.” 

By 1962, the group was giving patients four chemotherapy drugs, often in succession. “… the compass of leukemia medicine pointed unfailingly in one direction… what if four antileukemia drugs could be given together – in combination, as with TB?” They knew resistance would be fierce. Their ward was already being called “a butcher shop… Even Zubrod could not convince the consortium to try it.”

An Early Victory

In the 1950s, a Chinese nationalist (Li) at the NCI was experimenting with choriocarcinoma, a cancer of the placenta. He seemed interested in research, although he was apparently just lying low until the Korean War ended. To stay out of the war, he managed to get an assignment as an “assistant obstetrician.” Watching pregnant patients bleed to death in hours from metastatic choriocarcinoma, Li immediately thought of the antifolates used against leukemia. He and his team tried antifolates on a profusely bleeding choriocarcinoma patient and were surprised to find her still alive, with bleeding abated, the next morning. Four doses later they were absolutely stunned to discover the tumor had disappeared! The hormone secreted by the cancer cells plummeted toward (but not at) zero. “A metastatic, solid cancer had vanished with chemotherapy.”

In subsequent trials, it took dose after dose of additional chemotherapy to finally get the measurable hormone all the way to zero. The board was furious at Li, who was perceived as “poisoning” women “cured of cancer,” giving them “unpredictable doses of highly toxic drugs” when their tumors were already invisible. Li was fired, accused of “experimenting on people.”

Members of Zubrod’s group acknowledged that all of them had been, in a certain sense, experimenting. Eventually Li was proven correct: Patients who had stopped the drug early began to relapse, while Li’s patients remained free of disease for even months after the methotrexate had been stopped. He had demonstrated that “cancer needed to be systematically treated long after every visible sign of it had vanished.” Years later, it was discovered that Li’s patients would never relapse. “This strategy – which cost Min Chiu Li his job – resulted in the first chemotherapeutic cure of cancer in adults.”

Mice and Men

Freireich pointed out that even a week’s delay of treatment could mean the difference between the life and death of a child. “At the rate the leukemia consortium was moving, he argued, it would take dozens of years before any advance in leukemia was made.” In contrast, Zubrod’s strategy called for “sequential, systematic, and objective trials.” And then, in 1960, yet another new anticancer agent was introduced: vincristine. In small doses it was found to kill leukemia cells, and now researchers faced “the paradox of excess,” with methotrexate, prednisone, 6-MP, and vincristine all available to be put together into an effective regimen. The goal? To find the regimen that would kill the leukemia but not the child. It could take years to find the right combination and schedule.

Enter: Howard Skipper, a researcher from Alabama. He worked with mice, injecting them with leukemia he’d grown in a petri dish. Within a mouse, the cells divided over and over again “in a terrifying arc of numbers.” In sixteen or seventeen days, leukemia in a mouse could grow from one cell to a billion, outnumbering all the blood cells in a normal mouse. His work offered two important new insights: 1) Treating cancer is an iterative process which must be repeated over and over. Why? Because each treatment killed a certain percentage of cancer cells. The next treatment killed the same percentage of what remained. Offer enough iterative treatments, and you bring the surviving cancer cells to zero. 2) Using drugs in combination dramatically reduced resistance mechanisms. “With several drugs and several iterative rounds of chemotherapy in rapid-fire succession, Skipper cured leukemias in his mouse model.”

For Frei and Freireich, the prospect of treating a human child with such a regimen was terrifying. But they committed to trying it, combining vincristine, amethopterin, mercaptopurine, and prednisone. They called it VAMP. 

VAMP

Their colleagues were stunned. Zubrod was stunned. He viewed all medicines as poisons to be given only in the appropriate dose. “But chemotherapy was poison even at the correct dose… the threshold between a therapeutic (cancer-killing) dose and a toxic dose was extremely narrow.” Could a child survive even the first dose, let alone additional doses, week after week? Farber and others wanted to try one drug at a time and add the second only after relapse. Freireich recalled, “We were laughed at and then called insane, incompetent and cruel.” The leukemia consortium refused to sponsor VAMP. Frei resigned as the chair of the ALGB so he and Freireich could attempt their risky experiment independently.

The VAMP trial launched in 1961, with children already “terribly, terribly ill… by the end of the week, many of them were even worse than before.” Freireich admitted “it was a disaster.” Children went into coma, were put on respirators, and nearly died. Freireich hovered over his subjects, giving them aspirin or a blanket. The reputation of the NCI was also at stake.

Three weeks later a few patients pulled through. And then “the normal bone marrow cells began to recover gradually, but the leukemia went into remission.” Red and white blood cells began to appear, but the leukemia did not return. Weeks later, not a single leukemia cell was visible under the microscope. A few weeks later, the NCI tried the regimen on another set of patients. Again the subjects first experienced a nearly catastrophic dip in counts, and then the success was repeated. 

By 1962, only a handful of patients had been treated, but “remissions were reliable and durable… Critics were slowly turning into converts.” Other clinics tried the VAMP regimen. Quickly oncologists developed a mood of “aggressive optimism. The optimism was potent but short-lived. Within weeks children began to return to the clinic with minor complaints like headaches, a seizure, a tingling facial nerve. Frei and Freireich withdrew spinal fluid from the children and what they discovered “left them cold.” Leukemia cells were growing explosively, by the millions, colonizing the brain. All the children returned, with no leukemia cells in the bone marrow, but in each one, leukemia had invaded the nervous system.

“It was a consequence of the body’s own defense system subverting cancer treatment.” The ancient blood-brain barrier the human body had developed to keep poisons from reaching the brain kept VAMP out of the nervous system – “the one place that is fundamentally unreachable by chemotherapy. The children died one after the other…”

The failure pushed morale at the NCI to the breaking point. “In the winter of 1963, Frei left for a position at the MD Anderson Cancer Center in Houston, Texas.” Freireich soon joined him in Houston. But it is more the heroism of patients than the heroism of doctors that matters. Actually, just a few of the children did not relapse and die. About five percent lived for a full year and even remained in remission for years. They returned year after year, as they grew and matured, with never a visible sign of cancer.

The author, Dr. Mukherjee, visited one of those patients, Ella, in Maine 45 years later. She was treated with VAMP at the age of 11 and suffered severe collateral nerve damage. She became addicted to morphine and “detoxed herself by sheer force of will… Yet, remarkably, the main thing she remembers is the overwhelming feeling of being spared.” 

“Sidney Farber never met Ella, but he encountered patients just like her – long-term survivors of VAMP.” Farber testified before Congress about the successes, seeking more money, research and publicity to push toward a cure for all cancers.

An Anatomist’s Tumor

[Here the author relates the story of a 24-year-old athlete who discovers a lump in his neck that turns out to be Hodgkin’s lymphoma. Then he takes us to the Dana-Farber Cancer Center, affectionately called “the Farber,” of 2004: “a sprawling sixteen-story labyrinth… 2,934 employees,” a lab with clinic and conference rooms, dozens of pharmacies, scores of laboratories and libraries.]

“Wandering through these labs and clinics, you often felt as if you could stumble onto cancer history at any minute. One morning I did: bolting to catch the elevator, I ran headlong into an old man in a wheelchair whom I first took to be a patient. It was Tom Frei, a professor emeritus now, heading up to his office on the sixteenth floor.” 

[Now the author tells about his patient at the Farber Center, the day after he saw the 24-year-old athlete mentioned above. This is a 76-year-old woman weighing 85 pounds, a former U.S. Marine who served in two wars. She has pancreatic cancer, and they have exhausted all treatment possibilities. They are at the end of the road.]

“Two lumps seen on two different mornings. Two vastly different incarnations of cancer: one almost certainly curable, the second, an inevitable spiral into death.” He felt that medicine had not progressed beyond Hippocrates with his naïve term of “karkinos.” In the 1960s, “oncology was on a quest for cohesive truths – a ‘universal cure,’ as Farber put it in 1962.” They had imagined a common disease called cancer, and the cure of one form would surely lead to the cure of all the others. It had helped them envision a systematic, targeted war.”

Hodgkin’s lymphoma is a more recent form of cancer, discovered by an English Quaker, Thomas Hodgkin. His story is quite unusual, including his role in a dispute over “brains, hearts, stomachs and skeletons in pickling jars of formalin that had been hoarded for use as teaching tools” when a London hospital “divorced” into two. Hodgkin was recruited to collect specimens for one of them, called Guy’s Hospital, where he became “the Curator of the Museum and the Inspector of the Dead… Hodgkin’s genius came in organizing” the specimens, like a librarian. His work is still on display, although he was born in 1789. It represents the first attempt to organize preserved organs “by organ system rather than by date or disease.” Such an approach gave Hodgkin a new perspective on patterns within the human body. 

In 1832, Hodgkin announced that he’d collected several cadavers of young men who all “possessed a strange systemic disease… ‘a peculiar enlargement of lymph glands.’” Convinced they were not byproducts of tuberculosis or syphilis, he published a paper on his discovery. It garnered little attention. Realizing he had failed to offer any treatment options, he began to drift away from medicine. By 1844 “his anatomical studies slowly came to a halt.”

“In 1898, some thirty years after Hodgkin’s death, an Austrian pathologist, Carl Sternberg,” discovered giant glands within the “forests of the lymph” that looked like “owl eyes… malignant lymphocytes… lymph cells that had turned cancerous. Hodgkin’s disease was a cancer of the lymph glands – a lymphoma.” What Hodgkin had discovered, by focusing strictly on anatomy, was a localized cancer that moved “with a measured, ordered pace, from one contiguous node to another.” So, Farber had sought the bridge between liquid and solid tumors, and Hodgkin had explored another strange border: “a local disease on the verge of transforming into a systemic one.”

In the 1950s, more than 150 years after Hodgkin’s birth, a Stanford professor of radiology, Henry Kaplan, learned of the development of a “linear accelerator,” called a linac, that would fill electrons with massive amounts of energy to not only “pass through tissue, but to scald cells to death.” He got one for the Stanford hospital in 1956 and “could now direct tiny, controlled doses of a furiously potent beam of X-rays… on local sites… the most natural target for his investigation: Hodgkin’s disease.” Kaplan became the “most dogged… methodical… single-minded” doctor to treat Hodgkin’s with X-rays.

Kaplan was confident such treatment could provide relapse-free survival and, in 1962, challenged by a student, he set out to prove it. First he established that “extended field radiation – ‘meticulous radiotherapy’ – diminished the relapse rate,” but that was not a cure. Two years later, conducting trials only of patients with locally confined disease, he used radiation levels that were “daringly high.” The first batch of patients survived five years without relapse. Why the success? Patients were all in early-stage disease, and Hodgkin’s is a regional illness: His treatment fit the disease. “The meticulous matching of a particular therapy to a particular form and stage of cancer would eventually be given its due merit… the same treatment could not indiscriminately be applied to all.” But, Mukherjee concludes, “it would take decades for oncologists to come to the same realization.”

An Army on the March

In 1963, Tom Frei was found scribbling a long list of cancers along with chemicals from three sources, but the chemicals “were all rather indiscriminate inhibitors of cellular growth…” – the makings of cytotoxic chemotherapy. The author reminds us that, in the 1960s, “the fundamental biology of cancer was so poorly understood that defining such [specific] molecular targets was virtually inconceivable.” Frei and Zubrod decided to retrace their steps with leukemia, this time with a solid tumor. They “focused on Hodgkin’s disease – a cancer that lived on the ill-defined cusp between solid and liquid.”

They had been joined at NCI by Vincent DeVita, who set out in 1964 to prove the skeptics wrong: He meant to show that, with the right drugs, you could actually cure cancer. He used a new drug cocktail called MOPP, and he focused on young men and women in their twenties and thirties with Hodgkin’s disease, a group that had been called “hopeless cases.” He found 43 such patients and treated their disease with MOPP for six months. Now the new terror became “death by nausea.” Some subjects also became sterile, and peculiar infections sprang up. Nearly a decade later, a horrifying new side effect showed up: relapse with “an aggressive, drug-resistant leukemia.” Cytotoxic chemotherapy turned out to be both cancer-curing and cancer-causing. 

But there was “a payoff.” The swollen lymph nodes dissolved in weeks. “… combination chemotherapy had struck gold once again. At the end of half a year, thirty-five of the forty-three patients had achieved a complete remission.”

Still, cancer research was “at a strange and bleak point.” Reflecting on the VAMP trial, “combination chemo had cured most of the children of leukemia in their blood and bone marrow, but the cancer had explosively relapsed in the brain… Of the fifteen patients treated on the initial protocol, only two still survived… But having tasted the success of high-dose chemotherapy, many oncologists could not scale back their optimism.” A Farber protégé, Donald Pinkel, age 36, was in “medically speaking, a virtual no-man’s land… called St. Jude” in Memphis. When he’d arrived in 1961, St. Jude was “barely functional, with ‘no track record, uncertain finances, an unfinished building, no employees or faculty.’” 

Pinkel “got a chemotherapy ward up and running” and “hammered away in trial after trial.” His work provided “four crucial innovations to the prior regimens”:

1. Drug combinations were good, but perhaps combinations of combinations were the secret to success.

2. If chemo could not breach the blood-brain barrier, perhaps it should be injected directly into the fluid of the spinal cord.

3. And maybe the addition of high-dose radiation to the skull would help to kill cancer cells in the brain.

4. Chemotherapy probably needed to stretch far beyond weeks, probably into months or even years.

Pinkel launched a trial with treatment lasting up to two and a half years and including multiple exposures to radiation. “Even at St. Jude’s, the regimen was considered so overwhelmingly toxic… the senior researchers, knowing its risks, did not want to run it. Pinkel called it ‘total therapy.’ As fellows, we called it ‘total hell.’”

“Pinkel’s team would run eight consecutive trials between 1968 and 1979, each adding another modification to the regimen… The Memphis team had treated thirty-one patients in all. Twenty-seven of them had attained a full remission… more than twenty times the longest remissions achieved by most of Farber’s first patients… thirteen patients, about a third of the original cohort, had never relapsed… Overall, 278 patients in eight consecutive trials had completed their courses of medicine… about one-fifth relapsed… 80 percent remained disease-free after chemotherapy.”

The Cart and the Horse

By 1968, “the burden of proof had begun to shift dramatically.” Both lymphoblastic leukemia and Hodgkin’s disease had been cured with high-dose chemotherapy. DeVita believed a revolution had been set in motion. He said that “effective chemotherapy for systemic cancers had been discovered.” It clearly had been a war. Now cancer was “recast as a monolithic entity. It was one disease.”

And what was the cause of cancer? Cancer scientists believed in “a theory called the somatic mutation hypothesis of cancer.” Environmental carcinogens such as soot or radium were suspected to somehow permanently alter the structure of the cell and thus cause cancer. What was missing, the author says, was a deeper, more fundamental theory for carcinogenesis.

Meanwhile, way back in 1910, a man named Rous was experimenting with chickens, injecting cancerous sarcomas from one chicken to another. He ultimately attempted, through finer and finer filtering, to remove the tiny particle that was apparently causing the tumor. Unable to do so, he surmised that it was a virus he was working with, “the only biological particle that had these properties… The causal agent for cancer, it seemed, had been found.” By 1940, while viruses seemed to cause cancer in mice and cats, there was “still no sign of a bona fide cancer virus in humans.”

In 1958, such a virus was discovered in malaria-ridden children in sub-Saharan Africa, ultimately called Epstein-Barr virus. “The grand total of cancer-causing viruses in humans now stood at one.” But viruses were “the new rage in medicine,” with infectious diseases like polio now preventable. The notion that a cure for cancer lay on the same path was “simply too seductive to resist.” Hysteria and fear began to grow. Was there a “cancer germ”?

“Farber turned into a particularly fervent believer…” and Farber was capable of generating enormous support. Peyton Rous, the chicken researcher mentioned above, having been overlooked for 55 years, won the Nobel Prize in 1966. In his speech, he flatly denied the possibility of cancer being caused by somatic or genetic cell mutation. He offered, instead, “a unifying hypothesis that viruses caused cancer… The somatic mutation theory of cancer was dead.”

The comprehensive “whole” that evolved – with no proof – put the cart before the horse: viruses causedcancer, and a particular combination of cytotoxic poisons would cure cancer. This two-part theory raised more questions than answers. What was the explanation that would connect cause and cure? All that was needed to find it, some thought in 1968, was funding. “By the summer of 1969, the cancer crusade had acquired… its prophet [Mary Lasker]…its prophecy [a cure for childhood leukemia]…its book” [Cure for Cancer, Garb, 1968]. “The final missing element was a revelation… It would appear, quite literally, from the heavens.”

“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… this was a moment of reckoning… ‘a shining reaffirmation of the optimistic premise that whatever man imagines he can bring to pass.’” [Time Magazine] It seemed the “moonwalk had turned out to be a cakewalk.” The Laskerites picked up on all the analogies between the moon landing and curing cancer. “Cancer, like the moon, was also a landscape of magnificent desolation… on the verge of discovery.” Mary Lasker referred to her project as the conquest of “inner space” as opposed to outer space. She and her team moved “from backstage political maneuvering to front-stage public mobilization.”

The Apollo 11 success also created a seismic shift in public perception of science. The Laskerites now referred to “a ‘moon shot’ for cancer.”

“A Moon Shot for Cancer”

In December 1969, both the Washington Post and the New York Times ran an open “letter” to President Nixon, suggesting he had the power to find the cure for cancer just as he had the power to put a man on the moon. Cancer was now a public issue, with 450 cancer articles in the New York Times in 1971 and the movies Love Story and Brian’s Song. 

“Every era casts illness in its own image… So it was with cancer… by the early 1970s, the locus of anxiety… had dramatically shifted from outside [the Cold War, bombs and warheads, invaders from outer space] to the inside… Cancer epitomized this internal horror… the enemy from within.” Death was now expected to come “not with a bang but with a tumor.”

In the past, the Laskerites had pleaded to the nation for funding; now they pleaded for the nation, and “the cure for cancer became incorporated into the very fabric of the American dream.” During the Nixon administration, though, neither science nor scientists enjoyed much favor with the government, called “nuts” and “bastards,” and, according to Nixon, “didn’t ‘know a goddam thing’ about the management of science.” He favored “scientific bureaucrats.”

In 1969 Mary Lasker succeeded in getting the administration to form a “Commission on the Conquest of Cancer,” and “there was nothing neutral about the commission.” Sidney Farber co-chaired. “Politics, science, medicine, and finance were thus melded together to craft a national response.” A “façade of neutrality” was attempted. In its first paper, one year later, the panel proposed the creation of an independent cancer agency, starting with a $400 million budget, increasing to one billion by mid-decade.

Senators Ted Kennedy and Jacob Javits co-sponsored the Conquest of Cancer Act in 1971; even the advice columnist, Ann Landers, was convinced to write on its behalf, her message being that the cure for cancer was being slowed, not just for medical reasons but for political reasons. Soon truckloads (literally) of mail began to arrive in Washington for the Senate – about a million letters. The Kennedy/Javits bill was amended and passed on July 7, 1971.

The fight to pass the bill in the House was much more challenging. A “Columbia University cancer scientist argued, ‘An all-out effort at this time would be like trying to land a man on the moon without knowing Newton’s laws of gravity.’” The man who had discovered the structure of DNA suggested that “relevant” research is not necessarily “good” research; he said he feared “a massive expansion of well-intended mediocrity.” Many respected scientists warned that the comparison between the conquest of cancer and the moon walk was poorly conceived.

By the end of the year, with the war in Vietnam raging and an election looming, Nixon was eager to sign. A version of the bill, modified in the House, passed almost unanimously. “For the Laskerites, the date marked a bittersweet vindication.” Now the money was committed, but scientists called the attack on cancer “premature.” Both Lasker and Farber withdrew. Their two-decade crusade “dissipated slowly… Scientists, too, withdrew…Science… was pushed to the peripheries of this battle.” The priority now would be on massive, intensively funded trials. Even without Farber and Lasker, the army was now on the march 

“The act, then, was an anomaly, designed explicitly to please all of its clients, but unable to satisfy any of them.” The Chicago Tribune explained that “a crash program can produce only one result: a crash.” On March 30, 1973, Sidney Farber died of cardiac arrest at his desk in the Jimmy Fund Building 

[In 2005, at the Dana-Farber Cancer Institute, the author analyzed the bone marrow results of Carla, the woman who had participated, as a child, in the earliest leukemia trials. He declared her “in full remission.”]

PART THREE: “WILL YOU TURN ME OUT IF I CAN’T GET BETTER?”

“In God we trust. All others [must] have data”

By 1973 (the year of Sidney Farber’s death) the war on cancer seemed to have devolved into the war withincancer, beginning at the very center of oncology. “Radical surgery” had become “superradical” and “ultraradical,” disfiguring and debilitating. Every piece of cancer, which was thought to be a “malevolent pinwheel” spreading “in ever-growing arcs,” must be surgically removed from the body. “The more a surgeon cut, the more he cured.”

But that was among the followers of Halsted, in or near Baltimore. In London, a young doctor named Geoffrey Keynes “was not so convinced.” In 1924, facing an emaciated 47-year-old breast cancer patient, he had chosen to forego radical surgery and implant radiation in her chest. He thus reduced the mass and was able to perform much less invasive surgery. For several years he replicated this success, mixing radiation with surgery. He and his colleagues had recurrence rates similar to those in New York or Baltimore. “… the centrifugal theory had to be reconsidered.”

In America, though, Keynes’s efforts were a joke. They called his breast cancer approach “the lumpectomy… a cartoon surgery.” Keynes went on to pioneer blood transfusions during World War I, and his “challenge to radical surgery was quietly buried.” Until 1953, when a Keynes colleague, young doctor Criles, whose father had also pioneered blood transfusion during World War I, heard a lecture in Cleveland about Keynes’s minimal breast surgery.

Father and son (Drs. Crile) were “quintessential surgical insiders” from whom surgical revolution might come. They were both steeped in Halstedian radical surgical tradition, but Crile Jr. was starting to have doubts. He began a thoughtful study of metastatic cancer, beginning to doubt the concept of the centrifugal, whirling movement of a tumor’s growth, since it clearly metastasized to distant organs also. For localized cancer, minimally invasive surgery could work. If already spread (e.g. beyond the breast) no amount of surgery would be effective. Crile gave up on the radical mastectomy and focused on what he called the “simple mastectomy.”

Within six years, he had stumbled upon the same truth Keynes had demonstrated. But he had no means to prove it, no set of statistical measures to show a negative result: “that radical surgery was no better than conventional surgery.” Such a measure of success actually had been invented back in 1928: “power… a measure of the ability of a test or trial to reject a hypothesis.” The problem? To be conclusive, a trial would have to include a convincing number of samples – 1000 on each side of the hypothesis rather than a half-dozen of each. And breast surgeons committed to the Halsted approach would simply not risk it. The “gospel of the surgical profession… was ideally arranged to resist change and to perpetuate orthodoxy.” No surgeons would participate in the trial. 

It was a Pennsylvania surgeon named Bernie Fisher, steeped in the Halstedian tradition but “with enough critical distance from Halsted to be able to challenge the discipline,” who turned the focus from the surgeon to the patient. And he had lost faith in the “centrifugal theory of cancer.” A new champion now entered the arena. By the late 1960s, political feminism was giving birth to medical feminism. Women – patients – began to refuse to submit to radical mastectomy. Rachel Carson, author of Silent Spring (and a friend of Dr. Crile) refused. Respected female authors spoke out against disfiguring, possibly unnecessary radical surgery.

 In 1967 Fisher became the chair of a new consortium to run large-scale trials in breast cancer: the National Surgical Adjuvant Breast and Bowel Project. Eighty years after Halsted had described the radical mastectomy, in 1971 it was to be put to the test of randomized data collection. It took ten years to collect the data. Dr. Fisher explained, “To get a woman to participate in a clinical trial where she was going to have her breast off or have her breast not taken off, that was a pretty difficult thing to do.”

American surgeons dug in their heels, so Canadian surgeons were added to the study. In 34 centers in the two countries, 1,765 patients were randomly assigned to one of three groups: radical mastectomy; simply mastectomy; surgery followed by radiation. The results were made public in 1981: the rates of recurrence, relapse, death and distant metastasis were identical among the three groups. “When radical surgery fell, an entire culture of surgery thus collapsed with it. The radical mastectomy is rarely, if ever, performed by surgeons today.”

“The Smiling Oncologist”

Meanwhile, also in the 1970s, chemotherapy stumbled onto a new beginning with the discovery of a drug called cisplatin, short for cis-platinum. Its molecular structure had been identified nearly 100 years earlier, but it had then been shelved as having no obvious human use. In 1965 a Michigan biophysicist discovered, accidentally, that cisplatin would chemically attack DNA, preventing cells from dividing and replicating.

In those days, cancer patients were housed in chemotherapy wards, places of despair. In 1973, a 22-year-old graduate student entered such a ward, having been diagnosed, two months after his marriage, with metastatic testicular cancer. Following an extensive surgery, knowing his expected survival rate was less than 5%, the young man submitted to the conventional drug cocktail of the day, shrinking to 106 pounds and despair. A young oncologist named Larry Einhorn suggested, as a last-ditch effort, this new chemical called cisplatin; he combined it with two other drugs. Within ten days the tumors in the man’s lungs had disappeared. By 1975, Einhorn had treated 20 patients similarly, with remarkable success. He “had cured a solid cancer by chemotherapy.” He admitted, “In my own naïve mind I thought this was the formula that we had been missing all the while.”

Of course, there was another twist: “Cisplatin… provoked an unremitting nausea… on average, patients treated with the drug vomited twelve times a day… Most patients had to be given intravenous fluids… Even today, nurses on oncology floors who tended to patients in the early 1980s… can vividly recall the violent jolts of nausea that suddenly descended on patients…” However, Cisplatin was “the epic chemotherapeutic product of the late 1970s, the quintessential example of how curing cancer involved pushing patients nearly to the brink of death.”

The drug-discovery effort was now well funded, and an empirical strategy was employed to find chemical “cancer killers… Chemicals thus came pouring out of the NCI’s cauldrons.” Curing cancer – especially curing solid tumors with chemicals from all kinds of sources – was “almost a given.” As the Vietnam War raged, young doctors avoided the draft by enrolling in the federal cancer research program at the NCI. “We were a charged place.” In 1979 it was confidently proclaimed that “there is no cancer that is not potentially curable.” The full coffers of the NCI supported “enormous, expensive, multi-institutional trials.”

By 1979 there were 20 “Cancer Centers” around the nation. “It was trial and error on a giant human scale.” Toxicity of trial drugs skyrocketed, and horrific complications followed. Still, “the efficacy of the drug regimen remained minimal… [a] pattern… repeated with tiresome regularity for many forms of cancer.” Survival was ultimately measured in months, not years. “… it took a fanatical form of zeal to refuse to recognize that this was far from a ‘cure.’” In the mid-80s, nearly six thousand articles were published on this frenzied expansion of chemotherapy, but not one reported a definitive cure of an advanced solid tumor using chemotherapy alone. The “smiling oncologist” now seemed fiercely parted from his patient.

“I get shivers as I read this in 2023, knowing now, 34 years later, that my own chemotherapy treatment would begin in 1989, just a few years after this era of ‘trial and error… horrific complications… frenzied expansion.’ This might be a case in which ignorance was bliss.”

— Lynn

Knowing the Enemy

Dissenting voices now arose: Unleashing barrels of poisons, with the hope that one might turn out to be the cure, would never work. The solution must come from the bottom up: “… one needed to begin by identifying [cancer’s] biological behavior, its genetic makeup, its unique vulnerabilities.” 

The strongest such voice came from a Harvard-trained urologist, not a biologist but a physiologist: Charles Huggins. He had no formal training in either urology or cancer, but he was a surgeon! His only surgical innovation was an apparatus to collect prostatic fluid from dog urine. His tests confirmed that testosterone kept prostate cells alive just as estrogen kept breast cells alive. Huggins’s goal was to study “the metabolism of testosterone and the prostate cell,” but he had two challenges: only dogs, lions and humans were known to develop prostate cancer; and his research was not related to dogs with prostate cancer. “… but then a question formed in his mind. If testosterone deprivation could shrink normal prostate cells, what might testosterone deprivation do to cancer cells?” 

Very little, one might assume, as cancer cells were “deranged” and “uninhibited.” But Huggins knew that a few forms of cancer still followed the rules: Some thyroid cancer, for example, continued to make thyroid hormone. And he found that prostate cancer cells still remembered their origin. When he removed the testicles of a dog with prostate cancer, the cancer could not flourish! Huggins found that “cancer could be fed and nurtured by our own bodies.” 

Now he wondered whether he might trick the body of a male with prostate cancer into thinking it was a female by suppressing testosterone. Such sex hormone research had been ongoing since 1929, resulting in an artificial estrogen called Premarin (made from horse’s urine in Montreal, its name derived from pregnant mare urine), meant to “cure menopause.” Might an injection of Premarin into a male stop the production of testosterone in a patient with prostate cancer? He called it “chemical castration,” and it worked beautifully – some men even experienced hot flashes! Patients relapsed after several months, but Huggins had “proved that hormonal manipulations could choke the growth of a hormone-dependent cancer.” Remission, therefore, does not necessarily require poison. 

The obvious next step was to try the concept on breast cancer. Way back in the 1890s, a Scottish surgeon named George Beatson had learned from shepherds that removal of cows’ ovaries made them unable to lactate and changed their udders. But estrogen had not yet been discovered. Still, Beatson removed the ovaries of three women with breast cancer. It made no sense to the medical community of his time, but “the breast tumors shrank dramatically.” Ultimately, when surgeons repeated the procedure, it was successful only two-thirds of the time. Physiologists at the turn of the century were mystified. 

Within 30 years, Premarin research had provided an explanation. Still, not all breast cancers responded to removal of the ovaries. Why? In 1968, a young chemist named Jensen discovered the elusive “estrogen receptor – the molecule responsible for binding estrogen and relaying its signal to the cell.” Then he discovered that some breast cancer cells also possessed this estrogen receptor, and some did not. So, if a breast cancer cell retained its hunger for estrogen, it might be killed by removal of the ovaries, shutting off the estrogen source. Conversely, estrogen-negative tumors “had rid themselves of both the receptor and the hormone dependence.” 

How to test the theory? Surgical removal of ovaries had “fallen out of fashion.” It caused severe side effects, including osteoporosis. Might one inhibit estrogen function using Huggins’s “chemical castration” route, though? Maybe, but “no synthetic ‘antiestrogen’ was in development.” And pursuing such a drug “was widely considered a waste of effort, money, and time.” Cytotoxic poisons still seemed the most promising route to a cancer cure. 

Meanwhile, in Great Britain, chemists had developed tamoxifen, intended to be a birth control pill. Designed to be a potent stimulator of estrogen, it “turned out to have exactly the opposite effect… it was an estrogen antagonist – thus considered a virtually useless drug.” So, useless for contraception, might tamoxifen be useful against estrogen-sensitive breast cancer?

The British chemists found a perfect partner to test that theory just down the road, a female oncologist and radiotherapist with “a ward full of women with advanced, metastatic breast cancer, many of them hurtling inexorably toward their death.” Her name was Mary Cole. In 1969 she gave tamoxifen tablets to 46 of her patients, expecting little. Ten patients had an immediate response: tumors shriveled. Lung, bone and lymph node metastases shrunk. Some relapsed, but “the proof of principle was historic. A drug designed to target a specific pathway in a cancer cell – not a cellular poison discovered empirically by trial and error – had successfully driven metastatic tumors into remission.”

In 1973, in Massachusetts, a biochemist named Craig Jordan brought the research full circle, investigating tumors that did and did not respond to tamoxifen. He marked the estrogen receptors in cancer cells, and he discovered their ability to bind tamoxifen, thus shutting off estrogen responsiveness and choking the cancer cell’s growth. Estrogen receptor negative cells were insensitive to the drug. “For the first time in the history of cancer, a drug, its target, and a cancer cell had been conjoined by a core molecular logic.”

Halsted’s Ashes

Now Mary Cole unwittingly came full circle with Halsted’s logic: could this chemical, successful on “diffusely metastatic and aggressive stage IV cancers… work even better on more localized, stage II breast cancers, cancers that had spread only to the regional lymph nodes”? Just as Halsted had reasoned that radical surgery, required to rid a body of well-established cancer, might prevent the ultimate spread of early breast cancer, Cole wondered about such an application of tamoxifen. 

Ten years earlier, a young oncologist at the NCI had already had such a thought. Paul Carbone realized that the researcher who had, long ago, treated women with methotrexate long after their placental tumors had vanished (Dr. Li), had been run out on a rail. Still, the concept of cleansing the body of residual tumor with chemotherapy had gained respectability, so he launched a small trial. Discovering that adding chemotherapy after surgery decreased the rate of breast cancer relapse, he named the concept “adjuvant chemotherapy” – helpful drug therapy. “It would eradicate microscopic deposits of cancer left behind after surgery… in essence, completing the Herculean cancer-cleansing task that Halsted had set for himself.”

But there was no interest in helping Carbone mount a large-scale trial. Surgeons had no use for chemotherapists in the mid-60s, and “surgeons largely dominated the field of breast cancer.” Newly diagnosed patients were referred directly to surgeons; Carbone could not recruit patients for a new trial. Finally, in 1972, NCI was visited by Italian oncologist Gianni Bonadonna. He was interested in the chemotherapy trials Carbone and others were conducting at NCI to treat advanced breast cancer – and he had a close friendship back home with the chief breast surgeon, Umberto Veronesi. The Italian team “proposed a large, randomized trial to study chemotherapy after breast surgery for early-stage breast cancer.” NCI contracted with them, and the first major battle of America’s War on Cancer was relocated to Europe.

By late 1973, Bonadonna “had randomized nearly four hundred women to the trial – half to no treatment and half to treatment with CMF.” No surgeon besides Veronesi showed interest. In 1975 Bonadonna was able to report that “Adjuvant chemotherapy had prevented breast cancer relapses in about one in every six treated women. The news was so unexpected that it was greeted by a stunned silence in the auditorium.”

And then the question: Might tamoxifen, the antiestrogen therapy, have the same effect, used as an adjuvant chemotherapy in women with localized ER-positive breast cancer after surgery? It was Bernie Fisher, the Pennsylvania surgeon who had demonstrated that localized surgery with or without follow-up chemotherapy could get the same result as radical surgery, who could not resist seeking the answer to that question. In 1977, he recruited 1,891 women with ER-positive breast cancer spread only to the axillary nodes, and he treated half with adjuvant tamoxifen and half without. “Treatment with tamoxifen after surgery reduced cancer relapse rates by nearly 50 percent.” Women over 50, the age most resistant to standard chemotherapy, did particularly well.

In 1985, Fisher repeated the trial, and “the effect of tamoxifen treatment was even more dramatic… Fisher had altered the biology of breast cancer after surgery using a targeted hormonal drug that had barely any significant side effects… Halsted’s fantasy of attacking early-stage cancers was reborn as adjuvant therapy. Ehrlich’s ‘magic bullet’ for cancer was reincarnated as antihormone therapy for breast and prostate cancer.”

“Just 4 years later, I myself was told that my breast tumor was ‘estrogen positive,’ and it had metastasized to the axillary nodes under my arm. My therapy included tamoxifen. I had absolutely no knowledge that the drug was such a recent discovery. The doctor prescribed tamoxifen for five years following the conclusion of chemotherapy. I took it religiously and, when the five years ended, I confessed that I was afraid to stop. He explained that no data existed for treatment beyond five years, but I could continue on the drug if I wished. I did just that for two more years, and finally I found the confidence to let it go. It was my final breast cancer treatment. ”

— Lynn

Those two approaches were not “cures.” They produced long remissions that lengthened survival, but many patients eventually relapsed. Resistant cancers sometimes returned after decades of remission. Still, lessons about cancer were learned:

1. Cancer was “enormously heterogeneous,” and the “heterogeneity was genetic… and anatomic.” Cancers were not alike.

2. One must know the cancer intimately before rushing to treat it. Separation into stages of progression, for example, was critical.

The hard truth was that no single drug would offer a dramatic benefit. People stopped expecting “home runs” and were beginning to appreciate “single or doubles.” Still, oncology was in the thrall of “one cause, one cure.” Adjuvant chemotherapy and hormonal chemotherapy seemed to signal something wonderful to come through a more aggressive attack. “Pumped up with confidence… oncologists pushed their patients… to the brink of disaster.”

[Dr. Mukherjee here relates his experience with his own patient, an elderly woman clearly too ill with widely metastasized cancer to withstand aggressive chemotherapy. He suggested a palliative drug, and the patient’s daughter, a physician, rebuked him and sought another oncologist. He says, “I do not know whether the elderly woman died from cancer or its cure.”]

And so, the centuries-old concept of “caring for patients” who couldn’t be cured again came into consideration by some. Palliative care had been considered “an admission of failure.” To palliate means to cloak, and it seemed an effort to cloak the symptoms rather than attacking the disease. If surgery could not alleviate the pain, it was reasoned, then perform surgery on the sensory pathways where the pain abides. More surgery!  

The “counter discipline” of palliative care got its start in Europe, although the word “care” was avoided, since it sounded too “soft.” A doctor named Cicely Saunders decided that, if oncologists would not bring themselves to provide care for their terminally ill patients, she would bring in psychiatrists, anesthesiologists, physical therapists and others to help patients “die painlessly and gracefully.” And, to remove those dying patients from the hospital wards, in 1967 she created hospice in London.

Back in the U.S., resistance to that palliative care concept continued for a decade. One American nurse explained that “doctors were allergic to the smell of death.” A patient’s death meant defeat. Finally “trials on pain and pain relief… toppled several dogmas about pain… Opiates, used liberally and compassionately on cancer patients, did not cause addiction.” Antinausea drugs improved the quality of lives. The U.S. saw its first hospice center in 1974; they could be found worldwide within a decade. Saunders said, “This is not merely the phase of defeat… its principles are fundamentally the same as those which underlie all other stages of care and treatment, although its rewards are different.” 

Counting Cancer

By 1985, assessment of progress in the War on Cancer had been buried in “an overwhelming excess of information… obsessively reported to the media… it had become nearly impossible to discern the trajectory of the field as a whole.” This movement had been underway since the Fortune article of 1937. A Harvard biologist named John Cairns wanted to “offer a bird’s-eye view,” questioning the efficacy of the “war” since 1971. He began with the state-by-state cancer registry in place since World War II, focusing on possible results of therapeutic advances since the 1950s.

Cairns identified and tracked such advances in three categories:

• “Curative” chemotherapy

• “Adjuvant” chemotherapy

• Screening strategies (e.g. Pap smears and mammograms)

Considering the positive results “generously,” Cairns estimated that 35,000 to 40,000 lives were being saved each year by these measures. And how many lives were being lost to cancer each year? About one million new cancer diagnoses were made each year among Americans, and about 500,000 Americans were dying from cancer each year. “… even with relatively liberal estimates about lives saved, less than one in twenty patients diagnosed with cancer in America, and less than one in ten of the total number of patients who would die of cancer, had benefited from the advances in therapy and screening.” 

The biologist was not surprised at this modest success. Reviewing the trajectory of many modern diseases such as malaria, cholera, typhus, tuberculosis and others, he concluded that death rates “have dwindled in the US because humankind has learned how to prevent these diseases… to put most of the effort into treatment is to deny all precedent.”

The question remained: Are there fewer people dying of cancer now, in 1985, than there were in 1975? Just a year later, two of Cairns’ Harvard colleagues published such a study in the New England Journal of Medicine. They began by rejecting the popular measure of changes in survival rates over time as subject to bias in interpretation. For example, a population that is, overall, older than another will have a higher cancer rate: “Old age inevitably drags cancer with it…” Therefore, “some means is needed to normalize two populations to the same standard.”

The Harvard researcher, Bailar, “used a particularly effective form of normalization called age-adjustment.” He “divided the population for every year into age cohorts – 20-29 years, 30-39 years… Cancer rates were adjusted accordingly. Once all the distributions were fitted into the same standard demographic, the populations could be studied and compared over time.”

The resulting article, by Bailar and Smith, “shook the world of oncology by its roots.” From 1962 to 1985, cancer-related death rates had increased by 8.7%, mostly due to increased smoking and resulting rates of lung cancer. Thus thirty-five years of intensive study of the treatment of cancer had done nothing to lower its death rate. Other than progress in successfully treating childhood leukemia and Hodgkin’s disease, the effort focused on improving treatment was judged “a qualified failure.”

Doctors called Bailar “a naysayer, a hector, a nihilist, a defeatist, a crank.” Responses included the allegation that oncologists were simply holding back, not using the most potent chemotherapy regimens possible. “But the obverse idea – that maximizing chemotherapy would maximize gains in survival – was also untested.” A different type of response, from a respected UCLA epidemiologist (Breslow), suggested that Bailar and Smith had oversimplified the measure of progress by focusing on age. For example, a child cured of cancer results in many more years of additional life than an old man or woman cured of cancer. Years of life saved might be a better measure, Breslow posited. From that perspective, we might actually be winning the war on cancer! Breslow simply wanted to demonstrate that any measurement in and of itself is subjective. Is the value of cancer research to be measured by “how many absolute lives were being saved or lost by cancer therapeutics”?

Breslow suggested that we start by questioning the notion of “worth itself: was the life extension of a five-year-old ‘worth’ more than the life extension of a sixty-year-old?” He reasoned that the appraisal of diseases depends on our self-appraisal. Bailar’s response noted that true prevention as a strategy “had been neglected by the NCI in its ever-manic pursuit of cures.” Prevention had been funded at only 20%, while 80% of funding went toward treatment strategies. “The institute did not even consider cancer prevention a core strength.” In fact, across the country, almost no time, effort or funding was being directed at cancer prevention. For decades there had been a frenzied pursuit of a cure, Ehrlich’s “magic bullet.”

PART FOUR: PREVENTION IS THE CURE

“Coffins of Black”

Way back in 1775 a British surgeon named Pott had found a link between the work of chimney sweeps and a certain type of scrotal cancer. Because it never showed up before puberty, it was assumed to be a venereal disease among a lowly, “dirty, consumptive, syphilitic, pox-ridden” population. Pott wasn’t buying it. He pushed himself toward an epidemiological perspective and eventually found “chimney soot lodged chronically in the skin” as the likely culprit. He didn’t know it, but he’d discovered a carcinogen. “Remove the carcinogen – and cancer would stop appearing.” 

In eighteenth-century England, though, chimney sweeps were the backbone of a land of factories, coal and chimneys, and young boys were apprenticed early as sweeps. But, late in that century, the movement to regulate the industry had begun. A 1788 law forbade boys under age eight from being apprenticed. In just over 50 years, the age had been raised to 16. In 1875, the use of “climbing boys” was forbidden. “…the man-made epidemic of scrotal cancer among sweeps vanished over several decades,” although Pott did not live to see it.

Even before Pott’s discovery of soot as a carcinogen, a London apothecary had claimed that “snuff – oral tobacco – could also cause lip, mouth and throat cancer.” Just like Pott, he “had drawn a conjectural line between a habit… an exposure… and a particular form of cancer.” His warning pamphlet, however, was “considered a farce” because he, himself, presented as a buffoon as much as an apothecary.

The warning ignored, in England “tobacco was rapidly escalating into a national addiction.” The New World of America grew tobacco easily, and England happily bought it. In about 1855, lacking a clay pipe to smoke his tobacco (or so the story goes), a Turkish soldier rolled it in paper and so invented the cigarette. Soon Russian, English and French soldiers were smoking their tobacco in paper, and they brought the habit back to their homelands. Of course the habit leapt across the ocean to America.

By 1900, “Americans were consuming 3.5 billion cigarettes and 6 billion cigars every year.” By 1953, average annual cigarette consumption in the U.S. was 3500 per person. Americans, Englishmen and Scotsmen averaged 10-20 cigarettes per day. The cigarette became a symbol – for some of rebellion, for others of rugged machismo or generational rift. It offered to the world a sense of “camaraderie, a sense of belonging, and the familiarity of habits. If cancer is the quintessential product of modernity, then so, too, is its principal preventable cause: tobacco.”

“It was precisely this rapid, viral ascendancy of tobacco that made its medical hazards virtually invisible.” When two rare, unusual occurrences overlap, we are likely to see a connection. Conversely, when four out of five men smoke (and soon women would be added to that statistic), such a risk factor for a disease “paradoxically begins to disappear into the white noise of the background.” One epidemiologist commented that, by the early 1940s, connecting smoking to cancer made about as much sense as connecting sitting to cancer. A surgeon who was asked whether tobacco smoking might cause cancer suggested that sure, maybe it did, and maybe nylon stockings caused cancer. The connection simply could not be seen, and tobacco “vanished from the view of preventive medicine.” By the time the link was made, lung cancer was in full epidemic mode.

The Emperor’s Nylon Stockings

In 1947, government statisticians in Britain recognized that “lung cancer morbidity had risen nearly fifteen-fold in the prior two decades.” The Medical Research Council was asked to convene a conference of experts to study this. It was “a lunatic comedy.” The “experts” blamed pollution of the atmosphere, fog, road tar, automobile exhaust and more – “every breathable form of toxin except cigarette smoke.”

So they charged an eminent biostatistician to do a “more systematic study,” but they gave him ridiculously minimal resources. He recruited a 36-year-old medical researcher who had never performed such a study.

At the same time in the US, a medical student named Ernst Wynder came across an unforgettable case, a 42-year-old man, a smoker, who had died of bronchogenic carcinoma. The link between smoking and lung cancer was staring him in the face. Back at medical school, he sought money for a study and was told it would be “futile… Since nothing had been proved there exists a reason why experimental work should be conducted along this line.” And then Wynder recruited an unlikely mentor: Evarts Graham of the “nylon stockings” comment. Graham didn’t believe in the connection between smoking and cancer either and “was rarely seen without a cigarette himself.” But he agreed to help, intending to disprove the link.

Their trial followed a simple methodology. They simply asked both a group of lung cancer patients and a control group about their history of smoking. When the report was presented, the audience of lung biology experts showed absolutely no interest. On both sides of the Atlantic, no one was interested. Most epidemiologists believed that such a relationship could be established only for infectious diseases. “Chronic, noninfectious diseases such as cancer and diabetes were too complex and too variable to be associated with single vectors or causes.” The possible link between tobacco and cancer “was dismissed as nonsense.”

The inexperienced British researcher, Richard Doll, himself a habitual smoker, “believed tobacco was unlikely to be the true culprit,” so his study touched on a wide net of possible associations. He and Hill asked their trial groups about proximity of gasworks to their homes, how often they ate fried fish, and other far-reaching questions; somewhere in the haystack was a throw-away question about smoking. In May of 1948, they’d conducted 156 interviews, and “only one solid and indisputable statistical association with lung cancer leapt out: cigarette smoking.” Doll himself became sufficiently alarmed that he gave up smoking in the middle of the survey.

The American researchers in St. Louis, Wynder and Graham, arrived at the same results at about the same time. The two studies, on two different continents, “had converged on almost precisely the same magnitude of risk – a testament to the strength of the association.” Had they both proved the link between smoking and lung cancer? They had “in fact, proved something rather different.” These were case-control studies, certainly capable about informing us of a potential link. But the tobacco risk was “viewed as if from a rear-view mirror, risk assessed backward.” Subtle biases can creep into such a study. For example, they might have “unconsciously probed lung cancer victims more aggressively about their smoking.” Doll and Hill had “estimated risk retrospectively.” Now, “could an epidemiologist watch a disease such as lung cancer develop from its moment of inception?”

In the early 1940s, an eccentric British geneticist names Edmund Ford had considered the value of prospective rather than retrospective study. He is the man who convinced young people to track wild moths in a field and mark their wings with a pen, ultimately, over a decade, watching evolution in action as the moths reproduced. Doll and Hill had followed this work. They wondered if humans could somehow be “marked” as smokers or nonsmokers and then followed, watching for “the precise relative risk of lung cancer among smokers versus nonsmokers.”

By 1951, when Doll and Hill were ready to tackle their prospective study, Britain had a centralized registry of all doctors. Every time a doctor in the registry died, the registrar recorded the cause of death. The registry became “a fortuitous laboratory” for the researchers. They mailed letters to 59,600 doctors, inquiring only about their smoking habits. 41,024 responded! Each time one of those doctors died, the researchers simply contacted the registrar about cause of death. “Deaths from lung cancer were tabulated for smokers versus nonsmokers.” Within 29 months, 789 deaths were reported from this group. “Thirty-six of these were attributed to lung cancer… all thirty-six of the deaths occurred in smokers… The trial… barely required elementary mathematics to prove its point.”

“A Thief in the Night”

They published their results in 1956, the year smoking in America had reached its peak at 45% of adults. Both the world wars had contributed to this phenomenon. “Cigarette sales had climbed to stratospheric heights… as tobacco-addicted soldiers returned to civilian life.” The cigarette industry poured hundreds of millions of dollars into advertising. In fact, it “transformed advertising,” designing specific ads for segmented groups, including doctors themselves. (“More doctors smoke Camels.”) “Medical journals routinely carried cigarette advertisements.” Free cigarettes were distributed at medical conferences! “By the early 1960s, the gross annual sale…peaked at nearly $5 billion” in the US. On average, Americans were consuming a cigarette every hour. 

“Public health organizations… were largely unperturbed” by reports of the tobacco-cancer link. The tobacco industry, however, suddenly began touting the benefit of “filters” on their cigarettes. They saw bad publicity looming, and the industry launched a counterattack. Industry leaders wrote a 600-word “open letter” to the public; “it would nearly rewrite the research on tobacco and cancer.” They claimed the research being reported had been performed on mice, not men – an absolute lie.

Next the tobacco industry began to “gnaw at science’s own self-doubt.” They actually pledged “aid and assistance to the research effort into all phases of tobacco use and health.” They implied that, if more research was needed, well, then, there’s still a lot of doubt. The tobacco lobby even formed a “research committee.” They chose as the leader one Clarence Cook Little, a “contrarian” who had been deposed as president of the American Society for the Control of Cancer. He was “opinionated, forceful, voluble,” and a geneticist by training. And he believed all diseases, including cancer, were hereditary. To him, “blaming cigarettes for lung cancer, then, was like blaming umbrellas for bringing the rain.” And he insisted that correlation could not be equated with cause.

Meanwhile, back in St. Louis, Evarts Graham had invented a smoking machine! It created a deposit of tarry black residue, which he distilled in acetone and painted on the skins of mice. (Now he was starting to experiment on mice.) But “the classic triad of association, isolation, retransmission would simply not suffice; what preventive medicine needed was its own understanding of ‘cause.’” Hill worked on that angle, coming up with eight additional features of the association between lung cancer and smoking: strong, consistent, specific, temporal, plausible, coherent, possessed a “biological gradient,” and behaved similarly in analogous situations. For example, the more one smoked in quantity, the greater the increased risk; the precise site where tobacco smoke enters the body is where the cancer appears, etc.

Hill then advanced the radical proposition that one could “infer causality” by using those criteria. And the more criteria that applied, the stronger the causality. He was mocked, but he had introduced “pragmatic clarity” into epidemiological research: “… the preponderance of small bits of evidence, rather than a single definitive experiment, clinched cause. 

In 1956 Evarts Graham suddenly fell ill. An X-ray revealed “a tumor clogging the upper bronchioles and both lungs riddled with hundreds of metastatic deposits of cancer.” His tumor was deemed “inoperable and hopeless.” He wrote in a note to a friend: “You know, I quit smoking more than five years ago, but the trouble is that I smoked for 50 years.” Days later he slipped into a coma and died at the age of 74. Per his request, his body was donated for medical research. But, three years before his death, he had written “a strikingly prescient essay,” including the allegation that medicine was “not powerful enough to restrict tobacco’s spread… the solution had to be political.”

“A Statement of Warning”

Seven years after Graham’s death, in 1963, a lung pathologist named Oscar Auerbach had completed 1,522 autopsies of smokers and nonsmokers in New Jersey. He’d begun with precancerous symptoms, finding “the lung contained layer upon layer of precancerous lesions, beginning in the bronchial airways.” The next stage, he found, were atypical cells “dividing furiously.” The final stage was “a frankly invasive carcinoma.” Cancer, he said, was “a disease unfolded slowly in time. It did not run, but rather slouched to its birth.”

Three members of a ten-member advisory committee appointed by the US Surgeon General, Luther Terry, visited Auerbach. Their mandate was “to review the evidence connecting smoking to lung cancer” for the Surgeon General, who had been urged by the nation’s three major medical associations to publicize the link but pose “no obvious threat to the freedom of the tobacco industry.” Given a tough assignment, Terry elected to “somehow leverage the heft of science to reignite the link between tobacco and cancer in the public eye.”

In the fifteen previous years, the conclusions of the Doll and Wynder studies had been “validated, confirmed, and reconfirmed.” After Terry convened his committee (co-incidentally five smokers and five nonsmokers), they spent 13 months visiting dozens of labs, reviewing “data, interviews, opinions, and testimonies.” They relied on biologists, chemists, physicians, mathematicians and epidemiologists, studying the cases of well over one million men and women. “Piece by piece, a highly incontrovertible and consistent picture emerged. The relationship between smoking and lung cancer… was one of the strongest in the history of cancer epidemiology – remarkably significant, remarkably conserved between diverse populations, remarkably durable over time, and remarkably reproducible in trial after trial.”

In early 1964, Luther Terry released “a leatherbound, 387-page ‘bombshell.’” In a nation obsessed with cancer, one might have expected a powerful immediate response. But, “ever since the spectacularly flawed attempts to regulate alcohol during Prohibition, Congress had conspicuously disabled the capacity of any federal agency to regulate an industry.” There was little Washington could or would do to regulate the tobacco industry. For example, the Federal Trade Commission, “a moribund, torpid entity, thinning in authority and long in the tooth,” was supposed to be regulating tobacco advertisements. A Minnesota congressman, therefore, suggested the FTC should investigate claims about the relative safety of filtered cigarettes. The “actual hearings that ensued were like a semiotic circus.”

Then came the Surgeon General’s report, referenced above. The FTC declared that all cigarette packages must bear this warning: “Caution: Cigarette Smoking Is Dangerous To Health. It May Cause Death From Cancer and Other Diseases.” The tobacco industry cleverly turned to Congress to save them from the FTC. “The industry had bribed politicians and funded campaigns so extensively over the years that negative political action was inconceivable.” In 1965, the FTC’s warning was officially changed to “Caution: Cigarette smoking may be hazardous to your health… most notably the words, cancer, cause, and death” were “expunged.” The Atlantic Monthly referred to “an unabashed act to protect private industry from government regulation,” asserting that “Congress had turned out to be ‘the best filter yet.’”

Now “an unregulatable industry had been brought to heel – even if partially so.” A young attorney, in 1966, wondered whether the “fairness doctrine” of 1949, mandating a fair division of media airtime on controversial issues, might apply to television’s representation of the tobacco industry and the dangers of smoking. He appealed to the Federal Communications Commission, which regulates the airwaves. It turns out the FCC’s general counsel had already been contemplating that; he supported the young lawyer’s cause, and it went to court.

Asked to support the case against big tobacco, both the American Cancer Society and the American Lung Association refused. In 1968, the case went to court, and the young lawyer, up against “the best-paid lawyers in the country,” won the case: anti-tobacco advertising must be given as much airtime as pro-tobacco advertising. The FCC enthusiastically announced that they would monitor that balance and “seek to ban cigarette commercials from television altogether.” The Supreme Court refused to hear appeal after appeal.

The tobacco industry immediately planned to sow doubt about the cancer link, but the anti-smoking lobby intended to sow fear about “the ultimate illness.” Within two years, the industry caved and withdrew all cigarette advertising from broadcast media. Soon the trajectory of tobacco consumption changed in America: “having risen unfailingly for nearly six decades, annual cigarette consumption in America plateaued at about four thousand cigarettes per capita.”

Over the next 15 years, case after case had been brought against cigarette makers by smokers who were ill; not a single case “resulted in a judgment against a tobacco company.” In 1983, a New Jersey attorney realized that the rationale was not simply that the smokers knew the risks and chose to smoke anyway. His point was that “what mattered was what cigarette makers knew, and how much of the cancer risk they had revealed to consumers…”  

The attorney, Marc Edell, won access to internal files of three cigarette manufacturers. He “unearthed a saga of epic perversity” that revealed attempts to quash internal research about the addictive nature of nicotine. He even found a statement from the Tobacco Research Institute suggesting that the tobacco industry might be considered a part of the pharmaceutical industry because its products “contain and deliver nicotine, a potent drug with a variety of physiological effects.” Yet pharmacological research found that smokers failed to quit because “nicotine subverted will itself.”

In the epic 1987 trial, as Edell cross-examined “cigarette industry mavens… Cover-ups were covered up with nonsensical statistics: lies concealed within other lies.” Ultimately, though, “the verdict was a terrible disappointment for Edell.” The jury found the victim, a female 40-year smoker who had died of lung cancer, 80% responsible for her own cancer. Only the maker of her pre-1968 cigarettes – before the mandated warning – was assigned any guilt at all. The victim’s husband was awarded $400,000. “If this was counted as a win, then, as the tobacco industry pointed out gleefully, it was the very definition of a Pyrrhic victory. 

That cancer victim, Rose Cipollone, was lampooned as a dim-witted addict – BUT, she also became “a heroic icon of a cancer victim battling her disease – even from the grave.” A flurry of court cases and tort suits followed the 1987 trial, and cigarette makers were “demonized, demoralized and devastated…increasingly beleaguered and increasingly the butt of blame and liability.”

By 1994 cigarette consumption in America had fallen steadily for 20 years, “a long, slow battle of attrition,” the result of “the cumulative force of scientific evidence, political pressure, and legal inventiveness.” However, the “lag time between tobacco exposure and lung cancer is nearly three decades,” and America’s lung cancer epidemic has continued, especially among women. 

Since the Cipollone trial, “tort lawsuits against tobacco companies have… grown into a deluge.” The Master Settlement Agreement (MSL) of 1998, signed by 46 states in agreement with four of the largest tobacco companies, “represents one of the largest liability settlements ever reached, and… the most public admission of collusion and guilt in the history of the tobacco industry.” Forty-plus cigarette manufacturing companies have since joined the agreement, which restricts cigarette advertising, disbands trade associations and lobby groups, provides access to internal research documents, and provides an avenue for public health education.

Should we consider that a success? No. “… the agreement likely creates yet another safe harbor for the tobacco industry,” giving the signatories a virtual monopoly and making “big tobacco” even “bigger tobacco.” Annual settlement payments have been woven into healthcare budgets, and “the real cost of the agreement is borne by addicted smokers who now pay more for cigarettes, and then pay with their lives.” Cigarette advertising has simply moved to other countries, particularly developing countries. China and India are now facing the same smoking-related lung cancer rates the US faced. And big tobacco has quietly made an agreement with Mexico to contribute to healthcare costs in return for reduced restrictions on warnings in advertising. They’ve had success also in Uzbekistan. The British Medical Journal describes it as “a catastrophe in the making… a vector that spreads death and disease throughout the world.”

[Mukherjee comments on the overwhelmingly addictive nature of tobacco use, including patients continuing to smoke surreptitiously during chemotherapy and patients begging for cigarettes immediately after their tumor removal surgeries.]

“Tobacco consumption continues relatively unfettered.” Smoking rates are on the rise again, and the public seems to have tuned out the anti-smoking campaign. While every new drug in America “is subjected to rigorous scrutiny… one of the most potent and common carcinogens known to humans can be freely bought and sold at every corner store…”

“Curiouser and curiouser”

Classifying tobacco as a carcinogen was a victory, but the potential for such victories cannot be assumed. In order to find a causal link, an epidemiologist “must know the questions to ask.” In the 1970s “a rare and fatal form of lung cancer called mesothelioma” was quite easily linked to asbestos because the sickness had a “statistical confluence” with insulation installers, firefighters, ship builders, and heating equipment handlers. The incidence of the cancer was quickly limited by tort litigation and federal oversight that limited exposure to asbestos.

Another victory emerged in 1971 when the daughters of diethylstilbestrol (DES) users were being diagnosed with vaginal and uterine cancer. Their mothers had used the synthetic estrogen to prevent premature delivery of those very daughters! The cancer skipped a generation, but doctors knew to ask about “estrogens.”

“But what if the behavior or exposure responsible for the cancer is completely unknown… Could cancers be discovered… by some intrinsic property of all carcinogens?” In the late 1960s, a Berkeley bacteriologist, Bruce Ames, studying mutations in Salmonella, discovered that a strain of the bacteria unable to grow in a petri dish could acquire a gene mutation that enabled growth – by six times, even by sixty times. So Ames tested thousands of chemicals “to create a catalog of chemicals that increased the mutation rate – mutagens.” He discovered that chemicals that are mutagens also tend to be carcinogens. He tested the effect of X-rays too; he “transformed the unobservable and immeasurable to the observable and measurable.” He discovered that carcinogens could be discovered experimentally.

Chemicals were not the only carcinogens. About the same time, a biologist named Blumberg discovered that inflammation caused by a virus could cause cancer! Blumberg was interested in studying human genes, but in the 1950s, “human genes had not even been seen or analyzed.” What Blumberg did find were “blood antigens that varied between individuals and were inherited in families.” He catalogued them, hoping to link blood antigens to human disease. “It was a curiously inverted approach, like scouring a dictionary for a word and then looking for a crossword puzzle into which that word might fit.”

By the early 1970s Blumberg’s lab had purified particles of a new virus which he called hepatitis B virus, or HBV. The Japanese had already learned the virus was transmitted from person to person via blood transfusion. If they screened for it in the blood, “the blood-borne infection could be blocked.” Soon scientists discovered that persons infected with HBV experienced a cycle of “injury and repair in liver cells,” which led to the realization that HBV was a carcinogen – a “live carcinogen, capable of being transmitted from one host to another… a genetic anthropologist… had found a highly prevalent virus associated with a highly prevalent human cancer.” How did it work? “The inflammation induced by the virus in the liver cells, and the associated cycle of death and repair, appeared to be responsible for the cancer.”

By 1979 a vaccine for HBV was developed, sharply reducing susceptibility to HBV. “Blumberg had made a critical link from cause to prevention. He had identified a viral carcinogen, found a method to detect it before transmission, then found a means to thwart transmission.” 

The next carcinogen discovered was a bacterium! An Australian gastroenterologist was investigating the cause of stomach flu, also in 1979, because it led to peptic ulcers, which led to stomach cancer. He’d been taught that bacteria do not grow in the stomach, but he wondered… He could see a “hazy, blue layer overlying the craterlike depressions in the ulcers… spiral organisms teeming within it,” but he could not isolate it or grow it or, therefore, show it to anyone.

A junior investigator in the hospital also tried to grow that bacterium in petri dishes, also with no luck. And then staff took a long Easter weekend and forgot to empty the incubator, and, when they returned: voila! “… translucent pearls of bacteria… The long incubation period had been critical.” It was something microbiologists had never described. But, would this bacterium “recreate the disease when introduced into a naïve host”? The two Aussies tried inoculating pigs with the bacterium; they achieved no results. In July 1984, the young fellow, Barry Marshall, decided to try it on himself! He fasted all day and drank about 50 ml of “cloudy brown liquid” made of meat broth and a “4-day culture plate” of the lab-grown bacterium.

Within a few days Marshall was violently ill, but he insisted his colleagues perform serial biopsies. And there it was: “highly active gastritis, with a dense overlay of bacteria in his stomach and ulcerating craters beneath – precisely what Warren had found in his patients.” The two published in the Medical Journal of Australia. And they created a potent multi-drug regimen to treat Marshall’s illness, which “eradicated his infection.”

The direct link to cancer, however, still eluded them. Successful strategies depend on a clear understanding of causes, “to know not only what the carcinogen is, but what the carcinogen does.” The list of known cancer-causing agents was growing, but it was getting “curiouser and curiouser.” The medical profession understood the cause of diabetes and coronary heart disease, but they hadn’t found “a unifying mechanistic description of cancer.” They knew only that all carcinogens caused “abnormal, dysregulated cell division.” They would need to “return to the birth of cancer… carcinogenesis.”

“A spider’s web”

Carcinogenesis is “the methodical, step-by-step progression of early-stage lesions of cancer into frankly malignant cells.” So, how about attacking precancer? Enter: George Papanicolaou, originally from Greece, in 1913. His first research assignment in the US was to study the menstrual cycle of guinea pigs; he learned to “foretell the precise stage of the menstrual cycle often down to the day.” By the late 1920s he was studying human females, and he found, as with the guinea pigs, “cells sloughed off by the human cervix could also foretell the stages of the menstrual cycle.” But, so what? Women had been timing their own periods for centuries.

So Papanicolaou began to look for pathological conditions with his smears. He began collecting exfoliated cells from women with fibroids, cysts, tubal pregnancies, abscesses, tumors and more, “hoping to find some pathological mark in the exfoliated cells.” And so he did. “In nearly every case of cervical cancer… he found ‘aberrant and bizarre forms’… that looked nothing like normal cells. He believed, in the smears he’d been conducting, that he’d stumbled onto “a new test for malignant cells.”

He called it the Pap smear, but it was “neither accurate nor particularly sensitive.” The more invasive and cumbersome biopsy of the cervix was still preferred, and Papanicolaou “for two decades… virtually disappeared from the scientific limelight.” But he “delved back into his smears with nearly monastic ferocity.” And “a decades-old thought returned…might cancer cells change morphologically in time, in a slow, stepwise dance… could he identify intermediate stages of cancer?” In the winter of 1950 he realized that the Pap smear “was not to find cancer, but rather to detect its antecedent, its precursor… A Pap smear would give a woman a chance to receive preventive care.” And so Papanicolaou was able to “push the diagnostic clock backward – from incurable, invasive cancers to curable, preinvasive malignancies.”

Papanicolaou convinced the National Cancer Institute to conduct the largest clinical trial of secondary prevention ever undertaken: 150,000 women were tested with Pap smears and followed over time. “Invasive cervical cancer was found in 555 women… astonishingly, 557 women were found to have preinvasive cancers or even precancerous changes.” The women diagnosed at the preinvasive/precancerous level were twenty years younger, on average, than women diagnosed with invasive lesions. The Pap smear had corroborated “the long march of carcinogenesis.” And this study “changed the spectrum of cervical cancer from predominantly incurable to predominantly curable.”

As early as 1913, a German surgeon had X-rayed nearly 3,000 amputated breasts after mastectomies “to detect the shadowy outlines of cancer.” His technique, which he called mammography, was rudely interrupted by the Nazis, and mammography “languished in neglect. It was hardly missed: in a world obsessed with radical surgery, since small or large masses in the breast were treated with precisely the same gargantuan operation, screening for small lesions made little sense.”

In the mid-1960s, “mammography reentered X-ray clinics in America.” It was, essentially, “a photographer… taking photographs of cancer using X-rays, the most penetrating form of light.” At that point, “mammograms could now detect tumors as small as a few millimeters, about the size of a grain of barley.”

“Screening trials in cancer are among the most slippery of all clinical trials” due to both the possibility of overdiagnosis and of underdiagnosis. “False positives” launch “the familiar cycle of anxiety and terror.” Conversely, underdiagnosis “falsely reassures the patient.” And “finding the exquisite balance is often impossible… merely detecting a small tumor is not sufficient. Cancer demonstrates a spectrum of behavior. Some tumors are inherently benign… some tumors are intrinsically aggressive.”

“Using survival as an end point for a screening test is flawed because early detection pushes the clock of diagnosis backward.” A test must “improve mortality, not survival… A screening test’s path to success is thus surprisingly long and narrow… ‘Survival,’ seductively simple, cannot be its end point… proving mortality benefit in a genuinely randomized setting with an acceptable over- and underdiagnosis rate – can be judged a success… few tests are powerful enough to withstand this level of scrutiny and truly provide benefit in cancer.”

In 1963, three American researchers set out to test “whether screening a large cohort of asymptomatic women using mammography would prevent mortality from breast cancer… they would need a randomized, prospective trial using mortality as an end point.” Postwar America had undergone a “sweeping wave of privatization,” resulting in the employer-sponsored, subscriber-based health insurance groups we’ve come to know. And women now made up one-third of the workforce. The forerunner of the HMO, then called HIP, had enrolled more than 300,000 subscribers, and nearly 80,000 of them were women. 

Here was “a defined – captive – cohort of women.” The researchers chose women between the ages of 40 and 64 and divided them into two simple groups: One group would be screened with mammography; the control group would not. It was “an instantly logistic nightmare,” using a mammography machine “the size of a full-grown bull” and small photographic plates and toxic chemicals in a dark room. So they outfitted a mobile van, parked it near the food trucks, and “began an obsessive campaign of recruitment.” With “machine-like precision” in their processes, the team was able to screen thousands of women a day. “The merry-go-round ran through the day and late into the evening.” In six years they “completed a screening that ordinarily would have taken two decades to complete.”=

If the mammogram detected a tumor, the woman was treated, generally with a radical mastectomy. Once the screening was complete, the team watched the results unfold over time. Eight years after launch, in 1971, Drs. Strax, Venet and Shapiro revealed the initial findings of their HIP study. “The absolute number of lives saved was admittedly modest, but the fractional reduction in mortality from screening – almost 40 percent – was remarkable.” Within five years, mammography had widespread application. Recognizing the parallel between mammography and the Pap smear, the American Cancer Society launched a huge campaign backed by Mary Lasker and “virtually every cancer organization in America.”

But doubts about this HIP study were gathering. The control group had not even been told of its participation in the trial. If one of them died of breast cancer, it was duly noted, but… What if some women already diagnosed with breast cancer might have entered the trial? Members of the screened group could be asked of their past medical history and pulled from the study; control group members were asked nothing and pulled anonymously only to keep the numbers even. It might have been a fatal statistical mistake. “Mammography enthusiasts were devastated.” And so they “overcompensated… mammographic trial-running had turned into an arms race, with each group trying to better the efforts of the others.”

Such trials were launched around the globe. “The Canadian trial… epitomized precision and attention to detail.” However, it turns out women in that trial were randomized after their medical history and examination, and “that minute change completely undid the trial… Women with abnormal breast or lymph node examinations were disproportionately assigned to the mammography group… The reasons for this skew are still unknown.” Was it compassion, attempting to get high-risk women screened? “At one center, a trial coordinator selectively herded her friends to the mammography group.” There were reports of widespread tampering with randomization.  

The medical research community learned a hard lesson, but “little else was clear.”  The Canadian study had done the opposite of the HIP researchers: While the latter selectively depleted the mammography group of high-risk patients, the former study selectively enriched the mammography group with high-risk women. Both were failures. 

This “stuttering legacy” finally came to an end in Sweden in the late 1970s in a sad, economically battered city called Malmo. “Migration in and out of the city had shrunk to an astonishingly low 2 percent for twenty years… a captive cohort… the ideal place to run a difficult trial.” Forty-two thousand women enrolled in the study. Half were screened yearly, and the other half were not; all have been followed closely ever since. “The experiment ran like clockwork,” in part because there was only one breast clinic in all of Malmo. 

The Malmo study results were reported in 1988: 588 women had been diagnosed with breast cancer in the screened group, and 447 in the control group. 129 women had died of breast cancer, total, from the two groups, “with no statistically significant difference overall. “But there was a pattern behind the deaths. When the groups were analyzed by age, women above fifty-five years had benefited from the screening, with a reduction in breast cancer by 20 percent. In younger women, in contrast, screening with mammography showed no detectable benefit.”

Scores of additional studies were undertaken over the next quarter-century and, in 2002, an exhaustive analysis of all the data was published. A total of 247,000 women had participated in the many trials, and “mammography had resulted in 20-30 percent reductions in breast cancer mortality for women aged fifty-five to seventy. But for women below fifty-five, the benefit was barely discernible.” It was determined that, although mammography saves the lives of some women with breast cancer, “the overwhelming proportion of women experience no benefit.”

“No matter how intensively we test mammography in this group of women [between forty and fifty], it will always be a poor screening tool.” As a visual species, we want to take a picture of cancer, assuming a large tumor is worse, and a smaller tumor is better. But “cancer confounds this simple rule.” True, finding and removing a premetastatic tumor can save the woman’s life, but “just because a tumor is small does not mean that it is premetastatic.” Tumors carry different genetic programs that make them behave differently. Consequences are both quantitative and qualitative, and a static picture cannot capture the latter. Mammograms and Pap smears detect cancer in its infancy, but they do not reveal its “inner being, its future, its behavior.”

So, how can we move from simply seeing cancer to understanding it? By the late 1980s, little progress had been made in understanding carcinogenesis: How do normal cells become cancer cells? Study of Hepatitis B taught us the role of inflammation. Mutagens demonstrated a link to carcinogenesis, but mutations in whichgenes, and what makes them mutate? At the end of the decade, “We were trying to combat cancer without understanding the cancer cell… like launching rockets without understanding the internal combustion engine.” [Bruce Chabner]

Not everyone agreed with that sentiment, and “the impatience to deploy a large-scale therapeutic attack on cancer grew to its bristling tipping point.” Oncologists believed that a poison is a poison – and one doesn’t need to understand cancer to poison it. Enter: a generation of radical chemotherapists. “If every dividing cell in the body needed to be obliterated to rid it of cancer, then so be it. It was a conviction that would draw oncology into its darkest hour.”

“Stamp”

[Mukherjee shares a story of a 36-year-old patient suffering hopelessly from esophageal cancer, calling February 2004 “my cruelest month… my task was to repossess imagination from death.” He sought to sustain hope for his patients without bloating it into delusion.]

“In his poignant memory of his mother’s illness, Susan Sontag’s son” relates the totally pessimistic, insensitive messages her doctor shared with her family as she fought her third cancer, caused by the high-dose chemotherapy she’d received for the other two. The doctor’s very approach was nearly fatal to Sontag. After several months, she found another doctor who “told her precisely the same information, without ever choking off the possibility of a miraculous remission. He moved her in succession from standard drugs to experimental drugs to palliative drugs… a graded movement toward reconciliation with death. 

Another doctor who inspired Mukherjee during his residency was Thomas Lynch, who approached a post-surgery 66-year-old woman who faced a “high risk of recurrence” with “resuscitation.” He “emphasized process over outcome” and kept the conversation light. When he mentioned the fifty or sixty percent chance of recurrence or metastasis related to her type of cancer, he added, “there are ways that we will tend to it when that happens.” Still, “he said ‘when,’ not ‘if.’’’ He focused on care, not cure. “He nudged and shaped [information] like glass in the hands of a glassblower.” To accept effective treatment, one must know the facts and also imagine success.

The mid and late 1980s were “extraordinarily cruel years” in cancer therapeutics. Surgical techniques soared to amazing heights – but still patients did not survive. Some chemotherapists wondered whether “one could tip the human body even closer to the brink of death with even higher doses of cytotoxic drugs… What if one could double, or even quadruple, the dosage of drugs?”

“Once again I find myself breathless as I read those words, knowing that it was ‘the late 1980s’ when I was diagnosed with and treated for breast cancer – during ‘extraordinarily cruel years.’”

— Lynn

“… it was the bone marrow’s sensitivity to cytotoxic drugs that had defined the outer horizon of chemotherapeutic dosage.” But, in the late 1960s, one E. Donnall Thomas “had shown that bone marrow… could be harvested from one patient and transplanted back” into the same or another patient. “Allogenic transplantation” involved replacing the cancer patient’s bone marrow with marrow taken from someone else. But there was a risk the new marrow would attack the host body, called graft-versus-host disease. Still, that therapy could be, for some patients, “an exquisitely potent therapeutic weapon against cancer.” In the initial trial, only twelve out of 100 patients had survived, but “at least some patients were eventually cured.” 

“Autologous bone marrow transplantation” involved removing the patient’s own marrow, freezing it, and then replacing it into the same patient after thawed. In between those two steps, the patient was given “blisteringly high levels of drugs.” By the early 1980s, Tom Frei, whom we met at the Farber Center some pages back, was convinced that “a megadose combination regimen, bolstered by marrow transplantation, was the only conceivable solution in cancer therapy.” He called it Solid Tumor Autologous Marrow Program: STAMP.

At the Farber Institute at that time, “volley after volley of trials were launched… with a grim, nearly athletic determination.” Frei found a young doctor from New York, William Peters, who became his staunch ally in promoting STAMP.  Frei “began to introduce the idea of megadose combination chemotherapy with autologous marrow support… yet the surer Frei became about megadose chemotherapy, the less sure some others around him seemed to get.” Some colleagues had noticed that some chemotherapeutic drugs severely damaged the marrow and even “precipitated a premalignant syndrome called myelodysplasia… that tended to progress to leukemia.” The Institute split into “bitterly opposing camps.” But, by late 1982, Peters had written a detailed protocol for the STAMP regimen.

The first patient to make history with STAMP was a thirty-year-old truck driver whose huge breast tumor had failed all conventional treatments. She was considered terminal. Peters began harvesting bone marrow from the patient’s hip, “leaving a hip pockmarked with red bruises.” A needle broke in the woman’s hip, and, after an hour of “pandemonium,” Peters managed to withdraw it with a pair of orthopedic pliers. “For Peters and Frei, it was an all-too-obvious metaphor for the rustiness and obsolescence of the status quo.”

Peters continued his trial, though, having begun with “hopeless cases” like the one described above. Word spread, and patients began to enroll before having exhausted other treatment options. In 1983 a 36-year-old woman with previously untreated metastatic breast cancer entered the program. She’d suffered for a year, having watched her own mother die of aggressive breast cancer. “She wanted the most aggressive therapy up front.” She learned about STAMP and entered “without hesitation.” After only seven days of treatment, with “a congregation of curious doctors” huddled around the display, her chest X-ray showed visibly shrunken metastatic deposits. Peters called it “the most beautiful remission you could have imagined. 

STAMP continued to enjoy success. “By the summer of 1984, the database of transplanted cases was large enough to begin to discern patterns.” Medical complications had been severe and numerous, but “the remissions produced by STAMP… had all been more durable than those produced by conventional chemotherapy.” But it was still only a guess; now they needed a randomized trial. Peters went to Duke University to set up a STAMP program where he could “run a trial in peace.”

Meanwhile, in March 1981, a team of doctors reported on eight cases of a highly unusual form of cancer in men called Kaposi’s sarcoma. All of the men were homosexual; one of them had an additional condition – a rare form of pneumonia that caused lesions on his head and back. “An outbreak of one obscure illness in a cluster of young men was already outlandish. The confluence of two suggested a deeper and darker aberration – not just a disease, but a syndrome.” The CDC was also taking note and marveling at “young, previously healthy men who had suddenly succumbed to PCP [the rare condition described above] with their immune systems on the verge of collapse.”

Was an epidemiological catastrophe forming out of thin air? Around the country, clusters of young men were falling ill to rare diseases, including Kaposi’s carcinoma; they were gay men suffering massive, near-total collapse of their immune systems. It was cruelly named by some “gay cancer.” In July 1982, the disease was officially named acquired immune-deficiency syndrome, or AIDS, but it was still far from understood. Susan Sontag herself was able to “observe the AIDS epidemic swirling through the streets.” She recognized its intersection with cancer, as patients of both diseases were “paralyzed and shrouded” by unfair, punitive metaphors.

“In the early days, among the first doctors to encounter and treat AIDS patients were oncologists… [facing] an explosive variant of indolent cancer that had appeared without warning on the bodies of young men.” The first clinic established to treat AIDS patients was in San Francisco, led by a dermatologist and an oncologist because, for the earliest patients, “AIDS was cancer.” The clinic was very much modeled on an oncology clinic. Many of the nurses were gay men; some returned later as patients themselves. And, “pitting their wits against a hostile, mysterious disease they couldn’t quite fathom… rules were unshackled and reinvented, creating a ward that came to resemble the unorthodox lives of the men who inhabited it.” Soon a political lobbyist effort grew, borrowing tactics from cancer lobbyists.

A doctor in Paris found an identical virus in lymph nodes from a young gay man with Kaposi’s sarcoma and in an African woman who had died of immune deficiency. He argued that AIDS was “an RNA virus that could convert its genes into DNA and lodge in the human genome.” In 1984, the same retrovirus was detected in an AIDS patient in the US at the National Cancer Institute. A few months later the discovery was confirmed in San Francisco. Health and Human Services heralded the discovery of a causal agent, suggesting a vaccine would be ready for testing in about two years. 

In 1987, a group of AIDS activists, “facing the lethal upswirl of the epidemic that was decimating their community,” transformed “the landscape of AIDS treatment using a kind of militant activism.” Their spokesperson called the epidemic “genocide by neglect.”

The FDA was accused of extremely slow drug testing. “… patients afflicted by a deadly illness needed drugs now.” Activists paraded through the streets, “burning paper effigies of FDA administrators… should other patients with terminal illnesses not also make similar demands?” Frustrated with the slow pace of drug approval, people wondered: “why should bodies with cancer be left without drugs?”

At that very moment, at Duke University, in an area that had barely been touched by the AIDS epidemic, “William Peters could not possibly have predicted that this very storm was about to turn south and beat its way to his door.” Things had gone well for Peters with his STAMP trials. He’d completed phase I, a safety study to see “whether STAMP could be safely administered.” The cancer community was enthusiastic and optimistic. Megadose chemotherapy with bone marrow transplantation was testing well. Still, Peters had a huge challenge getting the Cancer and Leukemia Group to sponsor a Phase III randomized trial; they finally agreed to do so.

The Map and the Parachute

“By the late 1980s, hospitals and, increasingly, private clinics offering marrow transplantation for breast cancer had sprouted up all around America, Great Britain, and France.” A prominent and successful transplant program thrived in South Africa. “At large academic centers… entire floors were refitted into transplant units… Transplanters, as one oncologist put it, ‘became gods at the hospitals.’”  

The procedure generally cost $50,000 to $400,000, but insurance companies, viewing it as still “investigational,” refused to cover it. However, AIDS activism had changed the landscape. Patients had lost patience waiting for endless trials and experimentation. Demonstrations in the streets and private fund-raising events soon evolved into lawsuits against insurance companies. The companies continued to cite “lack of clinical evidence.”

Meanwhile, that program in South Africa enjoyed huge success and drew praise from around the world. The doctor, Werner Bezwoda, announced, in 1992, “The dose-limiting barrier has been overcome.” He and his clinic realized “stratospheric fame.” Invited to deliver one lecture after another, he delivered “the most exhilarating observations in the world of clinical oncology.” In his Johannesburg clinic, “more than 90 percent of women treated with the megadose regimen had achieved a complete response.”

“I don’t know about the ‘megadose’ treatment, personally, but, in early 1990, I was offered an additional course of chemotherapy, the reasoning being that I had done so well in the regular course, and I was so young (40) and healthy, that I could withstand it. My doctor explained that he’d never before had a patient so appropriate for it; he’d learned it in his residency but never offered it to a patient since. I didn’t have to think twice. So, after completing my six months of weekly infusions, I began a 3-month regimen of different drugs, infused every three weeks. These drugs were nasty; the nurse and I could see the liquid moving through the vein in my lower arm, and that vein became bruised and tender. BUT, that might have been the additional treatment that made it all go away. After 33 years, I certainly don’t worry about a relapse. ”

— Lynn

Now the pressure was on health insurance companies. “High-dose chemotherapy could… hardly be considered an ‘investigational’ procedure if nearly every major clinical center in the nation was offering it to patients, both on and off trial. In 1993 alone, 1,177 papers in medical journals had been written on the subject.” Were insurance companies simply aiming to save money? In December 1993, the first significant court decision was made on behalf of the family of a woman who’d died of breast cancer at age 38: $89 million in damages. (The final settlement was “an undisclosed smaller amount.”) Insurance companies and HMOs quickly got the message.

Almost immediately, the Massachusetts legislature mandated insurance coverage for aggressive chemotherapy and marrow transplantation. But the medical community was not entirely ready for that, citing a “litany of complications” such as infections, blood clots, heart failure, permanent infertility and more, including the risk that 5 to 10 percent of the women would develop “a second cancer or precancerous lesion as a result of the treatment itself – cancers doggedly recalcitrant to any therapy.”

Autologous transplantation for cancer, having “exploded into a major enterprise,” its scientific evaluation now faced recalcitrance in patients! A woman wondered: Would she be assigned to the treatment group or the nontreatment group? As 40,000 women underwent the treatment in the US at a possible total cost of $4 billion during the 1990s, patient accrual for trials “nearly trickled to a halt.” Hospital wards were overcrowded with women seeking the treatment, but “the seminal measure to test the efficacy of that regimen was pushed aside.”

By 1999, a strange imbalance was noted at the annual cancer meeting in Atlanta: While Bezwoda reported an amazing cure rate of 60% in South Africa, Peters had to report that he hadn’t even been able to complete his trial at Duke University. “The news from Philadelphia was even more grim”: not a “hint of benefit, not ‘even a modest improvement.’” The Swedish team reported “no obvious survival benefit in sight.” When a panel of experts was asked by the American Society of Clinical Oncologists to discuss the subject, “even the experts threw up their hands… Nothing was resolved.” Oncologists left the Atlanta meeting “exasperated and confused. 

In December 1999, “a team of American investigators” asked Bezwoda if they could “travel to Johannesburg to examine the data from his trial… Bezwoda readily agreed.” They found, strangely, that, “of the 154 patients in his study… only 58 files” were made available, and they were “all, oddly, from the treatment arm of the trial.” Asked to see the files from the control arm of the trial, the investigators were told they had been “lost.” The records they did review “were remarkably shoddy… Criteria for eligibility for the trial were virtually always missing.” Although “Bezwoda had claimed to have transplanted equal numbers of black and white women… nearly all the records belonged to poor, barely literate black women.” No consent forms were found.

“No one, it seemed, had approved the procedure or possessed even the barest knowledge of the trial. Many of the patients counted as ‘alive’ had long been discharged to terminal-care facilities with advanced, fungating lesions of breast cancer, presumably to die, with no designated follow-up.” One patient record was even traced back to a man! “The whole thing was a fraud, an invention, a sham.” Bezwoda “resigned from his university position.”

This was “a terminal blow to the ambitions of megadose chemotherapy.” The final trial of STAMP, in the summer of 1999, showed “no discernible benefit.” Maggie Keswick Jencks, a Scottish landscape artist who lived her own breast cancer nightmare, wrote an essay about her cancer experience before her death in 1995. She said cancer was like “being woken up midflight on a jumbo jet and then thrown out with a parachute into a foreign landscape without a map… No road. No compass. No map… The white coats are far, far away… up there in the Jumbo, involved with parachutes, not map-making.”

“I do not share Jencks’ perspective. As a cancer patient in treatment for ten months during 1989 and 1990, having undergone both a lumpectomy and a lymphadenectomy followed by six weeks of radiation and nine months of chemotherapy, I always envisioned myself on the road to recovery and health. It was a long road and not easy, but I never felt helpless or lost. ”

— Lynn

“The War on Cancer was ‘lost’ – in both senses of the word.” In May 1997, the New England Journal of Medicine declared cancer “undefeated.” In fact, “between 1970 and 1994, cancer mortality had, if anything, increased slightly, about 6 percent… Admittedly the death rate had plateaued… but even so, this could hardly be construed as a victory.” A closer study of the data revealed that, “When cancer mortality between 1970 and 1994 was split into two age groups… in men and women above fifty-five, cancer mortality had increased, while in men and women under fifty-five, cancer had decreased by exactly the same proportion. 

Similar conclusions were reached when cancers were examined by type: “Death rates from colon cancer… had fallen by nearly 30 percent, and from cervical and uterine cancer by 20. Both diseases could be detected by screening tests (colonoscopy for colon cancer, and Pap smears for cervical cancer) and at least part of the decrease in mortality was likely the consequence of earlier detection.” Death rates for most childhood cancers had declined, as well as mortality from Hodgkin’s disease and testicular cancer. “Treatment had fundamentally altered the physiognomy of these diseases.”

In stark contrast was lung cancer, “still the single biggest killer among cancers, responsible for nearly one-fourth of all cancer deaths.” Although overall mortality for lung cancer had increased from 1970 to 1994… lung cancer mortality had dramatically risen in women, particularly older women, and it was still rising.” For women over 55, deaths “had increased by 400 percent.”

“The incidence of lung cancer was highest in those above fifty-five and was lower in men and women below fifty-five, a consequence of changes in smoking behavior since the 1950s. The decrease in cancer mortality in younger men and women had been perfectly offset by the increase in cancer mortality in older men and women.”

“No single strategy for prevention or cure had been a runaway success… An era of oncology was coming to a close… the field… was grappling with fundamental questions about cancer.” What did all cancers have in common, and what made each one (e.g. breast, lung, prostate cancer) different from the others? And so the questions turned “toward basic biology, toward fundamental mechanisms… We must at last return to the cancer cell.”

PART FIVE: “A DISTORTED VERSION OF OUR NORMAL SELVES”

“A unitary cause”

[Here Dr. Mukherjee again reflects on his personal experience in his oncology fellowship in 2005. He describes his own study of leukemia cells, “seeking a chemical that can kill leukemia cells but spare normal stem cells.” He notes that the cells he’s working with have already been studied for three decades. “That these cells are still growing with obscene fecundity is a testament to the terrifying power of the disease.”]

As far back as 1858, Virchow understood that cancer was “cellular hyperplasia… but he could not fathom its cause.” He suggested inflammation as a cause. “He was almost right.” Normal response to inflammation does make cells divide. However, “in cancer, the cell acquires autonomous proliferation.” The true disturbance is within the cell itself. 

While Virchow worked in Berlin, Walther Flemming was studying salamander eggs in Prague. He discovered, deep within the cell, a “blue, threadlike substance” which he called chromosomes, meaning “colored bodies.” He could confidently discern only two things about chromosomes:

• Cells from different species have a distinct number of chromosomes.

• As cells divide, chromosomes are duplicated, always maintaining a constant number.

Following the clues of both Virchow and Flemming, David Paul von Hansemann (former assistant to Virchow) made the next leap, examining cancer cells with a microscope: chromosomes in cancer cells were “markedly abnormal.” They had split and frayed, were disjointed, some broken and then rejoined, some in triplets and quadruplets. While other scientists continued to search for “parasites in cancer cells,” von Hansemann found that “the abnormality lay in the structure… in chromosomes… in the cancer itself.”

Now arose the question of which came first: Did altered chromosomes cause cancer, or did cancer alter chromosomes? He needed “an experiment to causally connect the two.” Enter: another Virchow former assistant, Theodor Boveri, studying eggs from sea urchins. Contrary to the laws of egg fertilization in most of the animal kingdom, Boveri managed to forcibly fertilize an egg with two sperms. It “precipitated chromosomal chaos.” He now had three chromosomes, a number that could not be divided evenly. He witnessed “frantic internal disarray” and concluded that chromosomes “must carry information vital for the proper development and growth of cells.” Boveri asserted that the “striking aberrations in chromosomes might be the cause of the pathological growth characteristic of cancer.” Still somewhat confused, he was confident he’d found the “unitary cause” of carcinoma to which Galen had referred so long ago: the disarray or chaos of chromosomes.

But there was a hard contradictory fact: Four years before Boveri published his discovery, Peyton Rous had discovered RSV, cancer in chickens caused by a virus! The two assertions of causal agent – chromosome or virus – were incompatible. “How could an internal structure, a chromosome, and an external infectious agent, a virus, both create cancer?” It turns out that “a viral cause for cancer seemed far more attractive and believable.” Many illness-causing viruses had been discovered over the previous two decades. Besides, an external, infectious causal agent seemed more likely able to lead to a cure than did a solution related to a mysterious internal problem. 

While understanding of cancer cells remained fuzzy in the early twentieth century, understanding of normal cells had grown to a “revolution.” In the early 1860s, Gregor Mendel, the Austrian monk who bred pea plants, had discovered the concept of inherited characteristics flowing from one generation to the next: flower color, seed texture, plant height, etc. Trying to intercross these characteristics, he was able to cause not a happy medium color, texture or height, but one trait dominant over the other. He could not fathom the internal mechanism of inheritance; it would be identified by botanists in 1909 as the gene! And, still, that was only a name – not an explanation. For half a century botanists wondered “in what corporal, physical form was a ‘gene’ – the particle of inheritance – carried inside the cell?”

In 1910, an embryologist at Columbia University, Thomas Hunt, found the answer as he bred fruit flies. While he could cause certain traits, such as eye color or wing pattern, to be transmitted from generation to generation, he noted that “an occasional rare trait was linked to the gender of the fly: white eyes were found only in male flies.” Morgan knew sex was linked to chromosomes. Therefore genes must be carried on chromosomes. So, if chromosomal abnormalities caused dysfunction, “abnormal genes must have been responsible for this dysfunction.” He’d discovered that genes are borne on chromosomes.

Mendel had found that genes move from generation to generation; Morgan proved that genes were carried on chromosomes. In 1926, a bacteriologist named Avery discovered that genes could be transmitted laterally, from one organism to another. Then he discovered such a gene could be transmitted even from dead, inert bacteria. But how? Finally, in 1944, Avery and his team reported that one chemical carried genes: deoxyribonucleic acid, or DNA! It was “the central conveyor of genetic information between cells.” So, the genes were physically carried within chromosomes, but their chemical composition was DNA.

That begged the question: What goes on inside a cell? What does a gene do, and how does it do it? One of Morgan’s students, George Beadle, found the answer in slime mold: macromolecules, the “workhorses” of the cells, the instructions for building proteins. It was proteins that performed most cellular functions by “creating minuscule circuits inside the cell responsible for coordinating the life cycle of the cell.” Finally, in the late 1950s, an intermediary step was discovered: Genes build proteins from ribonucleic acid, or RNA, “the working copy of the genetic blueprint.” So, for example, eye color in a fly is transmitted from generation to generation, as cells divide, making a family of red-eyed flies. DNA flows to RNA which flows to protein – in all living organisms. It’s called “the ‘central dogma’ of molecular biology.”

So how did that inform the study of cancer? Not well, “except in two tantalizing instances.” Even in the nineteenth century, physicians had found that some cancers “run in families.” Still, that in itself did not prove a hereditary cause. A young boy in Brazil in 1872 was found to have retinoblastoma, cancer of the eye. His eye was removed, and he survived, grew up, married and had children. Two of them also developed retinoblastoma in their eyes and died. 

Several decades later, Morgan, the fruit fly breeder, “noticed that mutant flies occasionally appeared within his flock.” An enormous flock with normal wings, for example, might give birth to a “monster” with strange wings, a mutation the monster could pass on to his progeny. “But what caused the mutations?” One of Morgan’s students made quite a discovery: Bombarding flies with X-rays, he could produce hundreds of mutant flies very quickly. Now, radiation was known to cause cancer. “Recall Marie Curie’s leukemia, and the tongue cancers of radium-watch makers… Could cancer be a disease of mutations? And since mutations were changes in genes, could genetic alterations be the ‘unitary cause’ of cancer?”

Alas, Muller and Morgan, student and mentor, “became pitted and embittered rivals,” and so they failed to work together to achieve the next step. Even when Morgan received the Nobel Prize in Physiology or Medicine, he was convinced that genetics had not made a significant or meaningful contribution to medicine. “Pathological mitosis [cell division that results in two daughter cells each having the same number and kind of chromosomes as the parent] was visible in cancerous tissue.” But no one had answered the key question: Why does such an exquisitely regulated process abruptly turn to chaos? Scientists had seen the similarities from organism to organism, but it was much more difficult to extend that blueprint to human diseases. Fruit fly monsters did not resemble human afflictions. And doctors and geneticists weren’t about to collaborate on it. Only fifty years later would we return to “the true ‘unitary’ cause of cancer.

Under the Lamps of Viruses

Early biological experiments had to focus on the simplest model organisms – fruit flies, sea urchins, slime mold. Despite research confirming that X-rays, soot, cigarette smoke and asbestos were risk factors for cancer, and even recalling the Brazilian family that seemed to carry retinoblastoma in its genes, it was very difficult to manipulate cancer in the experimental environment – except for that virus that caused cancer in chickens! Now the Rous virus and RSV “stood center stage, occupying all the limelight.” And Peyton Rous was “bulldoggish, persuasive, and inflexible.” He felt viruses were the only real answer. 

By the early 1950s, three camps were feuding about the cause of cancer, and none of them had the data or the “exquisite experimental insights” to prove they were right:

• The virologists, led by Rous – but no such virus had been found in human studies

• The epidemiologists, led by Doll and Hill – but they couldn’t show the link between exogenous chemicals and cancer

• The geneticists, led by Boveri’s successors – but with no human data or experimental insight

Was the cause of cancer an infectious agent? An exogenous chemical? An internal gene? “How could three groups of scientists have examined the same elephant and returned with such radically variant opinions about its essential anatomy?”

In 1956, a “restless and imaginative” young virologist named Howard Temin began to study fruit flies in California. Quickly bored, he turned to the Rous sarcoma virus in chickens, hoping to discover “how the virus converted normal cells into cancer cells.” But he needed to simplify the work – no actual chickens or tumors. He sought a process “analogous to bacteria in a petri dish,” and so he “added Rous sarcoma virus to a layer of normal cells in a petri dish.” He watched the cells grow uncontrollably, to his mind, “cancer distilled into its essential, elemental form… [he] believed that the cell, and its interaction with the virus, had all the biological components necessary to drive the malignant process.” 

Now Temin could experiment with cancer-in-a-dish instead of with whole animals. And he discovered that, unlike other viruses that produce more viruses but do not directly affect genetic makeup (DNA), Rous sarcoma virus did just that! Having infected the cells, it “had physically attached itself to the cell’s DNA and thereby altered the cell’s genetic makeup, its genome.”

Temin knew that some viruses, including Rous sarcoma virus, are carried in the RNA, not the DNA. So, “how could a copy of its genes convert into DNA?” That violated the central dogma of molecular biology! The street from DNA to RNA proteins was supposed to be a one-way street. He “made a leap of faith: if the data did not fit the dogma, then the dogma – not the data – needed to be changed.” He postulated that the virus (or infected cell) had the capacity of “reverse transcription.” It earned him “little but ridicule and grief.”

And so, in 1960, Temin relocated his lab to Madison, Wisconsin. “Standing unknowingly at the edge of a molecular revolution, he wanted silence.” He planned his experiments as he walked through the snow. “RNA to DNA. Even the thought made him shiver.” This molecule would “turn back the relentless forward flow of biological information.” He hired a Japanese postdoc student to purify this enzyme from virus-infected cells; the student “was a catastrophe” – until he was moved to a project that called on his skills as a gifted chemist. He accomplished the job overnight, and Temin had his proof. They could “see” the RNA “creating a DNA copy – reversing transcription.” It wrote genetic information backward: a retrovirus!

At the same time, in Boston, one of Temin’s former science camp students was working on the very same experiment with a different virus.

In May 1970, Temin presented his findings in a 15-minute presentation at the Tenth Annual Cancer Congress. “… there was an awestruck silence” as he systematically dismantled one of the fundamental principles of biology: “RNA could generate DNA. A cancer-causing virus’s genome could become a physical part of a cell’s genes.” The next day his former student called him, and they confirmed that each had found the same enzyme in different viruses. Both reports were published in the same issue of Nature magazine that summer. Together they demonstrated to the world the life of a retrovirus, whose genes “exist as RNA outside cells.” When they infect a cell, they make a DNA copy of self and attach it to the cell’s genes. Now the retrovirus has created a provirus, and RNA becomes DNA becomes RNA becomes DNA… “ad infinitum.”

Cancer scientists embraced the discovery; clinical oncologists ignored it, demonstrating the “virtually insurmountable segregation between cancer therapy and cancer science.” On one side: cause; on the other side: cure. One virologist from Columbia University, however, “built a monumental theory out of it.” It was “fiercely logical.” The virologist, Sol Spiegelman, was now convinced that an RNA virus could activate a viral gene which would “induce the infected cell to proliferate – unleashing pathological mitosis, cancer… Spiegelman raced off to prove that retroviruses caused human cancers.” He quickly uncovered retrovirus genes in human leukemia, breast cancer, lymphomas, sarcomas, brain tumors, melanomas – in nearly every human cancer that he examined.”

His lab was inundated with funding, and he found more retroviruses in cancers, and so “more funds were sent his way.” Within a few years, though, a systematic flaw in Spiegelman’s work was revealed. He was trying so hard that he “saw viruses or traces of viruses that did not exist.” It was quickly found that a human retrovirus caused only one rare type of leukemia endemic to some parts of the Caribbean. All the hundreds of millions of dollars had produced no reliable result. But he “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.” In 1983 Spiegelman died of pancreatic cancer. One year later it was discovered that AIDS was caused by the retrovirus HIV!

“The hunting of the sarc”

Now the pendulum swung the other way. Even Temin understood that, although his discovery of reverse transcription had overturned the dogma of cellular biology, it had not contributed much to the understanding of human carcinogenesis. Temin realized that his focus should more likely be on the message, not the messenger: Maybe the virus just brings the message to the cell. Now science needed to pursue new questions: “What was the viral gene that had unleashed pathological mitosis in cells? And how was that gene related to an internal mutation in the cell?”

In the 1970s, three California virologists focused on RSV (Rous Sarcoma Virus, discovered in chickens), a disease that possesses only four genes. By making mutant RSV genes that were no longer able to create tumors, they were able to pinpoint the one gene able to cause cancer in the virus. They called it “src,” short for “sarcoma,” and pronounced it “sarc.” And now they had found Temin’s “message.” The src-less virus could “neither induce cell proliferation nor cause transformation.” They speculated that src was a “malformed gene acquired by RSV during its evolution and introduced into normal cells. It was termed an oncogene, a gene capable of causing cancer.”

The src’s function was further elucidated when a Colorado team discovered that its primary “function was to modify other proteins by attaching a small chemical, a phosphate group, to these proteins… an elaborate game of molecular tag… The attachment… acted like an ‘on’ switch.” Called a kinase, this strange enzyme turned on another kinase, which turned on another. “The signal was amplified at each step of the chain reaction.” Eventually it “produced a powerful internal signal to a cell to change its ‘state’ – moving, for instance, from a nondividing to a dividing state.” It ultimately induced “accelerated mitosis, the hallmark of cancer.”

All that in research with chickens. “But with no human cancer retroviruses in the study, none of this research seemed relevant immediately to human cancers.” Still, Temin was indefatigable, now interested in the evolutionary origin of this src gene. How did a virus acquire a gene with “such potent, disturbing qualities”? Temin knew evolution could build new genes out of old genes, but “where had Rous sarcoma virus found the necessary components of a gene to make a chicken cell cancerous?”

In San Francisco, a virologist named Michael Bishop wondered the same thing. He was joined by a researcher from the NIH, Harold Varmus. As the two set off to learn the origins of the src, other scientists nicknamed their project “the hunting of the sarc” in a droll reference to Lewis Carroll’s sardonic poem, “The Hunting of the Snark.”

Understanding that DNA molecules come in “sticky” pairs that, when separated, will easily “stick” to another complementary molecule, they tagged such DNA molecules with radioactivity, a substance they could trace. Then they watched for new pairings, but they were surprised. “When Varmus and Bishop looked in normal cells, they did not find a genetic third or fifth cousin of src. They found a nearly identical version of viral srclodged firmly in the normal cell’s genome.” They found them in duck cells, quail cells, and geese cells – “all over the bird kingdom.” Then they found “related homologues of the src gene” in mice, rabbits and fish. Then in a newborn emu at the zoo, and in sheep and cows. And, likewise, in human cells.

However, unlike the src gene in normal cells, the viral src gene “carried mutations that dramatically affected its function.” As had been discovered in Colorado, research at Rockefeller University found, again, that the viral src protein “was a disturbed, hyperactive kinase that relentlessly tagged proteins with phosphate groups and thus provided a perpetually blaring ‘on’ signal for cell division.” In contrast, cellular src turned on and off in regulated fashion during cell division. Viral src caused cancer because it “was cellular src on overdrive.”

From that discovery came “a theory so magnificent and powerful that it would explain decades of disparate observations”: Maybe src, the precursor to the cancer-causing gene, originated in the cell. “Perhaps viral srchad evolved out of cellular src.” The src gene had not originated in the virus; it had originated “from a precursor gene that existed in a cell – in all cells.” Rous had been wrong. “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 was “an accidental courier.” Yes, viruses did cause cancer, “but they did so, typically, by tampering with genes that originate in cells.”

And so, the “proto-oncogene, as Varmus and Bishop had called it – was a normal cellular gene.” When cancer was caused by chemicals (soot or nicotine, for example) or by X-rays that mutated the genes, no foreign genes were being inserted into cells. The chemical or X-ray was activating a proto-oncogene that originated in the cell itself. The Rous sarcoma virus had led virologists down a false path for six decades, but ultimately the research arrived at the correct destination: internal proto-oncogenes “sitting omnipresently in the normal cell’s genome.”

Just as Carroll’s poem has a surprise ending, the snark being not at all what the hunters expected, the “hunting of the sarc” revealed that “cancer genes came from within the human genome.” Varmus and Bishop were awarded the Nobel Prize in 1989. In accepting the award, Varmus conceded that he had not slain the dragon but had seen the monster more clearly, now understanding the cancer cell to be “a distorted version of ourselves.”

The Wind in the Trees

By the summer of 1976, cancer biology had firmly returned to genes. We now understood that substances like asbestos, radiation and cigarette smoke initiated cancer “by mutating and thus activating precursor oncogenes within the cell.” And now we understood that “both smokers and nonsmokers have the same proto-oncogenes in their cells, but smokers develop cancer at a higher rate because carcinogens in tobacco increase the mutation rate of these genes.”

At that time, genes could be “seen” in two ways: “as physical structures – pieces of DNA lined up along chromosomes,” and also from a functional perspective, “inheritance traits.” The structural image came first. In 1973 in Chicago, Janet Rowley stepped back in time with her reliance on the old art of chromosome staining, studying chronic myelogenous leukemia (CML)– what Bennett had called “suppuration of blood” back in 1854.

Rowley picked up a study from the late 1950s that had identified “an unusual chromosomal pattern in this form of leukemia: the cancer cell bore one consistently shortened chromosome.” Pathologists had found that “the twenty-second chromosome had its head lopped off.” They never discovered where the missing part had gone. Rowley found that the missing “head” of chromosome twenty-two had “attached itself… to the tip of chromosome nine. And a piece of chromosome nine had conversely attached itself to chromosome twenty-two.” It was called “a translocation. 

She found the very same translocation in every CML patient. This was not “disorganized chromosomal chaos. It was organized chromosomal chaos.” Such a new gene was called a chimera, although Rowley did not know its identity or function.

A California geneticist, Knudson, chose to focus on the other way of “seeing” a gene: as an inheritance trait. The obvious choice of cancer for his study was the familial retinoblastoma identified among families in Brazil. There is also a sporadic form of the disease, afflicting children with no known familial history and, interestingly, always affecting only one eye. Knudson wondered whether mathematical analysis might shed light on the difference between the two forms of the same cancer. By simply studying the onset of childhood retinoblastoma by examining patient records, he found that the inherited form typically develops two to six months after birth, while the sporadic type typically appears two to four years after birth.

Why would that be? Again using numbers and simple equations, he found a basic difference: “In children with the inherited form of retinoblastoma, only one genetic change was required to develop cancer. Children with the sporadic form required two genetic changes.” But why? Because, Knudson theorized, “every normal human cell has two copies of each chromosome and thus two copies of every gene… two independent mutations have to accumulate in the same cell.” Children with inherited retinoblastoma are born with one gene already defective.

That theory seemed at odds with the knowledge of the day: “Why was a single mutation in src sufficient to provoke cell division, while two were required for Rb?” The answer: Src, an onco-gene, “provokes perpetual cell division,” while Rb, an anti-oncogene, “suppresses cell proliferation.” This “exquisitely astute hypothesis” was made by a man who’d never seen a cancer cell “and knew his genes only in a statistical sense.” Both genes can be compared to an automobile – one with an accelerator forever depressed, speeding forward, and the other proceeding normally until the “brakes have been inactivated by mutation.” (“jammed accelerators” and “missing brakes.”) Those were the causes of cancer, as postulated by Bishop, Knudson, and Varmus in the late ‘70s.

A Risky Prediction

“Good theories… generate risky predictions.” Theory: precursors of oncogenes (proto-oncogenes) exist in all normal cells. Thus far, however, “no one had isolated an activated, mutated oncogene out of a cancer cell.” In 1978, a rather frustrated, hard-working virologist, Robert Weinberg, who had never achieved fame, had a brainstorm while walking to his lab at MIT in a Boston blizzard. “If activated oncogenes existed within cancer cells, then transferring these genes to normal cells should induce the normal cells to divide and proliferate.” What if one could introduce the approximately 20,000 genes from one cancer cell into the 20,000 genes of a normal cell, grow them all in a petri dish, and see which ones “reproduce insatiably,” forming a visible clump? Forget oncogenes!

First Weinberg had to figure out how to transfer DNA from a cancer cell to a population of normal cells. He had perfected that technical skill in his previous work with monkey viruses. Essentially, he was able to transform the cancer DNA into a white powder he could sprinkle like a blizzard on normal cells in a petri dish, “the blizzard of genes that Weinberg had so vividly imagined on his walk in Boston.” Then he just had to wait for the gene that had “ingested” cancer DNA to start growing wildly in the petri dish. “He would thus capture a real human oncogene.” 

In 1979, a graduate student named Shih, working in Weinberg’s lab, accomplished that very thing with mouse cells, using the “blizzard” method described above. The two scientists then secured human cancer cells from the Dana-Farber Cancer Institute, cells of a long-term smoker who had died of bladder cancer. They created their cancer snowstorm from that cache, dusted normal human cells, and waited. It worked just as it had with mouse cells, and they began the race to “isolate and identify the first native human oncogene.”

In fact, researchers at three other labs in the northeast were doing the same work at that very moment! “In late winter of 1981, all four laboratories rushed to the finish line. By the early spring, each lab had found its sought-after gene.” The next year, when three of them published independently, “all three labs had isolated the same fragment of DNA, containing a gene called ras.” Like src, it was a gene present in all normal cells, but it was “functionally different from the ras present in cancer cells… Mutated ras encoded a berserk, perpetually hyperactive protein permanently locked ‘on.’” They had all captured, in flesh and blood, the native human oncogene.

Weinberg thought, after that achievement, “the world would be at our feet.” Later he recalled that is was “all a wonderful pipe dream.” In 1983, the General Motors prize for research went to a scientist who had worked with src (cancer’s cause) and one who had advanced the cure for leukemia (cancer’s cure). But there was no enthusiasm “to synthesize the two poles of knowledge about cancer… The two halves of cancer, cause and cure, having feasted and been feted together, sped off in separate taxis into the night.”

One challenge had been brought to a close. Now to return to the other “risky prediction: that retinoblastoma cancer cells contained two inactivated copies of the Rb gene.” The fabled tumor suppressor gene would now have to be isolated and found to be inactive. But this is the working brake pedal. It won’t cause observable growth in a petri dish; quite the opposite. “’How can one capture genes that behave like ghosts,’ Weinberg wrote, ‘influencing cells from behind some dark curtain?’”

By the mid-1980s, using Janet Rowley’s technique, “geneticists had determined that the Rb gene ‘lived’ on chromosome thirteen.” But to isolate that gene from thousands – “particularly one whose functional presence was revealed only when inactive – seemed like an impossible task.” Researchers knew where Rb lived, but not what it was. 

An ophthalmologist-turned-geneticist, Thad Drjya, was studying the genetics of eye diseases. His obvious target would be retinoblastoma. He now knew that every normal cell “has two copies of the Rb gene, one in each copy of chromosome thirteen.” If Rb has to be inactivated to cause retinoblastoma, he reasoned, the problem probably occurred with the deletion of a gene. He anticipated an asymmetric inactivation, “affecting two different parts of the gene on the two chromosomes.” If the tumor “had deleted exactly the same part of the gene on the two sister chromosomes,” however, “that piece of chromosome would be completely missing from the cell.” Therefore, if chromosome thirteen is completely missing in a retinoblastoma tumor cell, he probably has found the Rb. He would need to test a vast sample of tumors to find one such “shared deletion,” and Dryja, more than anyone else, had an enormous bank of frozen tumors.

For weeks he “extracted the chromosomes from tumors and ran his probe set against the chromosomes… In one tumor he saw a blank space. One of his probes… was deleted in both chromosomes.” He felt he had found the retinoblastoma gene missing in tumor cells, but now he had to find “the corresponding piece present in normal cells.” He reached out for help to the Weinberg lab and engaged Steve Friend in that lab, a scientist who “had been building a collection of normal cells.” Friend was seeking genes present in normal retinal cells and then “working backward toward Dryja.”

The “complementarity… was obvious.” Using Dryja’s probe – the one identified as missing in the retinoblastoma cell – Friend quickly isolated the gene that lived, normally, on chromosome thirteen, just as expected. Further testing confirmed the candidate gene “was indisputably Rb.” In October 1986, the three scientists published their findings in Nature. They had accomplished “the isolation of an activated proto-oncogene (ras) and the identification of the anti-oncogene (Rb).” Now they had “a tumor suppressor.”

When scientists did further testing of this Rb gene in the early nineties, “they found it widely mutated in lung, bone, esophageal, breast and bladder cancers in adults.” It was far more than retinoblastoma. “Rb thus acts as a gatekeeper for cell division, opening a series of key molecular floodgates each time cell division is activated and closing them sharply when the cell division is completed. Mutations in Rb inactivate this function. The cancer cell perceives its gates as perpetually open and is unable to stop dividing.”

From 1983 to 1993, “a horde” of other oncogenes and anti-oncogenes were identified. The accidental carriers of such genes, retroviruses, “faded far into the distance… 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.”

About this time, geneticists had uncovered other families that seemed to carry cancer (not just retinoblastoma) in their genes. Cancer geneticists began to clone and identify some of these cancer-linked genes. Some were “quite frequently represented in the population… Perhaps the most striking among these… was BRCA-1, a gene that strongly predisposes humans to breast and ovarian cancer.” It is found in up to 1 percent of women, “making it one of the most common cancer-linked genes found in humans.”

Still, “no one had shown that a cancer gene, in and of itself, could create a bona fide tumor in an animal.” A Harvard team tried to do this with a mouse, careful to alter the c-myc gene only in breast tissue. Called the OncoMouse, it became the first animal in history to be patented. The OncoMice in the lab “developed small, unilateral breast cancers… late in life.” And surprisingly, such tumors developed only after pregnancy, suggesting hormones might be in play. “Cancer had artificially been created in an animal.”

The Hallmarks of Cancer

“Cancer is not merely a lump in the body; it is a disease that migrates, evolves, invades organs, destroys tissues, and resists drugs… much, evidently, remained to be understood.” How many activated proto-oncogenes and inactivated tumor suppressors are actually required to create a cancer? And what are the steps in the genetic process? In 1988, Bert Vogelstein “set out to describe the number of genetic changes required to initiate cancer.” It would take him two decades.

Vogelstein recalled the 1950s research that indicated cancer “slouched toward its birth,” slowly. He remembered discovery of the “whorls of noninvasive premalignant cells” in cervical, lung and colon cancer. He focused on the latter, finding a strikingly consistent pattern: “the transitions in the stages of cancer were paralleled by the same transitions in genetic changes” as he studied human samples from each stage. He found “a strict and stereotypical sequence.” He had proved that a “discrete genetic march existed.” Both the pathology and the genetics followed the same progression.

“This was a relief.” With about 100 proto-oncogenes and tumor suppressor genes having been discovered, people wondered: “why was the human body not exploding with cancer every minute?” Cancer geneticists already knew that the required “mutations are rare events.” And they knew that inactivation of a tumor suppressor was even rarer, as it requires two independent mutations. Vogelstein demonstrated that such activation or inactivation produced only the first steps toward carcinogenesis. It would take “many genes over many iterations,” in “graded, discrete steps,” to actually create a malignancy. 

Cancer biologists now knew that cancer mutations were either activations of proto-oncogenes or inactivations of tumor suppressor genes. But cancer cells do more than divide; they migrate, invade, destroy and colonize. So, how does gene mutation link to the “complex and multifaceted abnormal behavior” of cancer cells? Genes encode proteins, those “on/off” switches that create the “signaling pathway for a protein. Such pathways are constantly active in cells.” And right “at the hub” sit the proto-oncogenes and tumor suppressor genes. A tightly regulated cascade of steps in a normal cell becomes, in a cancer cell, permanent activation of a string of proteins “resulting in uncontrolled cell division – pathological mitosis.”

As the activated pathological pathway progresses, it intersects with other pathways. For example, some activated signaling pathways in cancer cells are able to “induce neighboring blood vessels to grow…[and] thus ‘acquire’ its own blood supply.” That’s called angiogenesis. Other activated pathways can even block the death of cells, allowing cancer cells to resist death signals. Still other pathways, it was discovered, allowed cancer cells to move from one tissue to another (metastasis) and to invade the “hostile environments” of other organs and not be rejected or destroyed.

“Cancer, in short, was not merely genetic in its origin; it was genetic in its entirety.” It became clear that everything about cancer is abnormal – which is what sustains its life. It takes over signaling pathways used by the body under normal circumstances such as those used for healing or suppression of infection. Cancer’s life is “a pathological mirror of our own.” Its cells are “hyperactive… inventive copies of ourselves.”

Consider a fire-safety-equipment installer who gets a tiny sliver of asbestos in his left lung. Inflammation begins, and the “cells around the sliver begin to divide furiously.” On the site of an original normal lung cell, a small clump now arises. “In one cell in that clump an accidental mutation occurs in the ras gene.” Uncontrolled cell division is partly unleashed, forming a clump within the clump.

Ten years later, those ras-mutant cells continue to proliferate, unnoticed. The man smokes cigarettes, and carcinogenic tar collides with the ras-mutated cells, igniting a second mutation in the genes and activating a second oncogene. Ten years later the man has a chest X-ray, and the X-ray touches a cell in that secondary mass, causing yet another mutation, “this time inactivating a tumor suppressor gene.” A year later, another mutation inactivates the other tumor suppressor gene. Now we have two activated oncogenes and an inactivated tumor suppressor gene.

“… an unraveling begins.” The mutated cells outgrow their brother lung cells, acquiring additional mutations, activating pathways that allow them to adapt and grow and survive. One mutation lets them co-opt nearby blood vessels; another allows them to survive on little oxygen. “Mutant cells beget cells beget cells.” A mobility gene lets them migrate to the bloodstream, and another mutation allows them to survive in the bone. It reaches the pelvis and “begins yet another cycle of survival, selection, and colonization.” Now the lung tumor has metastasized to the pelvis.

The man feels a few tingles and unusual sensations occasionally. A year later, these sensations have accelerated. A CT scan reveals a “mass wrapped around a bronchus of the lung. A biopsy reveals lung cancer.” The tumor is deemed inoperable. Three weeks later a bone scan reveals metastasis to the ribs and pelvis, accounting for pain in his ribs and hips. Chemotherapy begins, and the lung tumor responds. But one cell mutates and becomes resistant to the drugs. Seven months later, the tumor relapses “in the lungs, the bones, the liver.” He dies of lung cancer at the age of 76.

[The author reveals: “This man was the first patient to die in my care during my fellowship in cancer medicine.”]

In 2000, Weinberg and another cancer biologist, Douglas Hanahan, published an article called “The Hallmarks of Cancer,” in which they laid out the “rules that govern the transformation of normal human cells into malignant cancers.” They offered six “rules” that “explain the core behavior of more than a hundred distinct types and subtypes of tumors”:

1. Self-sufficiency in growth signals – When oncogenes are activated, cancer cells “acquire an autonomous drive to proliferate.”

2. Insensitivity to growth-inhibitory signals – “Cancer cells inactivate tumor suppressor genes.”

3. Evasion of programmed cell death – Cancer cells inactivate the genes and pathways that enable cells to die.

4. Limitless replicative potential – Cancer cells become immortal, growing for generations, after activating certain gene pathways that make this possible.

5. Sustained angiogenesis – They acquire the capacity to create their own blood supply.

6. Tissue invasion and metastasis – They acquire the capacity to migrate, invade and colonize throughout the body.

The next step would be to connect this causation to the cure. Hanahan and Weinberg looked forward to “a rational science, unrecognizable by current practitioners.”

PART SIX: THE FRUITS OF LONG ENDEAVORS

“No one had labored in vain”

Remember “Jimmy,” the presumed fictitious poster child of the Dana-Farber Cancer Institute? He was an actual boy with lymphoma of the intestines, a “lanky, cherubic, blue-eyed blond” whose real name was Einar Gustafson, introduced on the Truth or Consequences show as “Jimmy,” mascot of the “Jimmy Fund.” Well, in 1997, nearly 50 years later, while everyone presumed “Jimmy” had died of his cancer, his sister wrote the Dana-Farber Institute to share the good news that her brother, Einar, was alive and well, a truck driver in Maine, father of three children.

Indeed, the doctors themselves had assumed Jimmy was dead, and the letter was received with great skepticism – except for the details it included about Jimmy’s case from 1948, which could not be dismissed. Einar himself – “Jimmy” – was relieved to have the truth finally out. And Karen Cummings in the Jimmy’s Funddevelopment office immediately understood the letter’s potential. She arranged to meet Einar/Jimmy in early 1998; she played for him and his wife a tape of him singing “Take Me Out to the Ballgame” in 1948. Soon she drove to the town in Maine where, literally, “it had taken a village to save a child.” There she saw for herself the baseball uniform the Boston Braves had signed for Jimmy as he became the famous poster child. 

In May 1998, the real Jimmy, alive and well, returned to the Jimmy Fund building. “His wardmates… had long ago been buried in small graves.” He was “like a latter-day Rip van Winkle.” Everything had changed. “… now sixty-three years old, [he] had returned as the icon of a man beyond cancer.”

“Cancer… negates the possibility of life outside and beyond itself… the world fades away… Every last morsel of energy is spent tending the disease.” Patients see “not a world outside cancer, but a world taken over by it.” [Mukherjee comments on the final weeks of his fellowship in 2005, including the birth of his own daughter.] “… in the summer of 2005… patients whose faces had been pressed up against the glass of their mortality, began to glimpse an afterlife beyond cancer… like a poisonous tide receding, the bad news ebbed.”

[Here the author summarizes the cases of three patients in his care who survived cancer. These cases were not “miraculous,” he asserts, but “a routine spectrum of survivors… it was the most sublime moment of my clinical life to have watched that voyage in reverse, to encounter men and women returning from the strange country – to see them so very close, clambering back.”] By 2005, “the national physiognomy of cancer had subtly but fundamentally changed.” The mortality rate for nearly all major cancers had dropped for fifteen years, declining by about one percent per year. Still, more than a half-million Americans died of cancer in 2005, but cancer was “losing power, fraying at its borders.”

How did this happen? “There was no single answer.” Lung cancer had declined with the attrition rate for smoking, due in large part to political activism, “inventive litigation,” and medical advocacy. Cancer screening was the likely cause of the decline in colon and cervical cancer. Chemotherapy is the marker cited for the decline in leukemia, lymphoma, and testicular cancer. Chemotherapy toxicity and dosing were even being scaled back by 2005.

“… the decline in breast cancer mortality epitomized the cumulative and collaborative nature of these victories… Between 1990 and 2005, breast cancer mortality had dwindled an unprecedented 24 percent.” Three interventions – mammography, surgery, and adjuvant chemotherapy – shared equally in the glory.

These victories were “the results of discoveries made in the fifties and sixties,” all before the work on cell biology of cancer. It was the discovery of oncogenes and tumor suppressor genes, chromosomes and cellular pathways, unveiling “a fantastical new world…But the therapeutic advances that had led to the slow attrition of cancer mortality made no use of this novel biology of cancer.” In 1994, cancer geneticist Ed Harlow “captured both the agony and the ecstasy of the era.” His sobering assessment: “Our knowledge of … cancer has come from a dedicated twenty years of the best molecular biology research. Yet this information does not translate to any effective treatments nor to any understanding of why many of the current treatments succeed or why others fail. It is a frustrating time.”

More than a decade later, oncologists faced an all too familiar “disjunction.” They were “pushed, on one hand, by the increasing force of biological clarity about cancer, then pressed against the wall of medical stagnation…” At this critical point, cancer faced “the boil of science – an urgent, rhapsodic pressure that could only find release in technology… a new kind of cancer medicine.”

New Drugs for Old Cancers

Before the 1980s, cancer therapy relied on two “fundamental vulnerabilities of cancer cells”:

• Most originate locally before spreading, so they could be surgically excised or seared with local X-rays before spreading.

• Rapid growth of some (not all) cancer cells made them vulnerable to chemotherapy such as: antifolates that starve the cells; chemicals that damage the cancer cells’ DNA; and other poisons that interfere with molecular scaffolding required for cell division.

Focus on those two vulnerabilities, however, was successful only to a point. Radical surgery did not lead to more cures. Targeting cellular growth affected healthy cells also, which also needed to grow. “More drugs produce more toxicity without producing cures.” In the 1980s, though, three new vulnerabilities of cancer became apparent:

• The mutated genes – “accelerator” and “brakes” – could be targeted, “sparing their modulated normal precursors.”

• Unregulated cellular signaling pathways could be interrupted.

• Dependence of cancer cells on the relentless cycle of “mutation, selection, and survival… the hallmarks of cancer,” also offered a vulnerability.

The solution? Focus on the subtle differences between cancer cells and normal cells, “subtle differences in genes, pathways, and acquired capabilities… to drive a poisoned stake” into the heart of cancer.

In 1986, the first oncogene-targeted drug was discovered. It would “set the stage for the vast drug-hunting efforts of the next decade.” Once again it was a rare leukemia variant, APL, under the microscope. APL is a disease characterized by malignant proliferation of immature cells that seem to get frozen in development. “Most cancers refuse to stop growing. In APL, the cancer cells also refuse to grow up.”

An international team (Wang and Degos) from China and France launched a joint effort in 1985 to test a previously little-used maturation agent (trans-retinoic acid) on APL cells. The next year, Wang experienced amazing success with 23 of his 24 subjects. Within four days of treatment, the leukemic cells “underwent a brisk maturation into white blood cells.” And then, “having fully matured, the cancer cells began to die out.” Patients suffered “a short-lived metabolic disarray,” for which they were treated with medicines, and some of them had dry mouth or a rash, but the remissions lasted weeks and often months before relapse.

The team found they could prolong remission by adding some of the standard legacy chemotherapy drugs. Most of the patients now stayed in remission for a year – many up to five years! “By 1993, Wang and Degos concluded that 75 percent of their patients treated with the combination of trans-retinoic acid and standard chemotherapy would never relapse – a percentage unheard of in the history of APL.”

Now back to Janet Rowley, the Chicago scientist who had relied on “the old art of chromosome staining” to find, in leukemia, that twenty-second chromosome with its head lopped off. In 1984 she had examined APL cells and found “a fragment of a gene from chromosome fifteen fused with a fragment of a gene from chromosome seventeen.” This created a strange oncogene that drove proliferation of genes but blocked their maturation. In 1990 that oncogene was isolated by scientists in several countries, and they were ultimately able to replicate Wang’s use of trans-retinoic acid to cause remission.

 “… trans-retinoic acid represented the long-sought fantasy of molecular oncology – an oncogene-targeted cancer drug.” But it had been stumbled upon through guesswork. Now researchers wanted to reverse the process: begin with the oncogene and find the right drug. Interestingly, that search had been underway since the early 1980s in the Weinberg lab, although “Weinberg himself was largely oblivious of it.” In 1982, an Indian postdoc scientist, Padhy, had isolated an oncogene from a rat neuroblastoma; the oncogene was named neu. And Padhy discovered an important difference between this oncogene and the others: It produced a novel protein that was not hidden deep inside the cell (as the others were), but “tethered to the cell membrane with a large fragment that hung outside, freely accessible to any drug.”

While doing this research, Padhy had created, in the previous year, an antibody against the neu protein. Now, antibodies bind to other molecules and “can occasionally block and inactivate the bound protein. But antibodies are unable to cross the cell membrane and need an exposed protein…” And then Padhy found the protein, outside the cell membrane and therefore vulnerable! One only needed to try adding the antibody to the neuroblastoma cells.

Alas, the connection was not immediately made in the Weinberg lab. In fact, “Padhy and Weinberg never got around to doing their experiment.” Even when Padhy’s experiment was published in a respected journal, few scientists took notice. The connection to “a potential anticancer drug” was never made. 

A City of Strings

“Proto-oncogenes and tumor suppressors are the molecular pivots of the cell. They are the gatekeepers of cell division… [they] intersect with nearly every other aspect of our biology… you can ask any biological question… and you will end up, in fewer than six genetic steps, connecting with a proto-oncogene or tumor suppressor.” [“the six-degrees-of-separation-from-cancer rule”]

In 1984 on the campus of the pharmaceutical company Genentech, “a human homolog of the neu gene” was discovered. A growth-modulating gene, it was named Her-2. “The difference in venue, and the resulting difference in goals, would radically alter the fate of this gene… For Genentech, Her-2 represented a route to developing a new drug.”

Genentech had been formed in 1976 to leverage a new discovery at Stanford and UCSF: recombinant DNA. “This technology allowed genes to be manipulated – engineered.” For example: “a human protein synthesized in a dog… a cow gene… transferred into bacteria.” One might create “proteins never found in nature.” Proteins: “among the most complex drugs in medicine… although recognizably potent, had been notoriously difficult to produce.”

Now, using recombinant DNA, Genentech was able to synthesize human proteins rather than finding them in organs. By 1982 the company had produced a human insulin; two years later the team produced a human clotting factor for hemophilia, and one year later a version of human growth hormone. They had, essentially, “found a radical new way to produce old medicines.” To invent new drugs from scratch, they had to find target “proteins in cells that might play a critical role in the physiology of a disease,” one that might be turned on or off by the proteins they could now produce using recombinant DNA.

Genentech now had Her-2/neu, “the oncogene tethered to the cell membrane,” but what could they do with it? Unlike their past drug developments, they had to deal now with a signal in overabundance, not a signal that is missing. Essentially, they had to figure out how to “inactivate a hyperactive protein in a human cell.” Genentech’s Axel Ullrich gave a presentation on Her-2 – with no new-drug punchline. But listening in the audience was UCLA oncologist Dennis Slamon, with “a ‘murderous resolve’ to kill cancer… He needed a method to kill an oncogene.” 

Slamon “had been collecting and storing samples of cancer tissues from patients who had undergone surgery at UCLA, all saved in a vast freezer.” He and Ullrich agreed to collaborate: Ullrich would furnish DNA probes for Her-2, and Slamon would “test his collection of cancer cells for samples with hyperactive Her-2.” They’d bridge the gap between oncogene and cancer.

Within months Slamon found a pattern, although one not fully understandable. Cancers, he knew, could amplify a particular gene by making multiple copies of it in the chromosome, thus allowing the cancer to grow: oncogene amplification. He found some breast cancers that amplified Her-2 but others that did not: Her-2positive and Her-2 negative. Further research revealed that Her-2 positive breast cancers (which amplified the gene) “tended to be more aggressive, more metastatic, and more likely to kill… with the worst prognosis.”

That raised the question: “What would happen… if Her-2 activity could somehow be shut off?” Was the cancer “addicted” to Her-2? Here Ullrich, at Genentech, picked up the reins. He wondered “whether someone in immunology might be able to design a drug to bind Her-2 and possibly erase its signaling.” He was thinking of an antibody, an exquisitely specific protein, one of “nature’s magic bullets.” Until then, scientists had been unable to identify a target unique to cancer cells; Ullrich thought Her-2 might be the answer.

Meanwhile, Genentech had already produced a mouse antibody that bound and inactivated Her-2 on mice cancer cells in a petri dish. Slamon and Ullrich were able to try the process on living mice with breast cancer. “Her-2 worked in an animal model.” But, just as the two collaborators arrived at “the three essential ingredients for a targeted therapy for cancer: an oncogene, a form of cancer that specifically activated that oncogene, and a drug that specifically targeted it,” they discovered that Genentech “was abandoning its interest in cancer.” Several other drug companies had experienced miserable failure in their attempts to develop anticancer drugs. The approach offered by Slamon and Ullrich was “vastly more sophisticated and specific” than those attempts had been, but Genentech would not fund cancer projects now.

Ullrich left Genentech, but Slamon pursued the project, convincing “a tiny, entrepreneurial team [at Genentech] to push ahead with the Her-2 project.” They had to find a way to “humanize” the mouse antibody, as a foreign antibody would “provoke a potent immune response in humans and make terrible human drugs.” In 1990 they succeeded. It would be named “Herceptin, fusing the words Her-2, intercept, and inhibitor… They had moved from cancer to target to drug in an astonishing three years, a pace unprecedented in the history of cancer.” 

In that same year, 1990, a 48-year-old woman in Burbank, California, Barbara Bradfield, was diagnosed with metastatic breast cancer. She had a bilateral mastectomy and a lymphadenectomy followed by seven months of chemotherapy. The following year, a grape-sized lump appeared at her collarbone. “Her breast cancer had relapsed and metastasized – almost certainly a harbinger of death.” Offered another course of chemotherapy, she declined in favor of an alternative herbal-therapy program. She reluctantly agreed to allow samples of her cancer to be sent to Slamon at UCLA.

A few months later Slamon himself called Ms. Bradfield and told her about Her-2. “Her tumor, he said, had the highest levels of Her-2 that he had ever seen… she would be the ideal candidate for the new drug.” She refused, feeling at the end of her road. The next morning Slamon called her again and begged her to enter the drug trial. In August of 1992 Bradfield visited Slamon in his clinic at UCLA. Under the microscope he showed her the Her-2 in her tumor. He explained the research that led to Herceptin. “She agreed to join Slamon’s trial.” By the time she entered the trial and got her first Herceptin infusion, four months later, her “tumor had erupted, spraying sixteen new masses into her lung.”

Fifteen women entered the trial. (It would later grow to 37.) All were treated over nine weeks on the same day, at the same time, the drug given intravenously along with cisplatin, “a standard chemotherapy agent used to kill breast cancer cells… The lump on Bradfield’s neck… became the compass for the trial” for the group of women who came to know each other well. Two weeks after the first dose of the antibody, they could see and feel that the tumor “had softened and visibly shrunk.”

Not all the women responded well, but “Bradfield’s extraordinary response continued.” Two months into the trial a CT scan showed “the tumor in her neck had virtually disappeared, and the lung metastases had diminished both in number and size. The responses in many of the … other women were more ambiguous.” At the three-month point, “tumors had remained unchanged in some women – not shrunk but static.” Some reported reduced bone pain. After consideration, the decision was made to drop seven women “because their responses could not be quantified. One woman discontinued the drug herself.” Only five women, including Bradfield, finished the trial.

“Barbara Bradfield finished eighteen weeks of therapy in 1993.” [At the publication of this book in 2010, she was still surviving.] 

Drugs, Bodies, and Proof

By the summer of 1993, breast cancer patients and activists were “whipped up [in] a frenzy of hype and hope about Herceptin.” People urged release and use of the drug for women with this deadly form of breast cancer, but “Herceptin had not been approved by the FDA… Genentech wanted… carefully monitored drugs entering carefully monitored bodies in carefully monitored trials.” They intended to follow trial subjects “deeply and meticulously over time.” Comparing the situation to the AIDS movement seeking new HIV drugs not yet fully tested, people demanded action – “We cannot wait for proof.”

Some breast cancer patients begged to have their tumors checked for Her-2, but insurance companies refused to pay, since the treatment drug was not yet fully tested and approved. For its part, Genentech insisted giving Herceptin without Her-2 confirmation was untenable. It seemed “a Kafkaesque nightmare.” One such patient finally turned to a breast cancer activist group which was able, after several months, to get the woman’s tumor tested for Her-2. “It was strikingly Her-2 positive. She was an ideal candidate for the drug.” Nine days later, she died at age 41, still awaiting Herceptin “for compassionate use.” [She herself was a physician.] 

A few months later, activists with Breast Cancer Action “stormed through the Genentech campus… to hold a fifteen-car ‘funeral procession.’” They drove their cars through the manicured lawns and honked their horns. One woman, a nurse with breast cancer, handcuffed herself to her steering wheel. A researcher yelled at them to stop making noise, as he was busy researching a cure for AIDS.

Genentech, fearing a public relations disaster, had no choice but to join their effort. Working with the National Breast Cancer Coalition, the company agreed to a program that allowed “oncologists to treat patients outside clinical trials.” At the same time, Phase III trials of Herceptin began. “It was an uneasy triangle of forces – academic researchers, the pharmaceutical industry, and patient advocates – united by a deadly disease.” Together they launched “large-scale, randomized studies on thousands of women with metastatic Her-2positive cancer.” One trial, labeled “648,” tested women newly diagnosed with metastatic breast cancer in 150 cancer clinics around the world, randomizing them to standard chemotherapy alone versus chemotherapy with Herceptin added. It enrolled 469 women and cost Genentech $15 million. 

In May 1998 the results of the trials were reported at an annual meeting of clinical oncologists in Los Angeles. Eighteen thousand cancer specialists attended! Slamon did the honors, beginning with an image of a smudgy gel, part of a 1987 laboratory study – the one that had identified “a gene with no pedigree – no history, no function, no mechanism… [a reminder of] the fitful, unsanitized history of the drug.”

Eventually he shared the results of study 648. “In every conceivable index of response, women treated with the addition of Herceptin had shown a clear and measurable benefit… Tumors had shrunk in half the women treated with Herceptin compared with a third of the women in the control arm.” Slamon went on to report results “unheard of in recent clinical experience.”

Genentech threw a huge party that evening. “Just a few days earlier, the FDA had reviewed the data from the three Herceptin trials… and was on the verge of ‘fast-tracking’ the approval of Herceptin.” 

“In 2003, two enormous multinational studies were launched to test Herceptin in early-stage breast cancer treatment-naïve patients [those who had not received any previous treatment]. In one of the studies, Herceptin increased breast cancer survival at four years by a striking 18 percent over the placebo group.” When the results of all the studies were combined, “overall survival in women treated with Herceptin was increased by 33 percent.”

“It has not escaped me that this life-saving drug was discovered in the very year that I finished my treatment. On May 18, 1990, after I’d received my final adjuvant chemotherapy infusion, my oncologist told me with a big smile, ‘Today you may consider yourself cancer-free. Each year, on this day, you mark another year cancer-free.’ I walked on air the two blocks to my home, never feeling my feet touch the sidewalk – it was one of the most exhilarating moments of my life. This year I am 33 years cancer free and eternally grateful to that oncologist. I never missed the Herceptin that we didn’t even know about at that time.”

— Lynn

A Four-Minute Mile

In the summer of 1990, a “new era in cancer medicine” was at the doorstep, but the work would “again need to circle back to old observations.” And so, once again, we consider Janet Rowley who, in 1973, “identified a unique chromosomal aberration that existed in all the leukemia cells… in which the ‘head’ of chromosome twenty-two and the ‘tail’ of chromosome nine had been fused to create a novel gene.” This was our first look at a human oncogene.

Between 1982 and 1987, a team of Dutch researchers and a few American research teams built on each other’s work to identify the Bcr-abl oncogene that “drove the pathological proliferation of CML cells.” [CML is chronic myeloid leukemia.] Once the structure was identified, research turned to how does it cause leukemia? They found that Bcr-abl, like src, is a kinase, “a protein that tagged other proteins with a phosphate group” to unleash “a cascade of signals in a cell.” While Bcr and abl existed separately in normal cells, they joined in CML cells to unleash a pathway of incessant cell division.

Meanwhile, a team of Swiss chemists “was trying to develop drugs that might inhibit kinases… [which] act as molecular master-switches in cells – turning ‘on’ some pathways and turning ‘off’ others… [signaling cells] to grow, shrink, move, stop, or die.” Joined by a British biochemist, they sought a “druggable target” – a protein with deep crevices and pockets that would allow for binding. Most kinases “possess at least one deep druggable pocket.”

They engaged in “a painstaking, iterative game – chemistry by trial and error… [in a] relay race toward more and more specific and nontoxic chemicals.” Ultimately they discovered “dozens of new molecules that… possessed specificity”: each one inhibited a different kinase. Now they needed “a disease in which to apply this collection of chemicals – a form of cancer driven by a locked, overexuberant kinase that they could kill using a specific kinase inhibitor.”

So one of the researchers, Nick Lydon, traveled to the Dana-Farber Cancer Institute and met Brian Druker, “particularly interested in chronic myelogenous leukemia – the cancer driven by the Bcr-abl kinase. “Once again, as with Slamon and Ullrich, two halves of a puzzle came together.” One had the cohort of patients; the other had a freezer full of kinase inhibitors. Could they find a match? Sadly, due to lack of agreement in the legal departments of the two labs, the project “was quietly tabled.”

“But Druker was persistent. In 1993, he left Boston to start his own laboratory at… OHSU in Portland.” By then the Swiss lab (Ciba-Geigy) had made significant progress: “a molecule that might bind Bcr-abl with high specificity and selectivity.” They named it CGP57148. Druker nonchalantly got the legal department at OHSU to sign the papers. He recalled, “No one thought even faintly that this drug might work.” In two weeks he received a small collection of kinase inhibitors from Switzerland.

At that time, “the clinical world of CML was… reeling from disappointment… The principal treatment for CML in 1993 was allogeneic bone marrow transplantation, the protocol pioneered… in the sixties.” It had modest success. The thought was that CML might be an “intrinsically chemotherapy resistant disease.” By the time the disease was diagnosed, having been initiated by that one Bcr-abl gene, it had “long been overwhelmed by more powerful driver mutations. Using a kinase inhibitor… Druker feared, would be like blowing hard on a matchstick long after it had ignited a forest fire.”

But, when Druker received Lydon’s drug, he experienced immediate success, first in a petri dish, then in mice, and finally with actual human bone marrow from a CML patient. “He had cured leukemia in the dish.” He published his findings. It was “the ultimate dream child of oncology,” he thought. But Ciba-Geigy had now become Novartis, and they were unwilling to invest up to $200 million in a drug specific to an illness that affects a few thousand patients a year. Ironically, it was Novartis’s own drug Druker was promoting. He assembled a team of other physicians to help with the trial and, in 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 one shot.” Novartis already considered the drug a failure. They called it Gleevec.

[In 2002, Dr. Mukherjee himself came face to face with Gleevec in the ER with a middle-aged CML patient whose body was apparently rejecting his bone marrow transplant. Mukherjee, a medical resident, knew “the prognosis was grim.” But the rash was surprisingly minor. The man had actually been treated with CGP57148 (Gleevec), not foreign bone marrow, and it gave him a slight rash. Under the microscope, “his blood cells looked extraordinarily normal… not a single leukemic blast was to be seen… the disease had virtually vanished from sight.”]

Within months the researchers “had witnessed dozens of such remissions.” Finding no toxicity in his first trial patient, Druker “edged into higher and higher doses.” They had amazing success. Even patients whose blood vessels were “engorged with leukemia” and whose spleens were “heaving with leukemic cells” reached normal blood counts within a few weeks. Patients flocked to the three doctors for treatment, many having learned about the drug in an Internet chat room. Fifty-three of fifty-four patients in the Phase I trial “showed a complete response… It was an unsuppuration of blood.” Within a year “Gleevec was evidently a success.” It is still the drug of choice for CML today, and that form of cancer has moved from “fatal… with a median survival rate of three to five years” to “an indolent leukemia with an excellent prognosis… provided they take… Gleevec for the rest of their lives.”

“… cancer is a disease of symbols. Seminal ideas begin in the far peripheries of cancer biology, then ricochet back into the more common forms of the disease.” The story that began with leukemia in Sidney Farber’s clinic in 1948 took us from cancer in the blood to cancer of the blood. The success of Druker’s Gleevec was a touchstone, like Bannister’s four-minute mile run in May 1954, after which “track records fell like ripe apples.” Breaching the four-minute mile for the first time demonstrated that “intrinsic boundaries are mythical. What he broke permanently was not a limit, but the idea of limits.” Now the medical field knew that “highly specific, non-toxic therapy is possible.”

“Druker’s drug will alter the national physiognomy of cancer.” Now, due to lifelong therapy with an oral medication, likely 250,000 Americans are living with CML.

The Red Queen’s Race

As the Gleevec trials progressed, “The vast proportion of CML patients maintained deep, striking remissions on the drug, requiring no other therapy. But occasionally, a patient’s leukemia stopped responding… and resistant leukemia cells grew back… how might a cancer cell become resistant to a drug that directly inhibits its driving oncogene?” Such things happen with nontargeted therapy, but what was happening with Gleevec? Researchers discovered that leukemia cells can “acquire mutations that specifically alter the structure of Bcr-abl,” rendering it ineffective.

Just increasing the dosage of Gleevec would not be the answer, nor would a closely related molecular variant. Now they would need a second-generation drug to “block the protein through an independent mechanism.” Bristol-Meyers Squibb was able to generate another kinase inhibitor that entered through a second “molecular crevice on the protein’s surface.” It had remarkably positive results.

“Even targeted therapy, then, was a cat-and-mouse game… We were locked in a perpetual battle with a volatile combatant… If the vigilance was dropped, even for a moment, then the weight of the battle would shift,” reminiscent of Lewis Carroll’s “Red Queen,” who tells Alice she must keep running just to stay in place.

Within a decade of the discovery of Gleevec, the National Cancer Institute listed 24 novel drugs as cancer-targeted therapies, with more in development. [I found 31 approved targeted cancer therapies listed on the NHI National Cancer Institute website in August 2023.] These drugs work in diverse ways to disrupt cancer’s capacity to flourish.

Multiple myeloma (cancer of the immune system) is a case in point. The drugs used in the 1980s “ended up decimating patients about as quickly as they decimated the cancer.” But three new drugs emerged within a decade, “all of which interrupt activated pathways in myeloma cells.” Oncologists mix and match the drugs differently as tumors relapse. But “myeloma is still a fatal disease”: From 1971 to 2008, the life expectancy of a multiple myeloma patient in remission grew from two years, on average, to five years.

The Red Queen syndrome – “moving incessantly just to keep in place” – applies to all aspects of the cancer battle, including screening and prevention. While cancer researchers have, for decades, focused on risks associated with “the behaviors of individual actors,” in 2008 two Harvard epidemiologists began to consider “social networks” as a possible focus. Regarding “the dynamics of cigarette smoking,” Christakis and Fowler studied the “familiar and intuitive patterns” of a well-established and long-examined social network: “the Framingham cohort,” documented for decades. Their discovery? “… circles of relationships were found to be more powerful predictors of the dynamics of smoking than nearly any other factor. 

Who successfully quit smoking? Entire networks. Families that dined together. The social circuit surrounding the chief “socializers” at their center. “… smoking eventually became locked into the far peripheries of all networks… the loners… Smoking, this model argues, is entwined into our social DNA just as densely and as inextricably as oncogenes are entwined into our genetic material… The capacity of metastasis is thus built into smoking… When antitobacco campaigns lose their effectiveness or penetrance – as has recently happened among teens in America or in Asia – smoking often returns like an old plague. Social behavior metastasizes… Mini-epidemics of smoking-related cancers are sure to follow.”

Carcinogens proliferate in our culture. We “have begun to spin a new chemical universe around ourselves.” We are immersed “in a changing flux of molecules”: pesticides, pharmaceutical drugs, plastics, cosmetics, estrogens, food products, hormones, radiation, magnetism. “Some of these, inevitably, will be carcinogenic.” We must identify them. And mistakes have been made, a “sobering reminder of the methodological rigor needed to evaluate new carcinogens.” We are challenged to consider both the scientific knowledge and the “social challenge… customs, rituals, and behaviors.”

Thirteen Mountains

“Oncologists and their patients are bound, it seems, by an intense subatomic force.”

Until 2003, the science of cancer was limited to the accumulation of genetic mutations like ras, myc, Rb, neuand such. Scientists had isolated oncogenes and tumor suppressors, but they had so much more to learn. Then the Human Genome Project was completed, and science set out, worldwide, to create the Cancer Genome Atlas. “… this project will be geological… [it] will chart the entire territory of cancer… every single mutated gene will be identified.”

The first “landmark sequencing effort,” reported in 2006, analyzed “thirteen thousand genes in eleven breast and colon cancers.” In 2008 the two lead groups sequenced “hundreds of genes of several dozen specimens of brain tumors.” By 2009 “the genomes of ovarian cancer, pancreatic cancer, melanoma, lung cancer, and several forms of leukemia” had been sequenced. [Note: As of this writing, the Human Genome Atlas 2006 to 2018 is now complete and published on the website of the National Cancer Institute of the NHI.]

Bert Vogelstein is perhaps the most devoted and meticulous scientist behind this effort. He “drew” the human genome for an audience, beginning with the first gene of chromosome one and finally ending with the final gene of chromosome twenty-three – “the normal, unmutated human genome.” Then he added a dot for each known mutation to each gene. As the dots added up, the audience saw “ridges and hills and then mountains. The most commonly mutated genes in breast cancer samples were thus represented by towering peaks. 

“Mutations litter the chromosomes.” One typically finds around 50 mutated genes in each sample of breast, colon or brain cancer. A few types of cancer have only five or ten mutated genes. Scientists speculate that the latter might be more susceptible to drugs and, therefore, more curable. “The search for a ‘universal cure’ for cancer was predicated on a tumor that, genetically speaking, is far from universal.”

Common forms of cancer “are filled with genetic bedlam.” One sample of breast cancer showed 127 mutated genes! And the variety of mutations, even in a single type of cancer, is daunting. Vogelstein said, “Every patient’s cancer is unique because every cancer genome is unique.” The author points out that “Normal cells are identically normal; malignant cells become unhappily malignant in unique ways.” But, Vogelstein explained, some mutations are passive, just along for the ride, and others are “drivers” that “play a crucial role in the biology of a cancer cell.” Every cancer cell possesses both kinds, but many might be making no contribution to the growth and survival of the tumor. The driver genes “recur in sample upon sample… But when a mutation occurs in a previously unknown gene, it is impossible to predict whether that mutation is consequential or inconsequential.”

The genes mostly frequently mutated in a particular form of cancer can be organized into “key cancer pathways.” Vogelstein and his team next began to analyze those pathways. So, how many pathways typically become dysregulated in a cancer cell? Answer: on average, thirteen, and “the same core pathways were characteristically dysregulated in any tumor type.” Beneath the look of bedlam and overwhelming diversity is actually a set of “organizational principles… grammatical, methodical, and even – I hesitate to write – quite beautiful.”

So, as overwhelming as it is to plan how one might attack such a diversified target, Vogelstein did identify the core pathways, and the number is finite. “Gene by gene, and now pathway by pathway, we have an extraordinary glimpse into the pathway of cancer.” Now “science must make a leap from the molecular anatomy to the molecular physiology of cancer.” The real challenge is not just to identify the mutant genes but to understand what they do.

Cancer medicine will progress in three new directions:

1. Therapeutics: Matching to each identified driver mutation a drug that will inhibit those cancer cells without killing normal cells

2. Prevention: Focus to date has been on risk factors for specific cancers and identification of carcinogens that cause mutations. Either one might miss important carcinogens for a variety of reasons, including “blind spots” that might have been seen from a more integrated approach. “Thousands of chemicals proposed as carcinogens remain untested.” In addition, the link between nutrition and the risk of particular forms of cancer “remains in its infancy.” Molecular epidemiology might identify “the events intermediate between the exposure and disease occurrence or progression.” A molecular understanding of cancer will also make screening more efficacious, as it has for breast cancer related to BRCA-1 and BRCA-2.

3. Understanding the behavior of cancer as a whole: “Immortality” is one of the most provocative behavior of a cancer cell. How do cancers “continue to proliferate endlessly,” generation after generation, without exhaustion or depletion? Will a better understanding of stem cells contribute? “… the cancer cell’s capacity to consistently imitate, corrupt, and pervert normal physiology… raised the ominous question of what ‘normalcy’ is.”

“In 2010, (the year this book was published), living in Seattle, I was asked by my ‘breast health’ care provider to undergo testing for BRCA-1 and BRCA-2, although I had considered myself ‘cancer free’ for twenty years. I was negative for both, which indicated to me that my daughter and granddaughter, my sisters and nieces did not have to fear that my cancer had been hereditary and likely to befall them.”

— Lynn

Atossa’s War

“In the end, every biography must also confront the death of its subject… Is it possible to eradicate this disease from our bodies and our societies forever?” Cancer is “stitched into our genome… Mutations accumulate… by seemingly random errors in copying genes when cells divide… Cancer is a flaw in our growth… deeply entrenched in ourselves… We can rid ourselves of cancer, then, only as much as we can rid ourselves of the processes in our physiology that depend on growth – aging, regeneration, healing, reproduction… cancer might well be the final terminus in our development as organism.”  

“It is possible that we are fatally conjoined to this ancient illness… But, if cancer deaths can be prevented before old age… then it will transform the way we imagine this ancient illness.”

“Recall Atossa, the Persian queen who likely had breast cancer in 500 BC.” [Mukherjee’s footnote: “… there is uncertainty… Cancer was neither understood nor characterized in 500 BC.”] “Imagine her traveling through time… How has her treatment and prognosis shifted in the last four thousand years?”

• 2500 BC: Her case would have been closed with “there is no treatment.”

• In 500 BC, her actual time, she self-prescribed “the most primitive form of a mastectomy… performed by her Greek slave.”

• 200 years later, Hippocrates identified a tumor and called it “karkinos”

• AD 168: Galen suggests the cause of tumors is “a systemic overdose of black bile – trapped melancholia boiling out as a tumor.”

• 1000 years later, the “black bile” can be purged from her body, but “the tumor keeps growing, relapsing, invading and metastacizing… Medieval surgeons chisel away at her cancer with knives and scalpels. Some offer frog’s blood, lead plates, goat dung, holy water, crab paste, and caustic chemicals as treatments.”

• 1778: John Hunter assigns stages to cancer: “early, localized breast cancer or late, advanced, invasive cancer.”

• 1890: In Halsted’s Baltimore clinic, Atossa would have undergone a radical mastectomy, including “removal of the deep chest muscle and lymph nodes.”

• Early Twentieth Century: oncologists would “try to obliterate the tumor locally using X-rays.”

• 1950s: “Atossa’s cancer is treated locally with a simple mastectomy or lumpectomy followed by radiation.”

• 1970s: “Atossa’s surgery is followed by adjuvant combination chemotherapy.” If “her tumor tests positive for the estrogen receptor, Tamoxifen… is added.”

• 1986: If her tumor is discovered to be Her-2 amplified, she is treated with Herceptin. “… surgery, chemotherapy, radiation, hormonal therapy, and targeted therapy have likely added anywhere between seventeen and thirty years to her survival.”

• Mid-1990s: Atossa is tested for a BRCA-1 or BRCA-2 mutation. The results affect her future (including screening of her unaffected breast) and her daughters’ futures.

“Move Atossa into the future now”: By 2050, a flash drive will contain “the entire sequence of her cancer’s genome… the mutations will be organized into key pathways… Therapies will be targeted against these pathways to prevent relapse… She will likely take some form of medicine… for the rest of her life.”

“We might as well focus on prolonging life rather than eliminating death,” as Doll said. Perhaps our best bet is to “redefine victory.” With cancer, “no simple, universal, or definitive cure is in sight – and is never likely to be.” Remember that the Greeks called tumors “onkos, meaning ‘mass’ or ‘burden’… Cancer is indeed… the leaden counterweight to our aspirations for immortality.” In the ancient Indo-European language… onkos arises from the ancient word nek… load. It means to carry, to move the burden from one place to the next, to bear something a long distance…”

[Here the author relates the story of a dying patient, Germaine Reed, who fought for every option she could get over sixteen years as she battled “a rare kind of cancer called a gastrointestinal stromal tumor, or simply GIST.” She entered every trial available and made amazing progress several times, but nothing could produce a permanent response. Finally her cancer “spiraled out of control, growing so fast she could record its weight in pounds, as she stood on the scales…” He shares his final conversation with her before she headed for home to die. Then he returns to the history of cancer with reference to Germaine.]

“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… it was as if she had encapsulated herself as the essence of a four-thousand-year-old war.”

And so this beautifully crafted story ends. Every page (totaling more than 450) is a delight. The science is daunting at times, and the history is sometimes winsome and other times gripping. The human tale is heartwarming. A lifelong reader now at the age of 73, I can honestly say that The Emperor of All Maladies is absolutely one of the best books I’ve ever read. Maybe it means more to one who has had cancer – I don’t know. But I recommend it to you highly, for both enjoyment and self-education. For myself, I can only hope one day to meet this amazing physician, Dr. Siddhartha Mukherjee.