The Emperor of All Maladies

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In some ways disease

does not exist until we have agreed that it does—by perceiving, naming, and responding to it.

—C. E. Rosenberg

Even an ancient monster needs a name. To name an illness is to describe a certain condition of suffering—a literary act before it becomes a medical one. A patient, long before he becomes the subject of medical scrutiny, is, at first, simply a storyteller, a narrator of suffering—a traveler who has visited the kingdom of the ill. To relieve an illness, one must begin, then, by unburdening its story.

The names of ancient illnesses are condensed stories in their own right. Typhus, a stormy disease, with erratic, vaporous fevers, arose from the Greek tuphon, the father of winds—a word that also gives rise to the modern typhoon. Influenza emerged from the Latin influentia because medieval doctors imagined that the cyclical epidemics of flu were influenced by stars and planets revolving toward and away from the earth. Tuberculosis coagulated out of the Latin tuber, referring to the swollen lumps of glands that looked like small vegetables. Lymphatic tuberculosis, TB of the lymph glands, was called scrofula, from the Latin word for “piglet,” evoking the rather morbid image of a chain of swollen glands arranged in a line like a group of suckling pigs.

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, with its clutch of swollen blood vessels around it, reminded Hippocrates of a crab dug in the sand with its legs spread in a circle. The image was peculiar (few cancers truly resemble crabs), but also vivid. Later writers, both doctors and patients

, added embellishments. For some, the hardened, matted surface of the tumor was reminiscent of the tough carapace of a crab’s body. Others felt a crab moving under the flesh as the disease spread stealthily throughout the body. For yet others, the sudden stab of pain produced by the disease was like being caught in the grip of a crab’s pincers.

Another Greek word would intersect with the history of cancer—onkos, a word used occasionally to describe tumors, from which the discipline of oncology would take its modern name. Onkos was the Greek term for a mass or a load, or more commonly a burden; cancer was imagined as a burden carried by the body. In Greek theater, the same word, onkos, would be used to denote a tragic mask that was often “burdened” with an unwieldy conical weight on its head to denote the psychic load carried by its wearer.

But while these vivid metaphors might resonate with our contemporary understanding of cancer, what Hippocrates called karkinos and the disease that we now know as cancer were, in fact, vastly different creatures. Hippocrates’ karkinos were mostly large, superficial tumors that were easily visible to the eye: cancers of the breast, skin, jaw, neck, and tongue. Even the distinction between malignant and nonmalignant tumors likely escaped Hippocrates: his karkinos included every conceivable form of swelling—nodes, carbuncles, polyps, protrusions, tubercles, pustules, and glands—lumps lumped indiscriminately into the same category of pathology.

The Greeks had no microscopes. They had never imagined an entity called a cell, let alone seen one, and the idea that karkinos was the uncontrolled growth of cells could not possibly have occurred to them. They were, however, preoccupied with fluid mechanics—with waterwheels, pistons, valves, chambers, and sluices—a revolution in hydraulic science originating with irrigation and canal-digging and culminating with Archaemedes discovering his eponymous laws in his bathtub. This preoccupation with hydraulics also flowed into Greek medicine and pathology. To explain illness—all illness—Hippocrates fashioned an elaborate doctrine based on fluids and volumes, which he freely applied to pneumonia, boils, dysentery, and hemorrhoids. The human body, Hippocrates proposed, was composed of four cardinal fluids called humors: blood, black bile, yellow bile, and phlegm. Each of these fluids had a unique color (red, black, yellow, and white), viscosity, and essential character. In the normal body, these four fluids were held in perfect, if somewhat precarious, balance. In illness, this balance was upset by the excess of one fluid.

The physician Claudius Galen, a prolific writer and influential Greek doctor who practiced among the Romans around AD 160, brought Hippocrates’ humoral theory to its apogee. Like Hippocrates, Galen set about classifying all illnesses in terms of excesses of various fluids. Inflammation—a red, hot, painful distension—was attributed to an overabundance of blood. Tubercles, pustules, catarrh, and nodules of lymph—all cool, boggy, and white—were excesses of phlegm. Jaundice was the overflow of yellow bile. For cancer, Galen reserved the most malevolent and disquieting of the four humors: black bile. (Only one other disease, replete with metaphors, would be attributed to an excess of this oily, viscous humor: depression. Indeed, melancholia, the medieval name for “depression,” would draw its name from the Greek melas, “black,” and khole, “bile.” Depression and cancer, the psychic and physical diseases of black bile, were thus intrinsically intertwined.) Galen proposed that cancer was “trapped” black bile—static bile unable to escape from a site and thus congealed into a matted mass. “Of blacke cholor

[bile], without boyling cometh cancer,” Thomas Gale, the English surgeon, wrote of Galen’s theory in the sixteenth century, “and if the humor be sharpe, it maketh ulceration, and for this cause, these tumors are more blacker in color.”

That short, vivid description would have a profound impact on the future of oncology—much broader than Galen (or Gale) may have intended. Cancer, Galenic theory suggested, was the result of a systemic malignant state, an internal overdose of black bile. Tumors were just local outcroppings of a deep-seated bodily dysfunction, an imbalance of physiology that had pervaded the entire corpus. Hippocrates had once abstrusely opined that cancer was “best left untreated,

since patients live longer that way.” Five centuries later, Galen had explained his teacher’s gnomic musings in a fantastical swoop of physiological conjecture. The problem with treating cancer surgically, Galen suggested, was that black bile was everywhere, as inevitable and pervasive as any fluid. You could cut cancer out, but the bile would flow right back, like sap seeping through the limbs of a tree.

Galen died in Rome in 199 AD, but his influence on medicine stretched over the centuries. The black-bile theory of cancer was so metaphorically seductive that it clung on tenaciously in the minds of doctors. The surgical removal of tumors—a local solution to a systemic problem—was thus perceived as a fool’s operation. Generations of surgeons layered their own observations on Galen’s, solidifying the theory even further. “Do not be led away and offer

to operate,” John of Arderne wrote in the mid-1300s. “It will only be a disgrace to you.” Leonard Bertipaglia, perhaps the most influential surgeon of the fifteenth century, added his own admonishment: “Those who pretend

to cure cancer by incising, lifting, and extirpating it only transform a nonulcerous cancer into an ulcerous one. . . . In all my practice, I have never seen a cancer cured by incision, nor known anyone who has.”

Unwittingly, Galen may actually have done the future victims of cancer a favor—at least a temporary one. In the absence of anesthesia and antibiotics, most surgical operations performed in the dank chamber of a medieval clinic—or more typically in the back room of a barbershop with a rusty knife and leather straps for restraints—were disastrous, life-threatening affairs. The sixteenth-century surgeon Ambroise Paré described charring tumors

with a soldering iron heated on coals, or chemically searing them with a paste of sulfuric acid. Even a small nick in the skin, treated thus, could quickly suppurate into a lethal infection. The tumors would often profusely bleed at the slightest provocation.

Lorenz Heister, an eighteenth-century German physician, once described a mastectomy in his clinic as if it were a sacrificial ritual: “Many females can stand the operation

with the greatest courage and without hardly moaning at all. Others, however, make such a clamor that they may dishearten even the most undaunted surgeon and hinder the operation. To perform the operation, the surgeon should be steadfast and not allow himself to become discomforted by the cries of the patient.”

Unsurprisingly, rather than take their chances with such “undaunted” surgeons, most patients chose to hang their fates with Galen and try systemic medicines to purge the black bile. The apothecary

thus soon filled up with an enormous list of remedies for cancer: tincture of lead, extracts of arsenic, boar’s tooth, fox lungs, rasped ivory, hulled castor, ground white-coral, ipecac, senna, and a smattering of purgatives and laxatives. There was alcohol and the tincture of opium for intractable pain. In the seventeenth century, a paste of crab’s eyes, at five shillings a pound, was popular—using fire to treat fire. The ointments and salves grew increasingly bizarre by the century: goat’s dung, frogs, crow’s feet, dog fennel, tortoise liver, the laying of hands, blessed waters, or the compression of the tumor with lead plates.

Despite Galen’s advice, an occasional small tumor was still surgically excised. (Even Galen had reportedly performed such surgeries, possibly for cosmetic or palliative reasons.) But the idea of surgical removal of cancer as a curative treatment was entertained only in the most extreme circumstances. When medicines and operations failed, doctors resorted to the only established treatment for cancer, borrowed from Galen’s teachings: an intricate series of bleeding and purging rituals to squeeze the humors out of the body, as if it were an overfilled, heavy sponge.

Vanishing Humors (#ulink_498a6d01-6dd6-53bb-b481-63e412c92c03)

Rack’t carcasses

make ill Anatomies.

—John Donne

In the winter of 1533, a nineteen-year-old student from Brussels, Andreas Vesalius, arrived at the University of Paris hoping to learn Galenic anatomy and pathology and to start a practice in surgery. To Vesalius’s shock and disappointment, the anatomy lessons at the university were in a preposterous state of disarray. The school lacked a specific space for performing dissections. The basement of the Hospital Dieu, where anatomy demonstrations were held, was a theatrically macabre space where instructors hacked their way through decaying cadavers while dogs gnawed on bones and drippings below. “Aside from the eight muscles

of the abdomen, badly mangled and in the wrong order, no one had ever shown a muscle to me, nor any bone, much less the succession of nerves, veins, and arteries,” Vesalius wrote in a letter. Without a map of human organs to guide them, surgeons were left to hack their way through the body like sailors sent to sea without a map—the blind leading the ill.

Frustrated with these ad hoc dissections, Vesalius decided to create his own anatomical map. He needed his own specimens

, and he began to scour the graveyards around Paris for bones and bodies. At Montfaucon, he stumbled upon the massive gibbet of the city of Paris, where the bodies of petty prisoners were often left dangling. A few miles away, at the Cemetery of the Innocents, the skeletons of victims of the Great Plague lay half-exposed in their graves, eroded down to the bone.

The gibbet and the graveyard—the convenience stores for the medieval anatomist—yielded specimen after specimen for Vesalius, and he compulsively raided them, often returning twice a day to cut pieces dangling from the chains and smuggle them off to his dissection chamber. Anatomy came alive for him in this grisly world of the dead. In 1538, collaborating with artists in Titian’s studio, Vesalius began to publish his detailed drawings in plates and books—elaborate and delicate etchings charting the courses of arteries and veins, mapping nerves and lymph nodes. In some plates, he pulled away layers of tissue, exposing the delicate surgical planes underneath. In another drawing, he sliced through the brain in deft horizontal sections—a human CT scanner, centuries before its time—to demonstrate the relationship between the cisterns and the ventricles.

Vesalius’s anatomical project had started as a purely intellectual exercise but was soon propelled toward a pragmatic need. Galen’s humoral theory of disease—that all diseases were pathological accumulations of the four cardinal fluids—required that patients be bled and purged to squeeze the culprit humors out of the body. But for the bleedings to be successful, they had to be performed at specific sites in the body. If the patient was to be bled prophylactically (that is, to prevent disease), then the purging was to be performed far away from the possible disease site, so that the humors could be diverted from it. But if the patient was being bled therapeutically—to cure an established disease—then the bleeding had to be done from nearby vessels leading into the site.

To clarify this already foggy theory, Galen had borrowed an equally foggy Hippocratic expression, kat' 'i'xiu—Greek for “straight into”—to describe isolating the vessels that led “straight into” tumors. But Galen’s terminology had pitched physicians into further confusion. What on earth, they wondered, had Galen meant by “straight into”? Which vessels led “straight into” a tumor or an organ, and which led the way out? The instructions became a maze of misunderstanding. In the absence of a systematic anatomical map—without the establishment of normality—abnormal anatomy was impossible to fathom.

Vesalius decided to solve the problem by systematically sketching out every blood vessel and nerve in the body, producing an anatomical atlas for surgeons. “In the course of explaining the opinion

of the divine Hippocrates and Galen,” he wrote in a letter, “I happened to delineate the veins on a chart, thinking that thus I might be able easily to demonstrate what Hippocrates understood by the expression kat' 'i'xiu, for you know how much dissension and controversy on venesection was stirred up, even among the learned.”

But having started this project, Vesalius found that he could not stop. “My drawing of the veins pleased the professors of medicine and all the students so much that they earnestly sought from me a diagram of the arteries and also one of the nerves. . . . I could not disappoint them.” The body was endlessly interconnected: veins ran parallel to nerves, the nerves were connected to the spinal cord, the cord to the brain, and so forth. Anatomy could only be captured in its totality, and soon the project became so gargantuan and complex that it had to be outsourced to yet other illustrators to complete.

But no matter how diligently Vesalius pored through the body, he could not find Galen’s black bile. The word autopsy comes from the Greek “to see for oneself”; as Vesalius learned to see for himself, he could no longer force Galen’s mystical visions to fit his own. The lymphatic system carried a pale, watery fluid; the blood vessels were filled, as expected, with blood. Yellow bile was in the liver. But black bile—Galen’s oozing carrier of cancer and depression—could not be found anywhere.

Vesalius now found himself in a strange position. He had emerged from a tradition steeped in Galenic scholarship; he had studied, edited, and republished Galen’s books. But black bile—that glistening centerpiece of Galen’s physiology—was nowhere to be found. Vesalius hedged about his discovery. Guiltily, he heaped even more praise on the long-dead Galen. But, an empiricist to the core, Vesalius left his drawings just as he saw things, leaving others to draw their own conclusions. There was no black bile. 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, published a textbook called The Morbid Anatomy of Some of the Most Important Parts of the Human Body. Baillie’s book, written for surgeons and anatomists, was the obverse of Vesalius’s project: if Vesalius had mapped out “normal” anatomy, Baillie mapped the body in its diseased, abnormal state. It was Vesalius’s study read through an inverted lens. Galen’s fantastical speculations about illnesses were even more at stake here. Black bile may not have existed discernably in normal tissue, but tumors should have been chock-full of it. But none was to be found. Baillie described cancers of the lung (“as large as an orange”

), stomach (“a fungous appearance”

), and the testicles (“a foul deep ulcer”

) and provided vivid engravings of these tumors. But he could not find the channels of bile anywhere—not even in his orange-size tumors, nor in the deepest cavities of his “foul deep ulcers.” If Galen’s web of invisible fluids existed, then it existed outside tumors, outside the pathological world, outside the boundaries of normal anatomical inquiry—in short, outside medical science. 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, that had so gripped the minds of doctors and patients for centuries, vanished from the picture.

“Remote Sympathy” (#ulink_5572c14a-6ce8-5415-8620-c204a488cca3)

In treating of cancer

, we shall remark, that little or no confidence should be placed either in internal . . . remedies, and that there is nothing, except the total separation of the part affected.

—A Dictionary of Practical Surgery, 1836

Matthew Baillie’s Morbid Anatomy laid the intellectual foundation for the surgical extractions of tumors. If black bile did not exist, as Baillie had discovered, then removing cancer surgically might indeed rid the body of the disease. But surgery, as a discipline, was not yet ready for such operations. In the 1760s, a Scottish surgeon, John Hunter, Baillie’s maternal uncle, had started to remove tumors from his patients in a clinic in London in quiet defiance of Galen’s teachings. But Hunter’s elaborate studies—initially performed on animals and cadavers in a shadowy menagerie in his own house—were stuck at a critical bottleneck. He could nimbly reach down into the tumors and, if they were “movable” (as he called superficial, noninvasive cancers), pull them out without disturbing the tender architecture of tissues underneath. “If a tumor is not only movable

but the part naturally so,” Hunter wrote, “they may be safely removed also. But it requires great caution to know if any of these consequent tumors are within proper reach, for we are apt to be deceived.”

That last sentence was crucial. Albeit crudely, Hunter had begun to classify tumors into “stages.” Movable tumors were typically early-stage, local cancers. Immovable tumors were advanced, invasive, and even metastatic. Hunter concluded that only movable cancers were worth removing surgically. For more advanced forms of cancer, he advised an honest, if chilling, remedy reminiscent of Imhotep’s: “remote sympathy.”*

Hunter was an immaculate anatomist, but his surgical mind was far ahead of his hand. A reckless and restless man with nearly maniacal energy who slept only four hours a night, Hunter had practiced his surgical skills endlessly on cadavers from every nook of the animal kingdom—on monkeys, sharks, walruses, pheasants, bears, and ducks. But with live human patients, he found himself at a standstill. Even if he worked at breakneck speed, having drugged his patient with alcohol and opium to near oblivion, the leap from cool, bloodless corpses to live patients was fraught with danger. As if the pain during surgery were not bad enough, the threat of infections after surgery loomed. Those who survived the terrifying crucible of the operating table often died even more miserable deaths in their own beds soon afterward.

In the brief span between 1846 and 1867, two discoveries swept away these two quandaries that had haunted surgery, thus allowing cancer surgeons to revisit the bold procedures that Hunter had tried to perfect in London.

The first of these discoveries, anesthesia, was publicly demonstrated in 1846 in a packed surgical amphitheater at Massachusetts General Hospital, less than ten miles from where Sidney Farber’s basement laboratory would be located a century later. At about ten o’clock on the morning of October 16, a group of doctors gathered in a pitlike room at the center of the hospital. A Boston dentist, William Morton, unveiled a small glass vaporizer, containing about a quart of ether, fitted with an inhaler. He opened the nozzle and asked the patient, Edward Abbott, a printer, to take a few whiffs of the vapor. As Abbott lolled into a deep sleep, a surgeon stepped into the center of the amphitheater and, with a few brisk strokes, deftly made a small incision in Abbott’s neck and closed a swollen, malformed blood vessel (referred to as a “tumor,” conflating malignant and benign swellings) with a quick stitch. When Abbott awoke a few minutes later, he said, “I did not experience pain

at any time, though I knew that the operation was proceeding.”

Anesthesia—the dissociation of pain from surgery—allowed surgeons to perform prolonged operations, often lasting several hours. But the hurdle of postsurgical infection remained. Until the mid-nineteenth century, such infections were common and universally lethal, but their cause remained a mystery. “It must be some subtle principle

contained [in the wound],” one surgeon concluded in 1819, “which eludes the sight.”

In 1865, a Scottish surgeon named Joseph Lister made an unusual conjecture on how to neutralize that “subtle principle” lurking elusively in the wound. Lister began with an old clinical observation: wounds left open to the air would quickly turn gangrenous, while closed wounds would often remain clean and uninfected. In the postsurgical wards of the Glasgow infirmary, Lister had again and again seen an angry red margin begin to spread out from the wound and then the skin seemed to rot from inside out, often followed by fever, pus, and a swift death (a bona fide “suppuration”).

Lister thought of a distant, seemingly unrelated experiment. In Paris, Louis Pasteur, the great French chemist, had shown that meat broth left exposed to the air would soon turn turbid and begin to ferment, while meat broth sealed in a sterilized vacuum jar would remain clear. Based on these observations, Pasteur had made a bold claim: the turbidity was caused by the growth of invisible microorganisms—bacteria—that had fallen out of the air into the broth. Lister took Pasteur’s reasoning further. An open wound—a mixture of clotted blood and denuded flesh—was, after all, a human variant of Pasteur’s meat broth, a natural petri dish for bacterial growth. Could the bacteria that had dropped into Pasteur’s cultures in France also be dropping out of the air into Lister’s patients’ wounds in Scotland?

Lister then made another inspired leap of logic. If postsurgical infections were being caused by bacteria, then perhaps an antibacterial process or chemical could curb these infections. It “occurred to me,”

he wrote in his clinical notes, “that the decomposition in the injured part might be avoided without excluding the air, by applying as a dressing some material capable of destroying the life of the floating particles.”

In the neighboring town of Carlisle, Lister had observed sewage disposers cleanse their waste with a cheap, sweet-smelling liquid containing carbolic acid. Lister began to apply carbolic acid paste to wounds after surgery. (That he was applying a sewage cleanser to his patients appears not to have struck him as even the slightest bit unusual.)

In August 1867, a thirteen-year-old

boy who had severely cut his arm while operating a machine at a fair in Glasgow was admitted to Lister’s infirmary. The boy’s wound was open and smeared with grime—a setup for gangrene. But rather than amputating the arm, Lister tried a salve of carbolic acid, hoping to keep the arm alive and uninfected. The wound teetered on the edge of a terrifying infection, threatening to become an abscess. But Lister persisted, intensifying his application of carbolic acid paste. For a few weeks, the whole effort seemed hopeless. But then, like a fire running to the end of a rope, the wound began to dry up. A month later, when the poultices were removed, the skin had completely healed underneath.

It was not long before Lister’s invention was joined to the advancing front of cancer surgery. In 1869, Lister removed a breast tumor

from his sister, Isabella Pim, using a dining table as his operating table, ether for anesthesia, and carbolic acid as his antiseptic. She survived without an infection (although she would eventually die of liver metastasis three years later). A few months later, Lister performed an extensive amputation

on another patient with cancer, likely a sarcoma in a thigh. 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.

Antisepsis and anesthesia were twin technological breakthroughs that released surgery from its constraining medieval chrysalis. Armed with ether and carbolic soap, a new generation of surgeons lunged toward the forbiddingly complex anatomical procedures that Hunter and his colleagues had once concocted on cadavers. An incandescent century of cancer surgery emerged; between 1850 to 1950, surgeons brazenly attacked cancer by cutting open the body and removing tumors.

Emblematic of this era was the prolific Viennese surgeon Theodor Billroth. Born in 1821, Billroth studied music and surgery with almost equal verve. (The professions still often go hand in hand. Both push manual skill to its limit; both mature with practice and age; both depend on immediacy, precision, and opposable thumbs.) In 1867, as a professor in Berlin, Billroth launched a systematic study of methods to open the human abdomen to remove malignant masses. Until Billroth’s

time, the mortality following abdominal surgery had been forbidding. Billroth’s approach to the problem was meticulous and formal: 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 1880s, he had established the routes: “The course so far is already

sufficient proof that the operation is possible,” he wrote. “Our next care, and the subject of our next studies, must be to determine the indications, and to develop the technique to suit all kinds of cases. I hope we have taken another good step forward towards securing unfortunate people hitherto regarded as incurable.”

At the Allgemeines Krankenhaus, the teaching hospital in Vienna where he was appointed a professor, Billroth and his students now began to master and use a variety of techniques to remove tumors from the stomach, colon, ovaries, and esophagus, hoping to cure the body of cancer. The switch from exploration to cure produced an unanticipated challenge. A cancer surgeon’s task was to remove malignant tissue while leaving normal tissues and organs intact. But this task, Billroth soon discovered, demanded a nearly godlike creative spirit.

Since the time of Vesalius, surgery had been immersed in the study of natural anatomy. But cancer so often disobeyed and distorted natural anatomical boundaries that unnatural boundaries had to be invented to constrain it. To remove the distal end of a stomach filled with cancer, for instance, Billroth had to hook up the pouch remaining after surgery to a nearby piece of the small intestine. To remove the entire bottom half of the stomach, he had to attach the remainder to a piece of distant jejunum. By the mid-1890s, Billroth had operated on forty-one patients with gastric carcinoma using these novel anatomical reconfigurations. Nineteen of these patients had survived the surgery.

These procedures represented pivotal advances in the treatment of cancer. By the early twentieth century, many locally restricted cancers (i.e., primary tumors without metastatic lesions) could be removed by surgery. These included uterine and ovarian cancer, breast and prostate cancer, colon cancer, and lung cancer. If these tumors were removed before they had invaded other organs, these operations produced cures in a significant fraction of patients.

But despite these remarkable advances, some cancers—even seemingly locally restricted ones—still relapsed after surgery, prompting second and often third attempts to resect tumors. Surgeons returned to the operating table

and cut and cut again, as if caught in a cat-and-mouse game, as cancer was slowly excavated out of the human body piece by piece.

But what if the whole of cancer could be uprooted at its earliest stage using the most definitive surgery conceivable? What if cancer, incurable by means of conventional local surgery, could be cured by a radical, aggressive operation that would dig out its roots so completely, so exhaustively, that no possible trace was left behind? In an era captivated by the potency and creativity of surgeons, the idea of a surgeon’s knife extracting cancer by its roots was imbued with promise and wonder. It would land on the already brittle and combustible world of oncology like a firecracker thrown into gunpowder.