Physicians of the Utmost Fame8
Were called at once; but when they came
They answered, as they took their Fees,
âThere is no Cure for this Disease.â
âHilaire Belloc
Its palliation is a daily task9, its cure a fervent hope.
âWilliam Castle, describing leukemia in 1950
In a damp10 fourteen-by-twenty-foot laboratory in Boston on a December morning in 1947, a man named Sidney Farber waited impatiently for the arrival of a parcel from New York. The âlaboratoryâ was little more than a chemistâs closet, a poorly ventilated room buried in a half-basement of the Childrenâs Hospital, almost thrust into its back alley. A few hundred feet away, the hospitalâs medical wards were slowly thrumming to work. Children in white smocks moved restlessly on small wrought-iron cots. Doctors and nurses shuttled busily between the rooms, checking charts, writing orders, and dispensing medicines. But Farberâs lab was listless and empty, a bare warren of chemicals and glass jars connected to the main hospital through a series of icy corridors. The sharp stench of embalming formalin wafted through the air. There were no patients in the rooms here, just the bodies and tissues of patients brought down through the tunnels for autopsies and examinations. Farber was a pathologist. His job involved dissecting specimens, performing autopsies, identifying cells, and diagnosing diseases, but never treating patients.
Farberâs specialty was pediatric pathology11, the study of childrenâs diseases. He had spent nearly twenty years in these subterranean rooms staring obsessively down his microscope and climbing through the academic ranks to become chief of pathology at Childrenâs. But for Farber, pathology was becoming a disjunctive form of medicine, a discipline more preoccupied with the dead than with the living. Farber now felt impatient watching illness from its sidelines, never touching or treating a live patient. He was tired of tissues and cells. He felt trapped, embalmed in his own glassy cabinet.
And so, Farber had decided to make a drastic professional switch. Instead of squinting at inert specimens under his lens, he would try to leap into the life of the clinics upstairsâfrom the microscopic world that he knew so well into the magnified real world of patients and illnesses. He would try to use the knowledge he had gathered from his pathological specimens to devise new therapeutic interventions. The parcel from New York contained a few vials of a yellow crystalline chemical named aminopterin. It had been shipped to his laboratory in Boston on the slim hope that it might halt the growth of leukemia in children.
Had Farber asked any of the pediatricians circulating in the wards above him about the likelihood of developing an antileukemic drug, they would have advised him not to bother trying. Childhood leukemia had fascinated, confused, and frustrated doctors for more than a century. The disease had been analyzed, classified, subclassified, and subdivided meticulously; in the musty, leatherbound books on the library shelves at ChildrenâsâAndersonâs Pathology or Boydâs Pathology of Internal Diseasesâpage upon page was plastered with images of leukemia cells and appended with elaborate taxonomies to describe the cells. Yet all this knowledge only amplified the sense of medical helplessness. The disease had turned into an object of empty fascinationâa wax-museum dollâstudied and photographed in exquisite detail but without any therapeutic or practical advances. âIt gave physicians plenty to wrangle over12 at medical meetings,â an oncologist recalled, âbut it did not help their patients at all.â A patient with acute leukemia was brought to the hospital in a flurry of excitement, discussed on medical rounds with professorial grandiosity, and then, as a medical magazine drily noted, âdiagnosed, transfusedâand sent home to die.â13
The study of leukemia had been mired in confusion and despair ever since its discovery. On March 19, 1845, a Scottish physician, John Bennett, had described an unusual case, a twenty-eight-year-old slate-layer with a mysterious swelling in his spleen. âHe is of dark complexion,â14 Bennett wrote of his patient, âusually healthy and temperate; [he] states that twenty months ago, he was affected with great listlessness on exertion, which has continued to this time. In June last he noticed a tumor in the left side of his abdomen which has gradually increased in size till four months since, when it became stationary.â
The slate-layerâs tumor might have reached its final, stationary point, but his constitutional troubles only accelerated. Over the next few weeks, Bennettâs patient spiraled from symptom to symptomâfevers, flashes of bleeding, sudden fits of abdominal painâgradually at first, then on a tighter, faster arc, careening from one bout to another. Soon the slate-layer was on the verge of death with more swollen tumors sprouting in his armpits, his groin, and his neck. He was treated with the customary leeches and purging, but to no avail. At the autopsy a few weeks later, Bennett was convinced that he had found the reason behind the symptoms. His patientâs blood was chock-full of white blood cells. (White blood cells, the principal constituent of pus, typically signal the response to an infection, and Bennett reasoned that the slate-layer had succumbed to one.) âThe following case seems to me particularly valuable,â he wrote self-assuredly, âas it will serve to demonstrate the existence of true pus, formed universally within the vascular system.â
It would have been a perfectly satisfactory explanation except that Bennett could not find a source for the pus. During the necropsy, he pored carefully through the body, combing the tissues and organs for signs of an abscess or wound. But no other stigmata of infection were to be found. The blood had apparently spoiledâsuppuratedâof its own will, combusted spontaneously into true pus. âA suppuration of blood,â Bennett called his case. And he left it at that.
Bennett was wrong, of course, about his spontaneous âsuppurationâ of blood. A little over four months after Bennett had described the slaterâs illness, a twenty-four-year-old German researcher, Rudolf Virchow, independently published16 a case report with striking similarities to Bennettâs case. Virchowâs patient was a cook in her midfifties. White cells had explosively overgrown her blood, forming dense and pulpy pools in her spleen. At her autopsy, pathologists had likely not even needed a microscope to distinguish the thick, milky layer of white cells floating above the red.
Virchow, who knew of Bennettâs case, couldnât bring himself to believe Bennettâs theory. Blood, Virchow argued, had no reason to transform impetuously into anything. Moreover, the unusual symptoms bothered him: What of the massively enlarged spleen? Or the absence of any wound or source of pus in the body? Virchow began to wonder if the blood itself was abnormal. Unable to find a unifying explanation for it, and seeking a name for this condition17, Virchow ultimately settled for weisses Blutâwhite bloodâno more than a literal description of the millions of white cells he had seen under his microscope. In 1847, he changed the name to the more academic-sounding âleukemiaââfrom leukos, the Greek word for âwhite.â
Renaming the diseaseâfrom the florid âsuppuration of bloodâ to the flat weisses Blutâhardly seems like an act of scientific genius, but it had a profound impact on the understanding of leukemia. An illness, at the moment of its discovery, is a fragile idea, a hothouse flowerâdeeply, disproportionately influenced by names and classifications. (More than a century later, in the early 1980s, another change in name18âfrom gay related immune disease (GRID) to acquired immuno deficiency syndrome (AIDS)âwould signal an epic shift in the understanding of that disease.) Like Bennett, Virchow didnât understand leukemia. But unlike Bennett, he didnât 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.
The humility of the name (and the underlying humility about his understanding of cause) epitomized Virchowâs approach to medicine19. As a young professor at the University of WĂźrzburg, Virchowâs work soon extended far beyond naming leukemia. A pathologist by training, he launched a project that would occupy him for his life: describing human diseases in simple cellular terms.
It was a project born of frustration. Virchow entered medicine in the early 1840s, when nearly every disease was attributed to the workings of some invisible force: miasmas, neuroses, bad humors, and hysterias. Perplexed by what he couldnât see, Virchow turned with revolutionary zeal to what he could see: cells under the microscope. In 1838, Matthias Schleiden, a botanist, and Theodor Schwann, a physiologist, both working in Germany, had claimed that all living organisms were built out of fundamental building blocks called cells. Borrowing and extending this idea, Virchow set out to create a âcellular theoryâ 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 cellsâomnis cellula e cellula, as he put it.
The two tenets might have seemed simplistic, but they allowed Virchow to propose a crucially important hypothesis about the nature of human growth. If cells only arose from other cells, then growth could occur in only two ways: either by increasing cell numbers or by increasing cell size. Virchow called these two modes hyperplasia and hypertrophy. In hypertrophy, the number of cells did not change; instead, each individual cell merely grew in sizeâlike a balloon being blown up. Hyperplasia, in contrast, was growth by virtue of cells increasing in number. Every growing human tissue could be described in terms of hypertrophy and hyperplasia. In adult animals, fat and muscle usually grow by hypertrophy. In contrast, the liver, blood, the gut, and the skin all grow through hyperplasiaâcells becoming cells becoming more cells, omnis cellula e cellula e cellula.
That explanation was persuasive, and it provoked a new understanding not just of normal growth, but of pathological growth as well. Like normal growth, pathological growth could also be achieved through hypertrophy and hyperplasia. When the heart muscle is forced to push against a blocked aortic outlet, it often adapts by making every muscle cell bigger to generate more force, eventually resulting in a heart so overgrown that it may be unable to function normallyâpathological hypertrophy.
Conversely, and importantly for this story, Virchow soon stumbled upon the quintessential disease of pathological hyperplasiaâcancer. Looking at cancerous growths through his microscope, Virchow discovered an uncontrolled growth of cellsâhyperplasia in its extreme form. As Virchow examined the architecture of cancers, the growth often seemed to have acquired a life of its own, as if the cells had become possessed by a new and mysterious drive to grow. This was not just ordinary growth, but growth redefined, growth in a new form. Presciently (although oblivious of the mechanism) Virchow called it neoplasiaânovel, inexplicable, distorted growth, a word that would ring through the history of cancer.
By the time Virchow died in 1902, a new theory of cancer had slowly coalesced out of all these observations. Cancer was a disease of pathological hyperplasia in which cells acquired an autonomous will to divide. This aberrant, uncontrolled cell division created masses of tissue (tumors) that invaded organs and destroyed normal tissues. These tumors could also spread from one site to another, causing outcroppings of the diseaseâcalled metastasesâin distant sites, such as the bones, the brain, or the lungs. Cancer came in diverse formsâbreast, stomach, skin, and cervical cancer, leukemias and lymphomas. But all these diseases were deeply connected at the cellular level. In every case, cells had all acquired the same characteristic: uncontrollable pathological cell division.
With this understanding, pathologists who studied leukemia in the late 1880s now circled back to Virchowâs work. Leukemia, then, was not a suppuration of blood, but neoplasia of blood. Bennettâs earlier fantasy20 had germinated an entire field of fantasies among scientists, who had gone searching (and dutifully found) all sorts of invisible parasites and bacteria bursting out of leukemia cells. But once pathologists stopped looking for infectious causes and refocused the...
