The Emperor of All Maladies: A Biography of Cancer (7 page)

Farber’s supply of folic acid for his disastrous first trial had come from the laboratory of an old friend, a chemist, Yellapragada Subbarao—or Yella, as most of his colleagues called him. Yella was a pioneer in many ways, a physician turned cellular physiologist, a chemist who had accidentally wandered into biology. His scientific meanderings had been presaged by more desperate and adventuresome physical meanderings.
He had arrived in Boston in 1923
, penniless and unprepared, having finished his medical training in India and secured a scholarship for a diploma at the School of Tropical Health at Harvard. The weather in Boston, Yella discovered, was far from tropical. Unable to find a medical job in the frigid, stormy winter (he had no license to practice medicine in the United States), he started as a night porter at the Brigham and Women’s Hospital, opening doors, changing sheets, and cleaning urinals.

The proximity to medicine paid off. Subbarao made friends and connections at the hospital and switched to a day job as a researcher in the
Division of Biochemistry. His initial project involved purifying molecules out of living cells, dissecting them chemically to determine their compositions—in essence, performing a biochemical “autopsy” on cells. The approach required more persistence than imagination, but it produced remarkable dividends. Subbarao purified a molecule called ATP, the source of energy in all living beings (ATP carries chemical “energy” in the cell), and another molecule called creatine, the energy carrier in muscle cells. Any one of these achievements should have been enough to guarantee him a professorship at Harvard. But Subbarao was a foreigner, a reclusive, nocturnal, heavily accented vegetarian who lived in a one-room apartment downtown, befriended only by other nocturnal recluses such as Farber. In 1940, denied tenure and recognition, Yella huffed off to join Lederle Labs, a pharmaceutical laboratory in upstate New York, owned by the American Cyanamid Corporation, where he had been asked to run a group on chemical synthesis.

At Lederle, Yella Subbarao quickly reformulated his old strategy and focused on making synthetic versions of the natural chemicals that he had found within cells, hoping to use them as nutritional supplements.
In the 1920s, another drug company
, Eli Lilly, had made a fortune selling a concentrated form of vitamin B
₁₂
, the missing nutrient in pernicious anemia. Subbarao decided to focus his attention on the other anemia, the neglected anemia of folate deficiency.
But in 1946, after many failed attempts
to extract the chemical from pigs’ livers, he switched tactics and started to synthesize folic acid from scratch, with the help of a team of scientists including Harriet Kiltie, a young chemist at Lederle.

The chemical reactions to make folic acid brought a serendipitous bonus. Since the reactions had several intermediate steps, Subbarao and Kiltie could create variants of folic acid through slight alterations in the recipe. These variants of folic acid—closely related molecular mimics—possessed counterintuitive properties. Enzymes and receptors in cells typically work by recognizing molecules using their chemical structure. But a “decoy” molecular structure—one that nearly mimics the natural molecule—can bind to the receptor or enzyme and block its action, like a false key jamming a lock. Some of Yella’s molecular mimics could thus behave like
antagonists
to folic acid.

These were precisely the antivitamins that Farber had been fantasizing about. Farber wrote to Kiltie and Subbarao asking them if he could use their folate antagonists on patients with leukemia. Subbarao consented. In the late summer of 1947, the first package of antifolate left Lederle’s labs in New York and arrived in Farber’s laboratory.

*
In 1944, the NCI would become a subsidiary component of the National Institutes of Health (NIH). This foreshadowed the creation of other disease-focused institutes over the next decades.

*
In 1946–47, Neely and Senator Claude Pepper
launched a third national cancer bill. This was defeated in Congress by a small margin in 1947.

*
In New York in the 1910s, William B. Coley, James Ewing, and Ernest Codman had treated bone sarcomas with a mixture of bacterial toxins—the so-called Coley’s toxin. Coley had observed occasional responses, but the unpredictable responses, likely caused by immune stimulation, never fully captured the attention of oncologists or surgeons.

Throughout the centuries
the sufferer from this disease has been the subject of almost every conceivable form of experimentation. The fields and forests,
the apothecary
shop and the temple, have been ransacked for some successful means of relief from this intractable malady. Hardly any animal has escaped making its contribution, in hair or hide, tooth or toenail, thymus or thyroid, liver or spleen, in the vain search by man for a means of relief.

—William Bainbridge

The search for a way to eradicate this scourge
. . . is left to incidental dabbling and uncoordinated research.

—
The Washington Post
, 1946

Seven miles southwest of the Longwood hospitals in Boston, the town of Dorchester is a typical sprawling New England suburb, a triangle wedged between the sooty industrial settlements to the west and the gray-green bays of the Atlantic to its east. In the late 1940s, waves of Jewish and Irish immigrants—shipbuilders, iron casters, railway engineers, fishermen, and factory workers—settled in Dorchester, occupying rows of brick-and-clapboard houses that snaked their way up Blue Hill Avenue. Dorchester reinvented itself as the quintessential suburban family town, with parks and playgrounds along the river, a golf course, a church, and a synagogue. On Sunday afternoons, families converged at Franklin Park to walk through its leafy pathways or to watch ostriches, polar bears, and tigers at its zoo.

On August 16, 1947, in a house across from the zoo, the child of a ship
worker in the Boston yards fell mysteriously ill with a low-grade fever that waxed and waned over two weeks without pattern, followed by increasing lethargy and pallor.
Robert Sandler
was two years old. His twin, Elliott, was an active, cherubic toddler in perfect health.

Ten days after his first fever, Robert’s condition worsened significantly. His temperature climbed higher. His complexion turned from rosy to a spectral milky white. He was brought to Children’s Hospital in Boston. His spleen, a fist-size organ that stores and makes blood (usually barely palpable underneath the rib cage), was visibly enlarged, heaving down like an overfilled bag. A drop of blood under Farber’s microscope revealed the identity of his illness; thousands of immature lymphoid leukemic blasts were dividing in a frenzy, their chromosomes condensing and uncondensing, like tiny clenched and unclenched fists.

Sandler arrived at Children’s Hospital just a few weeks after Farber had received his first package from Lederle. On September 6, 1947, Farber began to inject Sandler with pteroylaspartic acid or PAA, the first of Lederle’s antifolates. (Consent to run a clinical trial for a drug—even a toxic drug—was not typically required. Parents were occasionally cursorily informed about the trial; children were almost never informed or consulted. The Nuremberg code for human experimentation, requiring explicit voluntary consent from patients, was drafted on August 9, 1947, less than a month before the PAA trial. It is doubtful that Farber in Boston had even heard of any such required consent code.)

PAA had little effect. Over the next month Sandler turned increasingly lethargic. He developed a limp, the result of leukemia pressing down on his spinal cord. Joint aches appeared, and violent, migrating pains. Then the leukemia burst through one of the bones in his thigh, causing a fracture and unleashing a blindingly intense, indescribable pain. By December, the case seemed hopeless. The tip of Sandler’s spleen, more dense than ever with leukemia cells, dropped down to his pelvis. He was withdrawn, listless, swollen, and pale, on the verge of death.

On December 28, however, Farber received a new version of antifolate from Subbarao and Kiltie, aminopterin, a chemical with a small change from the structure of PAA. Farber snatched the drug as soon as it arrived and began to inject the boy with it, hoping, at best, for a minor reprieve in his cancer.

The response was marked. The white cell count, which had been climbing astronomically—ten thousand in September, twenty thousand in
November, and nearly seventy thousand in December—suddenly stopped rising and hovered at a plateau. Then, even more remarkably, the count actually started to drop, the leukemic blasts gradually flickering out in the blood and then all but disappearing. By New Year’s Eve, the count had dropped to nearly one-sixth of its peak value, bottoming out at a nearly normal level. The cancer hadn’t vanished—under the microscope, there were still malignant white cells—but it had temporarily abated, frozen into a hematologic stalemate in the frozen Boston winter.

On January 13, 1948, Sandler returned to the clinic, walking on his own
for the first time
in two months. His spleen and liver had shrunk so dramatically that his clothes, Farber noted, had become “loose around the abdomen.” His bleeding had stopped. His appetite turned ravenous, as if he were trying to catch up on six months of lost meals. By February, Farber noted, the child’s alertness, nutrition, and activity were equal to his twin’s. For a brief month or so, Robert Sandler and Elliott Sandler seemed identical again.

Sandler’s remission—unprecedented in the history of leukemia—set off a flurry of activity for Farber. By the early winter of 1948, more children were at his clinic: a three-year-old boy brought with a sore throat, a two-and-a-half-year-old girl with lumps in her head and neck, all eventually diagnosed with childhood ALL. Deluged with antifolates from Yella and with patients who desperately needed them, Farber recruited additional doctors to help him: a hematologist named Louis Diamond, and a group of assistants, James Wolff, Robert Mercer, and Robert Sylvester.

Farber had infuriated the authorities at Children’s Hospital with his first clinical trial. With this, the second, he pushed them over the edge.
The hospital staff voted
to take all the pediatric interns off the leukemia chemotherapy unit (the atmosphere in the leukemia wards, it was felt, was far too desperate and experimental and thus not conducive to medical education)—in essence, leaving Farber and his assistants to perform all the patient care themselves. Children with cancer, as one surgeon noted, were typically “
tucked in the farthest recesses
of the hospital wards.” They were on their deathbeds anyway, the pediatricians argued; wouldn’t it be kinder and gentler, some insisted, to just “
let them die in peace
”? When one clinician suggested that Farber’s novel “chemicals” be reserved only as a last resort for leukemic children, Farber, recalling his prior life as a pathologist, shot back,
“
By that time, the only chemical
that you will need will be embalming fluid.”

Farber outfitted a back room of a ward near the bathrooms into a makeshift clinic.
His small staff was housed
in various unused spaces in the Department of Pathology—in back rooms, stairwell shafts, and empty offices. Institutional support was minimal.
Farber’s assistants sharpened their own
bone marrow needles, a practice as antiquated as a surgeon whetting his knives on a wheel. Farber’s staff tracked the disease in patients with meticulous attention to detail: every blood count, every transfusion, every fever, was to be recorded. If leukemia was going to be beaten, Farber wanted every minute of that battle recorded for posterity—even if no one else was willing to watch it happen.