The Emperor of All Maladies: A Biography of Cancer

In 1947, Sidney Farber, head of pediatric pathology at Boston Children’s Hospital, waits in his basement laboratory for the arrival of a chemical called aminopterin with which he hopes to treat leukemia. However, childhood leukemia has confused doctors for over 100 years. In 1845, a Scottish physician named John Bennett found a profusion of white blood cells in a slate-layer who died of tumors. Unable to figure out where the white blood cells came from, he deduced the blood had produced it on its own. A few months later, Rudolf Virchow, a German researcher, published a study of a similar case. He, too, struggled to find a cause for the white blood cells proliferating in the patient’s blood or for her enlarged spleen, so he came up with a name for it—weisses blut, or “white blood,” which he changed in 1847 to “leukemia,” using the Greek word for white, leukos.

Although this might not seem like a step forward, Virchow cleared the slate from the misunderstanding that the disease resulted from the suppuration of blood. As a pathologist, he began to use the theory that the cell was the building block of living things, developed by Schleiden and Schwann, into theories that would explain biology. The two main ideas were that cells made up all bodies and that cells came from other cells. This helped Virchow develop the idea that growth could only occur through “hyperplasia” (the growth in the number of cells) or “hypertrophy” (the growth of the size of cells).

Looking at cells in his microscope, he discovered hyperplasia, or the growth of abnormal cells. He referred to this as a “neoplasia.” By the time of his death in 1902, the theory of cancer—that it was a result of pathological hyperplasia—had development. The uncontrolled division of cells resulted in tumors, which invaded organs, destroyed tissues, and spread throughout the body. Scientists understood leukemia as a neoplasia of the blood that occurred in different forms—indolent and chronic or acute and violent. The acute form of the disease was categorized into two other forms: Acute myeloid leukemia (AML) affects the myeloid cells, while acute lymphoblastic leukemia (ALL) affects the lymphoid cells. Childhood leukemia was most often ALL, which could kill people very quickly.

Carla’s blood had five times the number of white blood cells as the average adult. Of these cell, 95% were blasts, which are unable to mature into developed cells, or lymphocytes, so they were useless in fighting illness. Bone marrow produces white blood cells, but blasts had taken over Carla’s bone marrow, so she could not produce blood. Her blood could not carry oxygen because her red blood cell count had dipped so low. Treatment would require killing what red blood cells remained in an attempt to save her.

Sidney Farber, born in Buffalo in 1903 to a former bargeman in Poland, grew up in an academically-challenging environment. The third of 14 children, he lived in a poor Jewish neighborhood and studied biology and philosophy at the University of Buffalo. Fluent in German, he studied medicine in Germany and was admitted to Harvard Medical School, rare for a Jewish student at the time. Known for his meticulous attitude, he became a pathologist at Children’s Hospital but yearned to help patients, and his interests settled on leukemia. In the years before MRIs and CT scans, doctors could not measure tumors, but they could count the cells in the blood, and this made Farber think he could develop a medicine to treat leukemia. He believed that working from the cellular level up, he could come to understand this disease, and he eagerly ripped open the package that arrived for him. 

Sidney Farber’s package arrived at an opportune time, as the market was flooded with pharmaceuticals, including penicillin and other antibiotics. In addition, improved public health measures were in part responsible for drastically lengthening the average American’s lifespan. As health care improved, people expected that cures would improve too, but cancer remained intractable. However, the two ways to treat it remained either cutting it out (called “extirpations”) or incinerating it with radiation. Cancer became a more prominent disease after other conditions, such as smallpox and tuberculosis, receded.

There were different attempts to raise funds for its cure. In 1910, a group of cancer surgeons, the American Association for Cancer Research, called on Taft to create a national laboratory for cancer research, but this proposal failed. In 1927, Matthew Neely, a US representative from West Virginia, asked Congress for a $5 million reward for information that could help cure cancer; after quick remedies poured in, Congress authorized a mere $50,000 for a Cancer Control Bill. In the 1930s, after articles in Fortune and Time called attention to cancer and generated alarm, Congress passed a law that Roosevelt signed called the National Cancer Institute Act, which created the National Cancer Institute (NCI) to coordinate research in Bethesda. During the war, however, the institute floundered as the government directed the nation’s efforts elsewhere.

By the time Farber began cancer research in 1947, the public outcry around cancer had quieted. Farber toiled in isolation, as leukemia was a medical orphan that both surgeons and internists had abandoned. Farber learned a great deal from a hematologist at Children’s Hospital named George Minot. Minot studied a condition called pernicious anemia and discovered that restoring a molecule called B12 to the blood could cure the patient. In a larger sense, he showed that “blood was an organ whose activity could be turned on and off by molecular switches” (28). A young English doctor named Lucy Wills found that Marmite could cure anemia among the malnourished mill workers of Bombay, India. This yeasty spread contained folic acid, which is necessary for cells to build DNA.

Using this information, Farber gave pediatric leukemia patients folic acid, but this only accelerated the course of their disease. While the pediatricians were upset with the results, Farber was energized and thought about trying to create something that had the opposite effect of the folate. He obsessed about this line of research during his dinners with his wife, Norma, a musician and writer.

Farber procured his folic acid supply from a chemist named Yellapragada Subbarao, or Yella. Yella arrived in Boston from India in 1923, and he worked as a night porter at Brigham and Women’s Hospital, despite his medical training in India. He then worked in the Division of Biochemistry during the day, where he purified molecules to determine their composition. He purified ATP, the energy source for the cell, and creatine, which carries energy in muscle cells. Because he was a reclusive foreigner, the administration denied him tenure despite his achievements, so he joined a pharmaceutical laboratory in New York called Lederle Labs. There, he tried to synthesize folic acid from scratch. At the same time, he created “antivitamins” that could mimic the natural molecule and bind to its receptor to block its effects. These were the antivitamins Farber wanted, and he received his first package of antifolate in the summer of 1947.

In 1947, a 2-year-old named Robert Sandler, the son of a ship worker in Dorchester, Massachusetts, came to Children’s Hospital with an enlarged spleen (the organ that makes and stores blood) and with his blood filled with lymphoid leukemic blasts. Faber began to inject the child with pteroylaspartic acid, or PAA, the first of the antifolates from Lederle, but it had little effect. The child was near to death. Then, Farber received a new antifolate called aminopterin. When he injected Robert Sandler with aminopterin, “the response was marked” (33). His white cell count stopped rising and then dropped, and his spleen, energy, and appetite returned. For a while, he was in remission—a state that was unprecedented in the treatment of leukemia.

By the winter of 1948, other children came to Farber for ALL treatment. The hospital, infuriated by his trials, removed all pediatric interns off the unit, and Farber and his assistants had to carry out all the trials on their own. The clinic was located in makeshift rooms in the Department of Pathology, where Farber kept meticulous records on his patients. The pattern for the patients remained the same. After some experienced remission for a few months, the cancer would return. Robert Sandler died in 1948 after his remission.

However, the remissions, though temporary, were remissions, and Farber published a paper in the New England Journal of Medicine in 1948 documenting that of the first 16 patients, 10 had responded to his intervention. Although the scientific community met his paper with skepticism, the findings suggested that doctors could treat cancer with a chemical. As the author writes about Farber, “He was throwing down a gauntlet for cancer medicine. It was then up to an entire generation of doctors and scientists to pick it up” (36).

Just as tuberculosis was emblematic of the 19th century, according to Susan Sontag, author of Illness as Metaphor, Mukherjee believes cancer is emblematic of the 20th century, with its metaphor of uncontrolled growth. Although both diseases extend one’s encounter with death, Mukherjee writes that tuberculosis is a “febrile” and “obsessive” disease indicative of “Victorian romanticism” (38). Cancer, however, is the disease of one cell growing out of proportion—the disease of individualism gone haywire. Consumption killed people by hollowing them out, while metastasis, meaning “beyond stillness” (38), fills someone up with cancerous cells.

Cancer is, the author writes, a perversion of the normal growth process. It is a clonal disease, evolving from the same cell, but it is also an evolving disease in which each generation is different from what came before. The cancer cells mutate, also perverting the Darwinian process of evolution and natural selection.

The author gives us the biography of cancer, as if it were a person. He writes about its birth and the discovery, in 1862, of an Egyptian papyrus containing a transcription from 2500 BCE of a manuscript from the 17th century BCE. An Egyptologist named Edwin Smith bought the artifact, called the Smith papyrus, in Luxor. The Smith papyrus contains the writings of Imhotep, an Egyptian physician from 2625 BCE, who wrote about medical cases. One case, involving a description of “bulging masses” (40), is an explanation of breast cancer. Although he wrote of other cures, Imhotep wrote that there was no cure for cancer.

Then, descriptions of cancer disappear from the medical literature until Herodotus’s Histories (circa 440 BCE), in which he describes Atossa, the queen of Persia, who was suffering from an inflammatory mass in her breast. She withdrew into a self-imposed quarantine until a Greek slave named Democedes convinced her to allow him to cut off the lump. Atossa survived, and thankful to Democedes, she convinced her husband, Darius, to invade Greece so that her slave could return home. Cancer, therefore, changed the course of history.

However, scientists don’t know if the tumors these two writers described were truly cancerous. In the Atacama Desert, located in the southern part of Peru, a professor named Arthur Aufderheide dug up 1,000-year-old mummified bodies and carried out autopsies on them. In one woman who died in her mid-30s, he found a tumor of the bone. Other paleopathologists (those who study ancient bodies) have found cases of cancer in mummies in Egypt from about 400 AD. Louis Leakey, an archeologist who dug up some of the oldest skeletons ever found, discovered lymphoma in a jaw bone that was from about 2 million years ago.

However, cancer in the ancient world was rare. Although the ancients were familiar with other diseases such as smallpox and tuberculosis, there is little mention of cancer. One reason for this is that the risk of cancer increases with age, and people didn’t live long enough to get it. Other diseases often killed people before they could reach advanced ages. In addition, modern technology has allowed us to detect and observe cancers that were undetectable in the past. Modern life has shifted the kinds of cancers that occur more often. Before modern hygiene, stomach cancer, the result of bacteria, was more common, and with the growth of smoking in the 1950s, lung cancer became more common. By the 1940s, cancer had become the leading cause of death in America, following heart disease.

Mukherjee explains how the naming of an illness is a kind of literary act that defines its suffering. During the time of Hippocrates, around 400 BC, a world for cancer first showed up in the medical literature. It was karkinos, from the Greek word for “crab,” as the tumor surrounded by swollen blood vessels made Hippocrates think of a crab. Another Greek word for cancer was onkos, meaning “a mass,” which would give rise to the word “oncology.” Karkinos, however, referred to visible tumors, as the Greeks did not have microscopes and could not see the growth of cells that cancer causes. Obsessed with fluid mechanics, the Greeks, through Hippocrates, developed the idea that the human body was composed of four humors: blood, yellow bile, black bile, and phlegm. Imbalance in these fluids resulted in illness.

Galen, who popularized the idea of the four humors, thought cancer resulted from an excess of black bile. Only one other illness—melancholia—resulted from this excess. He believed that the tumor was the outward expression of an underlying imbalance with too much black bile. This idea had a tenacious hold on medicine, and doctors did not believe in cutting out tumors because they believed that this would be an ineffective way to treat a systemic problem. This may have unwittingly been advantageous for cancer sufferers, as surgery was conducted without anesthesia or antibiotics. Instead, physicians often treated cancer with odd salves to purge the black bile, including fox lungs and paste of crab’s eyes. 

In 1533, a student from Brussels named Andreas Vesalius arrived at the University of Paris to learn anatomy and pathology, but he found the anatomy lessons at the school lacking. Frustrated, he went to the gibbet (gallows) in the city of Paris as well as to graveyards to procure bodies.

Vesalius used these bodies to produce detailed drawings of the bodies that were necessary if physicians used purging or bleeding to treat cancer. Soon, he embarked on a project to map every vein, artery, and nerve in the body, but he could not find the “black bile” that Galen spoke about. Although he began as a devotee of Galen, he couldn’t find empirical proof of Galen’s theories.

In 1793, Matthew Baillie, an anatomist in London, published a textbook of the body in its diseased state. He also found no evidence of black bile in cancerous tumors. The idea that black bile led to cancer no longer held sway in medicine.

Baillie’s book, Morbid Anatomy, set the stage for the surgical removal of tumors, but surgery wasn’t quite ready for these types of operations. John Hunter, a Scottish surgeon who was Baillie’s uncle, began to work on removing tumors surgically. He found that some tumors, in the early stage, were what he called “moveable” (55), but later-stage tumors were not, and he recommended a remedy that recalled Imhotep’s “remote sympathy” (55). A restless man who had practiced surgery on animals and cadavers, Hunter still found surgery was difficult on patients because of pain during surgery and infections afterward.

Two advances made surgery more feasible. One was the discovery of anesthesia, which was publicly demonstrated at Massachusetts General Hospital in 1846. Still, infections remained a problem until Scottish surgeon Joseph Lister deduced that bacteria caused postsurgical infections in 1865 and began to use carbolic acid to cure these infections. After using carbolic acid paste to clean wounds, he began to use it in surgeries to remove cancerous tumors.

In the period from 1850 to 1950, surgeons, armed with the twin weapons of ether (anesthesia) and antisepsis, began to remove tumors. Viennese surgeon Theodor Billroth studied how to safely remove abdominal and other tumors, which often required an understanding of how cancer subverted normal anatomy. By the early 20th century, surgery could remove many localized tumors. The idea remained of trying to root out cancer and eradicate it, leaving no trace of it behind.

William Stewart Halsted was a Yale- and Columbia-educated doctor who became a surgical intern at Bellevue hospital in New York in the mid-1870s, where he worked himself to the point of having a nervous breakdown. Returning from witnessing the surgical techniques in Europe, Halsted threw himself into surgical work in New York. He became addicted to a new kind of anesthesia, cocaine, as well as to morphine. While working toward addiction recovery, he started a surgical program at Johns Hopkins. There, he attacked breast cancer, which, despite surgical removal, had a way of recurring in patients. He noticed, as had the English surgeon Charles Moore, that the margins of the surgery were where the cancer had recurred, and he turned to excavating far into the chest to get even at the lymph nodes under the collarbone. He was willing to cause the disfiguration of his patients to prevent a recurrence of cancer.

Even though the scientific community regarded Halsted as a surgical master, the proof of his prowess could only come after the cancer went into remission for five years. The problem with his radical mastectomies is that women with metastatic cancer would not experience remission, while the women with a localized cancer did not need such a radical operation. Although Halsted’s numbers were lower than those of his predecessors, half of the 76 women he treated died within three years of the surgery. The survival rates of the women had less to do with his techniques and more to do with how extensively the cancer had riddled the body before the surgery. Nonetheless, “radicalism” became the focus of surgery and an obsession among patients and doctors. The mantra of surgeons became “the more radical the better” (70). Their attitude swung between desperation and optimism, but they still hadn’t effected a cure.

One of Halsted’s disciples, Hugh Hampton Young, turned to radical operations in the field of urological cancers, while Harvey Cushing, Halsted’s student, concentrated on surgically removing cancers from the brain. All these surgeons believed that any surgery that did not attempt to eradicate cancer from the body was a “makeshift operation” (72).

In 1895, Wilhelm Rontgen in Germany discovered X-rays, first thought to be a form of energy produced by electron tubes. Henri Becquerel, a French chemist, discovered that certain natural materials such as uranium gave off their own invisible rays, and Pierre and Marie Curie began to find other sources of rays, including the element uranium, in a waste ore called pitchblende. Radium could not only travel through tissues but could also deposit energy inside tissues. Marie Curie’s hands began to blister and peel as an effect of radium attacking the DNA. A Chicago medical student named Emil Grubbe noticed the X-rays’ ability to destroy cells, so he began to use radiation via X-ray tubes to shrink a woman’s breast cancer. This woman’s cancer had metastasized, and she died, but the use of radiation to treat local cancers spread as radiation therapy took off.

However, while it could be a blessing for local tumors, it was ineffective against cancer that had metastasized. In addition, while radiation could help kill dividing cells, it could also cause cancer, as was discovered with the radioactive Undark paint produced starting in the 1910s. Workers who applied radioactive paint were found to have necrosed bones in their jaws, and “Radium girls” died of cancers, as did Marie Curie and Emil Grubbe. Unwittingly, Galen twigged onto a crucial aspect of cancer: It is a systemic disease that invades the body like the black bile he imagined.

The trick in treating a systemic disease lies in treating it with specificity—only attacking cancer cells and leaving other cells alone. The answer to this problem came from the burgeoning English cotton industry, which needed a way to cheaply dye its clothing. The field of practical chemistry was born to fill this need. In 1856, an 18-year-old student at an institute for developing products for chemical dyeing produced a chemical called aniline mauve that did not bleach or bleed. It could also be used to produce other colors, and a new glut of synthetic dyes came on the market. Trying to catch up to the English, German chemists produced a dye called alizarin, a red chemical that looked like carmine. They also went on to produce a series of synthetic molecules.

While the early interactions between practical chemistry and medicine did not bear fruit, in 1828, a German scientist named Friedrich Wohler boiled an inorganic salt called ammonium cyanate to create urea, which the kidneys make. The creation of an organic material out of inorganic material destroyed the idea of vitalism (the belief that a special force imbued living things). Wohler tried to use synthetic chemicals on living cells, but he didn’t have the right materials, not realizing that the practical chemists had what he needed.

In 1878, a medical student named Paul Ehrlich used cloth dyes such as aniline to stain animal tissues to see them more clearly under the microscope. To his amazement, the dyes could stain some chemicals and not affect others. Working with Robert Koch, he found a stain for mycobacteria, which Koch had determined caused tuberculosis. Ehrlich also discovered that certain toxins could produce antitoxins, which inactivated poisons. He developed the idea of “chemotherapy”—of using chemicals to heal the body by killing the diseased cells while leaving the host alone.

He began to look for what he called “curative substances” (85) in the dye industry. He searched for antimicrobial chemicals and, after injecting mice and rabbits with the parasite that caused sleeping sickness, came up with the first antibiotic, which he named Trypan Red. In 1910, he announced that he had found another molecule with “special affinity” (86) that was effective against syphilis, which he named compound 606. He called these drugs “magic bullets” (86) and worked toward producing a medicine that would be effective against malignant human cells. However, he found that whatever killed cancer cells also killed normal cells. Ehrlich won the Nobel Prize for his discovery of special affinity, but when Kaiser Wilhelm of Germany, a hypochondriac, asked if he could cure cancer, Ehrlich hedged. Specific affinity relied on the differences between bacterial enzymes and human enzymes, but the similarity of cancer cells and normal cells made it hard to target cancer cells.

In 1915, Ehrlich became sick with tuberculosis, and he recovered in a spa town. He felt bitter about the way in which the industrial production of his country had turned toward producing mustard gas. Beyond the immediately harmful effects of mustard gas, it also had long-term effects, studied by American pathologists Edward and Helen Krumbhaar. Mustard gas depleted bone marrow and only destroyed certain cells. It was a chemical with a special affinity, but this went unnoticed at the time.

In 1943, German Luftwaffe planes bombed American planes off the Italian port of Bari. The ships, which were carrying mustard gas, immediately caught fire, and many sailors died even after rescue from the water, as did 1,000 men and women around Bari. The sailors’ bodies were sent back to the US, where autopsies revealed that white blood cells and bone marrow were depleted in those who had survived the initial bombing. A secret unit called the Chemical Warfare Unit formed to study war gases. The unit assigned Louis Goodman and Alfred Gilman at Yale to study nitrogen mustard. They were interested in the capacity of the mustard gas to destroy white blood cells and began to test mustards on rabbits and mice and then humans to investigate whether scientists could use it on malignant white cells. They convinced a thoracic surgeon named Gustaf Lindskog to use it on a patient with lymphoma, and the treatment worked to produce a remission of the cancer.

Using Erlich’s methods, biochemist George Hitchings in New York tried to manufacture decoy molecules that could kill cells when taken up by them. Most regarded his work as a “fishing expedition” (91). He hired an assistant named Gertrude Elion, a brilliant, driven chemist who had to work in a food laboratory when she couldn’t find a job in an academic laboratory. She focused on a group of chemicals called purines that could stop bacterial growth by inhibiting DNA. After trying many molecules, she found one called 6-mercaptopurine, or 6-MP.

In 1948, Cornelius “Dusty” Rhoads, formerly the director of the army’s Chemical Warfare Unit, became head of Memorial Hospital. This move solidified the connection between chemical warfare and chemotherapy. He collaborated with Hitchings and Elion at Burroughs Wellcome. They began testing 6-MP on humans, first on patients with acute lymphoblastic leukemia. Joseph Burchenal and Mary Lois Murphy began a trial at Memorial Hospital to use 6-MP on children with ALL, and the patients quickly entered remission, but these remissions were temporary.

Farber was interested in these temporary remissions, and he wondered if there were a chemical that could cure cancer. He studied the national campaign against polio. Franklin Roosevelt, himself a victim of polio, started a polio research center in Warm Springs, Georgia, and then, in 1936, launched a national foundation that spurred polio research. Eddie Cantor, an actor, started the March of Dimes fundraising campaign, and the money raised helped lead to Sabin and Salk’s vaccines. Farber wanted to launch a similar campaign for leukemia.

In 1947, a group from the Variety Club, made up of people from show business, toured Farber’s lab. Bill Koster, its head, toured Children’s Hospital to find a charity project for his group. Farber asked him to create a fund to build a hospital dedicated to researching children’s cancers. They started the Children’s Cancer Research Fund in 1948. When they sought a kind of mascot for their organization, they found a healthy-looking child patient named Einar Gustafson, who was receiving treatment for lymphoma in his intestines. Einar, from Maine, was a serious and quiet boy whom Koster and Farber renamed “Jimmy.” In 1948, the host of radio show called “Truth or Consequences” cut to “Jimmy’s” bedside in Boston, as ballplayers streamed into Jimmy’s hospital room, surprising the boy. The host asked listeners to contribute to a television set for Jimmy. As the author writes, “The public response was staggering” (99). The Jimmy Fund was launched, much like a political campaign, and Farber realized that “a disease needed to be transformed politically before it could be transformed scientifically” (99). 

By 1951, Farber’s work was outgrowing his old quarters and laboratory, and colleagues considered his ego too large to stay within the confines of Children’s Hospital. He and Koster were able to make the Jimmy Fund the official charity of the Boston Red Sox and to recruit player Ted Williams to be a figure in the charity. The Jimmy Fund became a familiar name and charity, and by 1952, the new building was almost ready. The waiting rooms filled with toys, and there was a library with books and toys.

However, a cure for cancer remained elusive. Farber had added a steroid to the antifolates, lengthening the time of remission. Although the atmosphere in the building was cheerful, the patients still died. Farber needed even more money and a greater drive to find a drug regimen that worked, and he already outgrew “the house that Jimmy had built” (104).