The Emperor of All Maladies: A Biography of Cancer (64 page)

Late that evening, having finished my notes, I return to the laboratory. It is a beehive of activity. Postdocs and graduate students hover around the microscopes and centrifuges. Medical words and phrases are occasionally recognizable here, but the dialect of the lab bears little resemblance to the dialect of medicine. It is like traveling to a neighboring country—one that has similar mannerisms but speaks a different language:

“But the PCR on the leukemia cells should pick up the band.”

“What conditions did you use to run this gel?”

“Agarose, four percent.”

“Was the RNA degraded in the centrifugation step?”

I retrieve a plate of cells from the incubator. The plate has 384 tiny wells, each barely large enough to hold two grains of rice. In each well, I have placed two hundred human leukemia cells, then added a unique chemical from a large collection of untested chemicals. In parallel, I have its “twin” plate—containing two hundred normal human blood-forming stem cells, with the same panel of chemicals added to every well.

Several times each day, an automated microscopic camera will photograph each well in the two plates, and a computerized program will calculate the number of leukemia cells and normal stem cells. The experiment is seeking a chemical that can kill leukemia cells but spare normal stem cells—a specifically targeted therapy against leukemia.

I aspirate a few microliters containing the leukemia cells from one well and look at them under the microscope. The cells look bloated and grotesque, with a dilated nucleus and a thin rim of cytoplasm, the sign of a cell whose very soul has been co-opted to divide and to keep dividing with pathological, monomaniacal purpose. These leukemia cells have come into my laboratory from the National Cancer Institute, where they were grown and studied for nearly three decades. That these cells are still growing with obscene fecundity is a testament to the terrifying power of this disease.

The cells, technically speaking, are immortal. The woman from whose body they were once taken has been dead for thirty years.

As early as 1858
, Virchow recognized this power of proliferation. Looking at cancer specimens under the microscope, Virchow understood that can
cer was cellular hyperplasia, the disturbed, pathological growth of cells. But although Virchow recognized and described the core abnormality, he could not fathom its cause. He argued that inflammation—the body’s reaction to a harmful injury, characterized by redness, swelling, and immune-system activation—caused cells to proliferate, leading to the outgrowth of malignant cells. He was almost right: chronic inflammation, smoldering over decades, does cause cancer (chronic hepatitis virus infection in the liver precipitates liver cancer), but Virchow missed the essence of the cause. Inflammation makes cells divide in response to injury, but this cell division is driven as a reaction to an external agent such as a bacteria or a wound. In cancer, the cell acquires
autonomous
proliferation; it is driven to divide by an internal signal. Virchow attributed cancer to the disturbed physiological milieu around the cell. He failed to fathom that the true disturbance lay within the cancer cell itself.

Two hundred miles south of Virchow’s Berlin laboratory,
Walther Flemming, a biologist working in Prague
, tried to uncover the cause of abnormal cell division, although using salamander eggs rather than human cells as his subject. To understand cell division, Flemming had to visualize the inner anatomy of the cell. In 1879, Flemming thus stained dividing salamander cells with aniline, the all-purpose chemical dye used by Paul Ehrlich. The stain highlighted a blue, threadlike substance located deep within the cell’s nucleus that condensed and brightened to a cerulean shade just before cell division. Flemming called his blue-stained structures
chromosomes
—“colored bodies.” He realized that cells from every species had a distinct number of chromosomes (humans have forty-six; salamanders have fourteen). Chromosomes were duplicated during cell division and divided equally between the two daughter cells, thus keeping the chromosome number constant from generation to generation of cell division. But Flemming could not assign any further function to these mysterious blue “colored bodies” in the cell.

Had Flemming moved his lens from salamander eggs to Virchow’s human specimens, he might have made the next crucial conceptual leap in understanding the root abnormality in cancer cells.
It was Virchow’s former assistant David Paul von Hansemann
, following Flemming’s and Virchow’s trails, who made a logical leap between the two. Examining cancer cells stained with aniline dyes with a microscope, von Hansemann noticed that Flemming’s chromosomes were markedly abnormal in cancer. The cells had split, frayed, disjointed chromosomes, chromosomes
broken and rejoined, chromosomes in triplets and quadruplets.

Von Hansemann’s observation had a profound corollary. Most scientists continued to hunt for parasites in cancer cells. (Bennett’s theory of spontaneous suppuration still held a macabre fascination for some pathologists.) But von Hansemann proposed that the real abnormality lay in the structure of these bodies internal to cancer cells—in chromosomes—and therefore in the cancer cell itself.

But was it cause or effect? Had cancer altered the structure of chromosomes? Or had chromosomal changes precipitated cancer? Von Hansemann had observed a correlation between chromosomal change and cancer. What he needed was an experiment to causally connect the two.

The missing experimental link emerged from the lab of Theodor Boveri, yet another former assistant of Virchow’s. Like Flemming, who worked with salamander cells, Boveri chose to study simple cells in simple organisms, eggs from sea urchins, which he collected on the windswept beaches near Naples. Urchin eggs, like most eggs in the animal kingdom, are strictly monogamous; once a single sperm has entered the egg, the egg puts up an instant barrier to prevent others from entering. After fertilization, the egg divides, giving rise to two, then four cells—each time duplicating the chromosomes and splitting them equally between the two daughter cells. To understand this natural chromosomal separation,
Boveri devised a highly unnatural experiment
. Rather than allowing the urchin egg to be fertilized by just one sperm, he stripped the outer membrane of the egg with chemicals and forcibly fertilized the egg with two sperms.

The multiple fertilization, Boveri found, precipitated chromosomal chaos. Two sperms fertilizing an egg results in three of each chromosome—a number impossible to divide evenly. The urchin egg, unable to divide the number of chromosomes appropriately among its daughter cells, was thrown into frantic internal disarray. The rare cell that got the right combination of all thirty-six sea urchin chromosomes developed normally. Cells that got the wrong combinations of chromosomes failed to develop or aborted development and involuted and died. Chromosomes, Boveri concluded, must carry information vital for the proper development and growth of cells.

This conclusion allowed Boveri to make a bold, if far-fetched, conjecture about the core abnormality in cancer cells. Since cancer cells possessed striking aberrations in chromosomes, Boveri argued that these chromosomal abnormalities might be the cause of the pathological growth
characteristic of cancer.

Boveri found himself circling back to Galen—to the age-old notion that all cancers were connected by a common abnormality—the “
unitary cause of carcinoma
,” as Boveri called it. Cancer was
not “an unnatural group of different maladies
,” Boveri wrote. Instead, a common feature lurked behind all cancers, a uniform abnormality that emanated from abnormal chromosomes—and was therefore
internal
to the cancer cell. Boveri could not put his finger on the nature of this deeper internal abnormality. But the “unitary cause” of carcinoma lay in this disarray—not a chaos of black bile, but a chaos of blue chromosomes.

Boveri published his chromosomal theory of cancer in an elegant scientific pamphlet entitled “Concerning the Origin of Malignant Tumors” in 1914. It was a marvel of fact, fantasy, and inspired guesswork that stitched sea urchins and malignancy into the same fabric. But Boveri’s theory ran into an unanticipated problem, a hard contradictory fact that it could not explain away.
In 1910, four years before Boveri had published his theory
, Peyton Rous, working at the Rockefeller Institute, had demonstrated that cancer in chickens could be caused by a virus, soon to be named the Rous sarcoma virus, or RSV.

The central problem was this: as causal agents, Rous’s virus and Boveri’s chromosomes were incompatible. A virus is a pathogen, an external agent, an invader exogenous to the cell. A chromosome is an internal entity, an endogenous structure buried deep inside the cell. The two opposites could not both claim to be the “unitary cause” of the same disease. How could an internal structure, a chromosome, and an external infectious agent, a virus, both create cancer?

In the absence of concrete proof for either theory, a viral cause for cancer seemed far more attractive and believable. Viruses, initially isolated in 1898 as minuscule infectious microbes that caused plant diseases, were becoming increasingly recognized as causes for a variety of animal and human diseases.
In 1909, a year before
Rous isolated his cancer-causing virus, Karl Landsteiner implicated a virus as the cause for polio. By the early 1920s, viruses that caused cowpox and human herpes infections had been isolated and grown in laboratories, further cementing the connection between viruses and human and animal diseases.

Undeniably, the belief in cause was admixed with the hope for a cure. If the causal agent was exogenous and infectious, then a cure for cancer seemed more likely. Vaccination with cowpox, as Jenner had shown, pre
vented the much more lethal smallpox infection, and Rous’s discovery of a cancer-causing virus (albeit in chickens) had immediately provoked the idea of a therapeutic cancer vaccine. In contrast, Boveri’s theory that cancer was caused by a mysterious problem lurking in the threadlike chromosomes, stood on thin experimental evidence and offered no prospect for a cure.

While the mechanistic understanding of the cancer cell remained suspended in limbo between viruses and chromosomes, a revolution in the understanding of normal cells was sweeping through biology in the early twentieth century. The seeds of this revolution were planted by a retiring, nearsighted monk in the isolated hamlet of Brno, Austria, who bred pea plants as a hobby.
In the early 1860s, working alone
, Gregor Mendel had identified a few characteristics in his purebred plants that were inherited from one generation to the next—the color of the pea flower, the texture of the pea seed, the height of the pea plant. When Mendel intercrossed short and tall, or blue-flowering and green-flowering, plants using a pair of minute forceps, he stumbled on a startling phenomenon. Short plants bred with tall plants did not produce plants of intermediate height; they produced tall plants. Wrinkle-seeded peas crossed with smooth-seeded peas produced only wrinkled peas.

The implication of Mendel’s experiment was far-reaching: inherited traits, Mendel proposed, are transmitted in discrete, indivisible packets. Biological organisms transmit “instructions” from one cell to its progeny by transferring these packets of information.