The Cancer Chronicles (20 page)

The closer scientists looked, the more varieties of RNA were found. Some of these molecules may be flotsam and jetsam—broken pieces left over from the day-to-day running of the cellular machine. But others seem to be there for a purpose. LincRNA (for large intervening noncoding), siRNA (for small interfering), and piRNA. That means Piwi-interacting, and Piwi (for P-element induced wimpy testis) is another of those genes with silly names. There is Xist RNA and Hotair RNA. Wherever their names come from, the important idea is that these molecules too can play a role in regulating cellular chemistry. They might cause runaway cell growth if their balance is upset. A few scientists, reluctant to jump on the bandwagon, think the importance of the new RNAs has been overblown. Others think they herald a revolution. Declaring that “the central dogma is broken,” a
Harvard scientist speaking in Orlando described
a sweeping new
theory in which genes talk to pseudogenes in a new language whose letters consist of these exotic RNAs. If he is right then there is another code to be deciphered. Only then can we truly understand the cellular circuits and how they can go wrong.

Junk that is not junk. Genes—99 percent of them—that reside in our microbes rather than in our own cells. Background seemed to be trading places with foreground, and I was reminded of what happened in cosmology when most of the universe turned out to be made of dark matter and dark energy. Yet for all the new elaborations,
the big bang theory itself was left standing. It wasn’t so clean and simple as before, but it provided the broad strokes of the picture, a framework in which everything, aberrations and all, made sense. The same appeared to be happening with the
hallmarks. One presentation after another in Orlando included a much-copied PowerPoint slide illustrating
Hanahan and
Weinberg’s six canons. Without that touchstone all would have been chaos. Just the month before, the two scientists
had published a follow-up: “
Hallmarks of
Cancer: The Next Generation.” Looking back on the decade that had elapsed since their paper, they concluded that the paradigm was stronger than ever. Certainly there were complications. In the microchip of the cancer cell what had appeared to be a single transistor might turn out to be a microchip within the microchip hiding more dense circuitry of its own.
Stem cells and
epigenetics might come to play a greater role. In the end there may be more than six hallmarks. The hope is that the number will be finite and reasonably small.

One evening during the meeting I came upon a crowd of scientists streaming into a hotel ballroom exhausted from a day of absorbing and exuding information. Inside lavish buffet tables were placed strategically—roast beef with Oregon blue cheese, roasted chicken breast caprese, miniature crab cakes, Southwest chicken empañadillas. Bartenders at six stations offered copious pours of good wines. It was the annual reception for the
MD Anderson Cancer Center. Since
Nancy and I had gone there one sad January for a second opinion, the institutional logo had been changed. A slash had been added through the word “Cancer.” I wondered what marketing fool had come up with that. It seemed tacky, and from the point of view of so many of cancer’s victims cruelly optimistic.

From the Anderson affair the crowds flowed onward into a larger ballroom for more drink and dessert and dancing courtesy of the AACR. A soul band, lit from behind with a blue and red spotlight, was playing an old Smokey Robinson tune as the singer, carrying a wireless microphone, tried to coax people onto the dance floor.
First there were two couples dancing, then half a dozen, and by ten o’clock there were fifty, swirling like a whirlpool and pulling others onto the floor. As I walked back out in the hallway, the rhythm had slowed and the lights had dimmed. The singer was singing “Killing Me Softly.” Which is exactly what cancer doesn’t do.

In 1928 in a laboratory at St. Mary’s
Hospital in
London,
Alexander Fleming discovered
penicillin. He had been growing
staphylococcus bacteria on a culture plate, and upon returning from a holiday he noticed that it had been contaminated by a spot of mold. Around the spot were the corpses of dead bacteria. Fleming isolated the fungus and found that he could dilute it a thousandfold and it was still potent enough to kill the microbes. He went on to show that the mold, from the genus
Penicillium,
was also effective against streptococcus, pneumococcus, meningococcus, gonococcus, diphtheria, anthrax—so many killers that can now be rendered harmless with a few shots of antibiotic, letting us live long enough to get
cancer.

St. Mary’s has since been absorbed as a campus of
Imperial College School of Medicine, and I was walking there one afternoon across Hyde Park to see
Elio Riboli, director of Imperial’s School of Public Health. Riboli’s career as an epidemiologist has spanned four decades, leaving him particularly well suited to reflect on the changes in our ideas of what does and does not cause cancer. Chemical
carcinogens appeared to be much less of a factor than I had suspected, and the case for or against certain foods was as blurry as
ever. Riboli seemed like a man who could help straighten out the confusion.

It was a clear spring day, and as I walked I tried to imagine the gloom of the
Industrial Revolution when the air was thick with smoke and coal dust. It was in London in the late 1700s that Percivall Pott drew the connection between
exposure to
soot and
scrotal
cancer among
chimney sweeps—one of the early observations in mankind’s groping toward a theory of cancer. Chimney sweeps were not such jolly characters as the one Dick Van Dyke played in the movie
Mary Poppins.
Boys thin from malnutrition were induced for a few farthings to slither, often naked, through the grimy passages. “
The fate of these people seems singularly hard,” Pott wrote. “In their early infancy they are most frequently treated with great brutality, and almost starved with cold and hunger; they are thrust up narrow, and sometimes hot chimneys, where they are buried, burned and almost suffocated; and when they get to puberty, become liable to a most noisome, painful, and fatal disease.” Treatment involved removal, without anesthetic, of the tumorous part of the scrotum. This had to be done immediately. Once the cancer had spread to a testicle it was usually too late even for
castration.

The cause of the cancer was presumably the grinding of soot into abraded skin.
Chimney sweeps on the European continent, who
wore protective clothing—their outfit resembled a diving suit—didn’t get the
cancer, and it was
unknown in Edinburgh, where chimneys, less angular and narrow than those in London, were usually cleaned from above with a broom and an attached weight. But it was impossible to draw a simple arrow between cause and effect. Even among the London sweeps, the cancer was very
rare and might take twenty years to develop. And why did it almost always affect the scrotum—there were a few reports of soot warts on the face—but not other parts of the body exposed to the same scraping application of the
carcinogen? There must have been other factors involved. I thought of the experiments in the early twentieth century when a
Japanese scientist,
Katsusaburo Yamagiwa, induced tumors varying in size “
from that of a grain of rice to that of a sparrow’s egg” by applying
coal tar to
rabbits’ ears. But it was a painstaking procedure, fraught with failure, and the tumors appeared only after repeated applications of the cancerous grime.

Occupational exposures were also the preoccupation of
Bernardino Ramazzini, an Italian physician who wrote
De
Morbis Artificum Diatriba (Diseases of Workers),
published in 1700. He was comprehensive in his interests, studying not only laborers and tradesmen but also apothecaries, singers, laundresses, athletes, farmers, and even “learned men,” which included mathematicians and philosophers as well as physicians like himself. All were prone to various afflictions, but the only cancer he mentioned in the book occurred
in nuns. Ramazzini noticed that they tended to get more breast cancer than other women. “
Every city in
Italy,” he wrote, “has several religious communities of nuns, and you can seldom find a convent that does not harbor this accursed pest, cancer, within its walls.” He attributed this to
celibacy and a “
mysterious sympathy” between the
uterus and breasts, one that also would explain how milk conveniently appears in the mammary glands of women when they become pregnant. “We must certainly believe that the Divine Architect fashioned the uterus and the breasts with some structure, some contrivance that so far escapes us,” he wrote. “Perhaps the
course of time will reveal it, since the whole domain of Truth has not yet been conquered.”

It was not until the twentieth century that scientists began to elaborate the complex system of
sex hormones that travel through the bloodstream to distant parts of the body. Among their many roles is coordinating the activity of the uterus and breasts. By forgoing the bearing and
nursing of children and experiencing more menstrual cycles, the nuns had unknowingly increased their exposure to their body’s own carcinogenic estrogen, accelerating cellular division and raising the odds of mutation.

There was also a benefit to a lifetime of celibacy. A century and a half later another Italian,
Domenico Rigoni-Stern, observed that nuns got less
cancer of the cervix, foreshadowing the discovery that the principal cause is the human
papillomavirus, acquired through sexual intercourse. Chimney soot, sex hormones, in a few cases viruses—there are so many things that can set off a cellular explosion and so many factors that remain to be understood.

Riboli, who earned an MD and a master’s degree in public health from the University of Milan in 1980, was part of a venerable line of Italian physicians seeking clues to the vagaries of cancer. From Milan he went to
Harvard for another master’s in
epidemiology. When I arrived at the
London campus he was waiting in his office. He is tall and thin, a courtly, soft-spoken man who has taken to heart the evidence that controlling one’s weight and exercising provides an edge over both
heart disease and cancer. For the next hour and a half, we talked about what he had learned in the course of his epidemiological research. Looking back months later, I was struck again by the whipsaw effect of nutritional science, where what is good for you one day may be bad for you the next, and I wondered: How much can we really control whether or not we get cancer?

By the time Riboli had begun his career it was clear that tobacco smoke was causing an epidemic of
lung cancer, and it seemed sensible that other cancers would also be traced to particular chemicals—the industrial contaminants that were being added to the air and water, the preservatives and
pesticide residues in food.
“The dogma
was that
cancer
must
be caused by carcinogens,” he said. Chemicals, viruses,
bacteria—some influence from beyond. But early on there were signs that the hypothesis wasn’t holding up. “Despite extensive
research for some of the most common cancers—like cancer of the breast, cancer of the colon, cancer of the
prostate—no single carcinogen was found to play a meaningful role in humans.” Riboli was not saying that cancer-causing agents were having no influence on the population. “People can be exposed to a large number of carcinogens in the air and the water which can and actually do cause cancer. But for as much as fifty or sixty percent of cancer, we didn’t have the slightest idea of where it comes from.”

Only in a minority of cases could the blame be put squarely on inherited genetic defects. The
migrant studies had established that. People moving to new countries, carrying along the same genes, had an increased risk of acquiring, within a generation, the cancers of their hosts, and they often left behind the cancers of their homeland. As Doll and
Peto’s influential study suggested, the most important factor was human behavior, and a consensus was beginning to form that the likeliest contributor was what we ate.

The first clues
came from laboratory experiments. Instead of applying coal tar to lab animals’ ears, researchers tried
feeding them different amounts and varieties of foods to see how fat—or
adipose—they would get. “In a number of experiments no chemical carcinogens were used, but by modulating the diet—by modulating the adiposity—it was shown that you could modulate the frequency of tumors,” Riboli said. At first it seemed that an excess of fatty foods was the reason. But further research suggested that it was not so much the fat or other ingredients that were to blame but the total intake of calories—that obesity itself was a primary force in cancer.

Some foods appeared to pose small risks.
Diets too rich in
salt were associated with
stomach cancer and red and processed
meat with
colon cancer, possibly because of
nitrosamines,
N-nitroso compounds, and other substances. “There was not a very strong association as there is with smoking and
lung cancer, where the effect is gigantic,” Riboli said. “We were talking about an increasing risk of
one and a half to twofold for some
lifestyle habits compared to others.” When a risk is very small to begin with, even doubling it leaves a person with very little chance of getting cancer. But spread across populations of millions, the effects could have a significant impact on public health. Investigating that further, however, would require large
epidemiological studies, which can be frustratingly difficult to interpret.