The Cancer Chronicles Page 15

  In the end what all of biology comes down to is genes talking to genes—within the cell or from cell to cell—in a constant molecular chatter. I hadn’t considered, however, that the genes in human tissues can also talk to the genes residing in the microbes that occupy our bodies. Maybe that should have been obvious. Our skin and our digestive and respiratory tracts are teeming with bacteria. Many of them play a symbiotic role—bacteria in the gut secrete enzymes that aid in digestion. The genes inside these single-celled creatures transmit signals from microbe to microbe, and they can also exchange signals with human cells. Although we think of the bacteria as passengers, they outnumber our own cells by about ten to one. Even more impressive, the total number of microbial genes each of us harbors—the microbiome—outnumbers our human genes by 100 to 1. There is even a Human Microbiome Project to sequence the genomes of these cellular free agents. Cancer is a disease of information, of mixed-up cellular signaling. Now there is another realm to explore.

  The genome, the epigenome, the microbiome—scientists also now speak of the proteome (the entire set of proteins that can be expressed in a cell) and the transcriptome (all of the RNA molecules of various sorts). There is the metabolome, lipidome, regulome, allelome … the degradome, enzymome, inflammasome, interactome, operome, pseudogenome.…The exposome is everything in the environment we are exposed to and the behaviorome includes the lifestyle factors that may alter our risk of cancer. The bibliome is the endlessly expanding library of papers on everything scientific, and the curse of this age of microspecialization and the proliferation of “ ’omics” is to separate the ridiculome from the relevantome.

  As I scribbled in my notebook or walked the hallways mulling some strange new idea, I thought of how much has changed over the years in our understanding of cellular biology. I remembered the thrill of reading James Watson’s The Double Helix during a backpacking trip in college and, later on, sitting by the fire in a mountain cabin, devouring the three-part New Yorker series excerpted from Horace Freeland Judson’s magnificent book The Eighth Day of Creation: Makers of the Revolution in Biology. Molecular genetics seemed as clean and crisp as structures assembled from Lego bricks. For all their power to create and govern life, genes were made from combinations of just four nucleic acid letters: G, C, A, and T. Each had a unique contour, and these patterns of bumps and grooves were copied from DNA to messenger RNA and then ferried to the ribosomes, the cellular structures that used the information to make proteins. At these foundries other molecules called transfer RNAs acted like adaptor plugs matching each triplet of nucleic acid letters to a particular amino acid—the twenty different units that, arranged in a certain order, became a particular kind of protein. These proteins include the enzymes that help make the genetic machinery run. The crowning simplification of the theory was what Francis Crick called the “central dogma”: DNA to RNA to protein.

  The complications were soon to follow. Not every bit of DNA was part of the protein code. Some sequences were used for making the messenger RNA and transfer RNA. Others served as control knobs, turning the volume of a gene up and down to modulate the production of its protein. With all of this intricate, interlocking machinery, you could almost entertain the fantasy that the whole thing was the product of an engineer. But nature was so much messier. Genes, for example, were not continuous. They were interrupted by scraps of gibberish. As the genetic message was reprinted into the messenger RNA, these blemishes (the introns) had to be edited out. They were accidents of evolution and of entropy. In fact, of the entire genome only a small percentage appeared to serve a purpose. The rest came to be known as junk DNA—a hodgepodge of detritus, genes that had become crippled and discarded over the course of millions of years. Some of these pseudogenes had been smuggled in by viruses. Others were created when a real gene was mistakenly copied and pasted elsewhere in the genome. With no compelling reason to get rid of the debris, it was carried along, generation by generation, for the ride.

  It seemed barely conceivable that so much of the genome sat silent and inert. In its incessant tinkering, evolution would surely find new purposes for the discarded parts. Early in the 1990s, scientists began to notice a new kind of RNA produced by the junk DNA. When they latched onto a messenger RNA, these molecules kept it from delivering its information. Because of their small size they were named microRNAs (in the lexicography of cellular biology, terms like this are squished together). They came in different varieties, and as they increased or decreased in number they regulated the production of various proteins. Like almost everything else in the cell they were bound to play a role in cancer. Suppose there was a microRNA whose role was to block the expression of a growth-promoting oncogene. If the cell produced too little of this regulator, that would encourage proliferation. An excess of another kind of microRNA might result in the stifling of a tumor suppressor. In fact just one of these molecules might regulate several different genes, leading to tangles of entwined effects. Mutations to the junk DNA had been thought to be harmless. But if they upset the balance of microRNAs they could nudge a cell closer to malignancy.

  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 wonde
red 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.

  Chapter 10

  The Metabolic Mess

  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.

  I have many times made the experiment; but though the sores, after such operation, have, in some instances, healed kindly, and the patients have gone from the hospital seemingly well, yet, in the space of a few months, it has generally happened, that they have returned either with the same disease in the other testicle, or in the glands of the groin, or with such wan complexions, such pale leaden countenances, such a total loss of strength, and such frequent and acute internal pains, as have sufficiently proved a diseased state of some of the viscera, and which have soon been followed by a painful death.

  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 wa
sn’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.