At first that didn’t seem so strange. There is an inverse correlation between life span and pulse rate. During a typical lifetime an elephant and a mouse will each use up roughly a billion heartbeats. The mouse will just do it much faster. With a metabolism on so high a burn, it seems sensible that mice might get more cancer. But what is true for the mouse is not true for other tiny mammals. Birds, despite their frenzied metabolic rate (a hummingbird’s heart can beat more than a thousand times a minute) appear to get very little cancer. If you graph mammalian size against cancer rate there is no telltale sloping line, just a scattering of dots. In our ignorance, each species seems like an exception.
Scientists have proposed several reasons for why cancer doesn’t correlate smoothly with size. While larger animals may indeed get more mutations, they might also have evolved more effective means for repairing DNA, or for warding off tumors in other ways. The authors of the Arizona paper suggested how that might occur: hypertumors. Cancer is a phenomenon in which a cell begins dividing out of control and accumulating genetic damage. Its children, grandchildren, and great-grandchildren go on to spawn broods of their own—subpopulations of competing cells, each with a different combination of traits. The stronger contenders—those that have evolved an ability to grow faster than the others or to poison their neighbors or to use energy more efficiently—will gain an upper hand. But before they can dominate, the authors proposed, they might become susceptible to “hypertumors”: clusters of weaker cancer cells opportunistically trying to latch on for a free ride. These parasites would sap energy continuously, destroying the tumor or at least keeping it in check. In large, long-lived animals cancer develops gradually enough for the leeches to form. They may indeed get more tumors, but they are much less likely to grow to a noticeable size. Cancer that can get cancer. For all the time I’d spent immersing myself in the literature, this was the first I had heard of that.
That still left me wondering about the hummingbirds, and a footnote in the paper about Peto’s paradox led me to yet another of cancer’s mysteries. It is well known to zoologists that virtually all mammals, no matter how tall or short, have precisely seven vertebrae in their necks: giraffes, camels, people, whales. (Manatees and sloths are exceptions.) Birds, amphibians, and reptiles are not bound by the rule—a swan can have twenty-two to twenty-five neck vertebrae. They also appear to get less cancer. Frietson Galis, a Dutch biologist, thought there must be some kind of connection. She considered what happens in rare instances when fetuses sprout an extra rib right where the seventh vertebra would normally be. As a result, children born with the defect have only six vertebrae in their necks. They are also more likely to die from brain tumors, leukemias, blastomas, and sarcomas. Galis suggests that it is why variation in the number of neck vertebrae is slowly being weeded out of the mammalian population.
I spent my last night on the road in Vernal, Utah, where a giant pink Brontosaurus (I mean Apatosaurus) with long flirtatious eyelashes held up a sign welcoming visitors. It was about nine o’clock and the town was already shutting down. I found a restaurant with a Wild West theme barely open on Main Street. After a long day of driving I was looking forward to a glass of wine. I tried to keep up with the latest studies on how this vice, in moderation, might conceivably be good for the circulatory system, staving off heart attacks and strokes. The most wishful research even suggested that the antioxidizing effects of the elixir might help suppress tumors and extend life. But the longer you live the more likely you are to get cancer. Every meal presents a calculus of probabilities: Alcohol increases the risk for some cancers (mouth, esophageal) but may decrease the risk for kidney cancer.
In a file on my laptop I had been keeping a list of headlines from recent news:
“Natural Compounds in Pomegranates May Prevent Growth of Hormone-dependent Breast Cancer”
“Green Tea Could Modify the Effect of Cigarette Smoking on Lung Cancer Risk”
“Soft Drink Consumption May Increase Risk of Pancreatic Cancer”
“Bitter Melon Extract Decreased Breast Cancer Cell Growth”
“Seaweed Extract May Hold Promise for Non-Hodgkin’s Lymphoma Treatment”
“Coffee May Protect Against Head and Neck Cancers”
“Strawberries May Slow Precancerous Growth in Esophagus”
I knew by now that the effects, if real, would be minuscule. How can anyone sensibly weigh the trade-offs, based inevitably on imperfect information—on findings that could be overturned tomorrow?
The carcinogenic effects of red wine turned out not to be an issue that night. This was Utah and there was nothing alcoholic on the menu. My fried chicken cutlet sandwich was washed down with lemonade made with powder from a jar and tap water. Back at my room at the Dinosaur Inn (guarded over by another smiling Apatosaurus), I thought again about those layers extending miles and millennia below me. Someday more layers would pile on top of us, and I wondered how much cancer would be there. It had been seven years almost to the day since Nancy, the woman I was married to, was diagnosed with a rabid cancer that sprouted for no good reason in her uterus and burned like a flame along a wick down the round ligament and into her groin. She lived to tell the tale, but ever since, I have been wondering how a single cell minding its own business can transmogrify into a science fiction alien, a monster growing within.
Chapter 2
Nancy’s Story
She always ate her vegetables. Obsessively, it sometimes seemed. Breakfast, lunch, dinner, throughout the day she would keep mental count. Never mind if it was 10:30 p.m., halfway through a Simpsons episode or a DVD. If she hadn’t consumed two or three servings of vegetables (some green, some yellow) and three or four servings of fruits, nuts, grains—whatever the food pyramidologists were recommending—she would slice up an apple or open a bag of carrots.
In the spirit of Pascal’s wager (there is no downside to believing in God), none of this probably hurt. It is often said that two-thirds of cancer cases are preventable—one-third by eliminating smoking and the other third by getting more exercise and eating healthier meals. But the evidence associating any particular diet with cancer is discouragingly thin. We were told, Nancy and I, to eat our spinach because it is rich in folates, and folates are a crucial ingredient used by cells to synthesize and repair the intertwining helices of DNA. That sounds great in theory, but the argument is weak at best that consuming more folate reduces the risk of three of the most common cancers: colorectal, breast, and prostate. For breast cancer, the effect, if there is one, may be primarily of benefit to alcoholics. Other research suggests that too much folic acid (the synthetic form of folate found in vitamin pills) can increase cancer risk. Once a neoplasm has taken root, extra doses might even accelerate its growth, adding fuel to the fire. Some cancers are combated by administering antifolates, which are among the oldest chemotherapeutic drugs. The most persuasive reason for eating spinach is that, sautéed with garlic or tossed in a salad, it tastes so good.
Just as dubious is the mythology surrounding antioxidants like vitamins C and E, which are consumed in fruits, vegetables, and pills and smeared on the face in the form of antiaging cosmetics. The hope is to counteract free radicals—products of cellular combustion that eat at the insides of cells. It is far from clear that the body needs help on that front. To blunt the impact of free radicals (the name conjures images of bomb-throwing anarchists), living cells come equipped with a built-in system of antioxidizing mechanisms, a finely strung molecular web crafted over the eons since life began. That is not the kind of thing you want to mess with. And no creature would want to eliminate free radicals. They are scavengers that prevent the inevitable accretion of cellular poisons, garbage collectors for the cells. Beta-carotene, an antioxidant that gives carrots, mangoes, and papayas their color, has been promoted as having anticarcinogenic powers. But in a clinical trial in Finland, smokers given beta-carotene supplements were more likely to get lung cancer. A similar trial in the United States was curtailed at an early st
age when it also appeared that the supplements were increasing the risk of the disease. “To go beyond the bounds of moderation is to outrage humanity”—Pascal again—and to outrage our cells.
These days grocery store packaging has descended to a new level of detail, luring shoppers with produce and other goods rich in phytochemicals, naturally occurring ingredients in plants reputed to help detoxify carcinogens, repair DNA damage, or otherwise discourage cells from going wild. Lycopene, quercetin, resveratrol, silymarin, sulforaphane, indole-3-carbinol—they go in and out of style. In a laboratory dish these substances might affect biochemical pathways believed to be involved in the numbingly complex processes of carcinogenesis. Far less clear is whether consuming more of them actually prevents anyone from getting cancer. Unless a person is severely malnourished there is little reason to believe that a shortage of any specific molecule is throwing the cellular processes seriously out of whack. You can hedge your bets by taking multivitamins, but the evidence here is also meager. If life were so delicate we probably wouldn’t be here worrying about what we eat.
There is so much that science doesn’t know about the molecular clockworks, and it is possible that substances in fruits and vegetables confer synergistic advantages whose logic is yet to be uncovered. Throughout the 1990s, the news was filled with reports of miraculous anticarcinogenic effects from consuming nature’s bounty. The National Cancer Institute began pushing its 5 A Day program. Eat that many servings of fruits and vegetables and you would be a long way toward beating the odds against cancer.
The evidence, alas, came mostly from case control studies in which people with and without cancer were asked to remember what they ate. Epidemiological studies like these are prone to error. Grasping to explain their predicament, cancer patients might be more likely to overestimate how badly they neglected their diets, while healthy people might remember eating more fruits and vegetables than they really did. Since cancers can take decades to develop, great feats of memory are required. Skewing things further, those most likely to volunteer for the control group may be relatively affluent health-conscious citizens who, in addition to eating nutritious meals, exercise more often and are less likely to binge on alcohol or cigarettes. A good study will try to strike a balance between the cases and the controls, but the best that retrospective epidemiology can do is hint at associations to be investigated more rigorously. In prospective cohort studies, large groups of people—the cohorts—are followed for years and interviewed regularly to see if patterns emerge among those who do and do not get cancer. Though these too suffer from biases, the evidence is considered stronger than for retrospective epidemiology. The largest prospective study on diet and health has found so far that eating fruits and vegetables has, at most, a very weak effect on cancer prevention. There are suggestions of possible benefits with a few cancers, but nothing that has lived up to the earlier hopes.
We were told to eat our fiber, and when Nancy went shopping she would bring home breakfast cereals that tasted like pieces of the cardboard box. Intuitively it made sense. You could imagine all that fiber scouring clean your intestines on its way through the digestive tract. Fiber was also said to nurture a mix of bacteria that reduces the risk of colon cancer. The case for fiber may be a little stronger than for other foods, but the evidence has been controversial. One big prospective study found an association while another did not.
This all might be less ambiguous if foods could be subjected to the same kind of rigorous trials used to test new drugs. A large group of people is randomly assigned to an experimental group, which receives the treatment, or a control group, which does not. In the end the results are compared. But these studies are rare in cancer nutrition research. It is hard enough to force people to arbitrarily eat or not eat a certain food. And to clinch the case, the enforcement would have to last for the decades it can take a cancer to develop. When a four-year controlled trial was carried out with a low-fat diet that was high in fiber as well as fruits and vegetables it found no evidence of a reduction in colorectal polyps, which are precursors to colon cancer. Another randomized trial of about equal duration found that a fibrous diet had no effect on the recurrence of breast cancer.
Reading these less than ringing endorsements, I was reminded of the biochemist Bruce Ames, who has reported that brussels sprouts, cabbage, broccoli, cauliflower, and other staples of the farmer’s market contain naturally occurring carcinogens, built-in pesticides like the ones that might have killed the poor Edmontosaurus. People apparently don’t ingest these foods in quantities that would cause a public health problem—or maybe we have acquired a natural resistance. But how did the superstition arise that plants have the opposite effect, conferring us with the power to beat back cancer? Fruits and vegetables evolved to promote their own propagation. Then people started eating them.
There was nothing very rigid about Nancy’s dietary pursuits. We both loved steaks and hamburgers, but we tried to moderate our consumption. Here the science sounds a little more persuasive. If the epidemiology can be believed, eating a lot of red meat every single day might have raised our chances of getting colorectal cancer during the next decade by as much as a third—from 1.28 percent to 1.71 percent. But given those odds, cooking a giant steak on the weekend seemed worth the trade-off. For penance we would have fish sometimes. Knowing that it is rich in omega-3 fatty acids may have made the salmon and halibut we grilled more satisfying. But any firm connection between fish, fish oils, and colon cancer prevention has remained elusive.
Fruits, vegetables, fibers, fish—if nothing else, loading up on these foods promised to reduce one’s intake of mammalian fat. Yet even that has come under challenge as a serious cancer risk, and it is possible that sugar may pose a greater danger by increasing blood insulin levels and stimulating the growth of tumors. In the end, it probably doesn’t matter so much what you eat as how much. Obesity—like old age, sunlight, radioisotopes, and cigarettes—has joined the short list of unambiguous instigators of cancer. Conversely there is evidence that caloric restriction reduces the likelihood of cancer. You lower your metabolism. Like a lizard.
Nancy included a variety of vegetables and fruits in our diet mostly because she liked them. But she had reason to worry more than some others about cancer. Her mother had suffered through a mastectomy and chemotherapy shortly before we married. After sixteen years of slumber, the cancer returned. We didn’t know if her breast cancer was among those linked to a familial genetic defect. If so Nancy might have inherited a susceptibility, though not a fate.
She had other risk factors. She was forty-three and we had no children, a source of constant contention. The less frequently a woman is pregnant, the more monthly menstrual cycles she endures. With each period a jolt of estrogen causes cells in the uterus and mammary glands to begin multiplying, duplicating their DNA—preparing for the bearing and the nursing of a child that may not come. Each menstrual cycle is a roll of the dice, an opportunity for copying errors that might result in a neoplasm. Estrogen (along with asbestos, benzene, gamma rays, and mustard gas) is on the list of known human carcinogens published by the federal government’s National Toxicology Program.
Women these days are also exposed to more monthly doses of estrogen because they are beginning to menstruate at much earlier ages, possibly increasing the risk of breast cancer. A few scientists blame the change on bisphenol A—a chemical in plastic bottles that mimics estrogen—but a more widely accepted explanation involves nutrition. With more food to eat, girls mature more rapidly, accumulating fat, and that may serve as a signal that the body is healthy enough to begin ovulation. Over a century the age of menarche, when menstruation begins, has dropped in the Western world from about seventeen to twelve. At the same time women are spending less of their fertile life either pregnant or nursing a child. Lactation also appears to hold estrogen in check. The result of all this is that a teenager today may have already experienced more menstrual cycles than her grandmother did during her entire li
fe.
There are other risks in being female. Hormone therapies, administered during menopause or pregnancy, have been associated with some cancers. And obesity, especially in older women, can increase estrogen along with cancer risk. But none of this is straightforward. Strangely enough, excess body fat can actually reduce the chances of premenopausal women getting breast cancer. And while oral contraceptives may slightly raise the odds for cancer of the breast, they appear to reduce the risk of getting ovarian and endometrial cancer. Nancy wasn’t using birth control pills and she was far from being overweight, but she worried, just a little, about another factor: the wine we liked to have with dinner. Alcohol might also tip the hormonal scales and has been associated for entirely different reasons with digestive cancers. Snuffed out by alcohol, epithelial cells lining the esophagus must be replaced—more DNA to be duplicated, more chances for error. There is evidence linking alcohol to liver cancer, but more certain is the risk from hepatitis viruses or long-term exposure to aflatoxin, a poison produced by funguses that can invade peanuts, soybeans, and other foods.
You could live your life with a calculator. Consuming two or three drinks a day might increase breast cancer risk by 20 percent. That is not as bad as it sounds. The chance that a woman between the ages of forty and forty-nine will get the cancer is 1 in 69, or 1.4 percent. Alcohol consumption would raise that to 1.7 percent. Even tallness is a risk factor. (Nancy was just five foot three.) An analysis of data from the Million Women Study found that every four inches over five feet increased cancer risk by 16 percent. A clue to the mechanism may be found in Ecuadoran villagers with a kind of dwarfism called Laron syndrome. Because of a mutation involving their growth hormone receptors, the tallest men are four and a half feet and the women are six inches shorter. Life is not easy for them. The children are prone to infections and adults frequently die from alcoholism and fatal accidents. But they hardly ever get cancer or diabetes, even though they are often obese.
The Cancer Chronicles Page 3