Good Calories, Bad Calories (40 page)

Higginson had repeatedly remarked on these two points during his tenure as director of IARC. In early reports, Higginson and the World Health Organization had referred to “extrinsic factors” and “environmental factors” as the cause of most cancers, by which they meant lifestyle and diet. The public and the environmental movement had perceived this to mean almost exclusively “man-made chemicals”—the “carcinogenic soup,” as it was known in the 1960s and 1970s. “It appears that only a very smal part of the total cancer burden can be directly related to industrialization,” Higginson wrote. The release of industrial chemicals into the environment could not explain, for example, why the nonindustrial city of Geneva had more cancer than Birmingham, “in the pol uted central val eys of England,” or why prostate cancer was ten times more frequent in Sweden than in Japan.*61

Nonetheless, this focus on carcinogenic chemicals as the primary cancer-causing agents in the environment also carried over to nutrition-related cancer research in the laboratory. It was assumed that whatever components of diet were responsible for cancer worked the same way that chemicals did: by inducing mutations and genetic damage in cel s. When cancer researchers from around the world met in September 1976 at the Cold Spring Harbor Laboratory to discuss the origins of human cancer, the talks focused on those chemicals shown to be carcinogens in animals, and the possibility that they might be found in infinitesimal or greater amounts in human diets, drinking water, or pharmaceuticals.

By the mid-1970s, when cancer epidemiologists began to convince politicians and the public that many cancers were caused by what Peto and Dol had cal ed the “gross aspects of diet,” rather than “ingestion of traces of powerful carcinogens or precarcinogens,” the focus was almost exclusively on fat, fiber, and red meat, or smoked-or salt-cured meat, as wel as the possibly protective nature of vitamins, vegetables, and fruits. The low incidence of cancer in vegetarians and Seventh-day Adventists was often cited as evidence that meat is carcinogenic and that green vegetables and fruit are protective. (Although the incidence of colon cancer, for instance, among Seventh-day Adventists was no lower than among Mormons, described by Dol and his col eague Bruce Armstrong as “among the biggest beefeaters in the United States.”) For the next twenty years, conferences, textbooks, and expert reports on nutrition and cancer continued to focus exclusively on these factors, although now aided by the advances in molecular biology.

By the end of the 1990s, clinical trials and large-scale prospective studies had demonstrated that the dietary fat and fiber hypotheses of cancer were almost assuredly wrong, and similar investigations had repeatedly failed to confirm that red meat played any role.*62 Meanwhile, cancer researchers had failed to identify any diet-related carcinogens or mutagens that could account for any of the major cancers. But cancer epidemiologists made little attempt to derive alternative explanations for those 10 to 70 percent of diet-induced cancers, other than to suggest that overnutrition, physical inactivity, and obesity perhaps played a role.

Throughout these decades, refined carbohydrates and sugars received little or no attention in discussions of cancer causation. Peter Cleave had suggested in The Saccharine Disease that the refining of carbohydrates might be involved in colon cancer. John Yudkin had noted that the five nations with the highest breast-cancer mortality in women in the late 1970s (in descending order: the United Kingdom, the Netherlands, Ireland, Denmark, and Canada) had the highest sugar consumption (in descending order: the United Kingdom, the Netherlands, Ireland, Canada, and Denmark), and those with the lowest mortality rates (Japan, Yugoslavia, Portugal, Spain, and Italy) had the lowest sugar consumption (Japan, Portugal, Spain, Yugoslavia, and Italy).

But in 1989, when the National Academy of Sciences published its 750-page report on Diet and Health, the authors spent only a single page evaluating the proposition that carbohydrates might cause cancer. “There is little epidemiologic evidence to support a role for carbohydrates per se in the etiology of cancer,” they noted. They did add two caveats. One was that “no definitive conclusion is justified…because carbohydrates have often been reported in epidemiologic studies only as a component of total energy and not analyzed separately.” The other was that Richard Dol and Bruce Armstrong had found sugar intake in international comparisons to be “positively correlated with both the incidence of and mortality from” colon, rectal, breast, ovarian, prostate, kidney, nervous-system, and testicular cancer, and that “other investigators have produced similar findings.”

The patterns of cancer incidence, for many cancers, are similar to those of heart disease, diabetes, and obesity, which alone suggests an association between these diseases that is more than coincidental. This was the basis of Cleave’s speculation, of Dennis Burkitt’s, and of those cancer epidemiologists who argued that dietary fat caused breast cancer. But if dietary fat, red meat, man-made chemicals, or even the absence of fiber cannot explain the “strikingly similar” patterns of disease distribution, as the Harvard epidemiologist Edward Giovannucci remarked about colon cancer and Type 2 diabetes in 2001, then something else most likely does.

Those cancers apparently caused by diet or lifestyle and not related to tobacco use are either cancers of the gastrointestinal tract, including colon and rectal cancer, or cancers of what are technical y known as endocrine-dependent organs—breast, uterus, ovaries, and prostate—the functions of which are regulated by hormones. This connection between these diet-and life-style-related cancers and hormones has been reinforced by the number of hormone-dependent factors linked to cancers of the breast and the endometrium (the lining of the uterus). Al suggest that estrogen plays an important role. Al these cancers, with the possible exception of pancreatic and prostate cancer, appear to increase in incidence with weight gain. These associations together imply both a metabolic and a hormonal connection between diet and cancer. This in turn led breast-cancer researchers to focus their attention on the likely possibility that obesity increases the incidence of breast cancer by increasing estrogen production.

The most direct evidence linking overweight or overnutrition to cancer comes from animal experiments. These date back to the eve of World War I, when Peyton Rous, who would later win a Nobel Prize, demonstrated that tumors grow remarkably slowly in semi-starved animals. This line of research lapsed until 1935, when the Cornel University nutritionist Clive McCay reported that feeding rats just barely enough to avoid starvation ultimately extended their lifespan by as much as 50 percent. Seven years later, Albert Tannenbaum, a Chicago pathologist, launched a cottage research industry after demonstrating that underfeeding mice on very low-calorie diets, as McCay had, resulted in a dramatic inhibition of “many types of tumors of divergent tissue origin.” In one experiment, twenty-six of fifty wel -fed mice developed mammary tumors by a hundred weeks of age—the typical lifespan of lab mice

—compared with none of fifty that were al owed only minimal calories. Tannenbaum’s semi-starved animals not only lived longer, but were more active, he reported, and had fewer “pathologic changes in the heart, kidneys, liver, and other organs.”*63

To explain this inhibitory effect, Tannenbaum considered an idea that had originated in the 1920s with Otto Warburg, a German biochemist and later Nobel Prize winner. Warburg had demonstrated that tumor cel s quickly develop the ability to survive without oxygen and to generate energy by a process of fermentation rather than respiration. Fermentation is considerably less efficient, and so tumors wil burn perhaps thirty times as much blood sugar as normal cel s. Incipient tumors in these calorie-restricted lab animals, it was thought, cannot obtain the huge amounts of blood sugar they need to fuel mitosis—division of the nucleus—and continue proliferating.

Insulin was not considered a primary suspect until just recently, but the evidence has existed for a while. The earliest such link between a dysfuntion in carbohydrate metabolism and cancer dates to 1885, when a German clinician reported that sixty-two of seventy cancer patients were glucose-intolerant.

One common observation by clinical investigators over the years was that women with adult-onset (Type 2) diabetes or glucose intolerance had a higher-than-average incidence of breast cancer. By the mid-1960s, researchers were reporting that insulin acts as a promoter of growth and proliferation in both healthy and malignant tissues. Howard Temin, who later won a Nobel Prize for his cancer research, reported that cel s turned malignant by a chicken virus would cease to proliferate in the laboratory unless insulin was added to the serum in which they were growing. This growth-factor effect of insulin was also demonstrated in adrenal and liver-cel cancers. Insulin “intensely stimulated cel proliferation in certain tumors,” noted one 1967 report. In 1976, Kent Osborne and his col eagues at the National Cancer Institute reported that one line of particularly aggressive breast-cancer cel s were “exquisitely sensitive to insulin.”

By the late 1970s, researchers had also reported that malignant breast tumors had more receptors for insulin than did healthy tissue. The more insulin receptors on the surface of a cel , the more sensitive it wil be to the insulin in its environment. Having a greater number of insulin receptors than healthy cel s, as one report noted, might confer “a selective growth advantage to tumor cel s.”

“Selective growth advantage” speaks directly to the process of Darwinian evolution that is considered the control ing force in tumor development. We can think of human cel s as existing in a microscopic ecosystem, living in harmony with their environment, and balanced, as are al species, between the opportunities for growth and proliferation and the processes that lead to aging and death. In such an environment, the bil ions of cel s that eventual y constitute a tumor wil be the descendants of a single cel that has accumulated a series of genetic mutations, each adding to its proclivity to proliferate unfettered by any of the normal inhibitions to growth. The process in which a healthy cel eventual y results in malignancy is a gradual evolution driven by a series of mutations in the DNA of the genes, each bestowing on the cel either the inclination to multiply or a breakdown in the control and repair mechanisms that have evolved to counter precisely such potential y deleterious mutations. The descendants of such a mutant cel would inherit this fitness advantage over other cel s in the tissue, and so, within a few years, a single such mutant cel wil leave mil ions of descendants. As one of those descendants in turn gains, purely by chance, yet another advantageous error or mutation, its descendants wil now come to dominate.

Each new mutation-bearing cel constitutes a new species, in effect, that is better suited to prevail in its local cel ular environment. Eventual y, with this continued accumulation of what to the body as a whole is simply bad luck, a single cel wil come to possess precisely that set of mutant genes that drive it and al ow it to grow and proliferate without limit. Because each single hit of genetic damage alone is not sufficient to produce a cancer cel , the accumulation of just the right half-dozen hits (actual y, the wrong half-dozen hits) takes years or decades, which is why virtual y al cancers become more common as we age.

Cancer researchers now believe that these cancer-causing mutations occur as errors in the replication of DNA during the process of cel division and multiplication. Each one of us is likely to experience some ten thousand tril ion cel divisions over the course of our lives, constituting an “enormous opportunity for disaster,” in the words of the MIT molecular biologist Robert Weinberg, author of the textbook The Biology of Cancer. This suggests that cancer-causing mutations are another unavoidable side effect of aging, which is why our cel s have also evolved to be exceedingly resistant to genetic damage. They have sophisticated mechanisms to search out defects in newly replicated DNA and repair them, and other mechanisms that actual y prompt a cel to commit suicide—programmed cel death, in the technical terminology—if the repair mechanisms are incapable of fixing the damage that occurred during replication. Alas, with time, these programs, too, can be disabled by the proper mutations.

Within this Darwinian environment, insulin provides fuel and growth signals to incipient cancer cel s. Its more lethal effects, however, might come through the actions of insulin-like growth factor (IGF). Growth hormone itself is secreted by the pituitary gland and works throughout the body; IGF is secreted both by the liver and by tissues and cel s throughout the body, and it then works local y, where concentrations are highest. Most tissues require at least two growth factors to grow at an optimal rate, and IGF is almost invariably one of the two, and perhaps the primary regulator.

Insulin-like growth factor is sufficiently similar in structure to insulin that it can actual y mimic its effects. IGF can stimulate muscle cel s to take up blood sugar, just as insulin does, though not as wel . Researchers now believe that IGF serves as the necessary intermediary between the growth hormone secreted by the pituitary gland, and the actual amount of food that is available to build new cel s and tissues. If insufficient food is available, then IGF levels wil stay low even if growth-hormone levels are high, and so cel and tissue growth wil proceed slowly if at al . Add the necessary food and IGF levels increase, and so wil the rate of growth. Unlike insulin, which responds immediately to the appearance of glucose in the bloodstream and so varies considerably from hour to hour, IGF concentrations in the circulation change only slowly over days or weeks, and thus better reflect the long-term availability of food in the environment.

Since the mid-1970s, researchers have identified many of the molecules that play a role in regulating the strength of the growth and proliferation signals that IGF communicates to the cel s themselves. There are several different insulin-like growth factors, for instance, and they bind to specific IGF receptors on the surfaces of cel s. The more IGF receptors on a cel ’s surface, the stronger the IGF signal to the cel . If insulin levels are high enough, insulin wil stimulate the IGF receptors and send IGF signals into cel s as wel as insulin signals.*64