Good Calories, Bad Calories

1960s and 1970s. “It appears that only a very small 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 polluted central valleys 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 cells. 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 Doll had called 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 well 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 Doll and his colleague 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 Doll 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 technically 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). All suggest that estrogen plays an important role. All 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 Cornell 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 well-fed mice developed mammary tumors by a hundred weeks of age—the typical lifespan of lab mice—compared with none of fifty that were allowed 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 cells 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 will burn perhaps thirty times as much blood sugar as normal cells. 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 cells 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-cell cancers. Insulin “intensely stimulated cell proliferation in certain tumors,” noted one 1967 report. In 1976, Kent Osborne and his colleagues at the National Cancer Institute reported that one line of particularly aggressive breast-cancer cells 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 cell, the more sensitive it will be to the