When we consider treating a disease with a new therapy, we always have to consider potential side effects such as these. If a drug prevents heart disease but can cause cancer, the benefits may not be worth the risk. If the drug prevents heart disease but can cause cancer in only a tiny percentage of individuals, and only causes rashes in a greater number, then the tradeoff might be worth it. No drug can be approved for treatment without such consideration. Why should diet be treated differently?
The Seven Countries Study, which is considered Ancel Keys’s masterpiece, is a pedagogical example of this risk-benefit problem. The study is often referred to as “landmark” or “legendary” because of its pivotal role in the diet-heart controversy. Keys launched it in 1956, with $200,000 yearly support from the Public Health Service, an enormous sum of money then for a single biomedical research project. Keys and his collaborators cobbled together incipient research programs from around the world and expanded them to include some thirteen thousand middle-aged men in sixteen mostly rural populations in Italy, Yugoslavia, Greece, Finland, the Netherlands, Japan, and the United States. Keys wanted populations that would differ dramatically in diet and heart-disease risk, which would allow him to find meaningful associations between these differences. The study was prospective, like Framingham, which means the men were given physical examinations when they signed on, and the state of their health was assessed periodically thereafter.
Results were first published in 1970, and then at five-year intervals, as the subjects in the study aged and succumbed to death and disease. The mortality rates for heart disease were particularly revealing. Expressed in deaths per decade, there were 9 heart-disease deaths for every ten thousand men in Crete, compared with 992 for the lumberjacks and farmers of North Karelia, Finland. In between these two extremes were Japanese villagers at 66 per ten thousand, Belgrade faculty members and Rome railroad workers at 290, and U.S. railroad workers with 570 deaths per ten thousand.
According to Keys, the Seven Countries Study taught us three lessons about diet and heart disease: first, that cholesterol levels predicted heart-disease risk; second, that the amount of saturated fat in the diet predicted cholesterol levels and heart disease (contradicting Keys’s earlier insistence that total fat consumption predicted cholesterol levels and heart disease with remarkable accuracy); and, third, a new idea, that monounsaturated fats protected against heart disease. To Keys, this last lesson explained why Finnish lumberjacks and Cretan villagers could both eat diets that were 40 percent fat but have such dramatically different rates of heart disease. Twenty-two percent of the calories in the Finnish diet came from saturated fats, and only 14 percent from monounsaturated fats, whereas the villagers of Crete obtained only 8 percent from saturated fat and 29 percent from monounsaturated fats. This could also explain why heart-disease rates in Crete were even lower than in Japan, even though the Japanese ate very little fat of any kind, and so very little of the healthy monosaturated fats, as well. This hypothesis could not explain many of the other relationships in the study—why eastern Finns, for instance, had three times the heart disease of western Finns, while having almost identical lifestyles and eating, as far as fat was concerned, identical diets—but this was not considered sufficient reason to doubt it. Keys’s Seven Countries Study was the genesis of the Mediterranean-diet concept that is currently in vogue, and it prompted Keys to publish a new edition of his 1959 best-seller, Eat Well and Stay Well, now entitled How to Eat Well and Stay Well the Mediterranean Way.
Despite the legendary status of the Seven Countries Study, it was fatally flawed, like its predecessor, the six-country analysis Keys published in 1953 using only national diet and death statistics to support his points. For one thing, Keys chose seven countries he knew in advance would support his hypothesis. Had Keys chosen at random, or, say, chosen France and Switzerland rather than Japan and Finland, he would likely have seen no effect from saturated fat, and there might be no such thing today as the French paradox—a nation that consumes copious saturated fat but has comparatively little heart disease.
In 1984, when Keys and his colleagues published their report on the data after fifteen years of observation, they explained that “little attention was given to longevity or total mortality” in their initial results, even though what we really want to know is whether or not we will live longer if we change our diets. “The ultimate interest being prevention,” they wrote, “it seemed reasonable to suppose that measures controlling coronary risk factors would improve the outlook for longevity as well as for heart attacks, at least in the population of middle-aged men in the United States for whom [coronary heart disease] is the outstanding cause of premature death.” Now, however, with “the large number of deaths accumulated over the years,” they realized that coronary heart disease accounted for less than one-third of all deaths, and so this “forced attention to total mortality.”
Now the story changed: High cholesterol did not predict increased mortality, despite its association with a greater rate of heart disease. Saturated fat in the diet ceased to be a factor as well. The U.S. railroad workers, for instance, had a death rate from all causes lower—and so a life expectancy longer—than the Finns, the Italians, the Yugoslavs, the Dutch, and particularly the Japanese, who ate copious carbohydrates, fruits, vegetables, and fish. Only the villagers of Crete and Corfu could still expect to live significantly longer than the U.S. railroad workers. Though this could be explained by other factors, it still implied that telling Americans to eat like the Japanese might not be the best advice. This was why Keys had begun advocating Mediterranean diets, though evidence that the Mediterranean diet was beneficial was derived only from the villagers of Crete and Corfu in Keys’s study, and not from those who lived on the Mediterranean coast of Yugoslavia or in the cities of Italy.
In discussions of dietary fat and heart disease, it is often forgotten that the epidemiologic tools used to link heart disease to diet were relatively new and had never been successfully put to use previously in this kind of challenge. The science of epidemiology evolved to make sense of infectious diseases, not common chronic diseases like heart disease. Though the tools of epidemiology—comparisons of populations with and without the disease—had proved effective in establishing that a disease such as cholera is caused by the presence of micro-organisms in contaminated water, as the British physician John Snow demonstrated in 1854, it is a much more complicated endeavor to employ those same tools to elucidate the subtler causes of chronic disease. They can certainly contribute to the case against the most conspicuous determinants of noninfectious diseases—that cigarettes cause lung cancer, for example. But lung cancer was an extremely rare disease before cigarettes became widespread, and smokers are thirty times as likely to get it as nonsmokers. When it comes to establishing that someone who eats copious fat might be twice as likely to be afflicted with heart disease—a very common disorder—as someone who eats little dietary fat, the tools were of untested value.
The investigators attempting these studies were constructing the relevant scientific methodology as they went along. Most were physicians untrained to pursue scientific research. Nonetheless, they decided they could reliably establish the cause of chronic disease by accumulating diet and disease data in entire populations, and then using statistical analyses to determine cause and effect. Such an approach “seems to furnish information about causes,” wrote the Johns Hopkins University biologist Raymond Pearl in his introductory statistics textbook in 1940, but it fails, he said, to do so.