Good Calories, Bad Calories

In 1950, the University of California medical physicist John Gofman wrote an article in Science that would be credited, albeit belatedly, with launching the modern era of cholesterol research. Gofman pointed out that cholesterol is only one of several fatlike substances that circulate through the blood and are known collectively as lipids or blood lipids. These include free fatty acids and triglycerides,^*41 the molecular forms in which fat is found circulating in the bloodstream. These could also be players in the heart-disease process, Gofman noted, and the fact that there was no easy way to measure their concentrations in the circulation didn’t change that. Both cholesterol and triglycerides are shuttled through the circulation in particles called lipoproteins, and these could also be players. The amount of cholesterol and triglycerides varies in each type of lipoprotein. So, when physicians measure total cholesterol levels, they have no way of knowing how the cholesterol itself is apportioned in individual lipoproteins. It is possible, Gofman noted, that in heart disease the problem may be caused not by cholesterol but by a defect in one of these lipoproteins, or an abnormal concentration of the lipoproteins themselves.

Eventually, researchers came to identify these different classes of lipoproteins by their density. Of those that appeared to play obvious roles in heart disease, three in particular stood out even in the early 1950s. Two of these are familiar today: the low-density lipoproteins, known as LDL, the bad cholesterol, and the high-density variety, known as HDL, the good cholesterol. (This is an oversimplification, as I will explain shortly.) The third class is known as VLDL, which stands for “very low-density lipoproteins,” and these play a critical role in heart disease. Most of the triglycerides in the blood are carried in VLDL; much of the cholesterol is found in LDL. That LDL and HDL are the two species of lipoproteins that physicians now measure when we get a checkup is a result of the oversimplification of the science, not the physiological importance of the particles themselves.

In 1950, the only instrument capable of measuring the density of lipoproteins was an ultracentrifuge, and the only ultracentrifuge available for this work in America was being used by Gofman at the University of California, Berkeley. Gofman was both a physician and a physical chemist by training. During World War II, he worked for the Manhattan Project, and developed a process to separate plutonium that would later be used to produce H-bombs. After the war, Gofman set out to use the Berkeley ultracentrifuge to study how cholesterol and fat are transported through the blood and how this might be affected by diet and perhaps cause atherosclerosis and heart disease.

This was the research Gofman first reported in Science in 1950. He described how his ultracentrifuge “fractionated” lipoproteins into different classes depending on their density, and he noted that one particular class of lipoproteins, which would later be identified as LDL,^*42 is more numerous in patients with atherosclerosis than in healthy subjects, in men than in women, in older individuals than in younger, and particularly conspicuous in diabetics, all of which suggested a possible role in heart disease. What these low-density lipoproteins did not do, Gofman reported, was to reflect consistently the amount of cholesterol in the blood, even though they carry cholesterol within them. Sometimes total cholesterol levels would be low in his subjects, he noted, and yet the concentration of these low-density lipoproteins would be abnormally high. Sometimes total cholesterol would be high while the cholesterol contained in the low-density lipoproteins was low. “At a particular cholesterol level one person may show 25 percent of the total serum cholesterol in the form of [low-density lipoproteins], whereas another person may show essentially none in this form,” Gofman wrote.

After Science published Gofman’s article, and after aggressive lobbying on Gofman’s part, the National Advisory Heart Council agreed to fund a test of his hypothesis that lipoproteins are the important factor in heart disease and that cholesterol itself is not. The test would be carried out by four research groups—led by Gofman at Berkeley, Irving Page at the Cleveland Clinic, Fred Stare and Paul Dudley White at Harvard, and Max Lauffer of the University of Pittsburgh—that collectively identified five thousand men who were free of heart disease. When heart disease eventually appeared, they would determine whether total cholesterol or Gofman’s lipoproteins was the more accurate predictor.