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.

While the three Eastern laboratories took three years to learn how to use an ultracentifruge for fractionating lipoproteins, Gofman proceeded with his own research, refined his understanding of how these lipoproteins predicted heart disease, and he then insisted that the analysis techniques be updated accordingly. The other investigators, however, were having considerable trouble duplicating Gofman’s original analysis, and so they refused to accept any further modifications.