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Donald S. Fredrickson was a leading scientist investigating the links between lipids and heart disease at a time when the study of lipid transport in the blood emerged as a new field of clinical research. Lipids, which include fats and cholesterol, are easily stored in the body, where they serve as a source of energy and are an important element in the structure of cells. They are also thought to contribute to coronary heart disease if consumed and stored in excess. In addition, Dr. Fredrickson discovered two genetic diseases related to the storage of lipids in the body.

Arriving at the National Institutes of Health in Bethesda in 1953 after two years of post-doctoral training in lipid chemistry at the Massachusetts General Hospital, Fredrickson specialized in the study of plasma lipoproteins and their genetic variation in man. Lipoproteins are compound molecules of lipids and proteins transported in the blood. Some forms of lipoproteins, called high-density lipoproteins (HDL), carry cholesterol out of the blood stream to the liver for excretion in the bile, and have been shown to reduce the risk of premature coronary heart disease. Other lipoproteins, called low-density proteins (LDL), deposit cholesterol within arteries and are thought to increase the risk of heart disease. Normally a minor constituent of plasma, LDL appears at greatly elevated levels in some individuals, apparently as a genetic trait.

Until the early 1950s, abnormal plasma lipids were characterized as one of two conditions, either as too much cholesterol (hypercholesterolemia) or as an excess of another component of lipoproteins, trygliceride (hypertrygliceridemia). Working with Robert Gordon, the co-discoverer of free fatty acids, and other researchers in the laboratory of protein chemist and future Nobel Laureate Christian B. Anfinsen, Fredrickson used high-speed centrifugation and other advanced laboratory techniques, as well as clinical and hereditary data, to arrive at a more complex understanding of abnormalities in blood lipoproteins. Ultimately they arrived at five major types of abnormalities, each of which differed in clinical signs and genetic expression. Each also responded to different diets or drugs, important information for physicians and nutritionists newly aware of the dangers of cholesterol abnormalities.

By the time he became Clinical Director of the National Heart Institute and Head of its Section on Molecular Diseases in 1961, Fredrickson had concentrated on the study of hereditary abnormalities in plasma lipoproteins, a new discipline he called Genetic Dyslipoproteinemia. His laboratory also isolated and described several new protein components of the lipoproteins.

In recognition of his path-breaking work, the New England Journal of Medicine, the preeminent American medical journal, invited Fredrickson to review his work in five serial issues published in 1967. He was one of the three editors and contributors who published The Metabolic Basis of Inherited Disease in 1960, a textbook that became a classic and that continues in print under new editors. His "five phenotypes" became a standard question on medical examinations, and stimulated further research on lipoprotein disorders that continues today. In the 1970s, the World Health Organization adopted the system as a standard of clinical practice in diagnosing conditions linked to hyperlipidemic conditions. The system remains in use throughout the world today. In the wake of his discoveries, Fredrickson was invited to lecture around the world. Fredrickson entitled one of his lectures, held before the Royal College of Physicians in London in 1970, "a requiem for the egg." Its high cholesterol content had raised sudden concerns about this dietary staple.

His interest in lipids led Fredrickson to the discovery of two related diseases linked to the disorders in the metabolism of lipids and lipoproteins. The first of these was cholesterol ester storage disease, the result of a deficiency of a fat-splitting enzyme called acid lipase. Another group of patients, the first of whom came from Tangier Island in the Chesapeake Bay in 1960, showed prominent deposits of cholesterol in body tissues, especially in greatly-enlarged tonsils, which accumulated due to a lack of high-density lipoproteins that help eliminate cholesterol from the body. Fredrickson named this condition Tangier disease. He concluded that both cholesterol ester storage disease and Tangier disease were hereditary in origin.

Fredrickson was a driving force behind the establishment of the Lipid Clinics Research Program, which conducted the much-publicized Coronary Primary Prevention Trial. This clinical trial offered conclusive evidence that reduction of cholesterol in the blood alone can prevent heart attack and death due to coronary heart disease. Moreover, the program was the first to measure lipoprotein levels in a large number of Americans of different ages and both sexes.

Fredrickson's pioneering investigations of the ways in which the body processes, or metabolizes, lipids alerted scientists, physicians, and the public to the dangers of a diet rich in fats and cholesterol. His research provided a scientific foundation for nutritional guidelines that emphasize the benefits of a low-fat, low-cholesterol diet. His research also led to the establishment of a system for classifying abnormalities in blood lipids. The scientific importance and policy implications of his findings made him the most frequently cited physiologist of the period 1961-1975, according to data from the Institute for Scientific Information. Fredrickson's discoveries about cholesterol have been turned into public policies designed to prevent diseases of the heart and vascular system. In recognition of his service to both science and to the public's health he received the Distinguished Service and Gold Medal Awards from the American College of Cardiology.