The discovery of thiamin.

Thiamin deficiency was long known as 'beriberi' in English and 'kakké' in Japan and China. The cause of beriberi was attributed to miasmas rising from wet soil and later to an unknown infectious organism. Systematic studies of beriberi began in the Dutch East Indies in the 1880s. Cornelis Pekelharing and Cornelis Winkler investigated beriberi in the Dutch East Indies and thought that they had isolated a micrococcus that was responsible for the disease. Christiaan Eijkman observed that chickens fed white rice developed a leg paralysis or 'polyneuritis', whereas chickens fed brown (unpolished) rice did not. Gerrit Grijns succeeded Eijkman in the beriberi studies in Java and concluded correctly that there were unknown substances in foods that were needed for the peripheral nervous system. In 1926, Barend Jansen and Willem Donath isolated and crystallized a substance that cured polyneuritis in pigeons. Robert Williams synthesized thiamin in 1936.

The discovery of vitamin C.

The term 'scurvy' for the disease resulting from prolonged vitamin C deficiency had origins in 'scorbutus' (Latin), 'scorbut' (French), and 'Skorbut' (German). Scurvy was a common problem in the world's navies and is estimated to have affected 2 million sailors. In 1747, James Lind conducted a trial of six different treatments for 12 sailors with scurvy: only oranges and lemons were effective in treating scurvy. Scurvy also occurred on land, as many cases occurred with the 'great potato famine' in Ireland in 1845. Many animals, unlike humans, can synthesize their own vitamin C. Axel Holst and Theodor Frölich fortuitously produced scurvy in the guinea pig, which like humans requires vitamin C in the diet. In 1928, Albert Szent-Györgyi isolated a substance from adrenal glands that he called 'hexuronic acid'. Four years later, Charles Glen King isolated vitamin C in his laboratory and concluded that it was the same as 'hexuronic acid'. Norman Haworth deduced the chemical structure of vitamin C in 1933.

Acute versus marginal deficiencies of nutrients.

Under experimental conditions, an acute nutrient deficiency (e.g., thiamin or folic acid) can be induced in both animal and human subjects. The signs and pathologic changes of an acute deficiency, however, may differ substantially from those seen clinically; often marginal deficiencies have been maintained over a long period of time.

History and impact of nutritional epidemiology.

The real and important role of epidemiology was discussed, noting heretofore unknown associations that led to improved understanding of the cause and prevention of individual nutritional deficiencies. However, epidemiology has been less successful in linking individual nutrients to the cause of chronic diseases, such as cancer and cardiovascular disease. Dietary changes, such as decreasing caloric intake to prevent cancer and the Mediterranean diet to prevent diabetes, were confirmed as successful approaches to modifying the incidence of chronic diseases. The role of the epidemiologist was confirmed as a collaborator, not an isolated expert of last resort. The challenge for the future is to decide which epidemiologic methods and study designs are most useful in studying chronic disease, then to determine which associations and the hypotheses derived from them are especially strong and worthy of pursuit, and finally to design randomized studies that are feasible, affordable, and likely to result in confirmation or refutation of these hypotheses.