The 1964 Nobel Prize for the discovery of the biosynthesis of cholesterol

The Nobel Prize for physiology or medicine for 1964 was awarded to Konrad Bloch (Fig. 1) at Chicago University and Feodor Lynen (Fig. 2) at Munich University for their discoveries of the elucidation of cholesterol and fatty acid metabolism. The same year, the Nobel Committee awarded the Peace Prize to Martin Luther King. Cholesterol was first isolated from gallstones about 200 years ago. It can be derived from the diet or synthesized de novo in humans and has a number of important functions, which have been the cause of extensive medical and nutritional interest. Cholesterol is an important constituent of cell membranes and myelinated structures, and is the precursor of metabolically active compounds such as bile acids, steroid hormones and vitamin D. Cholesterol also plays a pathogenic role in the development of atherosclerosis, shown by the relation between the plasma level of cholesterol and the development of this clinical condition. Because of the importance of sterols, the Nobel Prize for chemistry was awarded to Heinrich Otto Wieland in 1927 for his investigations into the constitution of bile acids and related substances, and to Adolf Windaus in 1928 for his studies of sterols and their association with vitamins. In the early 1930s, the chemical structure of cholesterol was elucidated. The next challenge was to understand the de novo biosynthesis of sterols, which occurs in virtually all cells and particularly in the liver, intestine, adrenal cortex and reproductive organs including the placenta. It was soon realized that the cholesterol skeleton was composed of acetate and that the tetracyclic steroid ring was formed from an appropriately folded long-chain precursor. This proposed structure, which was later found to be correct, was based on the speculation of Leopold Ružička (the Nobel Laureate for chemistry in 1939) that terpenes and steroids have a common origin (1) and of Sir Robert Robinson that cholesterol might be produced by cyclization of the hydrocarbon squalene (2). This proposal was supported by the finding in 1926 that feeding squalene to rats increased the cholesterol content of some tissues (3). DISCOVERIES BY BLOCH AND LYNEN The complete elucidation of cholesterol biosynthesis was the result of independent but parallel investigations by Feodor Lynen and co-workers at the University of Munich from 1938 (4) and by Konrad Bloch at Columbia University in New York and Chicago University from 1940 (5). During their studies, Bloch and Lynen were influenced by each other’s results. Lynen began his investigations into the biosynthesis of cholesterol, about 2 years ahead of Bloch; however, Lynen’s studies came to a standstill for about 3 years during the war, whereas Bloch could continue his investigations without any interruption. Both Bloch and Lynen had excellent mentors. Lynen started his scientific career as a research fellow to the Nobel Laureate Heinrich Otto Wieland, who was later Lynen’s father-in-law. Meanwhile, after obtaining his Ph.D., Bloch joined the research group of Rudolf Schoenheimer who together with David Rittenberg had begun the pioneering studies on intermediate metabolism with the aid of stable isotopes. From such investigations, they concluded that cholesterol is formed by the coupling of smaller molecules making up a skeleton of 30 carbon units (6). The first support for this hypothesis was obtained in 1937 by Robert Sonderhoff and Heinz Thomas who were research fellows to Wieland (7). When investigating the metabolism of tri-deuterated acetate by yeast, they found that formed citrate contained the expected amount of the isotope whereas succinate contained only half of the expected amount. On the basis of the findings that yeast cells form succinate from acetate and that deuterium was mainly recovered in fatty acids and sterols with only minor amounts in carbohydrates, Lynen proposed that fatty acids and sterols are directly formed from acetate (8). In the meantime, Wieland found that yeast cells that are shaken with oxygen will lack substrate for cellular respiration and need some incubation time before they are able to oxidize acetic acid. From this finding, Lynen concluded that an incubation time was needed to activate acetate by ATP as an energy donor and by a Acta Pædiatrica ISSN 0803–5253