In the early 1930's after decades of effort the structural elucidation of cholesterol had reached the stage of completion, and with this achievement one of the most brilliant chapters of organic chemistry came to a close. To chemists and biochemists alike the structure of cholesterol at once presented a biosynthetic problem of exceptional challenge. At first sight the molecular architecture of cholesterol seemed enigmatic and devoid of any clues as to how this complex molecule might be constructed from the smaller molecules available in the cell. It is, therefore, all the more remarkable that much of the early speculative thinking came so close to predicting some of the general principles that were eventually shown to operate in sterol biosynthesis. The early proposals were mainly concerned with the problem of ring formation, and quite uniformly they envisioned an origin of the tetracyclic steroidal ring system from an appropriately folded longchain precursor. This intuition proved to be correct. All of the speculative schemes have in some way influenced the research that was to take place later, but none equalled in perspicacity L. Ruzicka's unifying hypothesis on the common origin of terpenes and steroids and the suggestion by Sir Robert Robinson that cholesterol might arise by cyclization of the hydrocarbon squalene. These bold and appealing ideas carried perhaps more weight because they had some experimental evidence to support them. Already in 1926 Shannon, following a proposal by Copyright ? 1965 by the Nobel Foundation.The author is Higgins Professor of Biochemistry at Harvard University, Cambridge, Massachusetts. This article is the lecture he delivered in Stockholm, Sweden, 11 December 1964, when he received the Nobel Prize in medicine and physiology, a prize which he shared with Professor Feodor Lynen of the Max-Planck-Institut fiir Zellchemie, Munich. It is published here with the permission of the Nobel Foundation and will also be included in the complete volumes of Nobel lectures in English, published by the Elsevier Publishing Company, Amsterdam and New York.
OCTOBER 1965Heilbron, Kamm, and Owens (1), had shown that squalene fed to animals increases the cholesterol content of the tissues (2).The phase of continuous research on cholesterol biosynthesis begins in 1937 with two independent and remarkably complementary investigations. In the course of their pioneering studies on intermediary metabolism with the aid of stable isotopes, Rittenberg and Schoenheimer at Columbia arrived at the conclusion that the process of cholesterol formation involves the coupling of smaller molecules, "possibly those which have been postulated to be intermediates in the fat and carbohydrate metabolism" (3). During the same year Sonderhoff and Thomas, noting an incorporation of trideuterioacetate into the unsaponifiable materials of yeast, stated: "Es lasst Sich darauf schliessen dass die Sterine der Hefe auf einem recht unmittelbaren Wege aus der Essigsiure entstehen" (4).As a graduate student under Hans T. Clarke at Col...