The Nobel Prize in Physiology or Medicine 1985
Michael S. Brown, Joseph L. Goldstein
Presentation Speech by Professor Viktor Mutt
of the Karolinska Institute, December 10, 1985
Translation from the Swedish text
Your Majesties, Your Royal Highnesses,
Ladies and Gentlemen,
At the meeting of the French Academy of Sciences on August 26, 1816, the chemist Michel Chevreul suggested that a substance, with fat-like properties, discovered some decades previously in gallstones by physicians in France and in Germany, should be named cholesterine, from the Greek: chole, bile, and stereos, solid.
Cholesterin, or cholesterol, as it later came to be called, proved not to be confined to gallstones but to occur also in all organs in humans as in all vertebrates and to be a substance of vital importance for them. It participates in the formation of various cellular membranes and is a substance necessary for the synthesis of bile acids (of importance for digestion) and of the vitally important stereoid hormones. For their elucidation of the complicated structures of cholesterol and of bile acids, Wieland and Windaus were awarded a Nobel Prize in 1928.
Cholesterol is of vital importance but may also be deleterious, and far more so than by causing gallstones. Since the middle of the nineteenth century it has been known that in atherosclerosis, cholesterol, or rather cholesterol esters, accumulate in high concentrations in the lesioned areas of the blood vessels, and since the late 1930s a specific inheritable disease, familial hypercholesterolemia, has been recognized, with greatly increased concentrations of cholesterol in the blood, and severe alterations in the normal structure of blood vessels.
Cholesterol is almost insoluble in water. Its solubility in blood plasma is - like other lipids - due to its being packaged into submicroscopic spherical particles with completely hydrophobic components inside, surrounded outside by a mosaic layer of less hydrophobic ones, such as phospholipids and protein. Such particles are called lipoproteins. Cholesterol occurs mainly in a type of lipoproteins called low density lipoproteins, LDL.
Not all organisms require cholesterol, and some which do so, such as insects, are incapable of producing it by themselves and are, therefore, entirely dependent on dietary sources for it. The mammalian cell, however, is capable of producing its own cholesterol, but it also obtains dietary cholesterol by way of the blood. Schoenheimer's investigations from the 1930s suggested that there was some kind of equilibrium between the amount of cholesterol which the cell itself synthesized and that which it obtained from the diet. How this equilibrium was maintained was, however, completely unknown, as was the cause of the highly increased blood cholesterol concentrations in familial hypercholesterolemia. The complicated mechanism for the cellular synthesis of cholesterol had, however, been elucidated, and investigations in this field by Bloch and by Lynen had in 1964 been recognized by a Nobel Prize.
In elegant and systematic investigations - always in collaboration - the laureates of this year studied cholesterol metabolism in cultures of connective tissue cells from healthy persons and from patients with familial hypercholesterolemia, either without or with the addition of blood serum, and thereby cholesterol, to the culture medium. They made the surprising discovery that whereas cells from healthy persons had on their surfaces specific structures, receptors, for the binding of LDL, cells from the patients had either no such receptors or else decreased numbers of them, depending on whether the patient had acquired the disease from both parents or from only one. Equally surprising was the finding that the LDL, after being bound to the receptor moved together with the latter into the interior of the cell. There, the receptor was set free and returned to the cell surface, where it could again bind LDL. The LDL particle on the other hand disintegrated into its components, and the cholesterol thus released was found to have different functions: it contributed to meeting the requirements of the cell for cholesterol; it decreased the synthesis by the cell of endogenous cholesterol by suppressing the activity of a key enzyme, named HMG CoA reductase, for such synthesis; it decreased the number of LDL receptors and thereby the influx of more LDL; and it activated an enzyme in the cell which converts excessive cholesterol into a suitable storage form. The knowledge thus acquired concerning the normal intracellular metabolism of cholesterol, the "LDL pathway", has given not only insights into the causes of genetically determined rearrangements in cholesterol metabolism where, i.a. various defects in receptor structures have been revealed, but also insights into severe and common disease states where the amount of cholesterol in the diet may play a role. This suggests possibilities for the development of methods for treatment and prevention.
Research on cholesterol has been in continuous progress for two centuries and contains several fascinating chapters by eminent scientists. The chapter that this year's laureates have contributed is one of the most fascinating.
Professor Brown, Professor Goldstein,
In elegant and systematic studies you have discovered a physiological mechanism of great importance: the way in which mammalian cells strive to establish an equilibrium between their own synthesis of cholesterol and the cholesterol they obtain from the circulating blood influenced by diet. You have also elucidated important genetically determined aberrations from this mechanism.
This knowledge forms a rational basis for development of methods for the treatment and prevention of the widespread disabling diseases known to be a consequence of dearrangement in plasma cholesterol concentrations. You have also demonstrated something else: how successful cooperation can be a principle that should perhaps be more widely applied, both in science and in other areas of human endeavour.
As a representative of the Nobel Assembly of the Karolinska Institute, I convey to you the sincere congratulations of the Assembly and ask you now to receive your Prize from the hands of His Majesty the King.
From Nobel Lectures, Physiology or Medicine 1981-1990, Editor-in-Charge Tore Frängsmyr, Editor Jan Lindsten, World Scientific Publishing Co., Singapore, 1993
Copyright © The Nobel Foundation 1985
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