Record

EC - Certificates of election and candidature for Fellowship of the Royal Society
- 1991 - Certificates of Election 1991

RefNo	EC/1991/42
Level	Item
Title	Brown, Michael S: certificate of election to the Royal Society
Date	1989
Description	Certificate of Candidate for Election to Foreign Membership. Citation typed
Citation	In a singularly close and continuous collaboration beginning in 1973, Joseph Goldstein and Michael Brown have been responsible for the essentially complete elucidation of the basic mechamism [sic] controlling cholesterol metabolism, thereby opening the way to: 1) the understanding of receptor-mediated endocytosis, and 2) new approaches to the treatment of hypercholesterolaemia and coronary heart disease, the predominant cause of disability and death in the Western world. For this work they jointly received the Nobel Prize for Physiology or Medicine in 1985. Until the work of Brown and Goldstein, the control of cholesterol metabolism was largely a mystery. Plasma cholesterol was known to be contained in lipoproteins, the concentration of which varied in an unexplained manner with dietary, hormonal and genetic factors. Goldstein and Brown identified, purified and isolated the gene for the low density lipoprotein (LDL) receptor, one of the most important molecules to be identified in many years. The cell surface receptor binds plasma LDL and mediates its entry into cells through a process that Brown and Goldstein discovered and named "receptor-mediated endocytosis". Inside cells, LDL is digested in lysosomes, and its cholesterol becomes the building block for the synthesis of cell membranes, steroid hormones and bile acids, as well as the signal for regulating both cellular cholesterol synthesis and LDL receptor number. By mediating the degradation of the LDL, the LDL receptor controls the level of cholesterol in plasma. Discovery of the LDL receptor system has had monumental impact in two areas of physiology and medicine. 1) This discovery elucidated the molecular defect in familial hypercholesterolaemia, the most common inborn error of metabolism in humans and the first genetic cause of atherosclerosis to be unravelled. Affected individuals produce one of multiple mutant forms of the receptor; they degrade LDL at a low rate; and LDL accumulates in plasma, eventually becoming deposited in coronary arteries. Knowledge of this receptor defect pointed the way to the understanding of more subtle types of hypercholesterolaemia in which LDL receptors are reduced by faulty regulation rather than by genetic defects. It also pointed the way to new drugs that inhibit cholesterol synthesis, stimulate LDL receptors, and lower plasma LDL. 2) The discovery also opened the field of receptor-mediated endocytosis. To explain how LDL enters cells, Goldstein and Brown uncovered a new mechanism: LDL and its receptor enter cells through portals on the cell surface called coated pits. Using this paradigm, other scientists subsequently showed that many macromolecules (insulin, growth factors, viruses, toxins, plasma glycoproteins, transport proteins) also enter cells by receptor-mediated endocytosis in coated pits. Thus, a major biological process critical for understanding of normal and disease states was identified with wide ramifications in cell biology and in medicine.
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