In memoriam: Donald B. Zilversmit (1919–2010)

Donald B. Zilversmit, one of the 'founding fathers’ of this journal and its first Editor-in-Chief (1959–1961), died on September 16, 2010 at age 91. He was recognized as a world leader in lipid research and he will be missed. Zilversmit was very much his own man. He had a way of coming up with novel perspectives on biological phenomena. Perhaps the best example of this is his work on the lipid transfer proteins in plasma and in cells. He was intrigued by the question of how lipids, minimally soluble in aqueous media, could nevertheless move from membrane to membrane within the cell. In 1968, he described the exchange of phospholipids between isolated mitochondria and microsomes and went on to purify a protein from the cytosol that markedly accelerated that exchange. These pioneering studies opened up a new and fruitful line of research. In 1975, he showed that lipoprotein-free plasma contained a protein responsible for exchange of cholesterol esters among lipoproteins, which we now know as CETP (cholesterol ester transfer protein). Inhibitors of CETP are now under intensive investigation as a means of raising HDL. Another example of how Zilversmit thought ‘outside the box’ is found in his 1973 proposal that chylomicron remnants were critically important in atherogenesis. He knew that chylomicrons themselves were too large to get into the arterial wall but he visualized ‘remnants’ generated by the action of lipoprotein lipase on the chylomicron as being directly proatherogenic. Studies of remnants, such as those accumulating in patients with the E2/E2 phenotype, supported his hypothesis that at least some human atherosclerosis is remnant-related, but it is still not clear just how important remnants are in the common forms of hypertriglyceridemia. Zilversmit made a persuasive case for his hypothesis in his 1979 George Lyman Duff Lecture before the Council on Arteriosclerosis of the American Heart Association. Zilversmit was not one of those theoretical biologists who don’t deign to grapple with the messy realities at the bench. In fact, he was a bear for careful detailed evaluation of methods. He recognized that sound methodology is the bedrock of good science. He himself contributed importantly to the development of improved methods for the study of lipid and lipoprotein metabolism. His paper with Emil Van Handel describing a new ultrasensitive method for quantifying triglycerides became a Citation Classic akin to the Lowry article on protein quantification. Actually, Zilversmit's focus on methodology was a major factor in the birth of the Journal of Lipid Research. New, more sophisticated methods for analyzing lipids were developing rapidly in the 1950s, including silicic acid chromatography and gas-liquid chromatography. Zilversmit joined hands with E. A. Ahrens and his group at Rockefeller University to propose to the National Institutes of Health what was at first going to be just an informal loose-leaf 'methods notebook’ that would be exchanged among lipid researchers at interested labs. But, like Topsy, the concept grew. In 1958, the Council of the National Heart Institute approved the establishment of a formal journal (see Howard Eder's History of the Journal of Lipid Research, J. Lipid Res., 1984, and Edward Dennis’ history in the 50th Anniversary issue supplement, 2010, for details). Zilversmit got his PhD in the laboratory of I. L. Chaikoff at Berkeley and while there, was introduced to the use of radioisotopes for the study of kinetics in steady-state systems. He was the first to explore the turnover rates of phospholipids, using 32P, and among the first to use 14C in the study of glucose and glycogen metabolism. His interest in kinetics continued throughout his career. In the 1960s, he published classic papers showing that most of the cholesterol in atherosclerotic plaques originated in plasma lipoproteins. Later, he carefully quantified the rates of entry of lipoproteins and their component lipids into the normal artery wall. I knew Don Zilversmit well, admired him as a scientist, and was proud to have him as a friend. He was a gentle man, unassuming and easy to get along with. At the same time, he unfailingly insisted on rigor in matters scientific. Joseph L. Witztum and I were co-directors of one of the NHLBI Specialized Center of Research on Arteriosclerosis in La Jolla and had Zilversmit as one of the members of our Scientific Advisory Board. We quickly learned that Zilversmit did not suffer fools gladly. He was utterly frank in his comments, not unkind, but very direct. Our Fellows knew that they had best prepare their presentations carefully and they benefited greatly from his advice and suggestions. Don Zilversmit had a full and fulfilling life. He was born in the Netherlands in 1919. Being Jewish, his family fled to the United States in 1939, just before the Nazi invasion. His fiancee, Kitty, and her family decided to stay and hope for the best. All except Kitty were killed in the Holocaust. Kitty was hidden by righteous Netherlanders, survived, and was reunited with Don at the end of the war. They were married in 1945 and had three daughters (Lee, Susan, and Jo). Kitty predeceased Don by just a year. Her autobiography is a moving tale of her life during the war and her life with Don ('Yours Always: A Holocaust Love Story’ by Kitty Zilversmit, available at amazon.com). After completing his PhD training at Berkeley, Zilversmit joined the faculty at the University of Tennessee Medical College where he stayed until 1966 when he moved to Cornell at Ithaca, NY. PubMed lists over 200 publications under his authorship. His honors include the Duff Lectureship of the American Heart Association (1979), the Borden Award from the American Institute of Nutrition (1980), D.Sc., (hon.) from University of Utrecht (1980), election to the National Academy of Sciences (1989), and the Bristol-Myers Squibb/Mead Johnson Award for Distinguished Achievement in Nutrition Research (1990). He retired in 1990 and, with characteristic intensity, turned all of his energy to the pursuit of one of his life-long passions, the philosophy of science. Those who knew him and learned from him will miss him sorely. André Bensadoun, one of Zilversmit's longtime colleagues at Cornell, provided important insights and background information (see his more detailed memorial at http://www.theuniversityfaculty.cornell.edu/memorials/mem_main.html). Joseph L. Witztum made valuable suggestions that helped shape the final paper.