Biography
Dr. Small founded of the Department of Biophysics at Boston University School of Medicine and served as its Chair form 1988 to 2000. After merger with the Department of Physiology in 2000, he served as Chair of Physiology and Biophysics until 2006 when he passed the Chair to Dr. David Atkinson. In 1980 he initiated this Program Project (HL026335) and was Program Director from 1980 to 2001. He has been the Director of Project 2 since its inception. Thus he has a long experience with the Program Project, its changes and advances throughout the past 30 years. Dr. Small, after completing a residency in internal medicine, was trained as a physical chemist with expertise in the study of bulk and surface properties of lipids. Between 1966 and 1978, he studied the physical chemistry of bile lipids. He defined the solubility of cholesterol in phospholipid/bile salt micelles (1), and related it to human bile composition and gallstone formation (2). This ignited a whole field of gallstone research which culminated in translation to drug therapy in patients to dissolve and prevent stones. His interest turned to atherosclerosis and in 1974 published a seminal paper in Science on the physical-chemical basis of lipid deposition in atherosclerosis (3). In 1986 he was selected by the AHA to give the Duff Lecture on his extensive work on the physical-biochemistry of atherosclerotic lesions. Lipoproteins and their apolipoproteins also became a target of his research and along with colleagues he discovered the order/disorder phase transition in cholesterol esters in LDL (4), the irreversible denaturation transition of apo-B on LDL (4), and unfolding transitions in apo-A1, both as a free protein and on lipid particles (5). Over 40 years he and his colleagues have studied the physical biochemistry of lipoproteins, and throughout this period he also published over 50 studies on the physical behavior of a variety of lipids. In 1986 he published, “The Physical Chemistry of Lipids, From Alkanes to Phospholipids,” a highly acclaimed 672 page source book. By 1990 he began to explore how the primary sequence of apo-B related to its structure and how this drove the assembly with lipids to form nascent VLDL as apoB translocated across the ER. Project 2 was initiated first to study the lipoproteins secreted from cells transfected with C-terminal truncations of apo-B. In 1994, Robert Nolte (a student of Dr. Atkinson) and Dr. Jere Segrest independently showed that apoB100 and an a/?-?1-a1-?2-a2 secondary structure. In 1997, Drs. Small and Atkinson presented a more detailed model for the ?1 domain of apoB (apoB21-41) as an amphipathic beta sheet 50-60Å wide and 200Å long which could recruit triglycerides into nascent lipoproteins. He then showed that this ? region was responsible for recruiting triacylglycerol to the nascent particle during its translocation across the ER in cells. Since apolipoproteins are interfacial molecules, he pioneered a method to study the binding and surface properties of peptides and apolipoproteins to a drop of core lipid, e.g. triaclyglycerol. He showed that surface behavior of apolipoproteins were very different from the usual globular peptides which denature at surfaces. Amphipathic alpha helical peptides such as HDL apolipoproteins (apo-A1, apo-C1, etc.) bound TAG but could be pushed off into the aqueous phase at a specific pressure without being denatured. In contrast, amphipathic beta strands and native parts of the ?1 sheet region from apo-B bound irreversibly and had pure elastic properties and thus provided an anchor for apo-B at the nascent VLDL surface. Recently using an innovative combination of Langmuir balance and tensiometer studies and application of the Gibbs 2D phase rule, he was able to coat the surface with phosphatdylcholine (PC) to produce a more native lipoprotein-like surface. Here the concentration or surface density of PC and TAG is known and can be varied as a function of pressure. Ongoing studies of various apoproteins and peptides at PC-TO/W interfaces provide a unique opportunity of studying their absorption, potential for desorption, elasticity and other properties at a more physiologic interface.
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