Friday, March 28, 2003
Carnegie Mellon Biophysicists Garner Avanti Award from Biophysical Society
PITTSBURGH— Excellence in both theoretical and experimental physics is not usually found in the same individual. Rarer still is a husband-wife team whose accomplishments in these areas have dramatically altered the course of their field. For their significant contributions both to theory and experimental biophysics, Carnegie Mellon University scientists John Nagle and Stephanie Tristram-Nagle have recently received the Avanti Award in Lipids from the Biophysical Society.
The work of Nagle and Tristram-Nagle focuses on lipid bilayers, which form the fundamental core of the biological membranes that encapsulate a cell’s contents. Lipid bilayers are indispensable. They prevent cellular intruders, but also easily accommodate proteins that allow critical molecules —like neurotransmitters, ions and hormones—to bind to or enter cells. The chemical characteristics of lipids naturally drive them to form bilayers.
“Lipid molecules are surface active and have a schizophrenic reaction to water—one end of the molecule loves it and the other hates it. Therefore, these molecules self-assemble into sheets that have the nice property for biology in that they compartmentalize space. They are what divide us into pieces at the cellular level,” says Nagle, a professor of physics and biological sciences at Carnegie Mellon.
Like many materials, lipid bilayers form different phases that change with temperature, but only the “fluid” phase is biologically relevant. In the 1970s, Nagle accomplished the “holy grail” of his original theoretical field of statistical mechanics. To understand the transition of lipid bilayers into the biologically relevant phase, he developed a model that he then solved without mathematical approximation. This work then led him to experimental research that provided evidence supporting the physical ingredients of the model.
Nagle and Tristram-Nagle, a senior research biologist, advanced their field even more starting in the 1980s, when they began to employ the technique of x-ray diffraction to quantify structural properties of different lipid bilayers in several different phases. X-ray diffraction data from crystals appear on a 2-d detector as a series of well-defined spots; the spacing between the spots and their intensities provide the information for determining a crystal’s structure. In contrast, biologically relevant lipid bilayers produce an x-ray pattern of diffuse, fuzzy blobs that present, at first glance, an insurmountable obstacle to analysis.
Unlike crystals, stacks of lipid bilayers form liquid crystals that are highly disordered and fluctuating. “The challenge for doing structural studies on the biologically relevant phase of lipid bilayers is that they don’t have the usual kind of structure,” notes Tristram-Nagle. For most of the 1990s, they and their students struggled to overcome the effects of liquid crystal fluctuations to obtain reliable information about the structure of liquid crystals.
What their student Yufeng Liu and they recently discovered and incorporated into their analysis is that there is actually more information in the messy diffuse x-ray data than there is in the spots typical of crystal data. “By addressing the fluctuations between bilayers, you can tease out the structure,” says Tristram-Nagle. By characterizing these fluctuations using the methods of statistical mechanics, the team has pioneered the development of liquid crystallography. “We realized that the diffuse scattering of x-rays can be analyzed. It isn’t noise. That’s really our recent breakthrough,” comments Nagle.
While not high profile outside their field, the work of Nagle and Tristram-Nagle enables investigators in a variety of fields to conduct studies that address more specific aspects of lipid bilayers as encountered in biological membranes or synthetic materials. “We're really providing a cornerstone with our data and numbers that others use,” remarks Nagle. “Our work combines volume and x-ray data to give the area of a lipid bilayer, an important quantity that researchers need to know when running a simulation,” Tristram-Nagle adds.
Future studies in the laboratory of Nagle and Tristram-Nagle will focus on putting peptides such as the HIV fusion peptide into lipid bilayers to better understand how the HIV virus attacks cells. Another effort is understanding apoptosis. “When a cell dies, a lipid in the cell's plasma membrane called phosphatidylserine flips from the inside to the outside of the bilayer. This signals other cells called macrophages to eat the cell,” says Tristram-Nagle. “We need to get precise numbers on how phosphatidylserine fits in the bilayer and what its area is before we understand how it interacts with a macrophage.” Their research is currently funded by a $1 million, four-year grant from the National Institutes of Health.
The interchange between theory and experiment is ongoing, as evidenced by Nagle's model of a lipid structure hanging on his office wall. “It's like a good cartoon as it relates to a portrait,” he says. “A lot of details are distorted but the essence is there. You use models to get insight, the essence of something. Then you can ask what experiment to do next and use more theory to help analyze the data.”
Avanti Polar Lipids, Inc., bestows the Avanti Award biennially, alternating between the Biophysical Society and the American Society for Biochemistry and Molecular Biology. Winners, who receive a cash prize, are outstanding investigators known for their seminal studies in lipid metabolism, lipid enzymology, or lipids in membranes.
The Biophysical Society is a professional organization with nearly 7,000 members in the United States and more than 45 countries. The society encourages development and dissemination of knowledge in biophysics through its journal, Biophysical Journal, its annual meeting, smaller discussions workshops, subgroups, newsletter, and outreach programs conducted by society committees.
The Mellon College of Science at Carnegie Mellon University maintains innovative research and educational programs in biological sciences, chemistry, physics, mathematics and several interdisciplinary areas. For more information, visit http://www.cmu.edu/mcs.
By: Lauren Ward