Cell membrane researchers are eagerly bracing for a long-awaited cold wave. A new partnership involving the National Institute of Standards and Technology (NIST), the University of California-Irvine (UCI) and other organizations will use beams of super-chilled neutrons to probe the elusive structure and interactions of cell membranes and their components, gathering information key to improving disease diagnosis and treatment.
Led by UCI biophysicist Stephen White, the Cold Neutrons for Biology and Technology (CNBT) team received $5 million from the National Center for Research Resources of the National Institutes of Health to build the nation's first neutron-beam research station fully dedicated to biological membrane experiments. To be located at the NIST Center for Neutron Research (NCNR) in Gaithersburg, Md., the CNBT team will exploit the NIST center's ability to generate high-quality beams of "cold" neutrons. Stripped from the nuclei of heavy atoms and then cooled by liquid hydrogen, these uncharged particles are ideally suited for exploring the disordered, continually changing landscape of cell membranes.
"Cold neutrons provide a powerful tool for studying cell membrane systems," says White, "but the demand for beam time at the handful of neutron facilities in the United States is so great that the tool was nearly unavailable for this kind of research. Yet, for many challenges in biology and medicine, neutron probes offer the only realistic hope for answers."
For example, White says that only neutron probes can glimpse the process by which protein fragments, or peptides, are assembled into membrane-borne sentries that ward off harmful microorganisms.
To ease the neutron crunch for biologists, NIST offered to open a new port in a beamline at its NCNR. White then organized the CNBT partnership, which includes researchers from UCI, NIST, the University of Pennsylvania, Rice University, Carnegie Mellon University, the Duke University Medical Center and the Los Alamos National Laboratory. Neutrons are non-destructive, highly penetrating probes, valuable for studying changes in membranes over time. Because they behave like tiny waves of energy, neutrons also make excellent rulers. Depending on temperature, the length of the neutron ruler can be tuned over a range spanning from roughly the size of a single atom to the size of a molecule composed of hundreds or thousands of atoms.
The CNBT team is now building a unique instrument with dual capabilities: diffractometry and reflectometry. It will detect neutrons that are reflected or otherwise scattered after striking membrane samples. Reflected or diffracted neutrons will provide information on the location, orientation, size and composition of membrane components. In addition, the team is upgrading another instrument useful for studying large molecules—a small-angle neutron spectrometer—that will be shared with researchers in other fields.
The instruments are scheduled to be completed in 2003. They will provide cell membrane scientists with access to powerful technologies well beyond the resources of individual researchers.
"This is an extremely hard problem," says NIST biophysicist Susan Krueger, a CNBT collaborator interested in enhancing neutron-based measurement capabilities. "We'll be testing lots of membrane systems and lots of different approaches to capturing the data we need."
The job facing cell-membrane researchers is akin to assembling an intricate and dynamic three-dimensional puzzle. Many pieces have complex contours that not only are unknown but also are subject to change.
"No single instrument or set of techniques can supply all the missing information," says NIST's Krueger. In addition to neutron scattering, an array of other tools and methods—X-rays, nuclear magnetic resonance and many more—is required.
Ultimately, the team hopes to use painstakingly gathered experimental data to predict molecular structure and the course of cell-membrane interactions. Computer models already are under development. For example, UCI chemistry professor Douglas Tobias is working on a computer simulation that can provide three-dimensional images and may even show changes in membrane structure over time.
"We aim to close a big gap in our understanding of cell-membrane biology," White says.
As a non-regulatory agency of the U.S. Department of Commerce's Technology Administration, NIST develops and promotes measurement, standards, and technology to enhance productivity, facilitate trade, and improve the quality of life.