CU awarded $5.9 million NIH grant for national biomedical ESR center

By David Brand

The National Institutes of Health (NIH) has awarded Cornell $5,897,513 over five years to establish the National Biomedical Center for Advanced ESR Technology (ACERT). ESR is electron spin resonance, a technology for studying the bonds and structures of chemical and biological materials, such as molecular mechanisms in membranes and proteins. Basically, the technique elucidates how molecules move, react and interact with one another.

The NIH has established a national electron spin resonance (ESR) center at Cornell, with labs in Baker Laboratory. Standing in front of one of the lab's ESR spectrometers are, center, director Jack Freed, professor of chemistry and chemical biology, and associate directors Peter Borbat, left, and Keith Earle. Robert Barker/University Photography

The principal investigator on the grant, who will become director of the new national center, is Jack H. Freed, professor of chemistry and chemical biology at Cornell, who has pioneered new methods of ESR. The grant is administered by the NIH's National Center for Research Resources.

"One of the reasons the NIH is funding us is because of the uniqueness of what we can do. Being unique is pretty important," said Freed.

The center's research facilities, being established in 5,600 square feet of lab space in the basement of Baker Laboratory on campus, will be available to researchers worldwide, subject to review by the center. Because the work of ACERT will be basically in instrumentation and theory, it will have 21 collaborators from universities and medical schools in the United States, Canada, Israel and Germany providing expertise in biochemistry and molecular biology. In addition, the center will provide services, such as measurements and technology transfer, to 12 academic groups initially.

Of the grant money, $500,000 is earmarked for equipment. Currently, Freed's research group has three state-of-the-art ESR spectrometers operating. Three others will come on line within 18 months. Most of this equipment is built at Cornell to unique specifications, according to Freed.

The new center also will be used extensively for the training of graduate students and postdoctoral researchers. It will disseminate its research findings through software, online tutorials, biomedical summer schools and atlases of spectra. Among its collaborators in this respect are Ron Elber, professor of computer science at Cornell, and David Schneider, a computational biologist with the U.S. Department of Agriculture and a visiting fellow at the Cornell Theory Center.

Freed's group has pioneered the technology that has enabled ESR to go to very high frequencies, approaching the far infrared, by using quasi-optical methods. This equipment has been used to unravel the complex dynamics of biosystems such as proteins and membranes. Freed explains that a protein is not just a single crystal or a frozen object, but "is moving about and has internal motions, flexing and tumbling." In order to take what amounts to a fast-time snapshot of these dynamics, the Cornell researchers use high-frequency, high-field ESR (known as HFHF ESR), which freezes out the slow motions and is sensitive to the fast motions.

Freed's group also has studied the application of pulsed ESR (both HFHF ESR and two-dimensional Fourier transform ESR) to investigate dynamic molecular processes. "We believe that a very important aspect of pulsed technology is our development of powerful methods for measuring distances in biomolecules in ways that complement conventional X-ray crystallography," Freed said.

An important tool in ESR research employed by Freed is nitroxide spin labels (a spin label is a molecular subunit containing an unpaired electron -- a so-called free radical -- that attaches itself to a site in a macromolecule or biomolecule, producing spectra that provide information on changes in physical and chemical characteristics). Unpaired electrons are intrinsically unstable, but nitroxides can be prepared in a form that makes the free radicals highly stable, enabling the storing of samples for months, even years. "The essence of our research is this stability, combined with HFHF ESR and 2-D Fourier transform ESR," said Freed. "We are clearly world leaders in the physics end of ESR."

As for direct applications to medical research, Freed stresses his background in fundamental research. "It is our collaborators who are doing the basic biochemistry that we hope will increase our understanding to address diseases," he said. "We are providing the new instrumental and theoretical technologies to further many of these basic biomedical research programs."

Associate directors of the new center are Peter P. Borbat and Keith A. Earle, senior research associates in chemistry and chemical biology, and Jozef K. Moscicki, a visiting professor from Jagiellonian University, Krakow, Poland.