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UWM’s a game-changer in protein imaging quest

New technologies and techniques help solve cellular mysteries in days, not years.

UWM’s a game-changer in protein imaging quest by Laura L. Otto

The University Wisconsin-Milwaukee and partners at seven leading research institutions have landed a highly competitive $25 million grant to conduct work that could transform the way scientists study diseases and find new treatments.

The funding allows UWM and its partners to build on their pioneering work in determining the atomic structure and function of proteins. Malfunctioning proteins are often the cause of disease, but the ability to observe them at work within the body is currently limited.

Scientists need to know how the atoms in proteins are arranged in order to learn what they do.

The Science and Technology Center is a wonderful opportunity to further enhance excellence in interdisciplinary research on campus and in the region.

Abbas Ourmazd, Distinguished Professor of Physics and Electrical Engineering

The existing method, called X-ray crystallography, involves bombarding a pure crystal of the protein with X-rays. The pattern of rays as they diffract off the sample reveals a kind of fingerprint of the atoms in the molecule. A mathematical computation uses this fingerprint to deduce the locations of the atoms, producing a “snapshot.”

“Cell membrane proteins control the flow of information and material into and out of cells,” says Abbas Ourmazd, Distinguished Professor of Physics and Electrical Engineering, who leads the UWM team. “But they are notoriously difficult to crystallize – if it can be done at all, it takes a very long time.”

Fewer than 20 percent of proteins currently form the kind of crystals necessary for this imaging.

The grant, awarded by the National Science Foundation, establishes a Science and Technology Center (STC) that will explore the use of powerful X-ray lasers to reveal the structure of proteins and viruses, and the ways they change as they affect the body’s functions. This work has the potential to spur much-needed innovation in the pharmaceutical field.

The new approach uses millions of X-ray “snapshots” from a wide range of random orientations, says Senior Scientist Peter Schwander, a member of the UWM team that also includes Distinguished Professor of Physics Dilano Saldin, Associate Professor Marius Schmidt and Senior Scientist Russell Fung.

“The challenge is to reconstruct a 3-D image from 2-D snapshots,” says Schwander.

In their quest to image single proteins and viruses, STC researchers will rely on two game-changing technologies – one of which was developed at UWM.

The first is an X-ray free electron laser (XFEL), which produces X-ray light more than a billion times brighter than that made by any other equipment. Of the three that exist, the closest is at the SLAC National Accelerator Laboratory in California.

The XFEL will allow imaging to be accomplished with protein crystals a thousand times smaller than before – even those at the nanoscale, which are much easier to form. The brightness of an XFEL flash may also allow scientists to “see” protein molecules in action for the first time.

To analyze the millions of “snapshots” taken at one sitting, the team’s second game-changer is a computer program that uses algorithms to piece together a 3-D image of the molecule. The program was created by Ourmazd, Saldin, Schwander and Fung, with Roshan D’Souza, associate professor of mechanical engineering, and engineering graduate student Ali Dashti.

“Imaging with this new kind of X-ray scattering can speed the process of determining protein structures from years to only days,” says Ourmazd. “Part of the reason can be attributed to the mathematical procedure we have developed.”

For UWM students, the STC affords a unique opportunity to work across disciplines on groundbreaking research that will require expertise in computer science, biology, physics, mathematics and chemistry.

“The Science and Technology Center is a wonderful opportunity to further enhance excellence in interdisciplinary research on campus and in the region,” says Ourmazd.

Though still a way off, the XFEL technique offers tantalizing possibilities, such as perfecting techniques to make molecular “movies,” or imaging proteins without crystals.

The center also will emphasize applications of its research through its industrial partners in the Industrial Macromolecular Crystallography Association, composed of major pharmaceutical companies including Bristol-Myers Squibb, Pfizer, Abbott, Merck and Novartis.

SUNY Buffalo leads the grant. In addition to UWM, partners include Arizona State University; Cornell University; Rice University; Stanford University; the University of California, Davis; and the University of California, San Francisco.