Next-generation crystallography: UB and partner institutions awarded $25 million to develop new X-ray imaging of biomolecules

BUFFALO, N.Y. — The University at Buffalo, representing a national consortium of eight research universities and institutes, has been awarded a prestigious $25-million Science and Technology Center grant from the National Science Foundation to transform the field of structural biology, including drug development, using X-ray lasers.

This is the first Science and Technology Center grant UB has received. With the grant, UB and its partner institutions will establish The BioXFEL research center (www.bioxfel.org), headquartered in Buffalo. 

The BioXFEL (pronounced bio-x-fell) center will focus on developing new X-ray bioimaging techniques — including an advanced form of X-ray crystallography called serial femtosecond crystallography — to analyze a vast array of new molecular targets for drug discovery. 

This technique has the potential to spur much-needed innovation in the pharmaceutical field. It will provide scientists with new insights into how biological molecules function, what might be happening when disease occurs and what compounds might be designed as drugs to modify this activity.

“Together with its partners, UB is especially proud to announce this highly competitive award,” said UB President Satish K. Tripathi. “NSF selects just a handful of Science and Technology Center winners every four years from a pool of hundreds of applicants. This research builds on Western New York’s rich legacy of expertise in X-ray crystallography, historically based within the Hauptman-Woodward Medical Research Institute and UB’s Department of Structural Biology.”

SUNY Chancellor Nancy L. Zimpher said: “With this prestigious award, the University at Buffalo deepens its national leadership and long tradition of groundbreaking health research and the innovative treatment of disease. Congratulations to President Tripathi and the team of scientists who have secured this extraordinary grant.”

“Congratulations to President Tripathi, Professor Lattman and the extraordinary faculty team,” said Tim Killeen, PhD, president of the Research Foundation for SUNY and SUNY’s vice chancellor for research. “This is, without question, the premier award given out by NSF and truly exciting news for us all. The groundbreaking, cutting-edge research will, once again, showcase UB’s stature as a world-class research university. The collaborative work conducted through this award represents a major contribution to Chancellor Nancy Zimpher’s vision of the Power of SUNY and the SUNY Networks of Excellence announced recently by Gov. Cuomo.”

“This $25-million federal grant demonstrates the strength of Buffalo Niagara Medical Campus institutions to serve as outliers in science and medical innovation," said Rep. Brian Higgins.  "Not only will it advance critical research, this significant investment will advance economic growth in the City of Buffalo.”

Sens. Charles E. Schumer and Kirsten Gillibrand also offered their congratulations.

“This first of its kind federal investment in the important work being done by Hauptman-Woodward and the University at Buffalo just proves once again that Western New York is on the cutting edge of medical and scientific research," said Schumer. "This Science and Technology Center grant will not only lead to important new breakthroughs in drug development – but will also serve as a signal to new companies around the globe that Buffalo is the place to be when it comes to medical research.”

“This highly competitive award reflects the University at Buffalo's relevance as an innovator in the field of medical research and bio-tech," said Gillibrand. "With these resources, UB will be given the opportunity to make groundbreaking advancements in the pharmaceutical field, further adding to the university’s contribution to the region’s biomedical economy.”

Eaton E. Lattman, PhD, professor in the UB Department of Structural Biology in the School of Medicine and Biomedical Sciences and chief executive officer of the Hauptman-Woodward Medical Research Institute (HWI), will be director of the BioXFEL center.

John C.H. Spence, PhD, Regents’ Professor of Physics at Arizona State University, will serve as the center’s scientific director. The University of Wisconsin-Milwaukee also will have a primary role in the center, led by principal investigator Abbas Ourmazd, PhD, Distinguished Professor of Physics and Electrical Engineering.

Other partner institutions are Cornell University, Rice University, the University of California, San Francisco, and Stanford University. The University of California, Davis, also will help with creating and managing the educational program.

The establishment of the BioXFEL center will put UB and Western New York in the forefront of this technology. “It has the potential to transform the way scientists study diseases and develop new treatments,” said Alexander N. Cartwright, PhD, vice president for research and economic development at UB.

“The late Dr. Hauptman won the Nobel Prize in 1985 with Jerome Karle for the development of direct methods for determining the structures of molecules. This new UB center, in partnership with HWI, will take the extraordinary promise of that 20th-century technique and revolutionize it further for the 21st century.”

While current techniques in crystallography provide almost 90 percent of what scientists know about biomolecular structure, fewer than 20 percent of purified proteins currently form the crystals necessary for this technique.

In this video interview produced by UB, Lattman explained the research objectives and potential impact of the BioXFEL center: http://youtu.be/VQpqI5eNEJU.

“With the new bioimaging technique developed in the BioXFEL center, we will be able to analyze crystals 1,000 times smaller than the ones we can use now,” Lattman said. “These are crystals we could never use before and, in fact, may not have known existed. A whole new universe of drug targets will become accessible for study as a result.”

“In addition,” added Spence, “we will be developing new techniques for making movies of molecular machines at work, and of viruses and biomolecules in their natural wet environment undergoing chemical change. Some of the work, with Professor Petra Fromme at ASU, will try to image the detailed atomic processes responsible for photosynthesis. This occurs when sunlight falls on all green plants, allowing them to split water, creating the oxygen we breathe and converting the carbon dioxide responsible for global warming into carbohydrates.”

“The techniques the BioXFEL center will develop could shorten the process of determining protein structure from years to days,” said Ourmazd of the University of Wisconsin-Milwaukee. “This will rely heavily on mathematical algorithms we and others are developing to deduce structure from millions of ultralow-signal snapshots.”

The new technique enables the study of ultra-small crystals — nanocrystals, Lattman explained, which grow much more readily than the much larger ones required by current methodology.

“Many other aspects of the project, such as the patterns created by the X-ray laser, are different from what we are used to,” he said. “We have to figure out how to work with them, both experimentally and theoretically.”

He noted that the new technique offers tantalizing possibilities in the future. “Maybe down the road, we won’t even use crystals at all, but we’re a long way away from that,” he said.

Scientists involved with the BioXFEL center will use an extremely powerful new kind of X-ray beam developed at SLAC National Laboratory at Stanford University called an X-ray, free-electron laser (XFEL). The use of the XFEL to analyze protein crystals was chosen by the journal Science as one of the top 10 science breakthroughs of 2012. That work included a number of scientists who will be participants in the BioXFEL center.

“Because this technique is so new, much remains to be done before it can be used routinely,” explained Lattman. “The process needs to be streamlined. Right now, every single step takes a heroic effort. The purpose of the new BioXFEL center is to create the resources and knowledge necessary so that five years from now, scientists can apply XFEL routinely to the most pressing biomedical questions.”

A key advantage is that it will let scientists see the motions of molecules for the first time. “Most biological processes require movements within the molecules involved,” Lattman said, “but the pictures provided by current X-ray analysis contain very limited information about them.

“The XFEL beam is unbelievably intense and is composed of a sequence of unimaginably short pulses that act like flashbulbs to freeze the motions of protein molecules when the beam zaps them,” explains Lattman. “In the long run, the X-ray laser will allow us to make movies of molecules, rather than having to infer their motions from fixed pictures.”

HWI expertise will play a central role in the new center, particularly its National Institutes of Health-funded high-throughput screening laboratory, which has been growing crystals of proteins for hundreds of client labs throughout the U.S. for a decade.

Arizona State will be a major research partner, providing expertise through Spence’s lab, which specializes in determining the structures of membrane proteins and viruses, which are difficult to crystallize. University of Wisconsin-Milwaukee (UWM) will provide key theoretical and experimental contributions.

Together, UB, Arizona State and UWM will offer education programs to try to develop young scholars in this technique at the graduate and postdoctoral level, as well as the undergraduate and high school levels. Lattman said UB will be one of the key facilities in the U.S. with this focus.

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

The BioXFEL center’s headquarters will be located at 700 Ellicott St. on the Buffalo Niagara Medical Campus in the building that houses both HWI and UB’s Department of Structural Biology.

The NSF Science and Technology Centers: Integrative Partnerships program supports innovative, potentially transformative research and education projects that require large-scale, long-term awards. The centers foster cutting-edge research, education of the next generations of scientists and broad distribution of the knowledge and technology produced.