Structural biology center provides machines for large scale projects

by LESLIE CHURCH

With momentum gaining at the New York Genome Center and several new institutional partnerships beginning on Roosevelt Island and downtown Brooklyn, the academic landscape of New York City is poised for a new era of collaboration. But the idea behind these alliances — that more can be accomplished when institutions share resources than when they work alone — is not new.

At the New York Structural Biology Center (NYSBC), large scale facilities for studying macromolecules have been available for over a decade. The center was established by a consortium of nine biomedical research institutions to address a growing problem in research: newer, better technology is constantly being rolled out, but with costs in the millions of dollars, individual institutions might be disinclined to foot the bill if only one or two labs are using it.

The NYSBC’s membership, which includes the other Tri-Institutional affiliates and Columbia University, made an initial investment in the center totaling $9 million and thereafter have paid an annual member fee. Now worth $75 million, the facility gives members access to the latest-generation instruments for an allotted number of weeks each year.

The center sits on the south end of the City College of New York’s Harlem campus near 133rd Street. Nine NMR (nuclear magnetic resonance) machines are housed in an old gymnasium once used by the college, humming day and night with experiments that may run as long as one to two weeks. Although the center was initially devoted exclusively to NMR, it has since expanded to encompass several other technologies, including x-ray crystallography, cryoelectron microscopy and protein production.

NMR uses extremely powerful magnets — nearly half a million times the strength of the Earth’s magnetic field — and pulses of radio waves to determine the distance between the atoms that make up a protein.

The more powerful of the machines sit atop giant cylinders of solid concrete tied directly into the bedrock that lies underneath New York City, providing the utmost stability from outside vibrations that could disrupt the data. With its two 900 megahertz systems, the NYSBC is the premier facility for NMR in the western hemisphere. The center is also working to acquire a new dynamic nuclear polarization NMR device that will provide a 100-fold increase in sensitivity of the imaging process, the first of its kind in the United States.

Although Rockefeller has some on-site facilities for NMR, in the 400 to 600 megahertz range, and for x-ray crystallography, its capabilities are limited in comparison.

“The equipment at Rockefeller is valuable for certain aspects of NMR and crystallography work, but when the scientists need to look at larger proteins or get a higher resolution image, they access the Structural Biology Center,” says John Tooze, vice president of scientific and facility operations at Rockefeller.

The center’s cryoelectron facility, located in newly constructed, acoustically shielded rooms adjacent to the NMR equipment, consists of four machines of varying strength, providing a valuable supplement to Rockefeller’s less powerful equipment.

Cryoelectron microscopy is a more recent technology in the field of structural biology that allows a sample to be studied without staining or fixing it in any way, thus facilitating observations of it in its natural environment. The center recently added a dual-beam device that uses both an electron and an ion beam column to create a 3D image of the molecule.

Several labs at Rockefeller make regular use of the NYSBC equipment. The Laboratory of Cellular and Structural Biology, led by Michael P. Rout, has been doing NMR research at the center for the past few years. The lab studies nuclear pore complexes using a range of NMR machines, and is currently looking at the structure of FG nucleoporins, a family of proteins that act as a filter within the pore complex.

“The NYSBC allows us access to world class instrumentation in areas that are not our main expertise,” says Dr. Rout. “It has opened up projects in both NMR and cryoelectron microscopy that would otherwise not have been possible.”

Beyond the microscopes, the NYSBC also has a high throughput facility for protein production. The New York Consortium on Membrane Protein Structure can generate up to 1,000 clones per week. The consortium, which brings together researchers from NYU, Columbia, Rutgers, CUNY and elsewhere, is made possible by a $20 million grant as part of the NIH’s Protein Structure Initiative.

“Collaboration between researchers is a major goal of the center,” says Willa Appel, the center’s executive director. “The consortium on protein structure has created a tremendous intellectual enterprise to address membrane proteins, which are a huge challenge. They’re the least well-known class of proteins and perhaps the most important, particularly for the development of drugs.”

The lab developed methods for making membrane proteins and is continuously turning out new findings on their structure — producing rainbow-colored 3D images of twisting, tangled swirls of amino acids.

A new venture is also unfolding at the Brookhaven National Laboratory on Long Island, where the center operates two synchrotron beamlines for x-ray crystallography in collaboration with the National Synchrotron Light Source (NSLS). A third-generation synchrotron, dubbed NSLS-II, is currently under construction at Brookhaven as part of a project sponsored by the U.S. Department of Energy, and the center is building a new beamline there that will exploit NSLS-II’s novel capabilities.

The synchrotron, a particle accelerator that uses extremely bright x-ray, infrared and ultraviolet beams to study samples in intricate detail, will measure a half-mile in circumference and produce x-rays up to 10,000 times brighter than the current NSLS.

Thirty-six full-time staff members work at the NYSBC, the majority of them scientists who offer instruction and assistance for researchers who want to utilize the technology but may not know much about it.

“It started out that with x-ray crystallography and NMR, the scientists had to be card-carrying experts in the technology,” says Wayne Hendrickson, scientific director of NYSBC, a professor at Columbia University and a Howard Hughes Medical Institute investigator.

“We’ve created an environment where someone who doesn’t know anything about these techniques, but who has a project amenable to them, can come in and our staff will help that person apply the right tools to their work. The technologies available here can be used to supplement other avenues of investigation in any number of fields, and the researcher doesn’t need to become adept in them to take advantage of what they offer.”

With nine NMR spectrometers and four cryoelectron microscopes, the New York Structural Biology Center is a one-stop shop for scientists who want to create images of their proteins. Coming soon: watch a video of the science in action at www.rockefeller.edu/nysbcvideo.