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TECHNOLOGY
Advanced Device to Probe Atomic Structures, Build Knowledge, Novel TherapiesNW15 is a building on the MIT campus that looks like a scaled-down version of the Turbine Hall at London's Tate Modern. Like the Tate, it once housed giant power generators that have been ripped out, leaving a cavernous space with gray cement floors, ribbed metal walls, and tall factory-style windows that turn sunlight the color of fog.
Gerhard Wagner's HMS lab houses spectrometers that he and colleagues have used to study messenger and transfer RNAs in protein synthesis. (Photo by Leah Gourley) Come December, however, NW15 will be transformed when New England's most powerful magnetic resonance (MR) spectrometer is installed. The magnetic heart of this 21-tesla, 900-MHz device will be contained in a gleaming, nonmagnetic stainless steel capsule that stands nearly 13 feet tall on pneumatic legs that cushion against the tiniest shock. Caged in a colorfully framed, glass-walled protective structure, it could pass for an art installation at the Tate. When the spectrometer opens for business in early 2005, Harvard researchers will become one of only six U.S. scientific communities with access to such a tool. Many HMS investigators already rely on less powerful MR machines to determine structures for individual proteins and protein interactions, and to screen for ways to inhibit those interactions, said Gerhard Wagner, HMS professor of biological chemistry and molecular pharmacology. MR spectrometry's role in drug discovery is expanding, and Wagner also expects it to be prominent in "metabolomics." This new discipline seeks to predict risk, confirm diagnosis, or assess treatment efficacy by measuring levels of all metabolites in easily obtained clinical specimens such as urine or saliva. MR Center GrowthWagner and MIT professor of chemistry Robert Griffin are responsible for bringing the 900-MHz spectrometer to Boston. "All spectrometry is about signal and noise," said Griffin, and bigger magnets yield stronger signals that make it easier to distinguish real observations from misleading artifacts. Wagner and Griffin launched the Harvard/MIT Center for Magnetic Resonance (CMR) in 1998, and in 2003 they obtained $5 million from the NIH for the new machine. Harvard and MIT covered the $2 million cost of preparing NW15 for its arrival.The CMR already runs experiments around the clock, seven days a week, on 10 MR spectrometers housed at MIT's Francis Bitter Magnet Center, which Griffin heads. The two biggest are 17.6-tesla, 750-MHz machines, one of them owned by Harvard. On the HMS Quad, two 600-MHz and three 500-MHz spectrometers are heavily used by Wagner's team and collaborators.
When a liquid or solid sample is lowered into the rock-steady field inside the superconducting coil, the nuclear spins of various atoms line up in characteristic ways. An investigator at a remote terminal manipulates radio frequency pulses, which are generated by a console near the magnet. Spectra are produced when atoms resonate differently to these signals, and multiple spectra are combined to derive 3-D structures. In this way, researchers can see how two proteins interact in killing brain cells, for example, or where an anticancer drug might zero in on a target. Clinical Dimensions of StructureBoth Wagner and Griffin are engaged in collaborations that bring structural studies to bear on clinical questions. For about eight years, Wagner and apoptosis expert Junying Yuan of HMS have been exploring how malignant cells might be induced to die instead of relentlessly proliferating. In particular, they have been sorting through small molecules likely to inhibit Bcl-2, a protein over-expressed in certain cancer cells. Identifying the most promising ones is challenging because "it is very hard to prove the specificity of a chemical to a target when you're searching for a drug," said Yuan, HMS professor of cell biology. "One way to figure this out is to see the interaction by NMR." She is enthusiastic about software Wagner created that models different fits and lets them see how candidate molecules might be improved.A central concern in Wagner's own lab is how the translation is initiated and regulated in eukaryotic cells. Many of his experiments use MR spectrometry to study the complex interplay of messenger and transfer RNAs with "initiation factors" involved in protein synthesis. This provides a different perspective on cancer biology and has identified at least one potential target for antitumor drugs. While Wagner has spent his career studying soluble proteins, Griffin focuses on insoluble materials. He helped develop solid-state MR spectrometry at MIT in the 1980s and recently has analyzed structures of amyloids and membrane proteins that do not dissolve. Amyloids are involved in more than a dozen important diseases, ranging from Alzheimer's and Parkinson's to type 2 diabetes and bovine spongiform encephalopathy (mad cow disease). Thirty years ago, when Griffin and Wagner first got involved with MR spectrometry, iron magnets were state-of-the-art and results could be displayed only as jagged lines, traced on a big sheet of paper by an X-Y plotter. Monster machines like the new 900-MHz spectrometer would have seemed outlandish even to consider, and "nobody imagined you could do a structure as large as a protein with this technology," Wagner said. --Patricia Thomas |
