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Center for Integrative Molecular Biosciences Opens Today at The Scripps Research Institute

La Jolla, CA. April 10, 2002-- Seeking to speedily obtain and analyze the structures of the tiny machines that buzz with activity inside cells, the Center for Integrative Molecular Biosciences (CIMBio) officially opens today at The Scripps Research Institute (TSRI).

CIMBio is a new, interdisciplinary facility organized to bring together the talents of several groups within the institute who have backgrounds in divergent disciplines such as chemistry, biochemistry, structural biology, and cell biology but whose interests converge in one area.

What unites the members of CIMBio is their interest in the combined use of the x-ray crystallography and electron microscopy (EM) techniques as a means to unravel the structure and mechanism of action of the large molecular assemblies of the cell--such as the transcription complexes that make messages from the genes, membrane channels and pumps that import and export materials, and the tiny molecular tracks and motors that move cells and form important structures like the mitotic spindle.

The centerpiece of CIMBio and the focal point for the building design is a microscopy suite containing six state-of-the-art electron microscope rooms. Customized support rooms and large open laboratories contribute to an overall infrastructure that makes CIMBio one of the most advanced biological microscopy centers in the world.

"We had an almost unique opportunity to design an ideal electron microscopy suite, and we put a lot of effort into doing this," says CIMBio director Ron Milligan, Ph.D., Professor, Department of Cell Biology.

The design is predicated on six rooms for microscopes, which are at the center of the building. Currently, there are three microscopes in operation and three planned acquisitions for the near future.

These microscopes are mounted on three-foot-thick concrete slabs isolated from the building's foundation, which protect the instrumentation from vibrations. The rooms are climate-controlled with low humidity to prevent contamination of samples by water vapor, and they are sound-proofed so that noise from the corridors does not cause vibrations. The air supply coming into the rooms passes through a nylon sleeve that breaks up any air currents, and the microscopes can be controlled entirely from a separate room so that the samples can be left alone in the dark inside the microscopes.

Phase I of CIMBio will be devoted to working out the structure of the proteins and nucleic acids in complexes that carry out the work of the cell. Laboratory space was constructed last year, and the investigators began moving into their new laboratories in January of this year. In addition to Milligan, CIMBio members involved in phase I include investigators Francisco Asturias, Bridget Carragher, M.G. Finn, Jack Johnson, Elizabeth Wilson-Kubalek, Tianwei Lin, Mari Manchester, Clint Potter, Nigel Unwin, and Mark Yeager.

Phase II of CIMBio will concentrate on the dynamics of those cellular machines--their assembly, disassembly, and control over time. Laboratory space for that effort is already under construction in the building, and by the end of the year, investigators Velia Fowler, Klaus Hahn, Clare Waterman-Storer and Kevin Sullivan will relocate there to lead the Phase II efforts. Also relocating at the end of the year will be Geoffrey Chang, whose expertise in solving the high-resolution structures of integral membrane proteins is a valuable addition to the center.

The building combines several of these laboratories into large contiguous shared spaces built above and around the microscopes. The laboratories have an open design and some of the facilities--like the microscopes and an imaging area--are shared, something that the CIMBio researchers appreciate.

"This is a collection of widely diverse scientists, and we want to maintain and enrich our collaborations," says investigator M.G. Finn, whose group was the first to move into the new space. "Here we can't help running into each other."

CIMBio Innovations

When combined with the x-ray structures of the component parts of the structures, 3-D EM maps can yield a detailed description of the structure and action of an entire cellular machine. But calculating these structures manually--currently the only recourse--takes weeks or even months. It can be tedious.

So CIMBio investigators Bridget Carragher and Clint Potter are creating algorithms for automated data collection and analysis, which should simplify the technique of electron microscopy and enable throughput to be increased dramatically.

"What we really want is 100,000 to 1,000,000 molecule images and that just takes too long to do manually," says Carragher. "There are projects people just don't do because the manual labor required is too daunting."

Several years ago, Carragher and Potter suggested that automated data collection and analysis could be developed for EM. They succeeded in developing software for both the collection and the analysis, which they brought to TSRI when they came last year to form TSRI's CIMBio Automated Molecular Imaging group.

"What we have done over the past year is to show that you can insert a sample in the microscope and calculate a 3-D map fully automatically," says Potter.

In fact, Carragher and Potter constructed one of the best 3-D maps of the tobacco mosaic virus in less than two days. By comparison, the work would have taken several months just a few years ago and perhaps several weeks using conventional methods today.

"We can now go from inserting the virus into the microscope to having a 3-D map in 24 hours," says Milligan.

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