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Timothy Baker
Macromolecular, cryoelectron microscopy and three-dimensional, image-reconstruction techniques.
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| Contact Information |
| Professor of Chemistry & Biochemistry Department, UCSD |
| Office: NSB 4105 |
| Phone: (858) 534-5845 |
| Fax: (858) 534-0202 |
| Email: tsb@ucsd.edu |
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| View group members
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| Education and Appointments |
| 1976 |
Ph.D., University of California, Los Angeles
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| 1974 |
C.Phil., University of California, Los Angeles
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| 1971 |
B.S., Duke University
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| Awards and Academic Honors |
| 2004 |
NIH NIGMS Method to Extend Research in Time (MERIT) award |
| 2004 |
Appointed to the Faculty, UCSD |
| 1996 |
Herbert Newby McCoy Award for Scientific Achievement |
| 1980-1982 |
Charles A. King Trust Postdoctoral Fellow, Rosenstiel Research Center, Brandeis University; Structural Biology |
| 1979-1980 |
NIH Postdoctoral Fellow ; Rosenstiel Research Center, Brandeis University; Structural Biology |
| 1976-1978 |
Jane Coffin Childs Post-doctoral Fellow; MRC Lab of Molecular Biology, Cambridge, UK; Structural Biology |
| Research Interests |
Macromolecular, cryo-electron microscopy and three-dimensional (3D), image-reconstruction techniques are used in our research to visualize viruses and to determine how the viruses interact with their hosts, replicate and mature. Recent technological advances have led to an explosive growth in this field and have allowed researchers to observe molecules and molecular interactions at sub-nanometer resolutions. Microscopists are now able to trace protein chains, visualize protein-nucleic acid interactions, and study how lipids play a major role in some viruses.
The main benefit of cryo-electron microscopy is that it permits the structures of biological samples to be preserved in a near native state. To accomplish this, samples are flash-frozen in a sub-millisecond time frame which prevents ice crystal formation that would damage the sample. This technique avoids the artifacts produced by chemical fixatives and stains The specimens are then inserted into a transmission electron microscope and maintained at liquid nitrogen or even liquid helium temperatures. UCSD researchers now have access to two, new, state-of-the-art, cryo-electron microscopes. Modern instruments are computer controlled and this greatly assists the operator in day to day tasks. Automated, data-collection software is being used to record the massive amounts of data that are required to obtain high-resolution 3D reconstructions. Automatically-collected data is recorded digitally on CCD cameras and is stored in a database. Data is also collected on photographic film which is still the most accurate, electron-detection device available. A data set of virus images that is large enough to produce a reconstruction to sub-nanometer resolution may contain tens of thousands of individual images.
Computer reconstruction techniques are continuously being developed to more effectively and efficiently extract usable information from the noisy image data. Though many of our computer algorithms exploit the icosahedral symmetry inherent in a large number of the viruses we study, newer programs are being developed to handle images of viruses that dont exhibit such symmetry. Some viruses possess various symmetry-mismatched components and hence must be treated as asymmetric structures. This requires collecting even greater amounts of data. We have developed a new system, AUTO3DEM, that automates much of the tedious steps in the 3D reconstruction process and, in favorable instances, enables us to obtain sub-nanometer reconstructions in a manner of days after images have been recorded. AUTO3DEM runs on in-house PC clusters and also on the national Teragrid system maintained by the Supercomputer Center.
Current research efforts are focused on structural studies of a wide variety of viral pathogens: these include several fungal partitiviruses; bacteriophage F29; large, dsDNA viruses that infect algae and insects; reoviruses; adeno-associated viruses; and some members of the Flavivirdae and Togaviridae families such as West Nile, Sindbis, Dengue and Ross River virus. Some of these viruses are serious human pathogens and others have been identified as possible agents of bioterrorism.
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| Primary Research Area: |
Interdisciplinary Specialties: |
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Biochemistry
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Biophysics
Macromolecular Structure
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| Selected Publications |
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Yan X., K. A. Dryden, J. Tang, and T. S. Baker (2007) Ab initio random model method facilitates( 3D reconstruction of icosahedral particles. J. Struct. Bio. 157:211-225.
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Yan X., R. S. Sinkovits, and T. S. Baker (2007) AUTO3DEM - an automated and high throughput( program for image reconstruction of icosahedral particles. J. Struct. Bio. 157:73-82.
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Mukhopadhyay, S., W. Zhang, S. Gabler, P. R. Chipman, E. G. Strauss, J. H. Strauss, T. S. Baker, R. J. Kuhn and M. G. Rossmann (2006) Mapping the structure and function of the E1 and E2 glycoproteins in alphaviruses. Structure 14:63-73.
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Yan, X., P. R. Chipman, T. Castberg, G. Bratbak, and T. S. Baker (2005) The marine algal virus PpV01 has an icosahedral capsid with T=219 quasisymmetry. J. Virol. 79:9236-9243.
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Zhang, X., J. Tang, S. B. Walker, D. O'Hara, M. L. Nibert, R. Duncan, and T. S. Baker (2005) Structure of avian orthoreovirus virion by electron cryomicroscopy and image reconstruction. Virology 343:25-35.
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