The Department of Energy (DOE) supports research to acquire a fundamental understanding of biological and environmental processes. This includes the display of genomes as DNA sequences; the functional characterization of gene products, especially from DOE-relevant microbes; structural biology user stations at synchrotron sources and neutron sources; computational genomics; and the development of integrating information systems. This topic is focused on the goals of the Genomes to Life (GTL) program, namely, to develop a detailed understanding of the molecular machines of DOE-relevant microbes and their networking in living cells and microbial communities. Microbes with capabilities that can further several DOE programmatic missions are being used as the current subjects for these studies. The knowledge thus gained would enable both the public and private sectors to apply genome knowledge to the production of energy, promote environmental applications such as bioremediation and carbon sequestration, promote cleaner industrial processes using biotechnology, and enable increasingly effective computational models of the microbial cell. For some of the subtopics below, capabilities already exist in a few laboratories, but commercial involvement will be needed before the technology can be exported to the broader research community. Grant applications are sought only in the following subtopics:
a. Genome Scale Reagent Sets—There is an increasing availability of genomes as sequenced chromosomes with their constituent genes. These genes number in the thousands for bacteria and in the 10-100 thousand range for higher organisms. Each gene may give rise to numerous distinct mRNAs and proteins, through processes of alternative RNA splicing and post-translational modifications. Micro-arraying methodologies are enabling highly parallelized interrogations of these huge macromolecule collections. However, production and management systems are required to assure the availability of the numerous analytical reagents that are needed in small quantities. Grant applications are sought for: (1) systems that will produce thousands of affinity reagents (oligo-nucleotides, synthetic genes, antibodies, and other affinity reagents) in pico-molar quantities; (2) miniaturized delivery systems for such reagent sets; and (3) reagent sets for quantitation of RNA splicing.
b. Proteomics—A number of proteomics tasks are being pursued to achieve the goals of the GTL program. These tasks include high throughput production and purification of proteins, correlation of proteins with the genes encoding their primary structure, identification of protein isoforms encoded by the same gene, identification of memberships in functional complexes of proteins, and identification of the variations of proteome constituents under change to useful physiological states. However, a number of obstacles are preventing the accomplishment of these tasks. For example, several host-vector systems are available for the production of proteins encoded in a hyper-expressed source gene; yet, for some source genes, the proteins fail to fold into physiologically effective three-dimensional conformations (entrapment in insoluble inclusion bodies is one cause of such failures). Another difficulty is that proteins targeted to membranes are problematic. Lastly, the lack of affinity reagents that bind to proteins in their native conformations adversely impacts structure, protein association, and function analyses. Therefore, grant applications are sought for the improved recovery and analysis of effective proteins. Areas of interest include: (1) the production of solubilized proteins in active confirmations with or without post-translational modifications; (2) the development of synthetic membranes or nano-structures enabling analyses of membrane proteins; (3) and the development of improved affinity reagents.
c. Instrumentation for Single Macromolecule Analysis and Control—Over the last decade, research laboratories have made substantial progress in developing instrumentation for the interrogation and manipulation of single macromolecules. Techniques include the use of optical-laser tweezers, atomic force microscopy, and single molecule fluorescence microscopy. Although the effectiveness of these techniques has improved steadily and the instrumentation is now robust, most of these single-molecule biophysics instruments are locally built. The lack of commercial support has severely hindered the export of these technologies to the broader user community. Grant applications are sought to expand the commercialization of techniques, instrumentation, and software systems so as to enable the broader usage of single macromolecule analysis methods.
d. Informatics—The development of an effective computational model of the cell not only would contribute to the GTL program but also would have numerous applications, including the preliminary processing of genome scale data sets being generated by experimental groups. Grant applications are sought to improve one or more of the component software packages that have already been developed by laboratory groups, in order to enhance user friendliness and thereby support their broad export to the biologist community. Grant applications also are sought to develop novel software in support of cellular modeling tasks. Of particular interest are approaches related to: (1) systems biology, (2) the processing of proteomics and metabolomics data sets, (3) improved integration and or querying of heterogenous data sets, and (4) the automated development of cellular metabolic models from data sets on newly studied microbes.
References:
1. “Bioscience: A Most Singular Study [single molecule methods],” Berkeley Lab Highlights, Berkeley Lab Research Review, Special Issue, 23(3), Fall 2000. (Full text available at: http://www.lbl.gov/Science-Articles/Research-Review/Highlights/2000/stories/bioscience/singular2.html)
2. Parvin, B., et al., “BioSig: An Imaging Bioinformatic System for Studying Phenomics,” Computer, 35(7):65-71, July 2002. (ISSN: 0018-9162)
3. “Post Sequencing Research Challenges,” Human Genome News, 11(1-2), Washington, DC: U.S. DOE Human Genome Program, November 2000. (Full text available at: http://www.ornl.gov/hgmis/publicat/hgn/v11n1/07post.html)
4. DOE Joint Genome Institute (JGI), U.S. DOE Office of Biological and Environmental Research (OBER), http://www.jgi.doe.gov
5. Research abstracts from the JGI meeting, New Horizons in Genomics, Santa Fe, NM, Mar. 30-Apr. 1, 2003, http://www.ornl.gov/sci/techresources/Human_Genome/publicat/2003jgi/index.shtml
6. Genomes To Life: Biological Solutions for Energy Challenge, U.S. DOE OBER/Office of Advanced Scientific Computing Research, http://doegenomestolife.org/
7. Research Abstracts from the GTL-Genomics Workshop, Contractor-Grantee Workshop II, Washington, DC, Feb. 29-Mar. 2, 2004. (Available at: http://www.doegenomestolife.org/pubs/2004abstracts/html/index.shtml)
8.
Research Topics[of the] U.S. DOE Office of Biological and
Environmental Research, http://www.sc.doe.gov/production/ober/restopic.html
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