Using genomic data and high-throughput technologies, we're studying proteins encoded by genomes to explore the diverse natural capabilities in microbes. In doing so, we will help solve larger DOE challenges in energy production, environmental cleanup, and global climate change.

Berkeley Lab is playing a large role in achieving the four primary goals of the Genomics:GTL program:

1.  to identify the protein machines that carry out critical life functions;
2.  to characterize the gene regulatory networks that control these machines;
3.  to explore the functional repertoire of complex microbial communities in their natural environments to provide a  foundation for understanding and using their remarkably diverse capabilities to address DOE missions; and
4.  to develop the computational capabilities to integrate and understand these data and begin to model complex biological systems.

Berkeley Lab's integrated research effort includes seven projects:

1. Rapid Deduction of Stress Response Pathways in Metal/Radionuclide Reducing Bacteria
Adam Arkin, Principal Investigator (Physical Biosciences Division)

In July 2002, Berkeley Lab received one of five major research awards for the Genomes to Life initiative. The project is developing computational models that describe and predict the behavior of gene regulatory networks in microbes in response to the environmental conditions found in DOE waste sites. The research takes place within the Virtual Institute for Microbial Stress and Survival.

2. Microscopies of Molecular Machines (M3): Structural Dynamics of Gene Regulations in Bacteria
Carlos Bustamante, Principal Investigator (Physical Biosciences Division)

This project combines a number of powerful microscopies to elucidate interrelated aspects of the structural dynamics of molecular machines. Cryo-EM is used for structural characterization, lazer tweezers for mechano-chemistry, atomic force microscopy to image protein-RNA interactions, and single-molecule fluorescence to obtain dynamic information in real time. Using the complimentary strengths of these methods promises insights into how the bacteria gene regulation machinery allow microbes to survive in adverse conditions and carry out important functions such as bioremediation and nitrogen fixation.

3. Single Molecule Imaging of Macromolecular Dynamics in a Cell
Jamie Cate and Haw Yang, Principal Investigators

This new project will study the protein synthesis machinery in the model microbe Deinococcus radiodurans using a single-molecule spectrometer with 3D single-particle tracking capabilities. Biomolecules such as RNA and proteins will be tracked within the microbe to investigate how molecular machinery works at the molecular level. The novel instrumentation to be developed will provide unprecedented time and spatial resolution for imaging single molecules in a living cell.

4. New Technologies for Metabolomics
Jay Keasling, Principal Investigator (Physical Biosciences Division)

The goals of this new project are to develop methods for profiling metabolites and metabolic fluxes in microbes of DOE interest, and to develop strategies for perturbing metabolite levels and fluxes in order to study the influence of changes in metabolism on cellular function. The project involves identifying and measuring a wide range of metabolites in the presence of electron receptors, then identifying the genes associated with the involved metabolic pathways. The metabolic flux data will then be integrated with information from the annotated genomes of the microbes to better predict the effects of environmental changes on cell physiology and metal and actinide reduction.

5. High Throughput Identification and Structural Characterization of Multi-Protein Complexes During Stress Response in Desulfovibrio vulgaris
Mark Biggin, Principal Investigator (Life Sciences Division)

This project aims to characterize microbes under stress response to conditions commonly found in U.S. Department of Energy (DOE) metal and radionuclide contaminated sites, with an emphasis on high-throughput analysis of microbial multi-protein complexes. The project integrates microbiology (production of tagged protein expression strains and biomass production), multi-protein complex isolation and identification by mass spectrometry, imaging multi-protein complexes by electron microscopy, and computational analysis and modeling that seeks to understand how these complexes control a microorganism’s ability to survive in relevant contaminated environments while reducing metals and radionuclides. Data production and analysis methods will be automated to establish a pipeline that can analyze the majority of stable multi-protein complexes in a microbe as well as a number of unstable complexes. The project, awarded in October 2005, will build on the research and infrastructure of an on-going Genomics:GTL project “Rapid deduction of stress response pathways in metal and radionuclide bacteria” that established the Virtual Institute for Microbial Stress and Survival (VIMSS).

6. Molecular Assemblies, Genes, and Genomics Integrated Efficiently (MAGGIE)
John Tainer, Principal Investigator (Life Sciences Division)

MAGGIE will provide robust GTL technologies and comprehensive characterizations to efficiently couple gene sequences and genomic analyses with protein interactions and thereby elucidate functional relationships and pathways. The operational principle guiding MAGGIE objectives can be succinctly stated: protein functional relationships involve interaction mosaics that self-assemble from independent protein pieces that are tuned by modifications and metabolites. MAGGIE builds strong synergies among the Components to address long term and immediate GTL objectives by combining the advantages of specific microbial systems with those of advanced technologies. The objective for the proposed 5-year MAGGIE Program is therefore to comprehensively characterize the Protein Complexes (PCs) and Modified Proteins (MPs) underlying microbial cell biology. A compelling overall goal is to help reduce the immense complexity of protein interactions to interpretable patterns though an interplay among experimental efforts of MAGGIE Program members in molecular biology, biochemistry, biophysics, mathematics, computational science, and informatics. MAGGIE will address immediate GTL missions by accomplishing three specific goals: 1) provide a comprehensive, hierarchical map of prototypical microbial PCs and MPs by combining native biomass and tagged protein characterizations from hyperthermophiles (temperature-trapping otherwise reversible protein interactions) with comprehensive systems biology characterizations of a non-thermophilic model organism, 2) develop and apply advanced mass spectroscopy and SAXS technologies for high throughput characterizations of PCs and MPs, and 3) create and test powerful computational descriptions for protein functional interactions. In concert, MAGGIE investigators will characterize microbial metabolic modularity and provide the informed basis to design functional islands suitable to transform microbes for specific DOE missions.

7. Proteogenomic approaches for the molecular characterization of natural microbial communities
Jillian Banfield, Principal Investigator (Earth Sciences Division)

description coming soon

Read more about the October 2005 award of $49M in Genomics:GTL research to Berkeley Lab

Read more about the DOE's Genomics:GTL program