High-throughput genome sequencing of microbes, plants, and complex environmental assemblages of organisms has provided the vital blueprint necessary to understand the functional potential of organisms and interactive communities. By examining the translation of genetic codes into integrated networks of regulatory elements, catalytic proteins, and metabolic networks that define all living organisms, systems biology research sheds light on the fundamental principles that govern functional properties of organisms and how their processes respond to community interactions and environmental variables.
The Department of Energy (DOE) Genomic Science program supports systems biology research aimed at identifying these foundational principles driving biological systems of plants, microbes, and multispecies communities relevant to DOE missions in energy and the environment.
Genomic Science program research is conducted at national laboratories and universities and includes single-investigator projects, multi-institutional collaborations, and fundamental research centers. The genome sequences of organisms studied in these projects are provided largely by the DOE Joint Genome Institute (JGI), an important user facility and a world leader in generating sequences of microbes, microbial communities, plants, and other organisms.
Genomics and Metagenomics. Sequencing and analyzing DNA from individual organisms (genomics) or microbial communities in environmental samples (metagenomics) form the foundation of systems biology research. In addition to sequencing and annotating genomes, Genomic Science program research seeks to develop improved methods for rapidly identifying and characterizing functional and regulatory gene networks in microbes, microbial communities, and plants.
Analytical Omics. Transcriptomics, proteomics, and metabolomics—collectively described as omics analyses—identify and measure the abundance and fluxes of key molecular species indicative of organismal or community activity. Global analyses of RNA transcripts, proteins, and metabolites inform scientists about organisms’ physiological status. Such analyses, as well as stable isotope tracking and nano secondary ion mass spectrometry (NanoSIMS) characterization techniques, also provide insights into gene function and indicate which genes are activated and translated into functional proteins as organisms and communities develop or respond to environmental cues. Metamethods that analyze DNA, RNA, and proteins extracted directly from environmental communities enable discovery of new biological processes and provide novel insights into relationships between the composition of communities and functional processes that they perform.
Molecular Imaging and Structural Analysis. Genomic Science program investigators are developing and using new methods for characterizing the chemical reaction surfaces, organization, and structural components in molecular complexes and tracking molecules to view cellular processes as they are occurring. Depending on the spatial scale, a variety of imaging technologies can be used to visualize the complex molecular choreography within biological systems. Some of these structural and imaging tools (e.g., synchrotrons, neutron sources, and electron microscopes) are available or are being developed at DOE Office of Science national user facilities. These facilities provide photon, neutron, electron, magnetic, and mechanical instrumentation with state-of-the-art spatial, temporal, and chemical sensitivity.
Predictive Modeling. Computational models are used to capture, integrate, and represent current knowledge of biology at various scales. For example, researchers are using genome sequence and other comprehensive datasets (molecular, spatial, and temporal data) to build models of signaling networks, gene regulatory circuits, and metabolic pathways.
Genome-Scale Engineering. Growing interest in biological design research stems from its wide-ranging potential. Knowledge of the principles that govern biology will enable predictions of biological system behavior under changing conditions. Moreover, tailoring the behavior of these systems for defined purposes will necessitate their reengineering or the design of new systems. Novel genome-scale engineering tools and technologies, in turn, will improve understanding of natural systems and their response to changing environmental conditions.
The ultimate goal for the three DOE Bioenergy Research Centers (BRCs) is to provide the fundamental science to underpin a cost-effective, advanced cellulosic biofuels industry. Using systems biology approaches, the BRCs are focusing on new strategies to reduce the impact of key cost-driving processes in the overall production of cellulosic biofuels from biomass. For these biofuels to be adopted on a large scale, they must represent environmentally sustainable and economically competitive alternatives to existing fuel systems.
New strategies and findings emanating from the centers' fundamental research are addressing three grand challenges for cost-effective advanced biofuels production:
The BRCs are supported by multidisciplinary teams of top scientists from the nation’s leading universities, DOE national laboratories, nonprofit organizations, and a range of private companies. The three BRCs are located in geographically distinct areas and use different plants both for laboratory research and for improving feedstock crops.
The complexity of the three biological grand challenges that must be overcome to achieve industrial-scale bioenergy production requires the coordinated pursuit of numerous research approaches to ensure timely success. Collectively, the DOE BRCs provide a portfolio of diverse and complementary scientific strategies that address these challenges on a scale far greater than any effort to date.
Achieving a predictive understanding of biological systems is a daunting challenge and requires the integration of immense amounts of diverse information—functional descriptions assigned to DNA sequence, molecular interactions, images of molecules or physical structures within an organism, and details about the environment in which an organism lives. These information types typically have not been integrated and compared, and the heterogeneous mix of data emanating from the Genomic Science program will span diverse environmental conditions, spatial scales (nanometers to kilometers), and temporal scales (nanoseconds to decades). To address this grand challenge, DOE has funded a Systems Biology Knowledgebase (KBase) to facilitate a new level of scientific inquiry.
KBase is the first large-scale bioinformatics system to enable users to upload their own data, analyze it (along with collaborator or public data), build increasingly realistic models, and share and publish their workflows and conclusions. With features beyond those of a database or workbench, KBase aims to provide a knowledgebase: an integrated environment where knowledge and insights are created and multiplied. KBase’s enterprise-class computing capabilities enable data integration and analysis at a powerful scale. This environment will foster the intellectual engagement and inherent creativity of a collaborative scientific community needed to decipher biological principles underlying complex systems. These concepts are driving KBase design:
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