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Systems Biology-Enabled Biosystems Design

Rationale

Multidisciplinary systems biology approaches are necessary for analyzing disparate types of genome-scale data to enable a deeper understanding of biological systems embedded within both plants and microbes. Recent advances in the integration of computational biology with omics-enabled analytical technologies allow complex biological networks to be dynamically modeled and displayed. Genomics and systems-level predictive understanding of biological systems, pioneered by the Genomic Science program, are uncovering foundational design rules that govern system behavior to the extent that rational genome-scale redesign of organisms is becoming possible. Also referred to as "synthetic biology," this new but rapidly developing field already is providing novel tools for collaborating teams of biologists and chemical engineers to construct biological systems and organisms that address unique challenges and enhance understanding of complex biological systems.

The merging of biology, chemistry, physics, and engineering has the potential to transform fundamental and applied science by shedding light on the basic principles of biological system organization and evolution. This understanding can then be used to extend and enhance the capabilities of natural organisms to solve significant practical problems associated with the production of biofuels and related coproducts from renewable biomass. Extensive modification of existing networks or design of specific synthetic systems can both advance the understanding of biological systems and provide novel tools for interrogating basic biological function. Just as early trial and error in airplane design refined the understanding of fundamental fluid dynamics laws and enabled today's fully automated designs, iterative design cycles in biology will reveal the complex interconnections among biological laws, experimental observations of biological systems, and design of new biological behaviors.

A number of recent breakthroughs have piqued keen interest in genome engineering and biological design. New regulatory circuits can be constructed and evaluated for high-level function and control, and complete metabolic pathways can be assembled, engineered, and introduced into living cells to produce high-value compounds. Entire bacterial genomes can be replaced with modified synthetic counterparts. Orthogonal molecular processes have been developed to incorporate unnatural amino acids into proteins, conferring new functions by codon replacements through directed evolution. Novel nucleases with customizable specificity for genome engineering have been developed from bacterial transcription activator–like effectors (TALEs) and the type II clustered, regularly interspaced, short palindromic repeats (CRISPR)/Cas9 system. Substantial progress also has been made toward constructing synthetic eukaryotic chromosomes. Finally, the vast amount of comprehensive data available for genes, transcripts, proteins, and metabolites under different conditions for multiple individual organisms has dramatically advanced network analysis and computational modeling of biological systems.

Systems Biology Approaches

These advances open new doorways to understand the foundational principles governing the systems properties of living organisms and to develop novel approaches for large-scale manipulation of functional properties that would not be possible via more traditional metabolic engineering approaches. For example, biodesign approaches applied to biomass feedstock plants could lead to new crops that express their own nitrogen-fixing enzymes without the need for bacterial symbionts or that incorporate components of the C4 and crassulacean acid metabolism (CAM) carbon fixation pathway into C3 plants. Such modifications could result in plants with significantly decreased fertilizer requirements, more efficient water utilization, and greatly improved sustainability characteristics. Understanding and improving stress tolerance in microbes is another critical issue that could benefit from biosystems design approaches. Currently, almost every fermentation process is limited by the microbe's tolerance to the final product. A novel way to overcome this problem might be the complete redesign of cell membrane composition by introducing genes to synthesize new membrane lipids. For example, the lipids making up archaeal membranes are very different from those of bacteria. Thus, moving the pathways for lipid biosynthesis from archaea to other microbes could create engineered organisms more tolerant to alcohol and thus more resilient to the stress of biofuel production. In eukaryotes, subcellular compartmentalization in organelles allows cells to contain metabolic pathways and sequester toxic compounds. Engineering cells with repurposed organelles could enable the production of high intracellular concentrations of biofuel molecules without affecting cytoplasm conditions.

Specific knowledge gaps and developmental opportunities in biosystems design that the Genomic Science program can address include:

  • Biological design principles to understand foundational laws governing living systems and better define the "solution space" available to biosystems designers.
  • Genome-scale engineering tools enabling improved integration of large synthetic DNA constructs, highthroughput gene editing and recoding technologies, and incorporation of alternate amino acids and other synthetic design assemblies.
  • New DNA synthesis and assembly technologies for costeffective, high-efficiency synthesis and assembly of large DNA constructs.
  • Diverse platform microbes and plants with sufficient baseline understanding of systems biology properties and available molecular genetics tools that induce amenability to genome-scale engineering, providing a broader array of functional capabilities and growth characteristics.
  • Minimal cell and in vitro systems using highly streamlined platform organisms or entirely cell free in vitro systems with fully defined pathways and functional components that facilitate easier modification and increased process control.
  • Advanced computationally aided design tools for biological systems (e.g., BioCAD) to facilitate in silico design of synthetic parts and systems, accommodate a wider suite of biological parts and platform organisms, and enable efficient workflows for construction and experimental validation of large numbers of genetic design variants.
  • Biocontainment mechanisms permitting incorporation of multiple redundant safeguards at each step of the design process, thereby preventing inadvertent release or deliberate misuse of synthetic biological systems.

Advancing biosystems design principles in a range of microbial and plant species facilitates exploration of biological solutions toward DOE bioenergy and environmental missions and advances rigorous hypothesis testing of fundamental biological mechanisms.




BER Program Manager for Biosystems Design

Dr. Pablo Rabinowicz
U.S. Department of Energy
Office of Biological and Environmental Research
Phone: 301-903-0379
E-Mail: pablo.rabinowicz@science.doe.gov

Featuring

Biosystems Design to Enable Next-Generation Biofuels (Summary of Funded Projects) [9/12]


Biosystems Design Report [04/12]


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