Systems biotechnology
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Systems biotechnology applies systems-level science and technology to living organisms for the production of goods and services. It uses systems biological approaches like metabolic engineering to develop bioprocesses for producing valuable chemicals, fuels, and materials. Systems biotechnology optimizes the unit processes of bioprocess development like strain development, fermentation, and downstream processing in an integrated manner. Systems metabolic engineering allows purposeful modification of metabolic networks based on systems-level analysis to enhance production of desired products. Examples provided include developing amino acid, diamine, and succinic acid producers and polymer producers through systems metabolic engineering strategies.
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SYSTEMS BIOTECHNOLOGY
SANG YUP LEE1
leesy@kaist.ac.kr
1
Department of Chemical and Biomolecular Engineering (BK21 Program), BioProcess
Engineering Research Center, Bioinformatics Research Center, Center for Systems and
Synthetic Biotechnology, Institute for the BioCentury, KAIST, Daejeon 305-701, Korea
Systems biology has been changing the way biological and biotechnological research is performed.
Now, systems biological approaches can be taken to develop bioprocesses for the production of
valuable drugs, commodity and fine chemicals, fuels, and polymers and other materials; this is
termed systems biotechnology. Here I present the general strategies for systems biotechnology and
several examples of applying systems biotechnological strategies for the development of
bioprocesses for the efficient production of chemicals and materials. This also includes a strategy of
systems metabolic engineering for the development of microbial strains. It is expected that systems
biotechnology will be at the heart of successful industrial biotechnology towards low carbon green
growth of the world
Keywords: systems biology; systems biotechnology; metabolic engineering; industrial biotechnology
1. Strategy of Systems Biotechnology
Systems biotechnology [1] can be defined, following the OECD definition of
biotechnology, as the application of science and technology at systems level to living
organisms as well as parts, products and models thereof, for the production of knowledge,
goods and services. As we become equipped with many experimental and computational
tools and methods, we can better understand the cell as a whole. A typical bioprocess for
the production of a desired product will rely on the choice of a main substrate (e.g.,
carbon source), development of superior microorganism through metabolic engineering,
fermentation, and downstream processing for product recovery [2]. These unit processes
need to be optimized in an integrated manner to achieve the best performing process [3].
Systems biology contributes significantly to the strain development through metabolic
engineering; thus it is called systems metabolic engineering [3-5]. Of course, midstream
(fermentation) and downstream processes need to be carefully examined so that strains
can be further engineered for the best overall performance. This means that some of the
problems encountered during the mid- to down-stream processes can be tackled by
further metabolic engineering based on systems-level analysis [3,6].
2. Systems Metabolic Engineering
Systems metabolic engineering [3-6] allows purposeful modification of metabolic, gene
regulatory, and signaling networks based on systems-level analysis. One can set the
objective as enhanced production of a desired product, production of novel product, or](https://image.slidesharecdn.com/systemsbiotechnology-160202233007/85/Systems-biotechnology-1-320.jpg)
![Systems Biotechnology 215
utilization of inexpensive carbon source, or all of these. In addition to all the tools and
methods of metabolic engineering available, omics and computational methods [7,8] can
be applied to the development of superior strains. Here I will give examples on the
development of amino acid producers [4,6,9,10], diamine producer [11], succinic acid
producer [12], and polymer producer [13,14] by systems metabolic engineering. If time
permits, the strategies for drug target discovery by systems approach [15-17] will also be
described.
Acknowledgments
This work was supported by Korean Systems Biology Program of the Ministry of
Education, Science and Technology (MEST) through National Research Foundation of
Korea. Further supports by LG Chem Chair Professorship, Microsoft, and World Class
University Program of MEST are appreciated.
References
[1] Lee, S.Y., Lee, D.-Y., and Kim, T.Y., Systems biotechnology for strain
improvement, Trends Biotechnol., 23: 349-358, 2005.
[2] Kim, T.Y., Sohn, S.B., Kim, H.U., and Lee, S.Y., Strategies for systems-level
metabolic engineering, Biotechnol. J. 3:612-623, 2008.
[3] Park, J.H., Lee, S.Y., Kim, T.Y., and Kim, H.U., Application of systems biology
for bioprocess development, Trends Biotechnol., 26:404-412, 2008.
[4] Lee, K.H., Park, J.H., Kim, T.Y., Kim, H.U., and Lee, S.Y., Systems metabolic
engineering of Escherichia coli for L-threonine production, Mol. Sys. Biol., 3:149,
2007.
[5] Barrett, C.L., Kim, T.Y., Kim, H.U., Palsson, B.O., and Lee, S.Y., Systems
biology as a foundation for genome-scale synthetic biology, Curr. Opin.
Biotechnol., 17:488-492, 2006.
[6] Lee, S.Y. and Park, J.H., Integration of systems biology with bioprocess
engineering: L-threonine production by systems metabolic engineering of
Escherichia coli, Adv. Biochem. Eng. Biotechnol. in press, 2009.
[7] Park, J.M., Kim, T.Y., and Lee, S.Y., Constraints-based genome-scale metabolic
simulation for systems metabolic engineering, Biotechnol. Adv. in press, 2009.
[8] Kim, H.U., Kim, T.Y., and Lee, S.Y., Metabolic flux analysis and metabolic
engineering of microorganisms, Mol. Biosyst. 4:113-120, 2008.
[9] Park, J.H., Lee, K.H., Kim, T.Y., and Lee, S.Y., Metabolic engineering of
Escherichia coli for the production of L-valine based on transcriptome analysis
and in silico gene knockout simulation, Proc. Nat. Acad. Sci., 104:7797-7802,
2007.
[10] Park, J.H. and Lee, S.Y., Towards systems metabolic engineering of
microorganisms for amino acid production, Curr. Opin. Biotechnol. 19: 454-460,
2008.](https://image.slidesharecdn.com/systemsbiotechnology-160202233007/85/Systems-biotechnology-2-320.jpg)
![216 S. Y. Lee
[11] Qian, Z.-G., Xia, X.-X., and Lee, S.Y., Metabolic engineering of Escherichia coli
for the production of putrescine, a four carbon diamine, Biotechnol. Bioeng. in
press, 2009.
[12] Hong, S.H., Kim, J.S., Lee, S.Y., In, Y.H., Choi, S.S., Rih, J.K., Kim,
C.H., Jeong, H., Hur, C.G., and Kim, J.J., The genome sequence of the
capnophilic rumen bacterium Mannheimia succiniciproducens, Nature Biotechnol.
22: 1275-1281, 2004.
[13] Lee, S.Y., Deciphering bioplastic production, Nature Biotechnol., 24:1227-1229,
2006.
[14] Park, S.J. and Lee, S.Y., Systems biological approach for the production of various
polyhydroxyalkanoates by metabolically engineered Escherichia coli, Macromol.
Sympo., 224:1-9, 2005.
[15] Kim, T.Y., Kim, H.U., and Lee, S.Y., Metabolite-centric approaches for the
discovery of antibacterials using genome-scale metabolic networks, Metabolic
Eng., in press, 2009.
[16] Lee, S.Y., Kim, H.U., Park, J.H., Park, J.M., and Kim, T.Y., Metabolic
engineering of microorganisms: general strategies and drug production, Drug
Discovery Today, 14: 78-88, 2009.
[17] Kim, P.J., Lee, D.Y., Kim, T.Y., Lee, K.H., Jeong, H.W., Lee, S.Y., and Park,
S.W., Metabolite essentiality elucidates robustness of Escherichia coli metabolism,
Proc. Nat. Acad. Sci., 104:13638-13642, 2007.](https://image.slidesharecdn.com/systemsbiotechnology-160202233007/85/Systems-biotechnology-3-320.jpg)
Systems biotechnology
- 1. 214 SYSTEMS BIOTECHNOLOGY SANG YUP LEE1 leesy@kaist.ac.kr 1 Department of Chemical and Biomolecular Engineering (BK21 Program), BioProcess Engineering Research Center, Bioinformatics Research Center, Center for Systems and Synthetic Biotechnology, Institute for the BioCentury, KAIST, Daejeon 305-701, Korea Systems biology has been changing the way biological and biotechnological research is performed. Now, systems biological approaches can be taken to develop bioprocesses for the production of valuable drugs, commodity and fine chemicals, fuels, and polymers and other materials; this is termed systems biotechnology. Here I present the general strategies for systems biotechnology and several examples of applying systems biotechnological strategies for the development of bioprocesses for the efficient production of chemicals and materials. This also includes a strategy of systems metabolic engineering for the development of microbial strains. It is expected that systems biotechnology will be at the heart of successful industrial biotechnology towards low carbon green growth of the world Keywords: systems biology; systems biotechnology; metabolic engineering; industrial biotechnology 1. Strategy of Systems Biotechnology Systems biotechnology [1] can be defined, following the OECD definition of biotechnology, as the application of science and technology at systems level to living organisms as well as parts, products and models thereof, for the production of knowledge, goods and services. As we become equipped with many experimental and computational tools and methods, we can better understand the cell as a whole. A typical bioprocess for the production of a desired product will rely on the choice of a main substrate (e.g., carbon source), development of superior microorganism through metabolic engineering, fermentation, and downstream processing for product recovery [2]. These unit processes need to be optimized in an integrated manner to achieve the best performing process [3]. Systems biology contributes significantly to the strain development through metabolic engineering; thus it is called systems metabolic engineering [3-5]. Of course, midstream (fermentation) and downstream processes need to be carefully examined so that strains can be further engineered for the best overall performance. This means that some of the problems encountered during the mid- to down-stream processes can be tackled by further metabolic engineering based on systems-level analysis [3,6]. 2. Systems Metabolic Engineering Systems metabolic engineering [3-6] allows purposeful modification of metabolic, gene regulatory, and signaling networks based on systems-level analysis. One can set the objective as enhanced production of a desired product, production of novel product, or
- 2. Systems Biotechnology 215 utilization of inexpensive carbon source, or all of these. In addition to all the tools and methods of metabolic engineering available, omics and computational methods [7,8] can be applied to the development of superior strains. Here I will give examples on the development of amino acid producers [4,6,9,10], diamine producer [11], succinic acid producer [12], and polymer producer [13,14] by systems metabolic engineering. If time permits, the strategies for drug target discovery by systems approach [15-17] will also be described. Acknowledgments This work was supported by Korean Systems Biology Program of the Ministry of Education, Science and Technology (MEST) through National Research Foundation of Korea. Further supports by LG Chem Chair Professorship, Microsoft, and World Class University Program of MEST are appreciated. References [1] Lee, S.Y., Lee, D.-Y., and Kim, T.Y., Systems biotechnology for strain improvement, Trends Biotechnol., 23: 349-358, 2005. [2] Kim, T.Y., Sohn, S.B., Kim, H.U., and Lee, S.Y., Strategies for systems-level metabolic engineering, Biotechnol. J. 3:612-623, 2008. [3] Park, J.H., Lee, S.Y., Kim, T.Y., and Kim, H.U., Application of systems biology for bioprocess development, Trends Biotechnol., 26:404-412, 2008. [4] Lee, K.H., Park, J.H., Kim, T.Y., Kim, H.U., and Lee, S.Y., Systems metabolic engineering of Escherichia coli for L-threonine production, Mol. Sys. Biol., 3:149, 2007. [5] Barrett, C.L., Kim, T.Y., Kim, H.U., Palsson, B.O., and Lee, S.Y., Systems biology as a foundation for genome-scale synthetic biology, Curr. Opin. Biotechnol., 17:488-492, 2006. [6] Lee, S.Y. and Park, J.H., Integration of systems biology with bioprocess engineering: L-threonine production by systems metabolic engineering of Escherichia coli, Adv. Biochem. Eng. Biotechnol. in press, 2009. [7] Park, J.M., Kim, T.Y., and Lee, S.Y., Constraints-based genome-scale metabolic simulation for systems metabolic engineering, Biotechnol. Adv. in press, 2009. [8] Kim, H.U., Kim, T.Y., and Lee, S.Y., Metabolic flux analysis and metabolic engineering of microorganisms, Mol. Biosyst. 4:113-120, 2008. [9] Park, J.H., Lee, K.H., Kim, T.Y., and Lee, S.Y., Metabolic engineering of Escherichia coli for the production of L-valine based on transcriptome analysis and in silico gene knockout simulation, Proc. Nat. Acad. Sci., 104:7797-7802, 2007. [10] Park, J.H. and Lee, S.Y., Towards systems metabolic engineering of microorganisms for amino acid production, Curr. Opin. Biotechnol. 19: 454-460, 2008.
- 3. 216 S. Y. Lee [11] Qian, Z.-G., Xia, X.-X., and Lee, S.Y., Metabolic engineering of Escherichia coli for the production of putrescine, a four carbon diamine, Biotechnol. Bioeng. in press, 2009. [12] Hong, S.H., Kim, J.S., Lee, S.Y., In, Y.H., Choi, S.S., Rih, J.K., Kim, C.H., Jeong, H., Hur, C.G., and Kim, J.J., The genome sequence of the capnophilic rumen bacterium Mannheimia succiniciproducens, Nature Biotechnol. 22: 1275-1281, 2004. [13] Lee, S.Y., Deciphering bioplastic production, Nature Biotechnol., 24:1227-1229, 2006. [14] Park, S.J. and Lee, S.Y., Systems biological approach for the production of various polyhydroxyalkanoates by metabolically engineered Escherichia coli, Macromol. Sympo., 224:1-9, 2005. [15] Kim, T.Y., Kim, H.U., and Lee, S.Y., Metabolite-centric approaches for the discovery of antibacterials using genome-scale metabolic networks, Metabolic Eng., in press, 2009. [16] Lee, S.Y., Kim, H.U., Park, J.H., Park, J.M., and Kim, T.Y., Metabolic engineering of microorganisms: general strategies and drug production, Drug Discovery Today, 14: 78-88, 2009. [17] Kim, P.J., Lee, D.Y., Kim, T.Y., Lee, K.H., Jeong, H.W., Lee, S.Y., and Park, S.W., Metabolite essentiality elucidates robustness of Escherichia coli metabolism, Proc. Nat. Acad. Sci., 104:13638-13642, 2007.