214SYSTEMS BIOTECHNOLOGYSANG 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 andSynthetic 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 ofvaluable drugs, commodity and fine chemicals, fuels, and polymers and other materials; this istermed systems biotechnology. Here I present the general strategies for systems biotechnology andseveral examples of applying systems biotechnological strategies for the development ofbioprocesses for the efficient production of chemicals and materials. This also includes a strategy ofsystems 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 ofbiotechnology, as the application of science and technology at systems level to livingorganisms 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 forthe 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 metabolicengineering; 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 theproblems encountered during the mid- to down-stream processes can be tackled byfurther 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 theobjective as enhanced production of a desired product, production of novel product, orSystems Biotechnology 215
utilization of inexpensive carbon source, or all of these. In addition to all the tools andmethods of metabolic engineering available, omics and computational methods [7,8] canbe applied to the development of superior strains. Here I will give examples on thedevelopment of amino acid producers [4,6,9,10], diamine producer [11], succinic acidproducer [12], and polymer producer [13,14] by systems metabolic engineering. If timepermits, the strategies for drug target discovery by systems approach [15-17] will also bedescribed.

Acknowledgments
This work was supported by Korean Systems Biology Program of the Ministry ofEducation, Science and Technology (MEST) through National Research Foundation ofKorea. 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-levelmetabolic 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 metabolicengineering 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., Systemsbiology 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 bioprocessengineering: L-threonine production by systems metabolic engineering ofEscherichia 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 metabolicengineering of microorganisms, Mol. Biosyst. 4:113-120, 2008.
[9] Park, J.H., Lee, K.H., Kim, T.Y., and Lee, S.Y., Metabolic engineering ofEscherichia 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 ofmicroorganisms for amino acid production, Curr. Opin. Biotechnol. 19: 454-460,2008.

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. inpress, 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 thecapnophilic 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 thediscovery of antibacterials using genome-scale metabolic networks, MetabolicEng., in press, 2009.
[16] Lee, S.Y., Kim, H.U., Park, J.H., Park, J.M., and Kim, T.Y., Metabolicengineering of microorganisms: general strategies and drug production, DrugDiscovery 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.