Systesysbioms biology is an interdisciplinary field that draws on the use of systematic genomic, proteomic and metabolic measurements to construct models of complex biological systems, their components (e.g. molecules, cells, etc.), and their interactions. In the Keasling lab, we are interested in applying systems biology approaches to aid in the production of biochemicals. We also seek to develop new systems biology approaches to better understand microbial physiology and metabolism. Current projects include the optimization of metabolic pathway expression and understanding the physiological responses of production strains to biofuel toxicity.

FUNDING

Department of Energy

Lawrence Berkeley National Laboratory

Laboratory Directed Research and Development (LDRD) Program

LINKS

ENIGMA

LBL LDRD

REPRESENTATIVE PUBLICATIONS
  • S. T. Sharfstein, S. J. Van Dien, and J. D. Keasling. 1996. “Modulation of the phosphate-starvation response in Escherichia coli by genetic manipulation of the polyphosphate pathways.” Biotechnol. Bioeng. 51:434-438.
  • H. Kuo and J. D. Keasling. 1996. “A Monte Carlo simulation of plasmid replication during the bacterial division cycle.” Biotechnol. Bioeng. 52:633-647.
  • J. Elmen, W. Pan, S. Y. Leung, A. Magyarosy, and J. D. Keasling. 1997. “Kinetics of toluene degradation by a nitrate-reducing bacterium isolated from a groundwater aquifer.” Biotechnol. Bioeng. 55:82-90.
  • J. Pramanik and J. D. Keasling. 1997. “A stoichiometric model of Escherichia coli metabolism: incorporation of growth-rate dependent biomass composition and mechanistic energy requirements.” Biotechnol. Bioeng. 56:398-421.
  • T. A. Carrier and J. D. Keasling. 1997. “Mechanistic modelling of mRNA decay.” J. Theor. Biol. 189:195-209.
  • S. J. Van Dien and J. D. Keasling. 1998. “A dynamic model of the Escherichia coli phosphate-starvation response.” J. Theor. Biol. 190:37-49.
  • S. Cooper and J. D. Keasling. 1998. “Cycle-specific replication of chromosomal and F-plasmid origins.” FEMS Microbiol. Lett. 163:217-222.
  • J. Pramanik, P. L. Trelstad, and J. D. Keasling. 1998. “A flux-based stoichiometric model of enhanced biological phosphorus removal metabolism.” Wat. Sci. Tech. 37:609-613.
  • J. Pramanik and J. D. Keasling. 1998. “Effect of carbon source and growth rate on biomass composition and metabolic flux predictions of a stoichiometric model.” Biotechnol. Bioeng. 60:230-238.
  • J. Pramanik, P. L. Trelstad, A. J. Schuler, D. Jenkins, and J. D. Keasling. 1998. “Development and validation of a flux-based stoichiometric model for enhanced biological phosphorus removal metabolism.” Water Research 33:462-476.
  • E. Gilbert, A. Khlebnikov, W. Meyer-Ilse, and J. D. Keasling. 1999. “Use of soft X-ray microscopy for analysis of early-stage biofilm formation.” Wat. Sci. Tech. 39(7):269-272.
  • S. J. Van Dien and J. D. Keasling. 1999. “Effect of polyphosphate metabolism on the Escherichia coli phosphate-starvation response.” Biotechnol. Prog. 15(4):587-593.
  • S. E. Cowan, J. Black, J. D. Keasling, and R. M. White. 1999. “Ultrasonic flexural-plate-wave sensor for detecting the concentration of settling E. coli W3110 cells.” Analytical Chemistry. 71(16):3622-3625.
  • P. L. Trelstad, P. Purdhani, W. Geibdorfer, W. Hillen, and J. D. Keasling. 1999. “Polyphosphate kinase of Acinetobacter sp. Strain ADP1: purification and characterization of the enzyme and its role during changes in extracellular phosphate.” Appl. Environ. Microbiol. 65(9):3780-3786.
  • T. A. Carrier and J. D. Keasling. 1999. “Investigating autocatalytic gene expression systems through mechanistic modeling.” J. Theor. Biol. 201:25-36.
  • K. D. McMahon, D. Jenkins, and J. D. Keasling. 2002. “Polyphosphate kinase genes from activated sludge carrying out enhanced biological phosphorus removal.” Water Sci. Technol. 46:155-162.
  • K. D. McMahon, M. A. Dojka, N. R. Pace, D. Jenkins, and J. D. Keasling. 2002. “Polyphosphate kinase from activated sludge performing enhanced biological phosphorus removal.” Appl. Environ. Microbiol. 68:4971-4978.
  • S. K. Lee, J. D. Newman, and J. D. Keasling. 2005. “Catabolite repression of the propionate catabolic genes in Escherichia coli and Salmonella enterica: Evidence for involvement of the cyclic AMP receptor protein.” J. Bacteriol. 187:2793-2800.
  • M. J. Kang, Y. M. Lee, S. H. Yoon, J. H. Kim, S. W. Ock, K. H. Jung, Y. C. Shin, J. D. Keasling, and S. W. Kim. 2005. “Identification of genes affecting lycopene accumulation in Escherichia coli using a shot-gun method.” Biotechnol. Bioeng. 91:636-642.
  • A. Mukhopadhyay, Z. He, E. J. Alm, A. P. Arkin, E. E. Baidoo, S. C. Borglin, W. Chen, T. C. Hazen, Qiang He, H.-Y. Holman, K. Huang, R. Huang, D. C. Joyner, N. Katz, M. Keller, P. Oeller, A. Redding, J. Sun, J. Wall, J. Wei, Z. Yang , H.-C. Yen, J. Zhou, and J. D. Keasling. 2006. “Salt stress in Desulfovibrio vulgaris Hildenborough: An integrated genomics approach.” J. Bacteriol. 188:4068-4078.
  • A. M. Redding, A. Mukhopadhyay, D. Joyner, T. C. Hazen, and J. D. Keasling. 2006. “Study of nitrate stress in Desulfovibrio vulgaris Hildenborough using iTRAQ proteomics.” Brief. Funct. Genom. Proteom. 5:133-43.
  • Y. J. Tang, A. L. Meadows, and J. D. Keasling. 2007. “A kinetic model describing Shewanella oneidensis MR-1 growth, substrate consumption, and product secretion”. Biotechnol. Bioeng. 96:125-133.
  • Y. J. Tang, A. L. Meadows, J. Kirby, and J. D. Keasling. 2007. “Anaerobic central metabolic pathways in Shewanella oneidensis MR-1 reinterpreted in the light of isotopic metabolite labeling.” J. Bacteriol. 189:894-901.
  • Y. J. Tang, F. Pingitore, A. Mukhopadhyay, R. Phan, T. C. Hazen, and J. D. Keasling. 2007. “Pathway confirmation and flux analysis of central metabolic pathways in Desulfovibrio vulgaris Hildenborough using GC-MS and FT-ICR mass spectrometry. J. Bacteriol. 189:940-949.
  • Y. J. Tang, J. S. Hwang, D. E. Wemmer, and J. D. Keasling. 2007. “The Shewanella oneidensis MR-1 fluxome under various oxygen conditions.” Appl. Environ. Microbiol. 73:718-729.
  • F. Pingitore, Y. Tang, G. H. Kruppa, and J. D. Keasling. 2007. “Analysis of amino acid isotopomers by FT-ICR MS.” Anal. Chem. 79:2483-2490.
  • Y. Yoshikuni and J. D. Keasling. 2007. “Pathway engineering by designed divergent evolution.” Curr. Opin. Chem. Biol. 11:233-239.
  • Y. J. Tang, R. Chakraborty, H. G. Mart?n, J. Chu, T, C. Hazen, and J. D. Keasling. 2007. “Flux analysis of central metabolic pathways in Geobacter metallireducens during reduction of soluble Fe(III)-nitrilotriacetic acid.” Appl. Environ. Microbiol. 73:3859-3864.
  • A. Mukhopadhyay, A. M. Redding, M. P. Joachimiak, A. P. Arkin, S. E. Borglin, P. S. Dehal, R. Chakraborty, J. T. Geller, T. C. Hazen, Q. He, D. C. Joyner, V. J. J. Martin, J. D. Wall, Z. K. Yang, J. Zhou, and J. D. Keasling. 2007. “Cell wide responses to low oxygen exposure in Desulfovibrio vulgaris Hildenborough.” J. Bacteriol. 189:5996-6010.
  • R. E. Osterhout, I. A. Figueroa, J. D. Keasling, and A. P. Arkin. 2007. “Global analysis of host response to induction of a latent bacteriophage.” BMC Microbiology. 7:82.
  • P. F. Suthers, A. P. Burgard, M. S. Dasika, F. Nowroozi, S. Van Dien, J. D. Keasling, and C. D. Maranas. 2007. “Metabolic flux elucidation for large-scale models using 13C labeled isotopes.” Metab. Eng. 9:387-405.
  • A. S. Shaikh, Y, J. Tang, A. Mukhopadhyay, and J. D. Keasling. 2008. “Isotopomer distributions in amino acids from a high expressed protein as a proxy for those from total protein.” Anal. Chem. 80:886-890.
  • D. M. Wolf, L. Fontaine-Bodin, I. Bischofs, G. Price, J. Keasling, and A. P. Arkin. 2008. “Memory in microbes: quantifying history-dependent behavior in a bacterium.” PLoS ONE. 3:e1700.
  • L. Kizer, D. J. Pitera, B. Pfleger, and J. D. Keasling. 2008. “Functional genomics for pathway optimization: application to isoprenoid production.” Appl. Environ. Microbiol. 74:3229-3241.
  • A. Mukhopadhyay, A. M. Redding, B. J. Rutherford, and J. D. Keasling. 2008. “Importance of systems biology in engineering microbes for biofuel production.” Curr. Opin. Biotechnol. 19:228-234.
  • D. E. Garcia, E. E. Baidoo, P. I. Benke, F. Pingitore, Y. J. Tang, S. Villa, and J. D. Keasling. 2008. “Separation and mass spectrometry in microbial metabolomics.” Curr. Opin. Microbiol. 11:233-239.
  • S. P. Gaucher, A. M. Redding, A. Mukhopadhyay, J. D. Keasling, and A. K. Singh. 2008. “Post-translational modifications of Desulfovibrio vulgaris Hildenborough sulfate reduction pathway proteins.” J. Proteome Res. 7:2320-2331.
  • W. Shui, L. Sheu, J. Liu, B. Smart, C. J. Petzold, T. Y. Hsieh, A. Pitcher, J. D. Keasling, and C. R. Bertozzi. 2008. “Membrane proteomics of phagosomes suggests a connection to autophagy.” Proc. Natl. Acad. Sci. USA 105:16952-16957.
  • D.-K. Ro, M. Ouellet, E. M. Paradise, H. Burd, D. Eng, C. J. Paddon, J. D. Newman, and J. D. Keasling. 2008. “Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of antimalarial drug precursor, artemisinic acid.” BMC Biotechnol. 8:83 (doi:10.1186/1472-6750-8-83).
  • W. Shui, S. A. Gilmore, L. Sheu, J. Liu, J. D. Keasling, and C. R. Bertozzi. 2009. Quantitative proteomic profiling of host-pathogen interactions: the macrophage response to Mycobacterium tuberculosis. J. Proteome Res. 8:282-289.
  • Y. J. Tang, H. G. Martin, P. S. Dehal, A. Deutschbauer, X. Llora, A. Meadows, A. Arkin, and J. D. Keasling. 2009. “Metabolic flux analysis of Shewanella spp. reveals evolutionary robustness in central carbon metabolism.” Biotechnol. Bioeng. 102:1161-1169.
  • Y. J. Tang, H. Garcia Martin, S. Myers, S. Rodriguez, E. E. K. Baidoo, and J. D. Keasling. 2009. “Advances in analysis of microbial metabolic fluxes via 13C isotopic labeling.” Mass Spec. Rev. 28:362-375.
  • Y. J. Tang, R. Sapra, D. Joyner, T. C. Hazen, S. Myers, D. Reichmuth, H. Blanch, and J. D. Keasling. 2009. “Analysis of metabolic pathways and fluxes in a newly discovered thermophilic and ethanol-tolerant Geobacillus strain.” Biotechnol. Bioeng. 102:1377-1386.
  • D. A. Elias, A. Mukhopadhyay, M. P. Joachimiak, E. C. Drury, A. M. Redding, H. C. Yen, M. W. Fields, T. C. Hazen, A. P. Arkin, J. D. Keasling, J. D. Wall. 2009. “Expression profiling of hypothetical genes in Desulfovibrio vulgaris leads to improved functional annotation.” Nucl. Acids Res. 37:2926-2939.
  • Y. J. Tang, W. Shui, S. Myers, X. Feng, C. Bertozzi, J. D. Keasling. 2009. “Central metabolism in Mycobacterium smegmatis during the transition from O(2)-rich to O (2)-poor conditions as studied by isotopomer-assisted metabolite analysis.” Biotechnol. Lett. 31:1233-1240.
  • Y. J. Tang, S. Yi, W.-Q. Zhuang, S. H. Zinder, J. D. Keasling, L. Alvarez-Cohen. 2009. “Investigation of carbon metabolism in Dehalococcoides ethenogenes strain 195 using isotopomer and transcriptomic analyses.” J. Bacteriol. 191:5224-5231.
  • Y. J. Tang, H. G. Martin, A. Deutschbauer, X. Feng, R. Huang, X. Liora, A. Arkin, and J. D. Keasling. 2009. “Invariability of central metabolic flux distribution in Shewanella oneidensis MR-1 under environmental or genetic perturbations.” Biotechnol. Prog. 25:1254-1259.
  • M. Ouellet, P. D. Adams, J. D. Keasling, and A. Mukhopadhyay. 2010. “A rapid and inexpensive method for microarray gene expression analysis.” BMC Biotechnol. 9:97 (doi:10.1186/1472-6750-9-97).
  • Z. He, A. Zhou, E. Baidoo, Q. He, M. P. Joachimiak, P. Benke, R. Phan, A. Mukhopadhyay, C. L. Hemme, K. Huang, E. J. Alm, M. W. Fields, J. Wall, D. Stahl, T. C. Hazen, J. D. Keasling, A. P. Arkin, and J. Zhou. 2010. “Global transcriptional, physiological and metabolite analyses of Desulfovibrio vulgaris Hildenborough responses to salt adaptation.” Appl. Environ. Microbiol. 76:1574-1586.
  • A. S. Shaikh, Y. J. Tang, A. Mukhopadhyay, H. G. Martín, J. Gin, P. Benke, and J. D. Keasling. 2010. “Study of stationary phase metabolism via isotopomer analysis of amino acids from an isolated protein.” Biotechnol. Prog. 26:52-56.
  • B. J. Rutherford, R. H. Dahl, R. E. Price, H. L. Szmidt, P. L. Benke, A. Mukhopadhyay, and J. D. Keasling. 2010. “Functional genomic study of exogenous n-butanol stress in Escherichia coli.” Appl. Environ. Microbiol. 76:1935-1945.
  • M. J. Dunlop, J. D. Keasling, and A. Mukhopadhyay. 2010. “A model for improving microbial biofuel production using a synthetic feedback loop.” Syst. Synth. Biol. 4:95-104.
  • Q. He, Z. He, D. C. Joyner, M. Joachimiak, M. N. Price, Z. K. Yang, H.-C. B. Yen, C. L. Hemme, W. Chen, M. M. Fields, D. A. Stahl, J. D. Keasling, M. Keller, A. P. Arkin, T. C. Hazen, J. D. Wall, and J. Zhou. 2010. “Impact of elevated nitrate on sulfate-reducing bacteria: a comparative study of Desulfovibrio vulgaris.” ISME J. 4:1386-1397.
  • A. Zhou, Z. He, A. M. Redding-Johanson, A. Mukhopadhyay, C. L. Hemme, M. P. Joachimiak, F. Lou, Y. Deng, K. S. Bender, Q. He, J. D. Keasling, D. A. Stahl, M. W. Fields, T. C. Hazen, A. P. Arkin, J. D. Wall, and J. Zhou. 2010. “Hydrogen peroxide-induced oxidative stress responses in Desulfovibrio vulgaris Hildenborough.” Environ. Microbiol. 12:2645-2657.
  • A. M. Redding-Johanson, T. S. Batth, R. Chan, R. Krupa, H. L. Szmidt, P. D. Adams, J. D. Keasling, T. S. Lee, A. Mukhopadhyay, C. J. Petzold. 2011. “Targeted proteomics for metabolic pathway optimization: application to terpene production.” Metab. Eng. 13:194-203.
  • M. J. Dunlop, H. L. Szmidt, H. C. Chu, J. D. Keasling, M. Hadi, A. Mukhopadhyay. 2011. “A targeted bioprospecting approach for engineering microbial biofuel tolerance.” Mol. Sys. Biol. 7:487.
  • S. R. Chhabra, M. P. Joachimiak, C. J. Petzold, G. M. Zane, M. N. Price, S. A. Reveco, V. Fok, A. R. Johanson, T. S. Batth, M. Singer, J. M. Chandonia, D. Joyner, T. C. Hazen, A, P. Arkin, J. D. Wall, A. K. Singh, and J. D. Keasling. 2011. “Towards a rigorous network of protein-protein interactions of the model sulfate reducer Desulfovibrio vulgaris Hildenborough.” PLoS One 6:e21470.
  • M. Ouellet, S. Datta, D. C. Dibble, P. R. Tamrakar, P. I. Benke, C. Li, S. Singh, K. L. Sale, P. D. Adams, J. D. Keasling, B. A. Simmons, B. M. Holmes and A. Mukhopadhyay. 2011. “Impact of ionic liquid pretreated plant biomass on Saccharomyces cerevisiae growth and biofuel production.” Green Chem. 13:2743-2749.
  • J. M. Carothers, J. A. Goler, D. Juminaga, and J. D. Keasling. 2011. “Model-driven engineering of RNA devices to quantitatively program gene expression.” Science 334:1716-1719.
  • Y. Xiao, T. Savchenko, E. E. Baidoo, W. E. Chehab, D. M. Hayden, V. Tolstikov, J. A. Corwin, D. J. Kliebenstein, J. D. Keasling, and K. Dehesh. 2012. “Retrograde signaling by the plastidial metabolite MEcPP regulates expression of nuclear stress-response genes.” Cell 149:1525-1535.
  • M. E. Clark, Z. He, A. M. Redding, M. P. Joachimiak, J. D. Keasling, J. Zhou, A. P. Arkin, A. Mukhopadhyay, and M. W. Fields. 2012. “Transcriptomic and proteomic analyses of Desulfovibrio vulgaris biofilms: carbon and energy flow contribute to the distinct biofilm growth state.” BMC Genomics 13:138.
  • C. B. Walker, A. M. Redding-Johanson, E. Baidoo, L. Rajeev, Z. He, E. L Hendrickson, M.P. Joachimiak, S. Stolyar, A. P. Arkin, J. A. Leigh, J. Zhou, J. D. Keasling, A. Mukhopadhyay, and D. A. Stahl. 2012. “Functional response of methanogenic archaea to syntrophic growth.” ISME J. 6:2045-2055.
  • A. E. Mckee, B. J. Rutherford, D. C. Chivian, E. K. Baidoo, D. Juminaga, D. Kuo, P. I. Benke, J. A. Dietrich, S. M. Ma, A. P. Arkin, C. J. Petzold, P. D. Adams, J. D. Keasling and S. R. Chhabra. 2012. “Manipulation of the carbon storage regulator system for metabolite remodeling and biofuel production in Escherichia coli.” Microb. Cell Fact. 11:79 (doi:10.1186/1475-2859-11-79).
  • B. Ozaydin, H. Burd, T. S. Lee, and J. D. Keasling. 2013. “Carotenoid-based phenotypic screen of the yeast deletion collection reveals new genes with roles in isoprenoid production.” Met. Eng. 15:174-183.
  • A. Zhou, E. Baidoo, Z. He, A. Mukhopadhyay, J. K. Baumohl, P. Benke, M. P Joachimiak, M. Xie, R. Song, A. P. Arkin, T. C. Hazen, J. D. Keasling, J. D. Wall, D. A. Stahl and J. Zhou. 2013. “Characterization of NaCl tolerance in Desulfovibrio vulgaris Hildenborough through experimental evolution.” ISME J. 7(9):1790-1802.
  • N.C. Kyrpides, P. Hugenholtz, J. A. Eisen, T. Woyke, M. Göker, C. T. Parker, R. Amann, B. J. Beck, P. S. Chain, J. Chun, R. R. Colwell, A. Danchin, P. Dawyndt, T. Dedeurwaerdere, E. F. DeLong, J. C. Detter, P. De Vos, T. J. Donohue, X. Z. Dong, D. S. Ehrlich, C. Fraser, R. Gibbs, J. Gilbert, P. Gilna, F. O. Glöckner, J. K. Jansson, J. D. Keasling, R. Knight, D. Labeda, A. Lapidus, J. S. Lee, W. J. Li, J. Ma, V. Markowitz, E. R. Moore, M. Morrison, F. Meyer, K. E. Nelson, M. Ohkuma, C. A. Ouzounis, N. Pace, J. Parkhill, N. Qin, R. Rossello-Mora, J. Sikorski, D. Smith, M. Sogin, R. Stevens, U. Stingl, K. Suzuki, D. Taylor, J. M. Tiedje, B. Tindall, M. Wagner, G. Weinstock, Weissenbach J, White O, Wang J, L. Zhang, Y. G. Zhou, D. Field, W. B. Whitman, G. M. Garrity, H. P. Klenk. 2014. “Genomic encyclopedia of bacteria and archaea: sequencing a myriad of type strains.” PLoS Biol. 12(8):e1001920. doi: 10.1371/journal.pbio.1001920.
  • L. Rajeev, E. G. Luning, S. Altenburg, G. M. Zane, E. E. Baidoo, M. Catena, J. D. Keasling, J. D. Wall, M. W. Fields, and A. Mukhopadhyay. 2014. “Identification of a cyclic-di-GMP-modulating response regulator that impacts biofilm formation in a model sulfate reducing bacterium. Front Microbiol 5:382. Doi: 10.3389/fmicb.2014.00382.
  • J. Alonso-Gutierrez, E.-M. Kim; T. S. Batth, N. Cho, Q. Hu, L. J. G. Chan, C. J. Petzold, Nathan J Hillson, P. D. Adams, J. D. Keasling, H. Garcia-Martin, and T. S. Lee. 2015. “Principal component analysis of proteomics (PCAP) as a tool to direct metabolic engineering.” Met. Eng. 28:123-133.