Facilitate Collaborations among Synthetic Biology, Metabolic Engineering and Machine Learning

Metabolic engineering (ME) and synthetic biology (SynBio) are two intersecting fields with different focal points. While SynBio focuses more on genomic aspects to build novel cell devices, ME emphasizes the phenotypic outputs (e.g., production). SynBio has the potential to revolutionize the bio-productions; however, the introduction of synthetic devices/pathways often consumes significant cellular resources and incurs fitness costs. Currently, SynBio applications still lack guidelines in re-allocating cellular carbon and energy fluxes. To resolve this, ME principles may help the SynBio community. First, 13C MFA (metabolic flux analysis) can characterize the burdens of genetic infrastructures and reveal optimal strategies for distributing cellular resources. Second, novel microbial chassis should be explored to employ their unique metabolic features for product synthesis. Third, standardization and classification of bio-production papers will not only improve the communication between ME and SynBio, but also facilitate text mining and machine learning to harness information for rational strain design. Ultimately, the data-driven modeling and 13C MFA will be integral components of the SynBio design-build-test-learn cycle for generating novel microbial cell factories.

[1]  Michael Müller,et al.  Identifying the missing steps of the autotrophic 3-hydroxypropionate CO2 fixation cycle in Chloroflexus aurantiacus , 2009, Proceedings of the National Academy of Sciences.

[2]  J. Liao,et al.  Synthetic non-oxidative glycolysis enables complete carbon conservation , 2013, Nature.

[3]  O. White,et al.  Global transposon mutagenesis and a minimal Mycoplasma genome. , 1999, Science.

[4]  Thomas H Segall-Shapiro,et al.  Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome , 2010, Science.

[5]  Sorin Draghici,et al.  Machine Learning and Its Applications to Biology , 2007, PLoS Comput. Biol..

[6]  Costas D. Maranas,et al.  OptForce: An Optimization Procedure for Identifying All Genetic Manipulations Leading to Targeted Overproductions , 2010, PLoS Comput. Biol..

[7]  S. Ehrlich,et al.  Essential Bacillus subtilis genes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Erika Check Hayden Synthetic biology called to order. , 2015 .

[9]  Carlos Bustamante,et al.  Light-powering Escherichia coli with proteorhodopsin , 2007, Proceedings of the National Academy of Sciences.

[10]  Adam P. Arkin,et al.  A Method to Constrain Genome-Scale Models with 13C Labeling Data , 2015, PLoS Comput. Biol..

[11]  Joerg M. Buescher,et al.  A roadmap for interpreting (13)C metabolite labeling patterns from cells. , 2015, Current opinion in biotechnology.

[12]  D. Kell Metabolomics, modelling and machine learning in systems biology – towards an understanding of the languages of cells , 2006, The FEBS journal.

[13]  An-Ping Zeng,et al.  Non-stationary 13C metabolic flux analysis of Chinese hamster ovary cells in batch culture using extracellular labeling highlights metabolic reversibility and compartmentation , 2014, BMC Systems Biology.

[14]  Stephen J. Van Dien,et al.  From the first drop to the first truckload: commercialization of microbial processes for renewable chemicals. , 2013 .

[15]  Wolfgang Wiechert,et al.  The benefits of being transient: isotope-based metabolic flux analysis at the short time scale , 2011, Applied Microbiology and Biotechnology.

[16]  J E Bailey,et al.  Plasmid presence changes the relative levels of many host cell proteins and ribosome components in recombinant Escherichia coli , 1991, Biotechnology and bioengineering.

[17]  George M Church,et al.  Towards synthesis of a minimal cell , 2006, Molecular systems biology.

[18]  Christina D Smolke,et al.  Building outside of the box: iGEM and the BioBricks Foundation , 2009, Nature Biotechnology.

[19]  J. Collins,et al.  Construction of a genetic toggle switch in Escherichia coli , 2000, Nature.

[20]  Yinjie J. Tang,et al.  Statistics-based model for prediction of chemical biosynthesis yield from Saccharomyces cerevisiae , 2011, Microbial cell factories.

[21]  B. Glick Metabolic load and heterologous gene expression. , 1995, Biotechnology advances.

[22]  P. Adams,et al.  Analytics for Metabolic Engineering , 2015, Front. Bioeng. Biotechnol..

[23]  Jamey D. Young,et al.  Mapping photoautotrophic metabolism with isotopically nonstationary (13)C flux analysis. , 2011, Metabolic engineering.

[24]  A. Burgard,et al.  Optknock: A bilevel programming framework for identifying gene knockout strategies for microbial strain optimization , 2003, Biotechnology and bioengineering.

[25]  Hee-Ju Nah,et al.  Precise cloning and tandem integration of large polyketide biosynthetic gene cluster using Streptomyces artificial chromosome system , 2015, Microbial Cell Factories.

[26]  Peter D. Karp,et al.  Machine learning methods for metabolic pathway prediction , 2010 .

[27]  C. Maranas,et al.  13C metabolic flux analysis at a genome-scale. , 2015, Metabolic engineering.

[28]  Yinjie J. Tang,et al.  Engineering Escherichia coli to convert acetic acid to free fatty acids , 2013 .

[29]  G. Stephanopoulos,et al.  Improving fatty acids production by engineering dynamic pathway regulation and metabolic control , 2014, Proceedings of the National Academy of Sciences.

[30]  Jay D. Keasling,et al.  Improving Microbial Biogasoline Production in Escherichia coli Using Tolerance Engineering , 2014, mBio.

[31]  B. Palsson,et al.  Stoichiometric flux balance models quantitatively predict growth and metabolic by-product secretion in wild-type Escherichia coli W3110 , 1994, Applied and environmental microbiology.

[32]  Yinjie J. Tang,et al.  Effects of inhibitory compounds in lignocellulosic hydrolysates on Mortierella isabellina growth and carbon utilization. , 2015, Bioresource technology.

[33]  Michelle C. Y. Chang,et al.  Exploring bacterial lignin degradation. , 2014, Current opinion in chemical biology.

[34]  M. Elowitz,et al.  A synthetic oscillatory network of transcriptional regulators , 2000, Nature.

[35]  J. Keasling,et al.  Design of a dynamic sensor-regulator system for production of chemicals and fuels derived from fatty acids , 2012, Nature Biotechnology.

[36]  Miguel Rocha,et al.  OptFlux: an open-source software platform for in silico metabolic engineering , 2010, BMC Systems Biology.

[37]  Qing Zhang,et al.  Parsing citations in biomedical articles using conditional random fields , 2011, Comput. Biol. Medicine.

[38]  James D. Winkler,et al.  The LASER database: Formalizing design rules for metabolic engineering , 2015, Metabolic engineering communications.

[39]  Hongwei Wu,et al.  Yeast fermentation of carboxylic acids obtained from pyrolytic aqueous phases for lipid production. , 2012, Bioresource technology.

[40]  G. Stephanopoulos,et al.  Metabolic engineering: past and future. , 2013, Annual review of chemical and biomolecular engineering.

[41]  J. Brown,et al.  The iGEM competition: building with biology , 2007 .

[42]  C. Wittmann,et al.  The Key to Acetate: Metabolic Fluxes of Acetic Acid Bacteria under Cocoa Pulp Fermentation-Simulating Conditions , 2014, Applied and Environmental Microbiology.

[43]  Tanja Kortemme,et al.  Cost-Benefit Tradeoffs in Engineered lac Operons , 2012, Science.

[44]  Jamey D. Young,et al.  Isotopically nonstationary 13C flux analysis of changes in Arabidopsis thaliana leaf metabolism due to high light acclimation , 2014, Proceedings of the National Academy of Sciences.

[45]  Erika Check Hayden,et al.  Synthetic biologists seek standards for nascent field , 2015, Nature.

[46]  A. C. Chang,et al.  Construction of biologically functional bacterial plasmids in vitro. , 1973, Proceedings of the National Academy of Sciences of the United States of America.

[47]  U. Sauer,et al.  Non‐stationary 13C‐metabolic flux ratio analysis , 2013, Biotechnology and Bioengineering.

[48]  A. Lapidus,et al.  Complete genome sequence of the filamentous anoxygenic phototrophic bacterium Chloroflexus aurantiacus , 2011, BMC Genomics.

[49]  E. Koonin,et al.  A minimal gene set for cellular life derived by comparison of complete bacterial genomes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Costas D Maranas,et al.  OptStrain: a computational framework for redesign of microbial production systems. , 2004, Genome research.

[51]  Swapnil Bhatia,et al.  Functional optimization of gene clusters by combinatorial design and assembly , 2014, Nature Biotechnology.

[52]  Jens Nielsen,et al.  Synergies between synthetic biology and metabolic engineering , 2011, Nature Biotechnology.

[53]  Gregory Stephanopoulos,et al.  Synthetic biology and metabolic engineering. , 2012, ACS synthetic biology.

[54]  Jonathan A. Goler,et al.  Chemical synthesis using synthetic biology. , 2009, Current opinion in biotechnology.

[55]  B. Jørgensen,et al.  Microbial life under extreme energy limitation , 2013, Nature Reviews Microbiology.

[56]  S. Lee,et al.  Systems strategies for developing industrial microbial strains , 2015, Nature Biotechnology.

[57]  Harold Varmus,et al.  Rescuing US biomedical research from its systemic flaws , 2014, Proceedings of the National Academy of Sciences.

[58]  Yinjie J. Tang,et al.  Evaluating Factors That Influence Microbial Synthesis Yields by Linear Regression with Numerical and Ordinal Variables , 2011, Biotechnology and bioengineering.

[59]  G. Stephanopoulos,et al.  Distributing a metabolic pathway among a microbial consortium enhances production of natural products , 2015, Nature Biotechnology.

[60]  Yinjie J. Tang,et al.  13C-MFA delineates the photomixotrophic metabolism of Synechocystis sp. PCC 6803 under light- and carbon-sufficient conditions. , 2014, Biotechnology journal.

[61]  Hong Li,et al.  Thermodynamic analysis on energy densities of batteries , 2011 .

[62]  Yee Wen Choon,et al.  Differential Bees Flux Balance Analysis with OptKnock for In Silico Microbial Strains Optimization , 2014, PloS one.

[63]  Timothy S. Ham,et al.  Metabolic engineering of microorganisms for biofuels production: from bugs to synthetic biology to fuels. , 2008, Current opinion in biotechnology.

[64]  G. Stephanopoulos Metabolic fluxes and metabolic engineering. , 1999, Metabolic engineering.

[65]  Jay D Keasling,et al.  Narrowing the gap between the promise and reality of polyketide synthases as a synthetic biology platform. , 2014, Current opinion in biotechnology.

[66]  Yinjie J. Tang,et al.  Advances in analysis of microbial metabolic fluxes via (13)C isotopic labeling. , 2009, Mass spectrometry reviews.

[67]  Stefano Freguia,et al.  Microbial fuel cells: methodology and technology. , 2006, Environmental science & technology.

[68]  Christopher A. Voigt,et al.  Realizing the potential of synthetic biology , 2014, Nature Reviews Molecular Cell Biology.

[69]  Rahul Singh,et al.  The emerging role for bacteria in lignin degradation and bio-product formation. , 2011, Current opinion in biotechnology.

[70]  M. Antoniewicz Methods and advances in metabolic flux analysis: a mini-review , 2015, Journal of Industrial Microbiology & Biotechnology.

[71]  Michael C Jewett,et al.  Update on designing and building minimal cells. , 2010, Current opinion in biotechnology.

[72]  J E Bailey,et al.  Estimation of P-to-O ratio in Bacillus subtilis and its influence on maximum riboflavin yield. , 1999, Biotechnology and bioengineering.

[73]  M. Ghirardi,et al.  Phosphoketolase pathway contributes to carbon metabolism in cyanobacteria , 2015, Nature Plants.

[74]  J. Keasling,et al.  Absence of Diauxie during Simultaneous Utilization of Glucose and Xylose by Sulfolobus acidocaldarius , 2011, Journal of bacteriology.