Next-Generation Synthetic Gene Networks

Synthetic biology is focused on the rational construction of biological systems based on engineering principles. During the field's first decade of development, significant progress has been made in designing biological parts and assembling them into genetic circuits to achieve basic functionalities. These circuits have been used to construct proof-of-principle systems with promising results in industrial and medical applications. However, advances in synthetic biology have been limited by a lack of interoperable parts, techniques for dynamically probing biological systems and frameworks for the reliable construction and operation of complex, higher-order networks. As these challenges are addressed, synthetic biologists will be able to construct useful next-generation synthetic gene networks with real-world applications in medicine, biotechnology, bioremediation and bioenergy.

[1]  P. R. Jensen,et al.  Artificial promoters for metabolic optimization. , 1998, Biotechnology and bioengineering.

[2]  Priscilla E. M. Purnick,et al.  The second wave of synthetic biology: from modules to systems , 2009, Nature Reviews Molecular Cell Biology.

[3]  Martin J. Blaser,et al.  Substantial Alterations of the Cutaneous Bacterial Biota in Psoriatic Lesions , 2008, PloS one.

[4]  Kyung-Soon Park,et al.  Phenotypic alteration of eukaryotic cells using randomized libraries of artificial transcription factors , 2003, Nature Biotechnology.

[5]  S. Rammensee,et al.  Assembly mechanism of recombinant spider silk proteins , 2008, Proceedings of the National Academy of Sciences.

[6]  R. Weiss,et al.  Ultrasensitivity and noise propagation in a synthetic transcriptional cascade. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Choi,et al.  Secretory and extracellular production of recombinant proteins using Escherichia coli , 2004, Applied Microbiology and Biotechnology.

[8]  Weston R. Whitaker,et al.  Toward scalable parts families for predictable design of biological circuits. , 2008, Current opinion in microbiology.

[9]  I. Booth,et al.  Mechanosensitive channels in bacteria: signs of closure? , 2007, Nature Reviews Microbiology.

[10]  Farren J. Isaacs,et al.  Phenotypic consequences of promoter-mediated transcriptional noise. , 2006, Molecular cell.

[11]  M. Elowitz,et al.  Modeling a synthetic multicellular clock: repressilators coupled by quorum sensing. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Carson C. Chow,et al.  Noise shaping in populations of coupled model neurons. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Wei,et al.  Bacterial targeted tumour therapy-dawn of a new era. , 2008, Cancer letters.

[14]  Ron Weiss,et al.  A molecular noise generator , 2008, Physical biology.

[15]  Deepak Chandran,et al.  TinkerCell: modular CAD tool for synthetic biology , 2009, Journal of biological engineering.

[16]  Avi Ma’ayan,et al.  Systems biology of stem cell fate and cellular reprogramming , 2009, Nature Reviews Molecular Cell Biology.

[17]  M. L. Simpson,et al.  Gene network shaping of inherent noise spectra , 2006, Nature.

[18]  C. Hutchison,et al.  Essential genes of a minimal bacterium. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[19]  R. Weiss,et al.  Programmed population control by cell–cell communication and regulated killing , 2004, Nature.

[20]  C. Bustamante,et al.  Ten years of tension: single-molecule DNA mechanics , 2003, Nature.

[21]  R. Weiss,et al.  A universal RNAi-based logic evaluator that operates in mammalian cells , 2007, Nature Biotechnology.

[22]  B. Roe,et al.  A core gut microbiome in obese and lean twins , 2008, Nature.

[23]  J. Collins,et al.  DIVERSITY-BASED, MODEL-GUIDED CONSTRUCTION OF SYNTHETIC GENE NETWORKS WITH PREDICTED FUNCTIONS , 2009, Nature Biotechnology.

[24]  S. Basu,et al.  A synthetic multicellular system for programmed pattern formation , 2005, Nature.

[25]  Christopher A. Voigt,et al.  Spatiotemporal Control of Cell Signalling Using A Light-Switchable Protein Interaction , 2009, Nature.

[26]  M. Elowitz,et al.  Programming gene expression with combinatorial promoters , 2007, Molecular systems biology.

[27]  J. Chin,et al.  Evolved orthogonal ribosomes enhance the efficiency of synthetic genetic code expansion , 2007, Nature Biotechnology.

[28]  Ahmad S. Khalil,et al.  Kinesin's cover-neck bundle folds forward to generate force , 2008, Proceedings of the National Academy of Sciences.

[29]  L. Poulsen,et al.  New Unstable Variants of Green Fluorescent Protein for Studies of Transient Gene Expression in Bacteria , 1998, Applied and Environmental Microbiology.

[30]  M. Bennett,et al.  Metabolic gene regulation in a dynamically changing environment , 2008, Nature.

[31]  E. Wimmer,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2022 .

[32]  J. Ramos,et al.  Suicidal genetic elements and their use in biological containment of bacteria. , 1993, Annual review of microbiology.

[33]  K. Neuman,et al.  Single-molecule force spectroscopy: optical tweezers, magnetic tweezers and atomic force microscopy , 2008, Nature Methods.

[34]  Alfonso Jaramillo,et al.  Towards the automated engineering of a synthetic genome. , 2009, Molecular bioSystems.

[35]  M. L. Simpson,et al.  Frequency domain analysis of noise in autoregulated gene circuits , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  David A. LaVan,et al.  Designing artificial cells to harness the biological ion concentration gradient. , 2008, Nature nanotechnology.

[37]  M. Bennett,et al.  A fast, robust, and tunable synthetic gene oscillator , 2008, Nature.

[38]  S. Gambhir,et al.  Quantum Dots for Live Cells, in Vivo Imaging, and Diagnostics , 2005, Science.

[39]  Christopher A. Voigt,et al.  A Synthetic Genetic Edge Detection Program , 2009, Cell.

[40]  Christopher A. Voigt,et al.  Environmentally controlled invasion of cancer cells by engineered bacteria. , 2006, Journal of molecular biology.

[41]  David A. Drubin,et al.  Rational design of memory in eukaryotic cells. , 2007, Genes & development.

[42]  Peter G Schultz,et al.  A genetically encoded fluorescent amino acid. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Prahlad T. Ram,et al.  MAP Kinase Phosphatase As a Locus of Flexibility in a Mitogen-Activated Protein Kinase Signaling Network , 2002, Science.

[44]  Timothy K Lu,et al.  Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy , 2009, Proceedings of the National Academy of Sciences.

[45]  R. Aebersold,et al.  Proteome-wide cellular protein concentrations of the human pathogen Leptospira interrogans , 2009, Nature.

[46]  Jeremy Minshull,et al.  Engineering the Salmonella type III secretion system to export spider silk monomers , 2009, Molecular systems biology.

[47]  Drew Endy,et al.  Engineering BioBrick vectors from BioBrick parts , 2008, Journal of Biological Engineering.

[48]  Wendell A Lim,et al.  Engineering synthetic signaling proteins with ultrasensitive input/output control , 2007, Nature Biotechnology.

[49]  E. Mardis,et al.  An obesity-associated gut microbiome with increased capacity for energy harvest , 2006, Nature.

[50]  Timothy S. Ham,et al.  Design and Construction of a Double Inversion Recombination Switch for Heritable Sequential Genetic Memory , 2008, PloS one.

[51]  C. Deming,et al.  Topographical and Temporal Diversity of the Human Skin Microbiome , 2009, Science.

[52]  Martin Fussenegger,et al.  Engineering of synthetic mammalian gene networks. , 2009, Chemistry & biology.

[53]  G. Stephanopoulos,et al.  Tuning genetic control through promoter engineering. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[54]  C. Barbas,et al.  Positive and negative regulation of endogenous genes by designed transcription factors. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Farren J. Isaacs,et al.  Engineered riboregulators enable post-transcriptional control of gene expression , 2004, Nature Biotechnology.

[56]  T. Ichisaka,et al.  Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors , 2007, Cell.

[57]  Christopher A. Voigt,et al.  Synthetic biology: Engineering Escherichia coli to see light , 2005, Nature.

[58]  Farren J. Isaacs,et al.  Computational studies of gene regulatory networks: in numero molecular biology , 2001, Nature Reviews Genetics.

[59]  J. Craig Venter,et al.  Creating Bacterial Strains from Genomes That Have Been Cloned and Engineered in Yeast , 2009, Science.

[60]  Timothy B. Stockwell,et al.  Complete Chemical Synthesis, Assembly, and Cloning of a Mycoplasma genitalium Genome , 2008, Science.

[61]  K. Hamad-Schifferli,et al.  Remote electronic control of DNA hybridization through inductive coupling to an attached metal nanocrystal antenna , 2002, Nature.

[62]  O. King,et al.  A Systematic Survey Identifies Prions and Illuminates Sequence Features of Prionogenic Proteins , 2009, Cell.

[63]  Timothy S. Ham,et al.  A tightly regulated inducible expression system utilizing the fim inversion recombination switch. , 2006, Biotechnology and bioengineering.

[64]  Jeffrey P. Mower,et al.  RNAi in Budding Yeast , 2009, Science.

[65]  Ty C. Voss,et al.  Ultradian hormone stimulation induces glucocorticoid receptor-mediated pulses of gene transcription , 2009, Nature Cell Biology.

[66]  K. Svoboda,et al.  Biological applications of optical forces. , 1994, Annual review of biophysics and biomolecular structure.

[67]  J. Collins,et al.  Combinatorial promoter design for engineering noisy gene expression , 2007, Proceedings of the National Academy of Sciences.

[68]  Jay D. Keasling,et al.  Directed Evolution of AraC for Improved Compatibility of Arabinose- and Lactose-Inducible Promoters , 2007, Applied and Environmental Microbiology.

[69]  G. Church,et al.  Synthetic Gene Networks That Count , 2009, Science.

[70]  J. Chin,et al.  A network of orthogonal ribosome·mRNA pairs , 2005, Nature chemical biology.

[71]  C. Bashor,et al.  References and Notes Supporting Online Material Using Engineered Scaffold Interactions to Reshape Map Kinase Pathway Signaling Dynamics , 2022 .

[72]  Jean Peccoud,et al.  Writing DNA with GenoCAD™ , 2009, Nucleic Acids Res..

[73]  C. Koch,et al.  Attention activates winner-take-all competition among visual filters , 1999, Nature Neuroscience.

[74]  A. deMello,et al.  Opportunities for microfluidic technologies in synthetic biology , 2009, Journal of The Royal Society Interface.

[75]  Rahul Sarpeshkar,et al.  Scalable Hybrid Computation with Spikes , 2002, Neural Computation.

[76]  M. Win,et al.  Higher-Order Cellular Information Processing with Synthetic RNA Devices , 2008, Science.

[77]  Mark Goulian,et al.  Engineered single- and multi-cell chemotaxis pathways in E. coli , 2009, Molecular systems biology.

[78]  W. Lim,et al.  Rewiring cellular morphology pathways with synthetic guanine nucleotide exchange factors , 2007, Nature.

[79]  Maung Nyan Win,et al.  Frameworks for programming biological function through RNA parts and devices. , 2009, Chemistry & biology.

[80]  L. Looger,et al.  Computational design of receptor and sensor proteins with novel functions , 2003, Nature.

[81]  Chrisantha Fernando,et al.  Molecular circuits for associative learning in single-celled organisms , 2008, Journal of The Royal Society Interface.

[82]  M. Win,et al.  Codeine-binding RNA aptamers and rapid determination of their binding constants using a direct coupling surface plasmon resonance assay , 2006, Nucleic acids research.

[83]  Farren J. Isaacs,et al.  Programming cells by multiplex genome engineering and accelerated evolution , 2009, Nature.

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

[85]  G. Balázsi,et al.  Negative autoregulation linearizes the dose–response and suppresses the heterogeneity of gene expression , 2009, Proceedings of the National Academy of Sciences.

[86]  Robert T Sauer,et al.  Engineering controllable protein degradation. , 2006, Molecular cell.

[87]  C. Townsend,et al.  An externally tunable bacterial band-pass filter , 2009, Proceedings of the National Academy of Sciences.

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

[89]  J. Hasty,et al.  Synchronizing genetic relaxation oscillators by intercell signaling , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[90]  Jerome T. Mettetal,et al.  The Frequency Dependence of Osmo-Adaptation in Saccharomyces cerevisiae , 2008, Science.

[91]  James J. Collins,et al.  Dispersing biofilms with engineered enzymatic bacteriophage , 2007, Proceedings of the National Academy of Sciences.

[92]  Michael T. Laub,et al.  Rewiring the Specificity of Two-Component Signal Transduction Systems , 2008, Cell.

[93]  Travis S. Bayer,et al.  Programmable ligand-controlled riboregulators of eukaryotic gene expression , 2005, Nature Biotechnology.

[94]  Erik Remaut,et al.  A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[95]  James J. Collins,et al.  A Tunable Genetic Switch Based on RNAi and Repressor Proteins for Regulating Gene Expression in Mammalian Cells , 2007, Cell.

[96]  Dirk Schüler,et al.  Genomics, genetics, and cell biology of magnetosome formation. , 2009, Annual review of microbiology.

[97]  Nicholas J. Guido,et al.  A bottom-up approach to gene regulation , 2006, Nature.

[98]  G. Stephanopoulos,et al.  Assessing the potential of mutational strategies to elicit new phenotypes in industrial strains , 2008, Proceedings of the National Academy of Sciences.

[99]  J. Liao,et al.  A synthetic gene–metabolic oscillator , 2005, Nature.

[100]  Uri Alon,et al.  The incoherent feed-forward loop can generate non-monotonic input functions for genes , 2008, Molecular systems biology.

[101]  Y. Pilpel,et al.  Adaptive prediction of environmental changes by microorganisms , 2009, Nature.

[102]  P. R. Jensen,et al.  Synthetic promoter libraries--tuning of gene expression. , 2006, Trends in biotechnology.

[103]  R. Knight,et al.  Worlds within worlds: evolution of the vertebrate gut microbiota , 2008, Nature Reviews Microbiology.

[104]  Ronnie J Winfrey,et al.  Rapid "open-source" engineering of customized zinc-finger nucleases for highly efficient gene modification. , 2008, Molecular cell.

[105]  Farren J. Isaacs,et al.  Prediction and measurement of an autoregulatory genetic module , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[106]  S Brakmann,et al.  An Error‐Prone T7 RNA Polymerase Mutant Generated by Directed Evolution , 2001, Chembiochem : a European journal of chemical biology.

[107]  S. Chervitz,et al.  The two-component signaling pathway of bacterial chemotaxis: a molecular view of signal transduction by receptors, kinases, and adaptation enzymes. , 1997, Annual review of cell and developmental biology.

[108]  Saeed Tavazoie,et al.  Predictive Behavior Within Microbial Genetic Networks , 2008, Science.

[109]  Timothy S. Ham,et al.  Production of the antimalarial drug precursor artemisinic acid in engineered yeast , 2006, Nature.

[110]  J. Murray,et al.  Site-specific recombinases: tools for genome engineering. , 1993, Trends in genetics : TIG.

[111]  David J. Mooney,et al.  Growth Factors, Matrices, and Forces Combine and Control Stem Cells , 2009, Science.

[112]  Michele P Calos,et al.  Phage integrases: biology and applications. , 2004, Journal of molecular biology.

[113]  W. Fiers,et al.  Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. , 2000, Science.

[114]  Terence Hwa,et al.  Designing sequential transcription logic: a simple genetic circuit for conditional memory , 2007, Systems and Synthetic Biology.

[115]  Michael J Sailor,et al.  Nanoparticle self-assembly gated by logical proteolytic triggers. , 2007, Journal of the American Chemical Society.

[116]  G. Stephanopoulos.  Challenges in Engineering Microbes for Biofuels Production , 2007, Science.

[117]  Benjamin L Turner,et al.  Supporting Online Material Materials and Methods Som Text Figs. S1 to S3 Table S1 References Robust, Tunable Biological Oscillations from Interlinked Positive and Negative Feedback Loops , 2022 .

[118]  Peter G Schultz,et al.  Directed evolution of the site specificity of Cre recombinase , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[119]  M. Bennett,et al.  Microfluidic devices for measuring gene network dynamics in single cells , 2009, Nature Reviews Genetics.

[120]  L. Banaszynski,et al.  A Rapid, Reversible, and Tunable Method to Regulate Protein Function in Living Cells Using Synthetic Small Molecules , 2006, Cell.

[121]  M. Win,et al.  A modular and extensible RNA-based gene-regulatory platform for engineering cellular function , 2007, Proceedings of the National Academy of Sciences.

[122]  M. Fussenegger,et al.  An engineered epigenetic transgene switch in mammalian cells , 2004, Nature Biotechnology.

[123]  Randolph V Lewis,et al.  A protocol for the production of recombinant spider silk-like proteins for artificial fiber spinning , 2009, Nature Protocols.

[124]  Ahmad S. Khalil,et al.  Single M13 bacteriophage tethering and stretching , 2007, Proceedings of the National Academy of Sciences.

[125]  C. A. Hutchinson,et al.  Genome transplantation in bacteria: changing one species to another. , 2007, Nature Reviews Microbiology.

[126]  S. Lindquist,et al.  Creating a protein-based element of inheritance. , 2000, Science.

[127]  Gabriel C. Wu,et al.  Synthetic protein scaffolds provide modular control over metabolic flux , 2009, Nature Biotechnology.

[128]  C. Grigoropoulos,et al.  Bioelectronic silicon nanowire devices using functional membrane proteins , 2009, Proceedings of the National Academy of Sciences.

[129]  Qian Wang,et al.  Expanding the genetic code for biological studies. , 2009, Chemistry & biology.

[130]  Peter A Carr,et al.  Genome engineering , 2009, Nature Biotechnology.

[131]  Y. Yoon,et al.  Efficient cloning and engineering of entire mitochondrial genomes in Escherichia coli and transfer into transcriptionally active mitochondria. , 2003, Nucleic acids research.

[132]  L. Serpell,et al.  Spider silk and amyloid fibrils: a structural comparison. , 2007, Macromolecular bioscience.

[133]  P. Angrand,et al.  Improved properties of FLP recombinase evolved by cycling mutagenesis , 1998, Nature Biotechnology.

[134]  J. Chin,et al.  Synthesis of orthogonal transcription-translation networks , 2009, Proceedings of the National Academy of Sciences.

[135]  J. Stelling,et al.  A tunable synthetic mammalian oscillator , 2009, Nature.

[136]  K. Deisseroth,et al.  Millisecond-timescale, genetically targeted optical control of neural activity , 2005, Nature Neuroscience.

[137]  J. Collins,et al.  Programmable cells: interfacing natural and engineered gene networks. , 2004, Proceedings of the National Academy of Sciences of the United States of America.