TinkerCell: modular CAD tool for synthetic biology

BackgroundSynthetic biology brings together concepts and techniques from engineering and biology. In this field, computer-aided design (CAD) is necessary in order to bridge the gap between computational modeling and biological data. Using a CAD application, it would be possible to construct models using available biological "parts" and directly generate the DNA sequence that represents the model, thus increasing the efficiency of design and construction of synthetic networks.ResultsAn application named TinkerCell has been developed in order to serve as a CAD tool for synthetic biology. TinkerCell is a visual modeling tool that supports a hierarchy of biological parts. Each part in this hierarchy consists of a set of attributes that define the part, such as sequence or rate constants. Models that are constructed using these parts can be analyzed using various third-party C and Python programs that are hosted by TinkerCell via an extensive C and Python application programming interface (API). TinkerCell supports the notion of a module, which are networks with interfaces. Such modules can be connected to each other, forming larger modular networks. TinkerCell is a free and open-source project under the Berkeley Software Distribution license. Downloads, documentation, and tutorials are available at http://www.tinkercell.com.ConclusionAn ideal CAD application for engineering biological systems would provide features such as: building and simulating networks, analyzing robustness of networks, and searching databases for components that meet the design criteria. At the current state of synthetic biology, there are no established methods for measuring robustness or identifying components that fit a design. The same is true for databases of biological parts. TinkerCell's flexible modeling framework allows it to cope with changes in the field. Such changes may involve the way parts are characterized or the way synthetic networks are modeled and analyzed computationally. TinkerCell can readily accept third-party algorithms, allowing it to serve as a platform for testing different methods relevant to synthetic biology.

[1]  Raik Grünberg,et al.  BBF RFC 31 : Provisional BioBrick Language ( PoBoL ) , 2009 .

[2]  H. Sauro.  Modularity defined , 2008, Molecular systems biology.

[3]  Herbert M. Sauro,et al.  SBW - A Modular Framework for Systems Biology , 2006, Proceedings of the 2006 Winter Simulation Conference.

[4]  D. Endy.  Foundations for engineering biology , 2005, Nature.

[5]  Drew Endy,et al.  TABASCO: A single molecule, base-pair resolved gene expression simulator , 2007, BMC Bioinformatics.

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

[7]  Sarala M. Wimalaratne,et al.  The Systems Biology Graphical Notation , 2009, Nature Biotechnology.

[8]  Ertugrul M. Ozbudak,et al.  Multistability in the lactose utilization network of Escherichia coli , 2004, Nature.

[9]  Hiroaki Kitano,et al.  CellDesigner: a process diagram editor for gene-regulatory and biochemical networks , 2003 .

[10]  R. Knight,et al.  Accurate taxonomy assignments from 16S rRNA sequences produced by highly parallel pyrosequencers , 2008, Nucleic acids research.

[11]  Vassilios Sotiropoulos,et al.  SynBioSS: the synthetic biology modeling suite , 2008, Bioinform..

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

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

[14]  Raik Grünberg,et al.  Provisional BioBrick Language (PoBoL) , 2009 .

[15]  E. Davidson,et al.  Gene regulatory networks for development. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  Catherine M Lloyd,et al.  CellML: its future, present and past. , 2004, Progress in biophysics and molecular biology.

[17]  H M Sauro,et al.  SCAMP: a general-purpose simulator and metabolic control analysis program , 1993, Comput. Appl. Biosci..

[18]  Matthias Heinemann,et al.  Synthetic biology - putting engineering into biology , 2006, Bioinform..

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

[20]  Andreas Kremling,et al.  Modular Modeling of Cellular Systems with ProMoT/Diva , 2003, Bioinform..

[21]  Jonathan A. Goler.  BioJADE: A Design and Simulation Tool for Synthetic Biological Systems , 2004 .

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

[23]  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.

[24]  Herbert M. Sauro,et al.  Athena: Modular CAM/CAD Software for Synthetic Biology , 2009, WWW 2009.

[25]  Ernst Dieter Gilles,et al.  ProMoT: modular modeling for systems biology , 2009, Bioinform..

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

[27]  Jörg Stelling,et al.  Computational design of synthetic gene circuits with composable parts , 2008, Bioinform..

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

[29]  Richard M. Stallman,et al.  Using the GNU Compiler Collection , 2010 .

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

[31]  Drew Endy,et al.  Measuring the activity of BioBrick promoters using an in vivo reference standard , 2009, Journal of biological engineering.

[32]  Jeff Hasty,et al.  Designer gene networks: Towards fundamental cellular control. , 2001, Chaos.

[33]  Herbert M. Sauro,et al.  Design and implementation of three incoherent feed-forward motif based biological concentration sensors , 2007, Systems and Synthetic Biology.

[34]  M. A. Shea,et al.  The OR control system of bacteriophage lambda. A physical-chemical model for gene regulation. , 1985, Journal of molecular biology.

[35]  Jan-Hendrik S. Hofmeyr,et al.  Modelling cellular systems with PySCeS , 2005, Bioinform..

[36]  Carol S. Woodward,et al.  Enabling New Flexibility in the SUNDIALS Suite of Nonlinear and Differential/Algebraic Equation Solvers , 2020, ACM Trans. Math. Softw..

[37]  Julio Collado-Vides,et al.  RegulonDB (version 6.0): gene regulation model of Escherichia coli K-12 beyond transcription, active (experimental) annotated promoters and Textpresso navigation , 2007, Nucleic Acids Res..

[38]  Mirit I Aladjem,et al.  Circuit diagrams for biological networks , 2006, Molecular systems biology.

[39]  Hiroaki Kitano,et al.  Next generation simulation tools: the Systems Biology Workbench and BioSPICE integration. , 2003, Omics : a journal of integrative biology.

[40]  Jeremy Gunawardena,et al.  Programming with models: modularity and abstraction provide powerful capabilities for systems biology , 2009, Journal of The Royal Society Interface.

[41]  Eric Jones,et al.  SciPy: Open Source Scientific Tools for Python , 2001 .

[42]  Hiroaki Kitano,et al.  The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models , 2003, Bioinform..

[43]  William S. Hlavacek,et al.  BioNetGen: software for rule-based modeling of signal transduction based on the interactions of molecular domains , 2004, Bioinform..

[44]  Herbert M. Sauro.  A Biochemical “NAND” Gate and Assorted Circuits , 1993 .

[45]  Eduardo Sontag,et al.  Modular cell biology: retroactivity and insulation , 2008, Molecular systems biology.

[46]  D. Gillespie.  Exact Stochastic Simulation of Coupled Chemical Reactions , 1977 .

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

[48]  Herbert M. Sauro,et al.  Antimony: a modular model definition language , 2009, Bioinform..