Graphical Modeling Tools for Systems Biology

Modeling biological systems to understand their mechanistic behavior is an important activity in molecular systems biology. Mathematical modeling typically requires deep mathematical or computing knowledge, and this limits the spread of modeling tools among biologists. Graphical modeling languages have been introduced to minimize this limit. Here, we survey the main graphical formalisms (supported by software tools) available to model biological systems with a primary focus on their usability, within the framework of modeling reaction pathways with two-dimensional (2D) (possibly nested) compartments. Considering the main characteristics of the surveyed formalisms, we synthesise a new proposal (Style) and report the results of an online survey conducted among biologists to assess usability of available graphical formalisms. We consider this proposal a guideline developed from what we learned in the survey, which can inform development of graphical formalisms to model reaction pathways in 2D space.

[1]  David Zhang,et al.  SimBoolNet—a Cytoscape plugin for dynamic simulation of signaling networks , 2009, Bioinform..

[2]  Chris J. Myers,et al.  Tablet—next generation sequence assembly visualization , 2009, Bioinform..

[3]  Corrado Priami,et al.  Application of a stochastic name-passing calculus to representation and simulation of molecular processes , 2001, Inf. Process. Lett..

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

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

[6]  Adam Duguid,et al.  The Bio-PEPA Tool Suite , 2009, 2009 Sixth International Conference on the Quantitative Evaluation of Systems.

[7]  Jeremy Gunawardena,et al.  Modular model building , 2007, 0710.3421.

[8]  Samuil Angelov,et al.  Petri Net Technology for Communication-Based Systems , 2003, Lecture Notes in Computer Science.

[9]  Benjamin B. Bederson,et al.  A review of overview+detail, zooming, and focus+context interfaces , 2009, CSUR.

[10]  Vahid Shahrezaei,et al.  Scalable Rule-Based Modelling of Allosteric Proteins and Biochemical Networks , 2010, PLoS Comput. Biol..

[11]  Mudita Singhal,et al.  COPASI - a COmplex PAthway SImulator , 2006, Bioinform..

[12]  Peter Dittrich,et al.  Using the SRSim Software for Spatial and Rule-Based Modeling of Combinatorially Complex Biochemical Reaction Systems , 2010, Int. Conf. on Membrane Computing.

[13]  Salvatore Paxia,et al.  Simpathica: A Computational Systems Biology Tool Within the Valis Bioinformatics Environment , 2006 .

[14]  Corrado Priami,et al.  The Beta Workbench: a computational tool to study the dynamics of biological systems , 2008, Briefings Bioinform..

[15]  Tian Jin,et al.  Key Role of Local Regulation in Chemosensing Revealed by a New Molecular Interaction-Based Modeling Method , 2006, PLoS Comput. Biol..

[16]  Kentaro Inoue,et al.  Extended CADLIVE: a novel graphical notation for design of biochemical network maps and computational pathway analysis , 2007, Nucleic acids research.

[17]  Jonathan R. Karr,et al.  A Whole-Cell Computational Model Predicts Phenotype from Genotype , 2012, Cell.

[18]  Petra Himmel,et al.  Cells Building Blocks Of Life , 2016 .

[19]  Pedro Mendes,et al.  GEPASI: a software package for modelling the dynamics, steady states and control of biochemical and other systems , 1993, Comput. Appl. Biosci..

[20]  Peter Sorger,et al.  New approaches to modeling complex biochemistry , 2011, Nature Methods.

[21]  Roger Brent,et al.  Detailed Simulations of Cell Biology with Smoldyn 2.1 , 2010, PLoS Comput. Biol..

[22]  John A. Miller,et al.  The JSIM web-based simulation environment , 2000, Future Gener. Comput. Syst..

[23]  Andrzej M. Kierzek,et al.  STOCKS: STOChastic Kinetic Simulations of biochemical systems with Gillespie algorithm , 2002, Bioinform..

[24]  William S. Hlavacek,et al.  Simulation of large-scale rule-based models , 2009, Bioinform..

[25]  Andre S. Ribeiro,et al.  CellLine, a stochastic cell lineage simulator , 2007, Bioinform..

[26]  Sang Yup Lee,et al.  WebCell: a web-based environment for kinetic modeling and dynamic simulation of cellular networks , 2006, Bioinform..

[27]  Junbin Gao,et al.  A new algorithm for removing node overlapping in graph visualization , 2007, Inf. Sci..

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

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

[30]  Christopher R. Myers,et al.  Python Unleashed on Systems Biology , 2007, Computing in Science & Engineering.

[31]  William J. Bosl,et al.  Systems biology by the rules: hybrid intelligent systems for pathway modeling and discovery , 2007, BMC Systems Biology.

[32]  J C Schaff,et al.  Virtual Cell modelling and simulation software environment. , 2008, IET systems biology.

[33]  Patrick Lincoln,et al.  BioSPICE: access to the most current computational tools for biologists. , 2003, Omics : a journal of integrative biology.

[34]  H. Kitano.  Systems Biology: A Brief Overview , 2002, Science.

[35]  Ernst Dieter Gilles,et al.  ALC: automated reduction of rule-based models , 2008, BMC Systems Biology.

[36]  Gabriele Neyer.  Map Labeling with Application to Graph Drawing , 1999, Drawing Graphs.

[37]  William J R Longabaugh,et al.  BioTapestry: a tool to visualize the dynamic properties of gene regulatory networks. , 2012, Methods in molecular biology.

[38]  Nicolas Le Novère,et al.  STOCHSIM: modelling of stochastic biomolecular processes , 2001, Bioinform..

[39]  Chris North,et al.  Visualizing Biological Pathways: Requirements Analysis, Systems Evaluation and Research Agenda , 2005, Inf. Vis..

[40]  Clifford A. Shaffer,et al.  The JigCell Model Builder: a spreadsheet interface for creating biochemical reaction network models , 2006, IEEE/ACM Transactions on Computational Biology and Bioinformatics.

[41]  Chrystopher L. Nehaniv,et al.  The NetBuilder' project: development of a tool for constructing, simulating, evolving, and analysing complex regulatory networks , 2007, BMC Systems Biology.

[42]  Ben van Ommen,et al.  Transcriptomic Coordination in the Human Metabolic Network Reveals Links between n-3 Fat Intake, Adipose Tissue Gene Expression and Metabolic Health , 2011, PLoS Comput. Biol..

[43]  Ayellet Tal,et al.  Dynamic Drawing of Clustered Graphs , 2004, IEEE Symposium on Information Visualization.

[44]  Fabian J. Theis,et al.  Odefy -- From discrete to continuous models , 2010, BMC Bioinformatics.

[45]  Hans A. Kestler,et al.  BoolNet - an R package for generation, reconstruction and analysis of Boolean networks , 2010, Bioinform..

[46]  Ravi Iyengar,et al.  Decoding Information in Cell Shape , 2013, Cell.

[47]  Carlos F. Lopez,et al.  Programming biological models in Python using PySB , 2013, Molecular systems biology.

[48]  M. Pastor,et al.  Molecular modeling and simulation of membrane lipid-mediated effects on GPCRs. , 2012, Current medicinal chemistry.

[49]  Sb Ras,et al.  BioUML: VISUAL MODELING, AUTOMATED CODE GENERATION AND SIMULATION OF BIOLOGICAL SYSTEMS , 2006 .

[50]  David A. Carrington,et al.  User Preference of Graph Layout Aesthetics: A UML Study , 2000, GD.

[51]  B. Palsson,et al.  The evolution of molecular biology into systems biology , 2004, Nature Biotechnology.

[52]  Thiab R. Taha,et al.  KINSOLVER: A simulator for computing large ensembles of biochemical and gene regulatory networks , 2009, Comput. Math. Appl..

[53]  Nail M. Gizzatkulov,et al.  DBSolve Optimum: a software package for kinetic modeling which allows dynamic visualization of simulation results , 2010, BMC Systems Biology.

[54]  Jill D. Wright,et al.  Cells : Building Blocks of Life , 1994 .

[55]  Subhasis Ray,et al.  Multiscale modeling and interoperability in MOOSE , 2009, BMC Neuroscience.

[56]  N. Kikuchi,et al.  CellDesigner 3.5: A Versatile Modeling Tool for Biochemical Networks , 2008, Proceedings of the IEEE.

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

[58]  Andrew J. Millar,et al.  Robustness from flexibility in the fungal circadian clock , 2010, BMC Systems Biology.

[59]  D. Bray,et al.  Computer simulation of the phosphorylation cascade controlling bacterial chemotaxis. , 1993, Molecular biology of the cell.

[60]  Caroline C. Friedel,et al.  FERN – a Java framework for stochastic simulation and evaluation of reaction networks , 2008, BMC Bioinformatics.

[61]  Francine Berman,et al.  Distributing MCell Simulations on the Grid , 2001, Int. J. High Perform. Comput. Appl..

[62]  Corrado Priami,et al.  Algorithmic systems biology , 2009, CACM.

[63]  B. Alberts,et al.  Molecular Biology of the Cell (Fifth Edition) , 2008 .

[64]  Andre S. Ribeiro,et al.  SGN Sim, a Stochastic Genetic Networks Simulator , 2007, Bioinform..

[65]  共立出版株式会社.  コンピュータ・サイエンス : ACM computing surveys , 1978 .

[66]  김삼묘,et al.  “Bioinformatics” 특집을 내면서 , 2000 .

[67]  Hao Zhu,et al.  Cellware-a multi-algorithmic software for computational systems biology , 2004, Bioinform..

[68]  B. Kholodenko.  Cell-signalling dynamics in time and space , 2006, Nature Reviews Molecular Cell Biology.

[69]  Hamid Bolouri,et al.  Dizzy: Stochastic Simulation of Large-scale Genetic Regulatory Networks , 2005, J. Bioinform. Comput. Biol..

[70]  Rudolf Fleischer,et al.  Graph Drawing and Its Applications , 1999, Drawing Graphs.

[71]  Yao Sun,et al.  RuleBender: integrated modeling, simulation and visualization for rule-based intracellular biochemistry , 2012, BMC Bioinformatics.

[72]  Andrew Phillips,et al.  A Visual Process Calculus for Biology , 2009 .

[73]  Ekkart Kindler,et al.  The Petri Net Kernel , 2003, Petri Net Technology for Communication-Based Systems.

[74]  Robert Clewley,et al.  Hybrid Models and Biological Model Reduction with PyDSTool , 2012, PLoS Comput. Biol..

[75]  Jacky L. Snoep,et al.  Web-based kinetic modelling using JWS Online , 2004, Bioinform..