Evolving a lingua franca and associated software infrastructure for computational systems biology: the Systems Biology Markup Language (SBML) project.

Biologists are increasingly recognising that computational modelling is crucial for making sense of the vast quantities of complex experimental data that are now being collected. The systems biology field needs agreed-upon information standards if models are to be shared, evaluated and developed cooperatively. Over the last four years, our team has been developing the Systems Biology Markup Language (SBML) in collaboration with an international community of modellers and software developers. SBML has become a de facto standard format for representing formal, quantitative and qualitative models at the level of biochemical reactions and regulatory networks. In this article, we summarise the current and upcoming versions of SBML and our efforts at developing software infrastructure for supporting and broadening its use. We also provide a brief overview of the many SBML-compatible software tools available today.

[1]  Andreas Kremling,et al.  Application of the process modeling tool PROMOT to the modeling of metabolic networks , 2000 .

[2]  L. Loew,et al.  The Virtual Cell: a software environment for computational cell biology. , 2001, Trends in biotechnology.

[3]  Alison Abbott,et al.  Alliance of US labs plans to build map of cell signalling pathways , 1999, Nature.

[4]  Toni Kazic.  REASONING ABOUT BIOCHEMICAL COMPOUNDS AND PROCESSES , 1993 .

[5]  S. V. Aksenov,et al.  A spatially extended stochastic model of the bacterial chemotaxis signalling pathway. , 2003, Journal of molecular biology.

[6]  Leslie M Loew,et al.  Computational cell biology: spatiotemporal simulation of cellular events. , 2002, Annual review of biophysics and biomolecular structure.

[7]  Jeffrey Augen.  Information technology to the rescue! , 2001, Nature Biotechnology.

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

[9]  James Clark,et al.  XSL Transformations (XSLT) Version 1.0 , 1999 .

[10]  Chris D Cox,et al.  Analysis of noise in quorum sensing. , 2003, Omics : a journal of integrative biology.

[11]  Richard H. Enns,et al.  The Numerical Approach , 2004 .

[12]  Masaru Tomita,et al.  Computational Challenges in Cell Simulation: A Software Engineering Approach , 2002, IEEE Intell. Syst..

[13]  Sylvia Nagl,et al.  MicroCore: Mapping Genome Expression to Cell Pathways and Networks , 2004, Comparative and functional genomics.

[14]  P. Nurse.  A Long Twentieth Century of the Cell Cycle and Beyond , 2000, Cell.

[15]  Masaru Tomita,et al.  The E-CELL project: towards integrative simulation of cellular processes , 2000, RECOMB '00.

[16]  Ivayla Vatcheva,et al.  Case study: data management strategies in an integrated pathway tool , 2004, Applied bioinformatics.

[17]  Ádám M. Halász,et al.  Understanding the Bacterial Stringent Response Using Reachability Analysis of Hybrid Systems , 2004, HSCC.

[18]  Uri M. Ascher,et al.  Computer methods for ordinary differential equations and differential-algebraic equations , 1998 .

[19]  Hidde de Jong,et al.  Modeling and simulation of genetic regulatory systems: a literature review. , 2002, Journal of computational biology : a journal of computational molecular cell biology.

[20]  Naren Ramakrishnan,et al.  Modeling regulatory networks at Virginia Tech. , 2003, Omics : a journal of integrative biology.

[21]  Ravi Iyengar,et al.  Modeling Signaling Networks , 2002, Science.

[22]  Bruce E. Shapiro,et al.  Automatic model generation for signal transduction with applications to MAP-Kinase pathways , 2000 .

[23]  Masaru Tomita,et al.  A multi-algorithm, multi-timescale method for cell simulation , 2004, Bioinform..

[24]  Stephen Wolfram,et al.  The Mathematica Book , 1996 .

[25]  Susumu Goto,et al.  The KEGG databases at GenomeNet , 2002, Nucleic Acids Res..

[26]  L. Loew,et al.  Systems Analysis of Ran Transport , 2002, Science.

[27]  Bruce E. Shapiro,et al.  MathSBML: a package for manipulating SBML-based biological models , 2004, Bioinform..

[28]  Declan Butler,et al.  Are you ready for the revolution? , 2001, Nature.

[29]  David A. Fell,et al.  SCAMP: A metabolic simulator and control analysis program , 1991 .

[30]  J. L. Snoep,et al.  Java Web Simulation (JWS); A Web Based Database of Kinetic Models , 2004, Molecular Biology Reports.

[31]  A. Arkin.  Synthetic cell biology. , 2001, Current opinion in biotechnology.

[32]  I. Goryanin,et al.  Reconstructing whole-cell models , 2001 .

[33]  Suzanne M. Paley,et al.  Integrated pathway/genome databases and their role in drug discovery , 1999 .

[34]  Elizabeth Pennisi,et al.  Tracing Life's Circuitry , 2003, Science.

[35]  C. M. Sperberg-McQueen,et al.  eXtensible Markup Language (XML) 1.0 (Second Edition) , 2000 .

[36]  E. Mjolsness,et al.  Developmental simultations with cellerator , 2001 .

[37]  T. Ideker,et al.  A new approach to decoding life: systems biology. , 2001, Annual review of genomics and human genetics.

[38]  Daniel Hanisch,et al.  ProML - the Protein Markup Language for specification of protein sequences, structures and families , 2002, Silico Biol..

[39]  Hiroaki Kitano,et al.  An Overview of the ERATO Systems Biology Workbench Project , 2001 .

[40]  Herbert M. Sauro,et al.  33 JARNAC: a system for interactive metabolic analysis , 2000 .

[41]  Kathy Chen,et al.  Network dynamics and cell physiology , 2001, Nature Reviews Molecular Cell Biology.

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

[43]  Igor Goryanin,et al.  Mathematical simulation and analysis of cellular metabolism and regulation , 1999, Bioinform..

[44]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[45]  A Finney,et al.  Systems biology markup language: Level 2 and beyond. , 2003, Biochemical Society transactions.

[46]  M. Tomita.  Whole-cell simulation: a grand challenge of the 21st century. , 2001, Trends in biotechnology.

[47]  P Mendes,et al.  Biochemistry by numbers: simulation of biochemical pathways with Gepasi 3. , 1997, Trends in biochemical sciences.

[48]  J. Snoep,et al.  JWS online cellular systems modelling and microbiology. , 2003, Microbiology.

[49]  D. Butler.  Computing 2010: from black holes to biology , 1999, Nature.

[50]  中尾 光輝,et al.  KEGG(Kyoto Encyclopedia of Genes and Genomes)〔和文〕 (特集 ゲノム医学の現在と未来--基礎と臨床) -- (データベース) , 2000 .

[51]  Alberto Policriti,et al.  XS-systems: eXtended S-Systems and Algebraic Differential Automata for Modeling Cellular Behavior , 2002, HiPC.

[52]  Peter J. Ortoleva,et al.  Simulating cellular dynamics through a coupled transcription, translation, metabolic model , 2003, Comput. Biol. Chem..

[53]  J C Schaff,et al.  Physiological modeling with virtual cell framework. , 2000, Methods in enzymology.

[54]  Chris F. Taylor,et al.  A systematic approach to modeling, capturing, and disseminating proteomics experimental data , 2003, Nature Biotechnology.

[55]  Temple F. Smith,et al.  Overview of the Alliance for Cellular Signaling , 2002, Nature.

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

[57]  Vijay Kumar,et al.  Visual Programming for Modeling and Simulation of Biomolecular Regulatory Networks , 2002, HiPC.

[58]  P. Hunter,et al.  Integration from proteins to organs: the Physiome Project , 2003, Nature Reviews Molecular Cell Biology.

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

[60]  Elizabeth Pennisi,et al.  Systems biology. Tracing life's circuitry. , 2003, Science.

[61]  B CHANCE,et al.  Analogue and digital representations of enzyme kinetics. , 1960, The Journal of biological chemistry.

[62]  E. Zerhouni.  The NIH Roadmap , 2003, Science.

[63]  Michael A. Gibson,et al.  Efficient Exact Stochastic Simulation of Chemical Systems with Many Species and Many Channels , 2000 .

[64]  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..

[65]  Jörg Stelling,et al.  Towards a Virtual Biological Laboratory , 2001 .

[66]  Hiroaki Kitano,et al.  The ERATO Systems Biology Workbench: Enabling Interaction and Exchange Between Software Tools for Computational Biology , 2001, Pacific Symposium on Biocomputing.

[67]  Eric H Davidson,et al.  A provisional regulatory gene network for specification of endomesoderm in the sea urchin embryo. , 2002, Developmental biology.

[68]  Yuh-Mei Liao,et al.  The chemical markup language. , 2002, Analytical chemistry.

[69]  Aaron Skonnard,et al.  Essential XML Quick Reference: A Programmer's Reference to XML, XPath, XSLT, XML Schema, SOAP, and More , 2001 .

[70]  Hiroaki Kitano,et al.  The ERATO Systems Biology Workbench: Architectural Evolution , 2001 .

[71]  E. Davidson,et al.  Modeling transcriptional regulatory networks. , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[72]  Robert Triendl.  Computerized role models , 2002, Nature.

[73]  James C. Schaff,et al.  Electrodiffusion of ions inside living cells , 1999 .

[74]  L. Loew,et al.  Quantitative cell biology with the Virtual Cell. , 2003, Trends in cell biology.

[75]  D. Wilkinson,et al.  Towards an e-biology of ageing: integrating theory and data , 2003, Nature Reviews Molecular Cell Biology.

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

[77]  S. Shen-Orr,et al.  Networks Network Motifs : Simple Building Blocks of Complex , 2002 .

[78]  Dennis Bray,et al.  Binding and diffusion of CheR molecules within a cluster of membrane receptors. , 2002, Biophysical journal.

[79]  J. Tyson,et al.  Modeling the control of DNA replication in fission yeast. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[80]  D Garfinkel,et al.  Computer applications to biochemical kinetics. , 1970, Annual review of biochemistry.

[81]  D Normile,et al.  Building Working Cells 'in Silico' , 1999, Science.

[82]  Pedro Mendes,et al.  Artificial gene networks for objective comparison of analysis algorithms , 2003, ECCB.

[83]  Ion I. Moraru,et al.  Morphological Control of Inositol-1,4,5-Trisphosphate–Dependent Signals , 1999, The Journal of cell biology.

[84]  Peter J. Hunter,et al.  An Overview of CellML 1.1, a Biological Model Description Language , 2003, Simul..

[85]  C. M. Sperberg-McQueen,et al.  Extensible Markup Language (XML) , 1997, World Wide Web J..

[86]  Constance Holden.  Alliance Launched to Model E. coli , 2002, Science.

[87]  Masaru Tomita,et al.  E-Cell 2: Multi-platform E-Cell simulation system , 2003, Bioinform..

[88]  Masaru Tomita,et al.  A general computational model of mitochondrial metabolism in a whole organelle scale , 2004, Bioinform..

[89]  H. Kurata,et al.  CADLIVE for constructing a large-scale biochemical network based on a simulation-directed notation and its application to yeast cell cycle. , 2003, Nucleic acids research.

[90]  Melvin K. Simmons,et al.  Hybrid simulation of cellular behavior , 2004, Bioinform..

[91]  Leslie M Loew,et al.  The virtual cell: an integrated modeling environment for experimental and computational cell biology. , 2002, Annals of the New York Academy of Sciences.

[92]  J. Tyson.  Modeling the cell division cycle: cdc2 and cyclin interactions. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[93]  James C. Schaff,et al.  Numerical Approach to Fast Reactions in Reaction-Diffusion Systems , 2000 .

[94]  C. J.,et al.  Predicting Temporal Fluctuations in an Intracellular Signalling Pathway , 1998 .

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

[96]  Clifford A. Shaffer,et al.  Supporting creativity in problem solving environments , 2002, Creativity & Cognition.

[97]  B. Kholodenko,et al.  Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. , 2000, European journal of biochemistry.

[98]  James B. Bassingthwaighte,et al.  Strategies for the Physiome Project , 2000, Annals of Biomedical Engineering.

[99]  Masaru Tomita,et al.  [E-Cell simulation system and its application to the modeling of circadian rhythm]. , 2003, Seikagaku. The Journal of Japanese Biochemical Society.

[100]  Scott E Fraser,et al.  The Molecular Metamorphosis of Experimental Embryology , 2000, Cell.

[101]  Lisa Chong,et al.  Whole-istic Biology , 2002, Science.

[102]  Igor Goryanin,et al.  Simultaneous Modelling of Metabolic, Genetic and Product-interaction Networks , 2001, Briefings Bioinform..

[103]  Eric H Davidson,et al.  New computational approaches for analysis of cis-regulatory networks. , 2002, Developmental biology.

[104]  Douglas B. Kell,et al.  Non-linear optimization of biochemical pathways: applications to metabolic engineering and parameter estimation , 1998, Bioinform..

[105]  J. Hopfield,et al.  From molecular to modular cell biology , 1999, Nature.

[106]  James C. Schaff,et al.  Analysis of nonlinear dynamics on arbitrary geometries with the Virtual Cell. , 2001, Chaos.

[107]  Denis Noble,et al.  The rise of computational biology , 2002, Nature Reviews Molecular Cell Biology.

[108]  Douglas B. Kell,et al.  MEG (Model Extender for Gepasi): a program for the modelling of complex, heterogeneous, cellular systems , 2001, Bioinform..

[109]  Emmanuel Barillot,et al.  XML, bioinformatics and data integration , 2001, Bioinform..

[110]  David C. Fallside,et al.  Xml schema part 0: primer , 2000 .

[111]  G. Church,et al.  Analysis of optimality in natural and perturbed metabolic networks , 2002 .

[112]  Srikanta P Kumar,et al.  BioSPICE: a computational infrastructure for integrative biology. , 2003, Omics : a journal of integrative biology.

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

[114]  Peter D. Karp,et al.  Using functional and organizational information to improve genome-wide computational prediction of transcription units on pathway-genome databases , 2004, Bioinform..

[115]  John Doyle.  Computational biology: Beyond the spherical cow , 2001, Nature.

[116]  Lei Liu,et al.  Virtual Cell: A General Framework for Simulating and Visualizing Cellular Physiology , 1998, VDB.

[117]  W. J. Hedley,et al.  A short introduction to CellML , 2001, Philosophical Transactions of the Royal Society of London. Series A: Mathematical, Physical and Engineering Sciences.

[118]  Denis Noble,et al.  Cellular Open Resource (COR): a Public CellML Based Environment for Modeling Biological Function , 2003, Int. J. Bifurc. Chaos.

[119]  L M Loew,et al.  A general computational framework for modeling cellular structure and function. , 1997, Biophysical journal.

[120]  Hiroaki Kitano,et al.  Foundations of systems biology , 2001 .

[121]  Hiroaki Kitano,et al.  A graphical notation for biochemical networks , 2003 .

[122]  Jason E. Stewart,et al.  Design and implementation of microarray gene expression markup language (MAGE-ML) , 2002, Genome Biology.

[123]  T. Bray,et al.  XML and the Second-Generation WEB , 1999 .

[124]  H. Kitano,et al.  Computational systems biology , 2002, Nature.

[125]  James C. Schaff,et al.  The Virtual Cell , 2002, Annals of the New York Academy of Sciences.

[126]  B. Chance,et al.  The kinetics of the enzyme-substrate compound of peroxidase. 1943. , 1943, Advances in enzymology and related areas of molecular biology.

[127]  A. Arkin,et al.  Biological networks. , 2003, Current opinion in structural biology.

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

[129]  David Fenyö,et al.  The Biopolymer Markup Language , 1999, Bioinform..

[130]  Masaru Tomita,et al.  Integrative modeling of gene expression and metabolism with E-CELL System , 2006, Artificial Life and Robotics.

[131]  E. Minch,et al.  pathSCOUTTM: exploration and analysis of biochemical pathways , 2003, Bioinform..

[132]  C. Sander,et al.  The HUPO PSI's Molecular Interaction format—a community standard for the representation of protein interaction data , 2004, Nature Biotechnology.

[133]  S. Shen-Orr,et al.  Network motifs: simple building blocks of complex networks. , 2002, Science.

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

[135]  Bruce E. Shapiro,et al.  Cellerator: extending a computer algebra system to include biochemical arrows for signal transduction simulations , 2003, Bioinform..

[136]  L. Loew,et al.  An image-based model of calcium waves in differentiated neuroblastoma cells. , 2000, Biophysical journal.

[137]  A. Arkin,et al.  Motifs, modules and games in bacteria. , 2003, Current opinion in microbiology.

[138]  R. Service.  Exploring the Systems of Life , 1999, Science.

[139]  W. Bialek,et al.  Introductory Science and Mathematics Education for 21st-Century Biologists , 2004, Science.

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

[141]  D. Gillespie.  Approximate accelerated stochastic simulation of chemically reacting systems , 2001 .

[142]  N. A. Allen,et al.  Improving the Development Process for Eukaryotic Cell Cycle Models with a Modeling Support Environment , 2003, Proceedings of the 2003 Winter Simulation Conference, 2003..

[143]  Masaru Tomita,et al.  E-CELL: software environment for whole-cell simulation , 1999, Bioinform..

[144]  Yuh-Mei Liao,et al.  AC Webworks: The Chemical Markup Language , 2002 .

[145]  J. Keizer,et al.  A single-pool inositol 1,4,5-trisphosphate-receptor-based model for agonist-stimulated oscillations in Ca2+ concentration. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[146]  E. Mjolsness.  Developmental Simulations with Cellerator , 2001 .

[147]  William S. Hlavacek,et al.  Modeling the early signaling events mediated by FcepsilonRI. , 2002, Molecular immunology.

[148]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[149]  D. Bray,et al.  A free-energy-based stochastic simulation of the Tar receptor complex. , 1999, Journal of molecular biology.

[150]  Hiroaki Kitano,et al.  The ERATO Systems Biology Workbench: An Integrated Environment for Multiscale and Multitheoretic Simulations in Systems Biology , 2001 .

[151]  Jehoshua Bruck,et al.  Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. , 2000, Proceedings of the National Academy of Sciences of the United States of America.