Andrew Finney

The systems biology markup language (SBML) : a medium for representation and exchange of biochemical network models

MOTIVATION Molecular biotechnology now makes it possible to build elaborate systems models, but the systems biology community needs information standards if models are to be shared, evaluated and developed cooperatively. RESULTS We summarize the Systems Biology Markup Language (SBML) Level 1, a free, open, XML-based format for representing biochemical reaction networks. SBML is a software-independent language for describing models common to research in many areas of computational biology, including cell signaling pathways, metabolic pathways, gene regulation, and others. AVAILABILITY The specification of SBML Level 1 is freely available from http://www.sbml.org/

The BioPAX community standard for pathway data sharing

Biological Pathway Exchange (BioPAX) is a standard language to represent biological pathways at the molecular and cellular level and to facilitate the exchange of pathway data. The rapid growth of the volume of pathway data has spurred the development of databases and computational tools to aid interpretation; however, use of these data is hampered by the current fragmentation of pathway information across many databases with incompatible formats. BioPAX, which was created through a community process, solves this problem by making pathway data substantially easier to collect, index, interpret and share. BioPAX can represent metabolic and signaling pathways, molecular and genetic interactions and gene regulation networks. Using BioPAX, millions of interactions, organized into thousands of pathways, from many organisms are available from a growing number of databases. This large amount of pathway data in a computable form will support visualization, analysis and biological discovery.

Controlled vocabularies and semantics in systems biology

The use of computational modeling to describe and analyze biological systems is at the heart of systems biology. Model structures, simulation descriptions and numerical results can be encoded in structured formats, but there is an increasing need to provide an additional semantic layer. Semantic information adds meaning to components of structured descriptions to help identify and interpret them unambiguously. Ontologies are one of the tools frequently used for this purpose. We describe here three ontologies created specifically to address the needs of the systems biology community. The Systems Biology Ontology (SBO) provides semantic information about the model components. The Kinetic Simulation Algorithm Ontology (KiSAO) supplies information about existing algorithms available for the simulation of systems biology models, their characterization and interrelationships. The Terminology for the Description of Dynamics (TEDDY) categorizes dynamical features of the simulation results and general systems behavior. The provision of semantic information extends a models longevity and facilitates its reuse. It provides useful insight into the biology of modeled processes, and may be used to make informed decisions on subsequent simulation experiments.

SBMLToolbox: an SBML toolbox for MATLAB users

SUMMARY We present SBMLToolbox, a toolbox that facilitates importing and exporting models represented in the Systems Biology Markup Language (SBML) in and out of the MATLAB environment and provides functionality that enables an experienced user of either SBML or MATLAB to combine the computing power of MATLAB with the portability and exchangeability of an SBML model. SBMLToolbox supports all levels and versions of SBML. AVAILABILITY SBMLToolbox is freely available from http://sbml.org/software/sbmltoolbox

MathSBML: a package for manipulating SBML-based biological models

UNLABELLED MathSBML is a Mathematica package designed for manipulating Systems Biology Markup Language (SBML) models. It converts SBML models into Mathematica data structures and provides a platform for manipulating and evaluating these models. Once a model is read by MathSBML, it is fully compatible with standard Mathematica functions such as NDSolve (a differential-algebraic equations solver). MathSBML also provides an application programming interface for viewing, manipulating, running numerical simulations; exporting SBML models; and converting SBML models in to other formats, such as XPP, HTML and FORTRAN. By accessing the full breadth of Mathematica functionality, MathSBML is fully extensible to SBML models of any size or complexity. AVAILABILITY Open Source (LGPL) at http://www.sbml.org and http://www.sf.net/projects/sbml

CellML2SBML: conversion of CellML into SBML

UNLABELLED CellML and SBML are XML-based languages for storage and exchange of molecular biological and physiological reaction models. They use very similar subsets of MathML to specify the mathematical aspects of the models. CellML2SBML is implemented as a suite of XSLT stylesheets that, when applied consecutively, convert models expressed in CellML into SBML without significant loss of information. The converter is based on the most recent stable versions of the languages (CellML version 1.1; SBML Level 2 Version 1), and the XSLT used in the stylesheets adheres to the XSLT version 1.0 specification. Of all 306 models in the CellML repository in April 2005, CellML2SBML converted 91% automatically into SBML. Minor manual changes to the unit definitions in the originals raised the percentage of successful conversions to 96%. AVAILABILITY http://sbml.org/software/cellml2sbml/. SUPPLEMENTARY INFORMATION Instructions for use and further documentation available on http://sbml.org/software/cellml2sbml/

Escalating model sizes and complexities call for standardized forms of representation

The recent work of Kitano et al on a comprehensive EGFR Pathway Map (Mol Systems Biol, this issue) represents a tremendous amount of intellectual effort. The scale of the model is breathtaking. No doubt some readers will assail the effort on the grounds that models of this size and complexity are difficult to verify, but while this may be true for today’s methods, it is an unhelpful criticism. The inescapable reality in systems biology is that models (that is to say, hypotheses cast in a computational form) will continue to grow in size, complexity, and scope. Rather than grouse, we should be thinking about how to developways of analyzing and verifying models of this scale. We also need to improve our methods of sharing and understanding each other’s work in order to facilitate the iterative processes of review and refinement that are fundamental to modeling.

Developing SBML beyond level 2: proposals for development

The Systems Biology Markup Language (SBML) is an XML-based exchange format for computational models of biochemical networks. SBML Level 2, whose definition was established in June 2003, includes several enhancements to the original Level 1. This paper includes a brief overview of Level 2. Several proposals are under development to extend SBML to create Level 3. These include diagrams, 2-D and 3-D spatial characteristics, arrays, model composition and multi-component chemical species. This paper describes the current proposals for the last two features.

SBML Level 3 package: Hierarchical Model Composition, Version 1 Release 3.

Summary Constructing a model in a hierarchical fashion is a natural approach to managing model complexity, and offers additional opportunities such as the potential to re-use model components. The SBML Level 3 Version 1 Core specification does not directly provide a mechanism for defining hierarchical models, but it does provide a mechanism for SBML packages to extend the Core specification and add additional syntactical constructs. The SBML Hierarchical Model Composition package for SBML Level 3 adds the necessary features to SBML to support hierarchical modeling. The package enables a modeler to include submodels within an enclosing SBML model, delete unneeded or redundant elements of that submodel, replace elements of that submodel with element of the containing model, and replace elements of the containing model with elements of the submodel. In addition, the package defines an optional “port” construct, allowing a model to be defined with suggested interfaces between hierarchical components; modelers can chose to use these interfaces, but they are not required to do so and can still interact directly with model elements if they so chose. Finally, the SBML Hierarchical Model Composition package is defined in such a way that a hierarchical model can be “flattened” to an equivalent, non-hierarchical version that uses only plain SBML constructs, thus enabling software tools that do not yet support hierarchy to nevertheless work with SBML hierarchical models.

The BioPAX community standard for pathway data sharing (Nature Biotechnology (2010) 28, (935-942))

BioPAX (Biological Pathway Exchange) is a standard language to represent biological pathways at the molecular and cellular level. Its major use is to facilitate the exchange of pathway data (http://www.biopax.org). Pathway data captures our understanding of biological processes, but its rapid growth necessitates development of databases and computational tools to aid interpretation. However, the current fragmentation of pathway information across many databases with incompatible formats presents barriers to its effective use. BioPAX solves this problem by making pathway data substantially easier to collect, index, interpret and share. BioPAX can represent metabolic and signaling pathways, molecular and genetic interactions and gene regulation networks. BioPAX was created through a community process. Through BioPAX, millions of interactions organized into thousands of pathways across many organisms, from a growing number of sources, are available. Thus, large amounts of pathway data are available in a computable form to support visualization, analysis and biological discovery.