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In the context of SBML, “hierarchical model composition” refers to the ability to include models as submodels inside another model. The goal is to support the ability of modelers and software tools to do such things as (1) decompose larger models into smaller ones, as a way to manage complexity; (2) incorporate multiple instances of a given model within one or more enclosing models, to avoid literal duplication of repeated elements; and (3) create libraries of reusable, tested models, much as is done in software development and other engineering fields. SBML Level 3 Version 1 Core (Hucka et al., 2010), by itself, has no direct support for allowing a model to include other models as submodels. Software tools either have to implement their own schemes outside of SBML, or (in principle) could use annotations to augment a plain SBML Level 3 model with the necessary information to allow a software tool to compose a model out of submodels. However, such solutions would be proprietary and tool-specific, and not conducive to interoperability. There is a clear need for an official SBML language facility for hierarchical model composition. This document describes a specification for an SBML Level 3 package that provides exactly such a facility.

Reproducibility of experiments is a basic requirement for science. Minimum Information (MI) guidelines have proved a helpful means of enabling reuse of existing work in modern biology. The Minimum Information Required in the Annotation of Models (MIRIAM) guidelines promote the exchange and reuse of biochemical computational models. However, information about a model alone is not sufficient to enable its efficient reuse in a computational setting. Advanced numerical algorithms and complex modeling workflows used in modern computational biology make reproduction of simulations difficult. It is therefore essential to define the core information necessary to perform simulations of those models. The Minimum Information About a Simulation Experiment (MIASE, Glossary in Box 1) describes the minimal set of information that must be provided to make the description of a simulation experiment available to others. It includes the list of models to use and their modifications, all the simulation procedures to apply and in which order, the processing of the raw numerical results, and the description of the final output. MIASE allows for the reproduction of any simulation experiment. The provision of this information, along with a set of required models, guarantees that the simulation experiment represents the intention of the original authors. Following MIASE guidelines will thus improve the quality of scientific reporting, and will also allow collaborative, more distributed efforts in computational modeling and simulation of biological processes.

Computational systems biologists today have a healthy selection of software resources to help them do research. Many software packages, especially those concerned with computational modeling, have adopted SBML (the Systems Biology Markup Language) as a machine-readable format to permit users to exchange models. Our group has a keen interest in understanding the landscape of SBML support. To help us ascertain the state of modern SBML-compatible software, in mid-2011 we initiated a survey of software packages that support SBML. Here we report the preliminary survey results. Based on 81 packages for which we have data so far, we summarize the trends in six areas: (1) What are the major types of functionality offered by the software systems? (2) What mathematical frameworks do they support? (3) What are their SBML-specific capabilities? (4) What other standards do they support besides SBML? (5) What are their characteristics with respect to run-time environments? And finally, (6) what are the availability and licensing terms?

In the context of SBML, “hierarchical model composition” refers to the ability to include models as submodels inside another model. The goal is to support the ability of modelers and software tools to do such things as (1) decompose larger models into smaller ones, as a way to manage complexity; (2) incorporate multiple instances of a given model within one or more enclosing models, to avoid literal duplication of repeated elements; and (3) create libraries of reusable, tested models, much as is done in software development and other engineering fields.

This document defines Version 1 of the Systems Biology Markup Language (SBML) Level 3 Core, an electronic model representation format for systems biology. SBML is oriented towards describing biological processes of the sort common in research on a number of topics, including metabolic pathways, cell signaling pathways, and many others. SBML is defined neutrally with respect to programming languages and software encoding; however, it is oriented primarily towards allowing models to be encoded using XML, the eXtensible Markup Language (Bray et al., 2004). This document contains many examples of SBML models written in XML. Formal schemas describing the syntax of SBML, as well as other materials and software, are available from the SBML project web site, http://sbml.org/. The SBML project is not an attempt to define a universal language for representing quantitative models. The rapidly evolving views of biological function, coupled with the vigorous rates at which new computational techniques and individual tools are being developed today, are incompatible with a one-size-fits-all idea of a universal language. A more realistic alternative is to acknowledge the diversity of approaches and methods being explored by different software tool developers, and seek a common intermediate format—a lingua franca—enabling communication of the most essential aspects of the models. The definition of the model description language presented here does not specify how programs should communicate or read/write SBML. We assume that for a simulation program to communicate a model encoded in SBML, the program will have to translate its internal data structures to and from SBML, use a suitable transmission medium and protocol, etc., but these issues are outside the scope of this document.

Computational modeling in biology requires sophisticated software tools. Precise communication and effective sharing of the models developed by researchers requires standard formats for storing, annotating, and exchanging models between software systems. Developing such standards is the driving vision behind the Systems Biology Markup Language (SBML) and several related efforts that we discuss in this chapter. At the same time, such standards are only enablers and ideally should be hidden “under the hood” of modeling environments that provide users with high-level, flexible facilities for working with computational models. As an example of the modern software systems available today, we discuss the Virtual Cell and illustrate its support for typical modeling activities in biology.

MathSBML is an open-source, freely-downloadable Mathematica package that facilitates working with Systems Biology Markup Language (SBML) models. SBML is a tool-neutral, computer-readable format for representing models of biochemical reaction networks, applicable to metabolic networks, cell-signaling pathways, genomic regulatory networks, and other modeling problems in systems biology that is widely supported by the systems biology community. SBML is based on XML, a standard medium for representing and transporting data that is widely supported on the internet as well as in computational biology and bioinformatics. Because SBML is tool-independent, it enables model transportability, reuse, publication and survival. In addition to MathSBML, a number of other tools that support SBML model examination and manipulation are provided on the sbml.org website, including libSBML, a C/C++ library for reading SBML models; an SBML Toolbox for MatLab; file conversion programs; an SBML model validator and visualizer; and SBML specifications and schemas. MathSBML enables SBML file import to and export from Mathematica as well as providing an API for model manipulation and simulation.

The objective of the research is to develop mathematical and software infrastructure in support of post-genomics research in systems biology. One objective articulated in this effort centers on a deeper understanding of the organizational principles of biological networks. A distinguishing theme of this work is its focus on scalable methods of robustness and model validation and invalidation with data, as opposed to relying purely on simulation. The Systems Biology Markup Language (SBML) project is a machine-readable exchange language for computational models of biochemical networks. LibSBML, an embedded software library for SBML, was developed, providing an application programming interface for working with SBML. The LibSBML library provides an interface for working with SBML in a number of programming languages: C, C++, Java, Perl, MATLAB, Lisp, and Python. It is free, open-source, and portable to Linux, Windows, MacOS and Solaris. The effort led to (1) continued development of LibSBML, (increased support of SBML features and added functionality); and (2) supported SBML use and evolution (direct support for DARPA Bio-SPICE)., Sponsored in part by Defense Advanced Research Projects Agency (DARPA).

This paper reports progress in extending the Soar architecture to tasks that involve interaction with external environments. The tasks are performed using a Puma arm and a camera in a system called Robo-Soar. The tasks require the integration of a variety of capabilities including problem solving with incomplete knowledge, reactivity, planning, guidance from external advice, and learning to improve the efficiency and correctness of problem solving. All of these capabilities are achieved without the addition of special purpose modules or subsystems to Soar.

Until recently, the majority of computational models in biology were implemented in custom programs and published as statements of the underlying mathematics. However, to be useful as formal embodiments of our understanding of biological systems, computational models must be put into a consistent form that can be communicated more directly between the software tools used to work with them. In this chapter, we describe the Systems Biology Markup Language (SBML), a format for representing models in a way that can be used by different software systems to communicate and exchange those models. By supporting SBML as an input and output format, different software tools can all operate on an identical representation of a model, removing opportunities for errors in translation and assuring a common starting point for analyses and simulations. We also take this opportunity to discuss some of the resources available for working with SBML as well as ongoing efforts in SBML’s continuing evolution.

Systems Biology is aimed at analyzing the behavior and interrelationships of biological systems and is characterized by combining experimentation, theory, and computation. Dedicated to exploring current challenges, the panel brings together people from a variety of disciplines whose perspectives illuminate diverse facets of Systems Biology and the challenges for modeling and simulation methods.

We present the Systems Biology Markup Language (SBML) SBML Level 2 Version 2, a model representation formalism for systems biology. SBML is oriented towards describing systems of biochemical reactions of the sort common in research on a number of topics, including cell signaling pathways, metabolic pathways, biochemical reactions, gene regulation, and many others. SBML is defined in a neutral fashion with respect to programming languages and software encoding; however, it is primarily oriented towards allowing models to be encoded using XML, the eXtensible Markup Language (Bosak and Bray, 1999; Bray et al., 2000). This document contains many examples of SBML models written in XML, as well as the text of an XML Schema (Biron and Malhotra, 2000; Fallside, 2000; Thompson et al., 2000) that defines SBML Level 2 Version 2. A downloadable copy of the XML Schema and other related documents and software are also available from the SBML project web site, http://sbml.org/. The SBML project is not an attempt to define a universal language for representing quantitative models. The rapidly evolving views of biological function, coupled with the vigorous rates at which new computational techniques and individual tools are being developed today, are incompatible with a one-size-fits-all idea of a universal language. A more realistic alternative is to acknowledge the diversity of approaches and methods being explored by different software tool developers, and seek a common intermediate format—a lingua franca—enabling communication of the most essential aspects of the models. The definition of the model description language presented here does not specify how programs should communicate or read/write SBML. We assume that for a simulation program to communicate a model encoded in SBML, the program will have to translate its internal data structures to and from SBML, use a suitable transmission medium and protocol, etc., but these issues are outside of the scope of this document.

Escherichia coli K-12 is an ideal test bed for pushing forward the limits of our ability to understand cellular systems through computational modeling. A complete understanding will require arrays of mathematical models, a wealth of data from measurements of various life processes, and readily accessible databases that can be interrogated for testing our understanding. Accomplishing this will require improved approaches for mathematical modeling, unprecedented standardization for experimentation and data collection, completeness of data sets, and improved methods of accessing and linking information. Solving the whole cell problem, even for a simple E. coli model cell, will require the concerted efforts of many scientists with different expertise. In this chapter, we review advances in (i) computing for modeling cells, (ii) creating a common language for representing computational models (the Systems Biology Markup Language), and (iii) developing the International E. coli Alliance, which has been created to tackle the whole cell problem.

GENESIS (the GEneral NEural Simulation System) was developed as a research tool to provide a standard and flexible means for constructing structurally realistic models of biological neural systems. "Structurally realistic" simulations are computer-based implementations of models whose primary objective is to capture what is known of the anatomical structure and physiological characteristics of the neural system of interest. The GENESIS project is based on the belief that progress in understanding structure-function relationships in the nervous system specifically, or in biology in general, will increasingly require the development and use of structurally realistic models (Bower, 1995). It is our view that only through this type of modeling will general principles of neural or biological function emerge.

A realistic neuronal model represents a modeler's understanding of the structure and function of a part of the nervous system. The increasing number of such models represents a significant accumulation of knowledge about the structural and functional organization of nervous systems. However, locating appropriate models and interpreting them becomes increasingly more difficult as the number of online model and experimental databases grows. The central motivation for the Modeler's Workspace project is to address these problems. The Modeler's Workspace is a collection of software tools being created to enable users to interact with databases of models and data. It will provide facilities for: searching multiple remote databases for model components based on various criteria; visualizing the characteristics of the components retrieved; creating new components, either from scratch or derived from existing models; combining components into new models; linking models to experimental data as well as online publications; and interacting with simulation packages such as GENESIS to simulate the new constructs. It is being written in Java for portability and extensibility. It is modular in design and uses pluggable components. To increase the probability that the Modeler's Workspace will be compatible with future databases and tools, we arc using the XML, the eXtensible Markup Language, as the interchange format for communicating with databases.

Researchers in computational biology today make use of a large number of different software packages for modeling, analysis, and data manipulation and visualization. In this paper, we describe the ERATO Systems Biology Workbench (SBW), a software framework that allows these heterogeneous application components--written in diverse programming languages and running on different platforms--to communicate and use each others' data and algorithmic capabilities. Our goal is to create a simple, open-source software infrastructure which is effective, easy to implement and easy to understand. SBW uses a broker-based architecture and enables applications (potentially running on separate, distributed computers) to communicate via a simple network protocol. The interfaces to the system are encapsulated in client-side libraries that we provide for different programming languages. We describe the SBW architecture and the current set of modules, as well as alternative implementation technologies.

The goal of the ERATO Systems Biology Workbench (SBW) project is to create an integrated, easy-to-use software environment that enables sharing of resources for systems biology. Our initial focus is on achieving interoperability between 7 existing simulators. Our long-term goal is to develop a flexible and adaptable environment that provides the ability to interact with a wide variety of software tools applicable to the systems biology field including databases and experimental devices. We place high value on ease of use and ease of extensibility as important qualities of software for use in biological investigations. The software products of this project will be open source, and portable to Windows and Linux. The Systems Biology Workbench is a vehicle for collaboration between developers of bioinformatics technology. We are actively seeking other collaborators to extend the workbench. The motivation is to reduce the time spent by developers both creating software infrastructure and creating tools that exist in a similar form in other packages, allowing developers to concentrate on new algorithm and model development.

Systems biology researchers make use of a large number of different software packages for computational modeling and analysis as well as data manipulation and visualization. To help developers easily provide the ability for their applications to communicate with other tools, we have developed a simple, open-source, application integration framework, the ERATO Systems Biology Workbench (SBW). In this paper, we discuss the architecture of SBW, focusing on our motivations for various design decisions including the choice of the message-oriented communications infrastructure.

Over the years, a variety of biochemical network modeling packages have been developed and used by researchers in biology. No single package currently answers all the needs of the biology community; nor is one likely to do so in the near future, because the range of tools needed is vast and new techniques are emerging too rapidly. It seems unavoidable that, for the foreseeable future, systems biology researchers are likely to continue using multiple packages to carry out their work. In this chapter, we describe the ERATO Systems Biology Workbench (SBW) and the Systems Biology Markup Language (SBML), two related efforts directed at the problems of software package interoperability. The goal of the SBW project is to create an integrated, easy-to-use software environment that enables sharing of models and resources between simulation and analysis tools for systems biology. SBW uses a modular, plug-in architecture that permits easy introduction of new components. SBML is a proposed standard XML-based language for representing models communicated between software packages; it is used as the format of models communicated between components in SBW.