3. CellDesigner

CellDesigner is a structured diagram editor for drawing gene-regulatory and biochemical networks (8). Networks are drawn based on the process diagram, the graphical notation system described above, and are stored using the Systems Biology Markup Language (SBML), a standard for representing models of biochemical and gene-regulatory networks (9). Networks are able to link with simulation and other analysis packages through Systems Biology Workbench (SBW) (10). CellDesigner can be downloaded from http://www.systems-biology.org/ or corresponding links from the AfCS/Nature Signaling Gateway.

The aim of CellDesigner is to supply a process diagram editor with standardized technology for every computing platform so that it benefits as many users as possible. By using standardized technology, the model can be easily used with other applications, thereby reducing the need for users to create a specific model for each editing, simulation, or analysis task. The main standardized features that CellDesigner supports are in "graphical　notation," "model description," and "application integration environment." The standard for graphical notation shown in Fig. 4 and Fig. 5 plays an important role for efficient and accurate dissemination of knowledge (7), and the standard for model description will enhance the portability of models between software tools. Similarly, the standard for application integration environment will help software developers provide the ability for their applications to communicate with other tools.

Even if the proposed notation system satisfies the requirements of biologists, lack of software support will drastically decrease its advantages. CellDesigner supports a process diagram, and extension to include the other form of diagram, a block diagram, is now experimentally implemented. CellDesigner provides a user-friendly interface to organize information of biological networks (Fig. 6).

Fig. 6. Screenshot of CellDesigner.

CellDesigner enables models of biological networks for further analyses. There are two aspects that are essential: (1) a machine-readable standard model representation and (2) a seamless link with analysis software. CellDesigner is an SBML-compliant application, which means that it supports SBML reading and writing capabilities. SBML is the standard model definition language in the systems biology field; it is now used by the BASIS Project (http://www.basis.ncl.ac.uk/technology.html), the DARPA BioSPICE project (http://www.biospice.org), and the International E. coli Alliance. CellDesigner can read all SBML Level-1 documents, so users can use existing SBML models such as the KEGG database. We have already converted more than 12,000 metabolic pathways of KEGG to SBML (available from http://www.systems-biology.org/). Other SBML models are available from the SBML model repository (http://sbml.org/models/). The compliance of CellDesigner to SBML enables researchers to store models and use them for analyses by other SBML-compliant applications.

CellDesigner is also an SBW-enabled application. With SBW installed, CellDesigner can integrate with all SBW-enabled modules (Fig. 7). For example, users can browse or modify a model converted from an existing database with CellDesigner and launch a simulator from CellDesigner (by selecting “Simulation Service” from the SBW menu) to run simulations in real time. There are many other SBW-enabled modules, such as ODE-based simulator, stochastic simulator, MatLab translator, bifurcation analysis tool, and optimization module. These SBW-enabled modules are freely available from http://www.sbw-sbml.org/. Using these capabilities, CellDesigner enables researchers to carry out a range of analyses on biological networks, including parameter optimization based on experimental data and dynamical simulations.

Fig. 7. Illustration of the relationship between SBW Broker and SBW modules.

CellDesigner functions as an information organizer. For each molecule and interaction, notes and links can be added to store legacy data relevant to that molecule and interaction, as well as being linked to genome and proteome databases. While the current release of the macrophage map does not include stored legacy information for each molecule and interaction, future versions may include such information. In addition, links to AfCS Molecule Pages can be added to a note, which enables CellDesigner to function as an efficient interface to AfCS resources.

There are limitations in the current version of CellDesigner 2.0. First, representation of complexes and receptor substructures are too simplified. Second, transcription and translation processes are too simplified. However, these shortcomings, as well as other issues not mentioned, will be improved in future versions of the software. One of the major issues for future development of CellDesigner is possible implementation of community-ware that enables correction, updates, and insertion of additional information, so that community-based refinement can be accomplished. Such software is not only consistent with the philosophy behind the AfCS but also may explore novel and practical approaches to creating and maintaining large-scale network models of biological systems.