Cell Illustrator Online 4.0: A Platform for Systems Biology Masao Nagasaki Kazuko Ueno Emi Ikeda masao@ims.u-tokyo.ac.jp uepi@ims.ims.u-tokyo.ac.jp e-ikeda@ims.u-tokyo.ac.jp Chen Li Kaname Kojima Ayumu Saito chenli@ims.u-tokyo.ac.jp kaname@ims.u-tokyo.ac.jp s-ayumu@ims.u-tokyo.ac.jp

Satoru Miyano miyano@ims.u-tokyo.ac.jp

Human Genome Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

Keywords: biological pathway, simulation, Petri net, CSML, pathway modeling, ontology, Java 1 Introduction In this post-genome era, the system level understanding of life is one of the most important issues in Bioinformatics and Systems Biology. Cell Illustrator [1] is one of the platforms for modeling biological and simulating pathways, and is specially tailored for use by wet lab biologists. The project was launched in 1999 and this year marks the 10-year anniversary of Cell Illustrator. In the last eight years, many novel computational technologies and tools were proposed and developed in the field of computer science. Amongst them, useful key technologies like Java Web Start were either directly incorporated, or customized to fit into our platform. Simultaneously, various algorithms, formats and their tools related with pathway modeling and simulation, e.g. Cell System Markup Language and Cell System Ontology [2], were developed in the research field and also integrated into Cell Illustrator. In this demonstration, we describe the new features included in the latest online version of Cell Illustrator, Cell Illustrator Online (CIO) 4.0. 2 The Features of CIO 2.1 Automatic Graph Layout Along with the progress of Systems Biology, the demand for creating larger pathway models and importing other XML formats containing no layout information is increasing. To address these demands, the automatic layout functionality was born. We developed new grid-based layout algorithms, e.g. BLK, CB, SCCB and Grid Eades. These grid layout algorithms search for suitable positions of the components on the digitized grid points. With the feature of grid layout algorithms, even cellular location information having complicated shapes such as being torus-shaped can be handled naturally, as shown in Figure 1 (a). 2.2 Cell System Ontology and Standard Icons For the native XML format of CIO 4.0, CSML 3.0 is used, which is designed based on Cell System Ontology (CSO) 3.0. CSO allows ontology-based representation of signal transduction pathway, gene regulatory network, metabolic pathway, cell-cell interactions with kinetics and graphical information. Formally, the schema is defined by using Web Ontology Language (OWL). The major features of CSO are (i) CSO3.0 can be applied to a pathway model both with or without simulation. (ii) the core vocabularies essential for designing biopathways are prepared in CSO3.0 as entities, processes and cellular locations (entities: 92; processes: 275; cell components: 114) and all those vocabularies are equipped as standard icons.

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2.3 CSML 3.0 and Import from and Export to Other Formats Developed and optimized from XML, CSML 3.0 was created specifically to model and simulate biological pathways. The major features are (i) CSML3.0 has a full compatibility with the pathway modeling and simulation ontology format Cell System Ontology 3.0 (CSO). With this feature, it is possible to exchange information with the other ontology-based format, i.e. BioPAX. (ii) CSML3.0 can contain fact-based information that does not affect the simulation model, but holds very important information pertinent to biological pathways, e.g. indirect regulation from one gene to another gene. (iii) Not only can CSML3.0 represent high order Petri net models, but also ODE-based models, and CIO 4.0 faithfully implements this major feature. An added advantage with feature (iii) is that other modeling and simulation XML formats such as SBML and CellML can also be imported into CIO 4.0 more accurately. Other pathway databases, e.g. KEGG and TRANSPATH can be also imported to CSML3.0 format. 2.3 SaaS Technology and Cell Illustrator Online Various types of analysis requests are coming in from the R&D in Systems Biology. Some of them require a huge supercomputer system for such as optimal parameter, very expensive/large databases, or very specific analysis focused on a specific research topic. A single software cannot cover all of these, and software customization is very expensive or impossible to manage. Thus inevitably, we need the concept, Software as a Service (SaaS) technology as the computational platform for Systems Biology. SaaS is a software application delivery model which is usually associated with software business and is considered as a low-cost way to obtain the same merits without the associated complexity and high initial cost for licensing. The technology is introduced in CIO 4.0 and modules (described in the next section) are placed on the servers. Clients have the flexibility to select the desired modules from them on demand. The following six modules including the beta version are placed on the server side. (1) CSMLDB Search Module (2) Project Management Module (3) High-performance Simulation Module (4) Pathway Parameter Search Module (5) Pathway Model to Multiple Program Languages Export Module (Java, Fortran, C++, C, Perl and Python) (6) CSML to SVG Module and HTML Module (beta).

Figure 1: (a) Automatic Graph Layout function aplied to ASE cell fate simulation model. (b) Fas-induced apoptosis pathway model in CIO 4.0 and parameter search with Pathway Parameter Search Module. References [1] http://www.cellillustrator.org/

[2] http://www.csml.org/

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