The Pathalyzer: A Tool for Analysis of Signal Transduction Pathways [chapter]

David L. Dill, Merrill A. Knapp, Pamela Gage, Carolyn Talcott, Keith Laderoute, Patrick Lincoln
Systems Biology and Regulatory Genomics  
The Pathalyzer is a program for analyzing large-scale signal transduction networks. Reactions and their substrates and products are represented as transitions and places in a safe Petri net. The user can interactively specify goal states, such as activation of a particular protein in a particular cell site, and the system will automatically find and display a pathway that results in the goal state -if possible. The user can also require that the pathway be generated without using certian
more » ... s. The system can also find all individual places and all pairs of places which, if knocked out, would prevent the goals from being achieved. The tool is intended to be used by biologists with no significant understanding of Petri nets or any of the other concepts used in the implementation. This paper describes a prototype software tool, called the Pathalyzer, for querying large-scale qualitative information about signaling pathways. This tool, which uses Petri nets to represent signaling pathways, is unique in several ways. It has a high-level Boolean approach to modeling, based on the Pathway Logic system [3, 19], that enables the analysis of large biological networks. The analysis can answer questions, of types commonly asked by bench biologists, that require searching all possible pathways consisting of specific signaling molecules and their associated reactions. Thus, the model has no built-in concept of pathways; instead, pathways are generated dynamically from a collection of rules describing individual biochemical steps in signal transduction in response to queries from a user. This capability allows the Pathalyzer to generate a very large number of alternative pathways under the control of a user, who can display differences between the generated pathways. The tool uses sophisticated algorithms developed within the Petri net community for solving the computationally difficult reachability problem -in real time. The user needs to understand very little about Petri nets or the various algorithms used in the tool, because the tool provides an easy-to-use interface for entering queries and displaying the results. A model of a mammalian signaling network has been developed consisting of hundreds of signaling and other molecules involved in the epidermal growth factor receptor (EGFR) system. Cancer biologists are strongly interested in EGFR system, so it has been extensively studied experimentally as a paradigm for growth factor effects on the proliferation and survival of diverse mammalian cells. All of the information incorporated within the model was curated from the appropriate scientific literature. For this model, under development as part of the Pathway Logic project [3, 4, 18] , the analysis algorithms of the Pathalyzer run in real time and produce results consistent with the published literature. Briefly, in Pathway Logic biochemical processes are represented as rules written in Maude [1, 2], a system based on rewriting logic [13, 14] . The Petri nets used by the Pathalyzer are extracted automatically from these Maude rules, and displayed for analysis as described below. The models used by the Pathalyzer are not specific to Maude. It would be possible to generate them from SBML [7] models or to enter the models via a web form interface. Using an existing model requires no knowledge of the model data entry process. An interactive demonstration of the pathway logic viewer is available at
doi:10.1007/978-3-540-48540-7_2 dblp:conf/recomb/DillKGTLL05 fatcat:vjpksqklyjashoido5ol5ow3zu