An Intuitive Automated Modelling Interface for Systems Biology

We introduce a natural language interface for building stochastic pi calculus models of biological systems. In this language, complex constructs describing biochemical events are built from basic primitives of association, dissociation and transformation. This language thus allows us to model biochemical systems modularly by describing their dynamics in a narrative-style language, while making amendments, refinements and extensions on the models easy. We demonstrate the language on a model of Fc-gamma receptor phosphorylation during phagocytosis. We provide a tool implementation of the translation into a stochastic pi calculus language, Microsoft Research's SPiM

The Holland broadcast language

The broadcast language is a programming formalism devised by Holland in 1975, which aims at allowing Genetic Algorithms (GAs) to use an adaptable representation. A GA may provide an efficient method for adaption but still depends on the efficiency of the fitness function used. During long-term evolution, this efficiency could be limited by the fixed representation used by the GA to encode the problem. When a fitness function is very complex, it is desirable to adapt the problem representation employed by the fitness function. By adapting the representation, the broadcast language may overcome the deficiencies caused by fixed problem representation in GAs. This report describes an initial detailed specification and implementation of the broadcast language. Our first motivation is the fact that there is currently no published implementation of broadcast systems (broadcast language-based systems) available. Despite Holland presented the broadcast language in his book “Adaptation in Natural and Artificial systems”, he did not support this approach with experimental studies. Our second motivation is the affirmation made by Holland that broadcast systems could model biochemical networks. Indeed Holland also described how the broadcast language could provide a straightforward representation to a variety of biochemical networks (Genetic Regulatory Networks, Neural Networks, Immune system etc). As these biochemical models share many similarities with Cell Signaling Networks (CSNs), broadcast systems may also be considered to model CSNs. One of our goals, within the ESIGNET project, is to develop an evolutionary system to realize and evolve CSNs in Silico. Examining the broadcast language may provide us with valuable insights to the development of such a system. In this paper, we initially review the Holland broadcast language, we then propose a specification and implementation of the language which is later illustrated with an experiment: modeling different chemical reactions

A Language for Biochemical Systems

Abstract. CBS is a Calculus of Biochemical Systems intended to allow the modelling of metabolic, signalling and regulatory networks in a natural and modular manner. In this paper we extend CBS with features directed towards practical, large-scale applications, thus yielding LBS: a Language for Biochemical Systems. The two main extensions are expressions for modifying large complexes in a step-wise manner and parameterised modules with a notion of subtyping; LBS also has nested declarations of species and compartments. The extensions are demonstrated with examples from the yeast pheromone pathway. A formal specification of LBS is then given through an abstract syntax, static semantics and a translation to a variant of coloured Petri nets. Translation to other formalisms such as ordinary differential equations and continuous time Markov chains is also possible

Design and Development of Software Tools for Bio-PEPA

This paper surveys the design of software tools for the Bio-PEPA process algebra. Bio-PEPA is a high-level language for modelling biological systems such as metabolic pathways and other biochemical reaction networks. Through providing tools for this modelling language we hope to allow easier use of a range of simulators and model-checkers thereby freeing the modeller from the responsibility of developing a custom simulator for the problem of interest. Further, by providing mappings to a range of different analysis tools the Bio-PEPA language allows modellers to compare analysis results which have been computed using independent numerical analysers, which enhances the reliability and robustness of the results computed.

Runtime verification for biochemical programs

The biochemical paradigm is well-suited for modelling autonomous systems and new programming languages are emerging from this approach. However, in order to validate such programs, we need to define precisely their semantics and to provide verification techniques. In this paper, we consider a higher-order biochemical calculus that models the structure of system states and its dynamics thanks to rewriting abstractions, namely rules and strategies. We extend this calculus with a runtime verification technique in order to perform automatic discovery of property satisfaction failure. The property specification language is a subclass of LTL safety and liveness properties

Programmability of Chemical Reaction Networks

Motivated by the intriguing complexity of biochemical circuitry within individual cells we study Stochastic Chemical Reaction Networks (SCRNs), a formal model that considers a set of chemical reactions acting on a finite number of molecules in a well-stirred solution according to standard chemical kinetics equations. SCRNs have been widely used for describing naturally occurring (bio)chemical systems, and with the advent of synthetic biology they become a promising language for the design of artificial biochemical circuits. Our interest here is the computational power of SCRNs and how they relate to more conventional models of computation. We survey known connections and give new connections between SCRNs and Boolean Logic Circuits, Vector Addition Systems, Petri Nets, Gate Implementability, Primitive Recursive Functions, Register Machines, Fractran, and Turing Machines. A theme to these investigations is the thin line between decidable and undecidable questions about SCRN behavior

Biochemical Reaction Rules with Constraints

International audienceWe propose React(C), an expressive programming language for stochastic modeling and simulation in systems biology, that is based on biochemical reactions with constraints. We prove that React(C) can express the stochastic pi-calculus, in contrast to previous rule-based programming languages, and further illustrate the high expressiveness of React(C). We present a stochastic simulator for React(C) independently of the choice of the constraint language C. Our simulator must decide for a given reaction rule whether it can be applied to the current biochemical solution. We show that this decision problem is NP-complete for arbitrary constraint systems C, and that it can be solved in polynomial time for rules of bounded arity. In practice, we propose to solve this problem by constraint programming

Systems Biology Markup Language (SBML) Level 2: Structures and Facilities for Model Definitions

With the rise of Systems Biology as a new paradigm for understanding biological processes, the development of quantitative models is no longer restricted to a small circle of theoreticians. The dramatic increase in the number of these models precipitates the need to exchange and reuse both existing and newly created models. The Systems Biology Markup Language (SBML) is a free, open, XML-based format for representing quantitative models of biological interest that advocates the consistent specification of such models and thus facilitates both software development and model exchange.

Principally oriented towards describing systems of biochemical reactions, such as cell signalling pathways, metabolic networks and gene regulation etc., SBML can also be used to encode any kinetic model. SBML offers mechanisms to describe biological components by means of compartments and reacting species, as well as their dynamic behaviour, using reactions, events and arbitrary mathematical rules. SBML also offers all the housekeeping structures needed to ensure an unambiguous understanding of quantitative descriptions.

This is Release 1 of the specification for SBML Level 2 Version 4, describing the structures of the language and the rules used to build a valid model. SBML XML Schema and other related documents and software are also available from the SBML project web site, "http://sbml.org/":http://sbml.org/

SBML models and MathSBML

MathSBML is an open-source, freely-downloadable Mathematica package that facilitates working with Systems Biology Markup Language (SBML) models. SBML is a toolneutral,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