A molecular approach to complex adaptive systems

Complex Adaptive Systems (CAS) are dynamical networks of interacting agents which as a whole determine the behavior, adaptivity and cognitive ability of the system. CAS are ubiquitous and occur in a variety of natural and artificial systems (e.g., cells, societies, stock markets). To study CAS, Holland proposed to employ an agent-based system in which Learning Classifier Systems (LCS) were used to determine the agents behavior and adaptivity. We argue that LCS are limited for the study of CAS: the rule-discovery mechanism is pre-specified and may limit the evolvability of CAS. Secondly, LCS distinguish a demarcation between messages and rules, however operations are reflexive in CAS, e.g., in a cell, an agent (a molecule) may both act as a message (substrate) and as a catalyst (rule). To address these issues, we proposed the Molecular Classifier Systems (MCS.b), a string-based Artificial Chemistry based on Holland’s broadcast language. In the MCS.b, no explicit fitness function or rule discovery mechanism is specified, moreover no distinction is made between messages and rules. In the context of the ESIGNET project, we employ the MCS.b to study a subclass of CAS: Cell Signaling Networks (CSNs) which are complex biochemical networks responsible for coordinating cellular activities. As CSNs occur in cells, these networks must replicate themselves prior to cell division. In this paper we present a series of experiments focusing on the self-replication ability of these CAS. Results indicate counter intuitive outcomes as opposed to those inferred from the literature. This work highlights the current deficit of a theoretical framework for the study of Artificial Chemistries

Evolving artificial cell signaling networks using molecular classifier systems

Nature is a source of inspiration for computational techniques which have been successfully applied to a wide variety of complex application domains. In keeping with this we examine Cell Signaling Networks (CSN) which are chemical networks responsible for coordinating cell activities within their environment. Through evolution they have become highly efficient for governing critical control processes such as immunological responses, cell cycle control or homeostasis. Realising (and evolving) Artificial Cell Signaling Networks (ACSNs) may provide new computational paradigms for a variety of application areas. Our abstraction of Cell Signaling Networks focuses on four characteristic properties distinguished as follows: Computation, Evolution, Crosstalk and Robustness. These properties are also desirable for potential applications in the control systems, computation and signal processing field. These characteristics are used as a guide for the development of an ACSN evolutionary simulation platform. In this paper we present a novel evolutionary approach named Molecular Classifier System (MCS) to simulate such ACSNs. The MCS that we have designed is derived from Holland's Learning Classifier System. The research we are currently involved in is part of the multi disciplinary European funded project, ESIGNET, with the central question of the study of the computational properties of CSNs by evolving them using methods from evolutionary computation, and to re-apply this understanding in developing new ways to model and predict real CSNs

Computationally-efficient stochastic cluster dynamics method for modeling damage accumulation in irradiated materials

An improved version of a recently developed stochastic cluster dynamics (SCD) method {[}Marian, J. and Bulatov, V. V., {\it J. Nucl. Mater.} \textbf{415} (2014) 84-95{]} is introduced as an alternative to rate theory (RT) methods for solving coupled ordinary differential equation (ODE) systems for irradiation damage simulations. SCD circumvents by design the curse of dimensionality of the variable space that renders traditional ODE-based RT approaches inefficient when handling complex defect population comprised of multiple (more than two) defect species. Several improvements introduced here enable efficient and accurate simulations of irradiated materials up to realistic (high) damage doses characteristic of next-generation nuclear systems. The first improvement is a procedure for efficiently updating the defect reaction-network and event selection in the context of a dynamically expanding reaction-network. Next is a novel implementation of the $\tau$-leaping method that speeds up SCD simulations by advancing the state of the reaction network in large time increments when appropriate. Lastly, a volume rescaling procedure is introduced to control the computational complexity of the expanding reaction-network through occasional reductions of the defect population while maintaining accurate statistics. The enhanced SCD method is then applied to model defect cluster accumulation in iron thin films subjected to triple ion-beam ($\text{Fe}^{3+}$, $\text{He}^{+}$ and $$\text{H\ensuremath{{}^{+}}}$$) irradiations, for which standard RT or spatially-resolved kinetic Monte Carlo simulations are prohibitively expensive

Computational models for inferring biochemical networks

Biochemical networks are of great practical importance. The interaction of biological compounds in cells has been enforced to a proper understanding by the numerous bioinformatics projects, which contributed to a vast amount of biological information. The construction of biochemical systems (systems of chemical reactions), which include both topology and kinetic constants of the chemical reactions, is NP-hard and is a well-studied system biology problem. In this paper, we propose a hybrid architecture, which combines genetic programming and simulated annealing in order to generate and optimize both the topology (the network) and the reaction rates of a biochemical system. Simulations and analysis of an artificial model and three real models (two models and the noisy version of one of them) show promising results for the proposed method.The Romanian National Authority for Scientific Research, CNDI–UEFISCDI, Project No. PN-II-PT-PCCA-2011-3.2-0917

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

Controlled vocabularies and semantics in systems biology

The use of computational modeling to describe and analyze biological systems is at the heart of systems biology. Model structures, simulation descriptions and numerical results can be encoded in structured formats, but there is an increasing need to provide an additional semantic layer. Semantic information adds meaning to components of structured descriptions to help identify and interpret them unambiguously. Ontologies are one of the tools frequently used for this purpose. We describe here three ontologies created specifically to address the needs of the systems biology community. The Systems Biology Ontology (SBO) provides semantic information about the model components. The Kinetic Simulation Algorithm Ontology (KiSAO) supplies information about existing algorithms available for the simulation of systems biology models, their characterization and interrelationships. The Terminology for the Description of Dynamics (TEDDY) categorizes dynamical features of the simulation results and general systems behavior. The provision of semantic information extends a model's longevity and facilitates its reuse. It provides useful insight into the biology of modeled processes, and may be used to make informed decisions on subsequent simulation experiments

Bioengineering models of cell signaling

Strategies for rationally manipulating cell behavior in cell-based technologies and molecular therapeutics and understanding effects of environmental agents on physiological systems may be derived from a mechanistic understanding of underlying signaling mechanisms that regulate cell functions. Three crucial attributes of signal transduction necessitate modeling approaches for analyzing these systems: an ever-expanding plethora of signaling molecules and interactions, a highly interconnected biochemical scheme, and concurrent biophysical regulation. Because signal flow is tightly regulated with positive and negative feedbacks and is bidirectional with commands traveling both from outside-in and inside-out, dynamic models that couple biophysical and biochemical elements are required to consider information processing both during transient and steady-state conditions. Unique mathematical frameworks will be needed to obtain an integrated perspective on these complex systems, which operate over wide length and time scales. These may involve a two-level hierarchical approach wherein the overall signaling network is modeled in terms of effective "circuit" or "algorithm" modules, and then each module is correspondingly modeled with more detailed incorporation of its actual underlying biochemical/biophysical molecular interactions

A generic approach to behaviour-driven biochemical model construction

This thesis was submitted for the degree of Doctor of Philosophy and awarded by Brunel University.Modelling of biochemical systems has received considerable attention over the last decade from bioengineering, biochemistry, computer science, and mathematics. This thesis investigates the applications of computational techniques to computational systems biology, for the construction of biochemical models in terms of topology and kinetic rates. Due to the complexity of biochemical systems, it is natural to construct models representing the biochemical systems incrementally in a piecewise manner. Syntax and semantics of two patterns are defined for the instantiation of components which are extendable, reusable and fundamental building blocks for models composition. We propose and implement a set of genetic operators and composition rules to tackle issues of piecewise composing models from scratch. Quantitative Petri nets are evolved by the genetic operators, and evolutionary process of modelling are guided by the composition rules. Metaheuristic algorithms are widely applied in BioModel Engineering to support intelligent and heuristic analysis of biochemical systems in terms of structure and kinetic rates. We illustrate parameters of biochemical models based on Biochemical Systems Theory, and then the topology and kinetic rates of the models are manipulated by employing evolution strategy and simulated annealing respectively. A new hybrid modelling framework is proposed and implemented for the models construction. Two heuristic algorithms are performed on two embedded layers in the hybrid framework: an outer layer for topology mutation and an inner layer for rates optimization. Moreover, variants of the hybrid piecewise modelling framework are investigated. Regarding flexibility of these variants, various combinations of evolutionary operators, evaluation criteria and design principles can be taken into account. We examine performance of five sets of the variants on specific aspects of modelling. The comparison of variants is not to explicitly show that one variant clearly outperforms the others, but it provides an indication of considering important features for various aspects of the modelling. Because of the very heavy computational demands, the process of modelling is paralleled by employing a grid environment, GridGain. Application of the GridGain and heuristic algorithms to analyze biological processes can support modelling of biochemical systems in a computational manner, which can also benefit mathematical modelling in computer science and bioengineering. We apply our proposed modelling framework to model biochemical systems in a hybrid piecewise manner. Modelling variants of the framework are comparatively studied on specific aims of modelling. Simulation results show that our modelling framework can compose synthetic models exhibiting similar species behaviour, generate models with alternative topologies and obtain general knowledge about key modelling features

Visual Network Analysis of Dynamic Metabolic Pathways

Abstract. We extend our previous work on the exploration of static metabolic networks to evolving, and therefore dynamic, pathways. We apply our visualization software to data from a simulation of early metabolism. Thereby, we show that our technique allows us to test and argue for or against different scenarios for the evolution of metabolic pathways. This supports a profound and efficient analysis of the structure and properties of the generated metabolic networks and its underlying components, while giving the user a vivid impression of the dynamics of the system. The analysis process is inspired by Ben Shneiderman’s mantra of information visualization. For the overview, user-defined diagrams give insight into topological changes of the graph as well as changes in the attribute set associated with the participating enzymes, substances and reactions. This way, “interesting features” in time as well as in space can be recognized. A linked view implementation enables the navigation into more detailed layers of perspective for in-depth analysis of individual network configuration