Boolean Models of Bistable Biological Systems

This paper presents an algorithm for approximating certain types of dynamical systems given by a system of ordinary delay differential equations by a Boolean network model. Often Boolean models are much simpler to understand than complex differential equations models. The motivation for this work comes from mathematical systems biology. While Boolean mechanisms do not provide information about exact concentration rates or time scales, they are often sufficient to capture steady states and other key dynamics. Due to their intuitive nature, such models are very appealing to researchers in the life sciences. This paper is focused on dynamical systems that exhibit bistability and are desc ribedby delay equations. It is shown that if a certain motif including a feedback loop is present in the wiring diagram of the system, the Boolean model captures the bistability of molecular switches. The method is appl ied to two examples from biology, the lac operon and the phage lambda lysis/lysogeny switch

Odefy -- From discrete to continuous models

<p>Abstract</p> <p>Background</p> <p>Phenomenological information about regulatory interactions is frequently available and can be readily converted to Boolean models. Fully quantitative models, on the other hand, provide detailed insights into the precise dynamics of the underlying system. In order to connect discrete and continuous modeling approaches, methods for the conversion of Boolean systems into systems of ordinary differential equations have been developed recently. As biological interaction networks have steadily grown in size and complexity, a fully automated framework for the conversion process is desirable.</p> <p>Results</p> <p>We present <it>Odefy</it>, a MATLAB- and Octave-compatible toolbox for the automated transformation of Boolean models into systems of ordinary differential equations. Models can be created from sets of Boolean equations or graph representations of Boolean networks. Alternatively, the user can import Boolean models from the CellNetAnalyzer toolbox, GINSim and the PBN toolbox. The Boolean models are transformed to systems of ordinary differential equations by multivariate polynomial interpolation and optional application of sigmoidal Hill functions. Our toolbox contains basic simulation and visualization functionalities for both, the Boolean as well as the continuous models. For further analyses, models can be exported to SQUAD, GNA, MATLAB script files, the SB toolbox, SBML and R script files. Odefy contains a user-friendly graphical user interface for convenient access to the simulation and exporting functionalities. We illustrate the validity of our transformation approach as well as the usage and benefit of the Odefy toolbox for two biological systems: a mutual inhibitory switch known from stem cell differentiation and a regulatory network giving rise to a specific spatial expression pattern at the mid-hindbrain boundary.</p> <p>Conclusions</p> <p>Odefy provides an easy-to-use toolbox for the automatic conversion of Boolean models to systems of ordinary differential equations. It can be efficiently connected to a variety of input and output formats for further analysis and investigations. The toolbox is open-source and can be downloaded at <url>http://cmb.helmholtz-muenchen.de/odefy</url>.</p

Combining Boolean Networks and Ordinary Differential Equations for Analysis and Comparison of Gene Regulatory Networks

This thesis is concerned with different groups of qualitative models of gene regulatory networks. Four types of models will be considered: interaction graphs, Boolean networks, models based on differential equations and discrete abstractions of differential equations. We will investigate the relations between these modeling frameworks and how they can be used in the analysis of individual models. The focus lies on the mathematical analysis of these models. This thesis makes several contributions in relating these different modeling frameworks. The first approach concerns individual Boolean models and parametrized families of ordinary differential equations (ODEs). To construct ODE models systematically from Boolean models several automatic conversion algorithms have been proposed. In Chapter 2 several such closely related algorithms will be considered. It will be proven that certain invariant sets are preserved during the conversion from a Boolean network to a model based on ODEs. In the second approach the idea of abstracting the dynamics of individual models to relate structure and dynamics will be introduced. This approach will be applied to Boolean models and models based on differential equations. This allows to compare groups of models in these modeling frameworks which have the same structure. We demonstrate that this constitutes an approach to link the interaction graph to the dynamics of certain sets of Boolean networks and models based on differential equations. The abstracted dynamics – or more precisely the restrictions on the abstracted behavior – of such sets of Boolean networks or models based on differential equations will be represented as Boolean state transitions graphs themselves. We will show that these state transition graphs can be considered as asynchronous Boolean networks. Despite the rather theoretical question this thesis tries to answer there are many potential applications of the results. The results in Chapter 2 can be applied to network reduction of ODE models based on Hill kinetics. The results of the second approach in Chapter 4 can be applied to network inference and analysis of Boolean model sets. Furthermore, in the last chapter of this thesis several ideas for applications with respect to experiment design will be considered. This leads to the question how different asynchronous Boolean networks or different behaviours of a single asynchronous Boolean network can be distinguishedDiese Arbeit beschäftigt sich mit unterschiedlichen Typen von qualitativen Modellen genregulatorischer Netzwerke. Vier Typen von Modellen werden betrachtet: Interaktionsgraphen, Boolesche Netzwerke, Modelle, die auf Differentialgleichungen basieren und diskrete Abstraktionen von Differentialgleichungen. Wir werden mehr über die Beziehungen zwischen diesen Modellgruppen lernen und wie diese Beziehungen genutzt werden können, um einzelne Modelle zu analysieren. Der Schwerpunkt liegt hierbei auf der mathematischen Analyse dieser Modellgruppen. In dieser Hinsicht leistet diese Arbeit mehrere Beiträge. Zunächst betrachten wir Boolesche Netzwerke und parametrisierte Familien von gewöhnlichen Differentialgleichungen (ODEs). Um solche ODE-Modelle systematisch aus Booleschen Modellen abzuleiten, wurden in der Vergangenheit verschiedene automatische Konvertierungsalgorithmen vorgeschlagen. In Kapitel 2 werden einige dieser Algorithmen näher untersucht. Wir werden beweisen, dass bestimmte invariante Mengen bei der Konvertierung eines Booleschen Modells in ein ODE-Modell erhalten bleiben. Der zweite Ansatz, der in dieser Arbeit verfolgt wird, beschäftigt sich mit diskreten Abstraktionen der Dynamik von Modellen. Mit Hilfe dieser Abstraktionen ist es möglich, die Struktur – den Interaktionsgraphen – und die Dynamik der zugehörigen Modelle in Bezug zu setzen. Diese Methode wird sowohl auf Boolesche Modelle als auch auf ODE-Modelle angewandt. Gleichzeitig erlaubt dieser Ansatz Mengen von Modellen in unterschiedlichen Modellgruppen zu vergleichen, die dieselbe Struktur haben. Die abstrahierten Dynamiken (genauer die Einschränkungen der abstrahierten Dynamiken) der Booleschen Modellmengen oder ODE-Modellmengen können als Boolesche Zustandsübergangsgraphen repräsentiert werden. Wir werden zeigen, dass diese Zustandsübergangsgraphen wiederum selber als (asynchrone) Boolesche Netzwerke aufgefasst werden können. Trotz der theoretischen Ausgangsfrage werden in dieser Arbeit zahlreiche Anwendungen aufgezeigt. Die Ergebnisse aus Kapitel 2 können zur Modellreduktion benutzt werden, indem die Dynamik der ODE-Modelle auf den zu den Booleschen Netzwerken gehörigen “trap spaces” betrachtet wird. Die Resultate aus Kapitel 4 können zur Netzwerkinferenz oder zur Analyse von Modellmengen genutzt werden. Weiterhin werden im letzten Kapitel dieser Arbeit einige Anwendungsideen im Bezug auf Experimentdesign eingeführt. Dies führt zu der Fragestellung, wie verschiedene asynchrone Boolesche Netzwerke oder unterschiedliche Dynamiken, die mit einem einzelnen Modell vereinbar sind, unterschieden werden können

Boolean Delay Equations: A simple way of looking at complex systems

Boolean Delay Equations (BDEs) are semi-discrete dynamical models with Boolean-valued variables that evolve in continuous time. Systems of BDEs can be classified into conservative or dissipative, in a manner that parallels the classification of ordinary or partial differential equations. Solutions to certain conservative BDEs exhibit growth of complexity in time. They represent therewith metaphors for biological evolution or human history. Dissipative BDEs are structurally stable and exhibit multiple equilibria and limit cycles, as well as more complex, fractal solution sets, such as Devil's staircases and ``fractal sunbursts``. All known solutions of dissipative BDEs have stationary variance. BDE systems of this type, both free and forced, have been used as highly idealized models of climate change on interannual, interdecadal and paleoclimatic time scales. BDEs are also being used as flexible, highly efficient models of colliding cascades in earthquake modeling and prediction, as well as in genetics. In this paper we review the theory of systems of BDEs and illustrate their applications to climatic and solid earth problems. The former have used small systems of BDEs, while the latter have used large networks of BDEs. We moreover introduce BDEs with an infinite number of variables distributed in space (``partial BDEs``) and discuss connections with other types of dynamical systems, including cellular automata and Boolean networks. This research-and-review paper concludes with a set of open questions.Comment: Latex, 67 pages with 15 eps figures. Revised version, in particular the discussion on partial BDEs is updated and enlarge

Modeling and Analysis of Germ Layer Formations Using Finite Dynamical Systems

The development of an embryo from a fertilised egg to a multicellular organism proceeds through numerous steps, with the formation of the three germ layers (endoderm, mesoderm, ectoderm) being one of the first. In this paper we study the mesendoderm (the tissue that collectively gives rise to both mesoderm and endoderm) gene regulatory network for two species, \textit{Xenopus laevis} and the axolotl (\textit{Ambystoma mexicanum}) using Boolean networks. We find that previously-established bistability found in these networks can be reproduced using this Boolean framework, provided that some assumptions used in previously-published differential equations models are relaxed. We conclude by discussing our findings in relation to previous work modeling gene regulatory networks with Boolean network models