Towards a Boolean network-based Computational Model for Cell Differentiation and its applications to Robotics

Living organisms are the ultimate product of a series of complex processes that take place within—and among—biological cells. Most of these processes, such as cell differentiation, are currently poorly understood. Cell differentiation is the process by which cells progressively specialise. Being a fundamental process within cells, its dysregulations have dramatic implications in biological organisms ranging from developmental issues to cancer formation. The thesis objective is to contribute to the progress in the understanding of cell differentiation and explore the applications of its properties for designing artificial systems. The proposed approach, which relies on Boolean networks based modelling and on the theory of dynamical systems, aims at investigating the general mechanisms underlying cell differentiation. The results obtained contribute to taking a further step towards the formulation of a general theoretical framework—so far missing—for cellular differentiation. We conducted an in-depth analysis of the impact of self-loops in random Boolean networks ensembles. We proposed a new model of differentiation driven by a simplified bio-inspired methylation mechanism in Boolean models of genetic regulatory networks. On the artificial side, by introducing the conceptual metaphor of the “attractor landscape” and related proofs of concept that support its potential, we paved the way for a new research direction in robotics called behavioural differentiation robotics: a branch of robotics dealing with the designing of robots capable of expressing different behaviours in a way similar to that of biological cells that undergo differentiation. The implications of the results achieved may have beneficial effects on medical research. Indeed, the proposed approach can foster new questions, experiments and in turn, models that hopefully in the next future will take us to cure differentiation-related diseases such as cancer. Our work may also contribute to address questions concerning the evolution of complex behaviours and to help design robust and adaptive robots

Quantifying the implicit process flow abstraction in SBGN-PD diagrams with Bio-PEPA

For a long time biologists have used visual representations of biochemical networks to gain a quick overview of important structural properties. Recently SBGN, the Systems Biology Graphical Notation, has been developed to standardise the way in which such graphical maps are drawn in order to facilitate the exchange of information. Its qualitative Process Diagrams (SBGN-PD) are based on an implicit Process Flow Abstraction (PFA) that can also be used to construct quantitative representations, which can be used for automated analyses of the system. Here we explicitly describe the PFA that underpins SBGN-PD and define attributes for SBGN-PD glyphs that make it possible to capture the quantitative details of a biochemical reaction network. We implemented SBGNtext2BioPEPA, a tool that demonstrates how such quantitative details can be used to automatically generate working Bio-PEPA code from a textual representation of SBGN-PD that we developed. Bio-PEPA is a process algebra that was designed for implementing quantitative models of concurrent biochemical reaction systems. We use this approach to compute the expected delay between input and output using deterministic and stochastic simulations of the MAPK signal transduction cascade. The scheme developed here is general and can be easily adapted to other output formalisms

Petri nets for systems and synthetic biology

We give a description of a Petri net-based framework for modelling and analysing biochemical pathways, which uni¯es the qualita- tive, stochastic and continuous paradigms. Each perspective adds its con- tribution to the understanding of the system, thus the three approaches do not compete, but complement each other. We illustrate our approach by applying it to an extended model of the three stage cascade, which forms the core of the ERK signal transduction pathway. Consequently our focus is on transient behaviour analysis. We demonstrate how quali- tative descriptions are abstractions over stochastic or continuous descrip- tions, and show that the stochastic and continuous models approximate each other. Although our framework is based on Petri nets, it can be applied more widely to other formalisms which are used to model and analyse biochemical networks

Online adaptation in Boolean network robots

Questa tesi si concentra su molteplici processi di adattamento online utilizzati su un robot autonomo, che è controllato da una rete booleana; l’obiettivo è adattare il suo comportamento ad un ambiente e ad un compito specifici. I risultati mostrano che il robot può adattarsi per navigare l’ambiente ed evitare le collisioni, seguendo inoltre un altro robot in movimento; riesce anche a generalizzare, quando posizionato in un’arena diversa rispetto a quella usata in allenamento. Con due dei processi di adattamento testati, il robot può esprimere più fenotipi (comportamenti) dallo stesso genotipo (nodi e connessioni della rete booleana), ottenendo così la plasticità fenotipica. Ciò si ottiene modificando l’accoppiamento tra i sensori o gli attuatori del robot con la rete

Modeling and Simulation of Biological Systems through Electronic Design Automation techniques

Modeling and simulation of biological systems is a key requirement for integrating invitro and in-vivo experimental data. In-silico simulation allows testing different experimental conditions, thus helping in the discovery of the dynamics that regulate the system. These dynamics include errors in the cellular information processing that are responsible for diseases such as cancer, autoimmunity, and diabetes as well as drug effects to the system (Gonalves, 2013). In this context, modeling approaches can be classified into two categories: quantitative and qualitative models. Quantitative modeling allows for a natural representation of molecular and gene networks and provides the most precise prediction. Nevertheless, the lack of kinetic data (and of quantitative data in general) hampers its use for many situations (Le Novere, 2015). In contrast, qualitative models simplify the biological reality and are often able to reproduce the system behavior. They cannot describe actual concentration levels nor realistic time scales. As a consequence, they cannot be used to explain and predict the outcome of biological experiments that yield quantitative data. However, given a biological network consisting of input (e.g., receptors), intermediate, and output (e.g., transcription factors) signals, they allow studying the input-output relationships through discrete simulation (Samaga, 2013). Boolean models are gaining an increasing interest in reproducing dynamic behaviors, understanding processes, and predicting emerging properties of cellular signaling networks through in-silico experiments. They are emerging as a valid alternative to the quantitative approaches (i.e., based on ordinary differential equations) for exploratory modeling when little is known about reaction kinetics or equilibrium constants in the context of gene expression or signaling. Even though several approaches and software have been recently proposed for logic modeling of biological systems, they are limited to specific contexts and they lack of automation in analyzing biological properties such as complex attractors, and molecule vulnerability. This thesis proposes a platform based on Electronic Design Automation (EDA) technologies for qualitative modeling and simulation of Biological Systems. It aims at overtaking limitations that affect the most recent qualitative tools

Robust filtering for gene expression time series data with variance constraints

This is the post print version of the article. The official published version can be obtained from the link below - Copyright 2007 Taylor & Francis Ltd.In this paper, an uncertain discrete-time stochastic system is employed to represent a model for gene regulatory networks from time series data. A robust variance-constrained filtering problem is investigated for a gene expression model with stochastic disturbances and norm-bounded parameter uncertainties, where the stochastic perturbation is in the form of a scalar Gaussian white noise with constant variance and the parameter uncertainties enter both the system matrix and the output matrix. The purpose of the addressed robust filtering problem is to design a linear filter such that, for the admissible bounded uncertainties, the filtering error system is Schur stable and the individual error variance is less than a prespecified upper bound. By using the linear matrix inequality (LMI) technique, sufficient conditions are first derived for ensuring the desired filtering performance for the gene expression model. Then the filter gain is characterized in terms of the solution to a set of LMIs, which can easily be solved by using available software packages. A simulation example is exploited for a gene expression model in order to demonstrate the effectiveness of the proposed design procedures.This work was supported in part by the Engineering and Physical Sciences Research Council (EPSRC) of the UK under Grants GR/S27658/01 and EP/C524586/1, the Biotechnology and Biological Sciences Research Council (BBSRC) of the UK under Grants BB/C506264/1 and 100/EGM17735, the Nuffield Foundation of the UK under Grant NAL/00630/G, and the Alexander von Humboldt Foundation of Germany

Evolving always‐critical networks

Living beings share several common features at the molecular level, but there are very few large‐scale “operating principles” which hold for all (or almost all) organisms. However, biology is subject to a deluge of data, and as such, general concepts such as this would be extremely valuable. One interesting candidate is the “criticality” principle, which claims that biological evolution favors those dynamical regimes that are intermediaries between ordered and disordered states (i.e., “at the edge of chaos”). The reasons why this should be the case and experimental evidence are briefly discussed, observing that gene regulatory networks are indeed often found on, or close to, the critical boundaries. Therefore, assuming that criticality provides an edge, it is important to ascertain whether systems that are critical can further evolve while remaining critical. In order to explore the possibility of achieving such “always‐critical” evolution, we resort to simulated evolution, by suitably modifying a genetic algorithm in such a way that the newly‐generated individuals are constrained to be critical. It is then shown that these modified genetic algorithms can actually develop critical gene regulatory networks with two interesting (and quite different) features of biological significance, involving, in one case, the average gene activation values and, in the other case, the response to perturbations. These two cases suggest that it is often possible to evolve networks with interesting properties without losing the advantages of criticality. The evolved networks also show some interesting features which are discussed