Identification of control targets in Boolean molecular network models via computational algebra

Motivation: Many problems in biomedicine and other areas of the life sciences can be characterized as control problems, with the goal of finding strategies to change a disease or otherwise undesirable state of a biological system into another, more desirable, state through an intervention, such as a drug or other therapeutic treatment. The identification of such strategies is typically based on a mathematical model of the process to be altered through targeted control inputs. This paper focuses on processes at the molecular level that determine the state of an individual cell, involving signaling or gene regulation. The mathematical model type considered is that of Boolean networks. The potential control targets can be represented by a set of nodes and edges that can be manipulated to produce a desired effect on the system. Experimentally, node manipulation requires technology to completely repress or fully activate a particular gene product while edge manipulations only require a drug that inactivates the interaction between two gene products. Results: This paper presents a method for the identification of potential intervention targets in Boolean molecular network models using algebraic techniques. The approach exploits an algebraic representation of Boolean networks to encode the control candidates in the network wiring diagram as the solutions of a system of polynomials equations, and then uses computational algebra techniques to find such controllers. The control methods in this paper are validated through the identification of combinatorial interventions in the signaling pathways of previously reported control targets in two well studied systems, a p53-mdm2 network and a blood T cell lymphocyte granular leukemia survival signaling network.Comment: 12 pages, 4 figures, 2 table

Control of complex networks requires both structure and dynamics

The study of network structure has uncovered signatures of the organization of complex systems. However, there is also a need to understand how to control them; for example, identifying strategies to revert a diseased cell to a healthy state, or a mature cell to a pluripotent state. Two recent methodologies suggest that the controllability of complex systems can be predicted solely from the graph of interactions between variables, without considering their dynamics: structural controllability and minimum dominating sets. We demonstrate that such structure-only methods fail to characterize controllability when dynamics are introduced. We study Boolean network ensembles of network motifs as well as three models of biochemical regulation: the segment polarity network in Drosophila melanogaster, the cell cycle of budding yeast Saccharomyces cerevisiae, and the floral organ arrangement in Arabidopsis thaliana. We demonstrate that structure-only methods both undershoot and overshoot the number and which sets of critical variables best control the dynamics of these models, highlighting the importance of the actual system dynamics in determining control. Our analysis further shows that the logic of automata transition functions, namely how canalizing they are, plays an important role in the extent to which structure predicts dynamics.Comment: 15 pages, 6 figure

Therapeutic target discovery using Boolean network attractors: avoiding pathological phenotypes

Target identification, one of the steps of drug discovery, aims at identifying biomolecules whose function should be therapeutically altered in order to cure the considered pathology. This work proposes an algorithm for in silico target identification using Boolean network attractors. It assumes that attractors of dynamical systems, such as Boolean networks, correspond to phenotypes produced by the modeled biological system. Under this assumption, and given a Boolean network modeling a pathophysiology, the algorithm identifies target combinations able to remove attractors associated with pathological phenotypes. It is tested on a Boolean model of the mammalian cell cycle bearing a constitutive inactivation of the retinoblastoma protein, as seen in cancers, and its applications are illustrated on a Boolean model of Fanconi anemia. The results show that the algorithm returns target combinations able to remove attractors associated with pathological phenotypes and then succeeds in performing the proposed in silico target identification. However, as with any in silico evidence, there is a bridge to cross between theory and practice, thus requiring it to be used in combination with wet lab experiments. Nevertheless, it is expected that the algorithm is of interest for target identification, notably by exploiting the inexpensiveness and predictive power of computational approaches to optimize the efficiency of costly wet lab experiments.Comment: Since the publication of this article and among the possible improvements mentioned in the Conclusion, two improvements have been done: extending the algorithm for multivalued logic and considering the basins of attraction of the pathological attractors for selecting the therapeutic bullet

Reverse-engineering of polynomial dynamical systems

Multivariate polynomial dynamical systems over finite fields have been studied in several contexts, including engineering and mathematical biology. An important problem is to construct models of such systems from a partial specification of dynamic properties, e.g., from a collection of state transition measurements. Here, we consider static models, which are directed graphs that represent the causal relationships between system variables, so-called wiring diagrams. This paper contains an algorithm which computes all possible minimal wiring diagrams for a given set of state transition measurements. The paper also contains several statistical measures for model selection. The algorithm uses primary decomposition of monomial ideals as the principal tool. An application to the reverse-engineering of a gene regulatory network is included. The algorithm and the statistical measures are implemented in Macaulay2 and are available from the authors

Parameters identification of unknown delayed genetic regulatory networks by a switching particle swarm optimization algorithm

The official published version can be found at the link below.This paper presents a novel particle swarm optimization (PSO) algorithm based on Markov chains and competitive penalized method. Such an algorithm is developed to solve global optimization problems with applications in identifying unknown parameters of a class of genetic regulatory networks (GRNs). By using an evolutionary factor, a new switching PSO (SPSO) algorithm is first proposed and analyzed, where the velocity updating equation jumps from one mode to another according to a Markov chain, and acceleration coefficients are dependent on mode switching. Furthermore, a leader competitive penalized multi-learning approach (LCPMLA) is introduced to improve the global search ability and refine the convergent solutions. The LCPMLA can automatically choose search strategy using a learning and penalizing mechanism. The presented SPSO algorithm is compared with some well-known PSO algorithms in the experiments. It is shown that the SPSO algorithm has faster local convergence speed, higher accuracy and algorithm reliability, resulting in better balance between the global and local searching of the algorithm, and thus generating good performance. Finally, we utilize the presented SPSO algorithm to identify not only the unknown parameters but also the coupling topology and time-delay of a class of GRNs.This research was partially supported by the National Natural Science Foundation of PR China (Grant No. 60874113), the Research Fund for the Doctoral Program of Higher Education (Grant No. 200802550007), the Key Creative Project of Shanghai Education Community (Grant No. 09ZZ66), the Key Foundation Project of Shanghai (Grant No. 09JC1400700), the Engineering and Physical Sciences Research Council EPSRC of the UK under Grant No. GR/S27658/01, the International Science and Technology Cooperation Project of China under Grant No. 2009DFA32050, an International Joint Project sponsored by the Royal Society of the UK, and the Alexander von Humboldt Foundation of Germany

ADAM: Analysis of Discrete Models of Biological Systems Using Computer Algebra

Background: Many biological systems are modeled qualitatively with discrete models, such as probabilistic Boolean networks, logical models, Petri nets, and agent-based models, with the goal to gain a better understanding of the system. The computational complexity to analyze the complete dynamics of these models grows exponentially in the number of variables, which impedes working with complex models. Although there exist sophisticated algorithms to determine the dynamics of discrete models, their implementations usually require labor-intensive formatting of the model formulation, and they are oftentimes not accessible to users without programming skills. Efficient analysis methods are needed that are accessible to modelers and easy to use. Method: By converting discrete models into algebraic models, tools from computational algebra can be used to analyze their dynamics. Specifically, we propose a method to identify attractors of a discrete model that is equivalent to solving a system of polynomial equations, a long-studied problem in computer algebra. Results: A method for efficiently identifying attractors, and the web-based tool Analysis of Dynamic Algebraic Models (ADAM), which provides this and other analysis methods for discrete models. ADAM converts several discrete model types automatically into polynomial dynamical systems and analyzes their dynamics using tools from computer algebra. Based on extensive experimentation with both discrete models arising in systems biology and randomly generated networks, we found that the algebraic algorithms presented in this manuscript are fast for systems with the structure maintained by most biological systems, namely sparseness, i.e., while the number of nodes in a biological network may be quite large, each node is affected only by a small number of other nodes, and robustness, i.e., small number of attractors