title: Novel recurrent neural network for modelling biological networks: oscillatory p53 interaction dynamics.
abstract: Understanding the control of cellular networks consisting of gene and protein interactions and their emergent properties is a central activity of Systems Biology research. For this, continuous, discrete, hybrid, and stochastic methods have been proposed. Currently, the most common approach to modelling accurate temporal dynamics of networks is ordinary differential equations (ODE). However, critical limitations of ODE models are difficulty in kinetic parameter estimation and numerical solution of a large number of equations, making them more suited to smaller systems. In this article, we introduce a novel recurrent artificial neural network (RNN) that addresses above limitations and produces a continuous model that easily estimates parameters from data, can handle a large number of molecular interactions and quantifies temporal dynamics and emergent systems properties. This RNN is based on a system of ODEs representing molecular interactions in a signalling network. Each neuron represents concentration change of one molecule represented by an ODE. Weights of the RNN correspond to kinetic parameters in the system and can be adjusted incrementally during network training. The method is applied to the p53-Mdm2 oscillation system - a crucial component of the DNA damage response pathways activated by a damage signal. Simulation results indicate that the proposed RNN can successfully represent the behaviour of the p53-Mdm2 oscillation system and solve the parameter estimation problem with high accuracy. Furthermore, we presented a modified form of the RNN that estimates parameters and captures systems dynamics from sparse data collected over relatively large time steps. We also investigate the robustness of the p53-Mdm2 system using the trained RNN under various levels of parameter perturbation to gain a greater understanding of the control of the p53-Mdm2 system. Its outcomes on robustness are consistent with the current biological knowledge of this system. As more quantitative data become available on individual proteins, the RNN would be able to refine parameter estimation and mapping of temporal dynamics of individual signalling molecules as well as signalling networks as a system. Moreover, RNN can be used to modularise large signalling networks.
authors.affiliation: German Cancer Research Centre, Heildelberg, Germany; Centre for Advanced Computational Solutions (C-fACS), Lincoln University, Christchurch, New Zealand. Electronic address: h.ling@dkfz-heidelberg.de.
authors.forename: Hong
authors.initials: H
authors.lastname: Ling
authors.forename: Sandhya
authors.initials: S
authors.lastname: Samarasinghe
authors.forename: Don
authors.initials: D
authors.lastname: Kulasiri
mesh_terms: D003198:Computer Simulation; D006801:Humans; D016571:Neural Networks, Computer; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D049490:Systems Biology / Q000379:methods*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Artificial neural network; Biological robustness; Nonlinear ordinary differential equations; Recurrent neural networks; p53-Mdm2 oscillation system