Synthetic biology: advancing biological frontiers by building synthetic systems

Advances in synthetic biology are contributing to diverse research areas, from basic biology to biomanufacturing and disease therapy. We discuss the theoretical foundation, applications, and potential of this emerging field

Model Checking Tap Withdrawal in C. Elegans

We present what we believe to be the first formal verification of a biologically realistic (nonlinear ODE) model of a neural circuit in a multicellular organism: Tap Withdrawal (TW) in \emph{C. Elegans}, the common roundworm. TW is a reflexive behavior exhibited by \emph{C. Elegans} in response to vibrating the surface on which it is moving; the neural circuit underlying this response is the subject of this investigation. Specifically, we perform reachability analysis on the TW circuit model of Wicks et al. (1996), which enables us to estimate key circuit parameters. Underlying our approach is the use of Fan and Mitra's recently developed technique for automatically computing local discrepancy (convergence and divergence rates) of general nonlinear systems. We show that the results we obtain are in agreement with the experimental results of Wicks et al. (1995). As opposed to the fixed parameters found in most biological models, which can only produce the predominant behavior, our techniques characterize ranges of parameters that produce (and do not produce) all three observed behaviors: reversal of movement, acceleration, and lack of response

Algorithmic Verification of Continuous and Hybrid Systems

We provide a tutorial introduction to reachability computation, a class of computational techniques that exports verification technology toward continuous and hybrid systems. For open under-determined systems, this technique can sometimes replace an infinite number of simulations.Comment: In Proceedings INFINITY 2013, arXiv:1402.661

Qualitative System Identification from Imperfect Data

Experience in the physical sciences suggests that the only realistic means of understanding complex systems is through the use of mathematical models. Typically, this has come to mean the identification of quantitative models expressed as differential equations. Quantitative modelling works best when the structure of the model (i.e., the form of the equations) is known; and the primary concern is one of estimating the values of the parameters in the model. For complex biological systems, the model-structure is rarely known and the modeler has to deal with both model-identification and parameter-estimation. In this paper we are concerned with providing automated assistance to the first of these problems. Specifically, we examine the identification by machine of the structural relationships between experimentally observed variables. These relationship will be expressed in the form of qualitative abstractions of a quantitative model. Such qualitative models may not only provide clues to the precise quantitative model, but also assist in understanding the essence of that model. Our position in this paper is that background knowledge incorporating system modelling principles can be used to constrain effectively the set of good qualitative models. Utilising the model-identification framework provided by Inductive Logic Programming (ILP) we present empirical support for this position using a series of increasingly complex artificial datasets. The results are obtained with qualitative and quantitative data subject to varying amounts of noise and different degrees of sparsity. The results also point to the presence of a set of qualitative states, which we term kernel subsets, that may be necessary for a qualitative model-learner to learn correct models. We demonstrate scalability of the method to biological system modelling by identification of the glycolysis metabolic pathway from data

Techniques for automated parameter estimation in computational models of probabilistic systems

The main contribution of this dissertation is the design of two new algorithms for automatically synthesizing values of numerical parameters of computational models of complex stochastic systems such that the resultant model meets user-specified behavioral specifications. These algorithms are designed to operate on probabilistic systems – systems that, in general, behave differently under identical conditions. The algorithms work using an approach that combines formal verification and mathematical optimization to explore a model\u27s parameter space. The problem of determining whether a model instantiated with a given set of parameter values satisfies the desired specification is first defined using formal verification terminology, and then reformulated in terms of statistical hypothesis testing. Parameter space exploration involves determining the outcome of the hypothesis testing query for each parameter point and is guided using simulated annealing. The first algorithm uses the sequential probability ratio test (SPRT) to solve the hypothesis testing problems, whereas the second algorithm uses an approach based on Bayesian statistical model checking (BSMC). The SPRT-based parameter synthesis algorithm was used to validate that a given model of glucose-insulin metabolism has the capability of representing diabetic behavior by synthesizing values of three parameters that ensure that the glucose-insulin subsystem spends at least 20 minutes in a diabetic scenario. The BSMC-based algorithm was used to discover the values of parameters in a physiological model of the acute inflammatory response that guarantee a set of desired clinical outcomes. These two applications demonstrate how our algorithms use formal verification, statistical hypothesis testing and mathematical optimization to automatically synthesize parameters of complex probabilistic models in order to meet user-specified behavioral propertie

Advancing functional connectivity research from association to causation

Cognition and behavior emerge from brain network interactions, such that investigating causal interactions should be central to the study of brain function. Approaches that characterize statistical associations among neural time series-functional connectivity (FC) methods-are likely a good starting point for estimating brain network interactions. Yet only a subset of FC methods ('effective connectivity') is explicitly designed to infer causal interactions from statistical associations. Here we incorporate best practices from diverse areas of FC research to illustrate how FC methods can be refined to improve inferences about neural mechanisms, with properties of causal neural interactions as a common ontology to facilitate cumulative progress across FC approaches. We further demonstrate how the most common FC measures (correlation and coherence) reduce the set of likely causal models, facilitating causal inferences despite major limitations. Alternative FC measures are suggested to immediately start improving causal inferences beyond these common FC measures

Modelling coordination in biological systems

We present an application of the Reo coordination paradigm to provide a compositional formal model for describing and reasoning about the behaviour of biological systems, such as regulatory gene networks. Reo governs the interaction and flow of data between components by allowing the construction of connector circuits which have a precise formal semantics. When applied to systems biology, the result is a graphical model, which is comprehensible, mathematically precise, and flexibl