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We present a framework called the Reasoning Engine, which implements Satisfiability Modulo Theories (SMT)-based methods within a unified computational environment to address diverse biological analysis problems. The Reasoning Engine was used to reproduce results from key scientific studies, as well as supporting new research in stem cell biology. The framework utilizes an intermediate language for encoding partially specified discrete dynamical systems, which bridges the gap between high-level domain-specific languages and low-level SMT solvers. We provide this framework as open source together with various biological case studies, illustrating the synthesis, enumeration, optimization, and reasoning over models consistent with experimental observations to reveal novel biological insights.

Computational modelling of metabolic processes has proven to be a useful approach to formulate our knowledge and improve our understanding of core biochemical systems that are crucial to maintaining cellular functions. Towards understanding the broader role of metabolism on cellular decision-making in health and disease conditions, it is important to integrate the study of metabolism with other core regulatory systems and omics within the cell, including gene expression patterns. After quantitatively integrating gene expression profiles with a genome-scale reconstruction of human metabolism, we propose a set of combinatorial methods to reverse engineer gene expression profiles and to find pairs and higher-order combinations of genetic modifications that simultaneously optimize multi-objective cellular goals. This enables us to suggest classes of transcriptomic profiles that are most suitable to achieve given metabolic phenotypes. We demonstrate how our techniques are able to compute beneficial, neutral or "toxic" combinations of gene expression levels. We test our methods on nine tissue-specific cancer models, comparing our outcomes with the corresponding normal cells, identifying genes as targets for potential therapies. Our methods open the way to a broad class of applications that require an understanding of the interplay among genotype, metabolism, and cellular behaviour, at scale.

Background: Reconstruction of executable mechanistic models from single-cell gene expression data represents a powerful approach to understanding developmental and disease processes. New ambitious efforts like the Human Cell Atlas will soon lead to an explosion of data with potential for uncovering and understanding the regulatory networks which underlie the behaviour of all human cells. In order to take advantage of this data, however, there is a need for general-purpose, user-friendly and efficient computational tools that can be readily used by biologists who do not have specialist computer science knowledge., Results: The Single Cell Network Synthesis toolkit (SCNS) is a general-purpose computational tool for the reconstruction and analysis of executable models from single-cell gene expression data. Through a graphical user interface, SCNS takes single-cell qPCR or RNA-sequencing data taken across a time course, and searches for logical rules that drive transitions from early cell states towards late cell states. Because the resulting reconstructed models are executable, they can be used to make predictions about the effect of specific gene perturbations on the generation of specific lineages., Conclusions: SCNS should be of broad interest to the growing number of researchers working in single-cell genomics and will help further facilitate the generation of valuable mechanistic insights into developmental, homeostatic and disease processes.

We consider the problem of automatically and efficiently computing models of constraints, in the presence of complex background theories such as floating-point arithmetic. Constructing models, or proving that a constraint is unsatisfiable, has various applications, for instance for automatic generation of test inputs. It is well-known that a naïve encoding of constraints into simpler theories (for instance, bit-vectors or propositional logic) often leads to a drastic increase in size, or that it is unsatisfactory in terms of the resulting space and runtime demands. We define a framework for systematic application of approximations in order to improve performance. Our method is more general than previous techniques in the sense that approximations that are neither under- nor over-approximations can be used, and it shows promising performance on practically relevant benchmark problems.

Studying the gene regulatory networks (GRNs) that govern how cells change into specific cell types with unique roles throughout development is an active area of experimental research. The fate specification process can be viewed as a biological program prescribing the system dynamics, governed by a network of genetic interactions. To investigate the possibility that GRNs are not fixed but rather change their topology, for example as cells progress through commitment, we introduce the concept of Switching Gene Regulatory Networks (SGRNs) to enable the modelling and analysis of network reconfiguration. We define the synthesis problem of constructing SGRNs that are guaranteed to satisfy a set of constraints representing experimental observations of cell behaviour. We propose a solution to this problem that employs methods based upon Satisfiability Modulo Theories (SMT) solvers, and evaluate the feasibility and scalability of our approach by considering a set of synthetic benchmarks exhibiting possible biological behaviour of cell development. We outline how our approach is applied to a more realistic biological system, by considering a simplified network involved in the processes of neuron maturation and fate specification in the mammalian cortex., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)