Yes / We present the Infobiotics Workbench (IBW), a user-friendly, scalable, and integrated computational environment for the computer-aided design of synthetic biological systems. It supports an iterative workflow that begins with specification of the desired synthetic system, followed by simulation and verification of the system in high- performance environments and ending with the eventual compilation of the system specification into suitable genetic constructs. IBW integrates modelling, simulation, verification and bicompilation features into a single software suite. This integration is achieved through a new domain-specific biological programming language, the Infobiotics Language (IBL), which tightly combines these different aspects of in silico synthetic biology into a full-stack integrated development environment. Unlike existing synthetic biology modelling or specification languages, IBL uniquely blends modelling, verification and biocompilation statements into a single file. This allows biologists to incorporate design constraints within the specification file rather than using decoupled and independent formalisms for different in silico analyses. This novel approach offers seamless interoperability across different tools as well as compatibility with SBOL and SBML frameworks and removes the burden of doing manual translations for standalone applications. We demonstrate the features, usability, and effectiveness of IBW and IBL using well-established synthetic biological circuits. / The work of S.K. is supported by EPSRC (EP/R043787/1). N.K., A.W., and B.B. acknowledge a Royal Academy of Engineering Chair in Emerging Technologies award and an EPSRC programme grant (EP/N031962/1).

By increasing the level of abstraction in the representation of regulatory network models, we can hope to allow modelers to create models that are beyond the threshold of what can currently be expressed reliably. As hundreds of reactions are difficult to understand, maintain, and extend, thousands of reactions become next to impossible without any automation or aid. Using the multistate-species concept we can reduce the number of reactions needed to represent certain systems and thus, lessen the cognitive load on modelers. A multistate species is an entity with a defined range for state variables, which refers to a group of different forms for a specific species. A multistate reaction involves one or more multistate species and compactly represents a group of similar single reactions. In this work, we have extended JCMB (the JigCell Model Builder) to comply with multistate species and reactions modeling and presented a proposal for enhancing SBML (the Systems Biology Markup Language) standards to support multistate models. / Master of Science

Over the past 10 years, several synthetic biology research groups have proposed tools and domain-specific languages to help with the design of artificial DNA molecules. Community standards for exchanging data between these tools, such as the Synthetic Biology Open Language (SBOL), have been developed. It is increasingly important to be able to perform in silico simulation before the time and cost consuming wet lab realization of the constructs, which, as technology advances, also become in themselves more complex. By extending the concept of describing genetic expression as a language, we propose to model relations between genotype and phenotype using formal language theory. We use attribute grammars (AGs) to extract context-dependent information from genetic constructs and compile them into mathematical models, possibly giving clues about their phenotypes. They may be used as a backbone for biological Domain-Specific Languages (DSLs) and we developed a methodology to design these AG based DSLs. We gave examples of languages in the field of synthetic biology to model genetic regulatory networks with Ordinary Differential Equations (ODEs) based on various rate laws or with discrete boolean network models. We implemented a demonstration of these concepts in GenoCAD, a Computer Assisted Design (CAD) software for synthetic biology. GenoCAD guides users from design to simulation. Users can either design constructs with the attribute grammars provided or define their own project-specific languages. Outputting the mathematical model of a genetic construct is performed by DNA compilation based on the attribute grammar specified; the design of new languages by users necessitated the generation on-the-fly of such attribute grammar based DNA compilers. We also considered the impact of our research and its potential dual-use issues. Indeed, after the design exploration is performed in silico, the next logical step is to synthesize the designed construct's DNA molecule to build the construct in vivo. We implemented an algorithm to identify sequences of concern of any length that are specific to Select Agents and Toxins, helping to ensure safer use of our methods. / Ph. D.

The ever-growing size and complexity of molecular network models makes them difficult to construct and understand. Modifying a model that consists of tens of reactions is no easy task. Attempting the same on a model containing hundreds of reactions can seem nearly impossible. We present the JigCell Model Connector, a software tool that supports large-scale molecular network modeling. Our approach to developing large models is to combine together smaller models, making the result easier to comprehend. At the base, the smaller models (called modules) are defined by small collections of reactions. Modules connect together to form larger modules through clearly defined interfaces, called ports. In this work, we enhance the port concept by defining different types of ports. Not all modules connect together the same way, therefore multiple connection options need to exist. / Master of Science