Until very recently Systems Biology has, despite its stated goals, been too reductive in terms of the models being constructed and the methods used have been, on the one hand, unsuited for large scale adoption or integration of knowledge across scales, and on the other hand, too fragmented. The thesis of this dissertation is that better computational languages and seamlessly integrated tools are required by systems and synthetic biologists to enable them to meet the significant challenges involved in understanding life as it is, and by designing, modelling and manufacturing novel organisms, to understand life as it could be. We call this goal, where everything necessary to conduct model-driven investigations of cellular circuitry and emergent effects in populations of cells is available without significant context-switching, “one-pot” in silico synthetic systems biology in analogy to “one-pot” chemistry and “one-pot” biology. Our strategy is to increase the understandability and reusability of models and experiments, thereby avoiding unnecessary duplication of effort, with practical gains in the efficiency of delivering usable prototype models and systems. Key to this endeavour are graphical interfaces that assists novice users by hiding complexity of the underlying tools and limiting choices to only what is appropriate and useful, thus ensuring that the results of in silico experiments are consistent, comparable and reproducible. This dissertation describes the conception, software engineering and use of two novel software platforms for systems and synthetic biology: the Infobiotics Workbench for modelling, in silico experimentation and analysis of multi-cellular biological systems; and DNA Library Designer with the DNALD language for the compact programmatic specification of combinatorial DNA libraries, as the first stage of a DNA synthesis pipeline, enabling methodical exploration biological problem spaces. Infobiotics models are formalised as Lattice Population P systems, a novel framework for the specification of spatially-discrete and multi-compartmental rule-based models, imbued with a stochastic execution semantics. This framework was developed to meet the needs of real systems biology problems: hormone transport and signalling in the root of Arabidopsis thaliana, and quorum sensing in the pathogenic bacterium Pseudomonas aeruginosa. Our tools have also been used to prototype a novel synthetic biological system for pattern formation, that has been successfully implemented in vitro. Taken together these novel software platforms provide a complete toolchain, from design to wet-lab implementation, of synthetic biological circuits, enabling a step change in the scale of biological investigations that is orders of magnitude greater than could previously be performed in one in silico “pot”.

Unconventional computing is an area of research in which novel materials and paradigms are utilised to implement computation and data storage. This includes attempts to embed computation into biological systems, which could allow the observation and modification of living processes. This thesis explores the storage and computational capabilities of a biocompatible light-sensitive (photochromic) molecular switch (NitroBIPS) that has the potential to be embedded into both natural and synthetic biological systems. To achieve this, NitroBIPS was embedded in a (PDMS) polymer matrix and an optomechanical setup was built in order to expose the sample to optical stimulation and record fluorescent emission. NitroBIPS has two stable forms - one fluorescent and one non-fluorescent - and can be switched between the two via illumination with ultraviolet or visible light. By exposing NitroBIPS samples to specific stimulus pulse sequences and recording the intensity of fluorescence emission, data could be stored in registers and logic gates and circuits implemented. In addition, by moving the area of illumination, sub-regions of the sample could be addressed. This enabled parallel registers, Turing machine tapes and elementary cellular automata to be implemented. It has been demonstrated, therefore, that photochromic molecular memory can be used to implement conventional universal computation in an unconventional manner. Furthermore, because registers, Turing machine tapes, logic gates, logic circuits and elementary cellular automata all utilise the same samples and same hardware, it has been shown that photochromic computational devices can be dynamically repurposed. NitroBIPS and related molecules have been shown elsewhere to be capable of modifying many biological processes. This includes inhibiting protein binding, perturbing lipid membranes and binding to DNA in a manner that is dependent on the molecule's form. The implementation of universal computation demonstrated in this thesis could, therefore, be used in combination with these biological manipulations as key components within synthetic biology systems or in order to monitor and control natural biological processes.

Le ZX-Calculus est un langage graphique puissant et intuitif, issu de la théorie des catégories, et qui permet de raisonner et calculer en quantique. Les évolutions quantiques sont vues dans ce formalisme comme des graphes ouverts, ou diagrammes, qui peuvent être transformés localement selon un ensemble d’axiomes qui préservent le résultat du calcul. Un aspect des plus importants du langage est sa complétude : Étant donnés deux diagrammes qui représentent la même évolution quantique, puis-je transformer l’un en l’autre en utilisant seulement les règles graphiques permises par le langage ? Si c’est le cas, cela veut dire que le langage graphique capture entièrement la mécanique quantique. Le langage est connu comme étant complet pour une sous-classe (ou fragment) particulière d’évolutions quantiques, appelée Clifford. Malheureusement, celle-ci n’est pas universelle : on ne peut pas représenter, ni même approcher, certaines évolutions. Dans cette thèse, nous proposons d’élargir l’ensemble d’axiomes pour obtenir la complétude pour des fragments plus grands du langage, qui en particulier sont approximativement universels, voire universels. Pour ce faire, dans un premier temps nous utilisons la complétude d’un autre langage graphique et transportons ce résultat au ZX-Calculus. Afin de simplifier cette fastidieuse étape, nous introduisons un langage intermédiaire, intéressant en lui-même car il capture un fragment particulier mais universel de la mécanique quantique : Toffoli-Hadamard. Nous définissons ensuite la notion de diagramme linéaire, qui permet d’obtenir une preuve uniforme pour certains ensembles d’équations. Nous définissons également la notion de décomposition d’un diagramme en valeurs singuliaires, ce qui nous permet de nous épargner un grand nombre de calculs. Dans un second temps, nous définissons une forme normale qui a le mérite d’exister pour une infinité de fragments du langage, ainsi que pour le langage lui-même, sans restriction. Grâce à cela, nous reprouvons les résultats de complétude précédents, mais cette fois sans utiliser de langage tiers, et nous en dérivons de nouveaux, pour d’autres fragments. Les états contrôlés, utilisés pour la définition de forme normale, s’avèrent en outre utiles pour réaliser des opérations non-triviales telles que la somme, le produit terme-à-terme, ou la concaténation. / The ZX-Calculus is a powerful and intuitive graphical language, based on category theory, that allows for quantum reasoning and computing. Quantum evolutions are seen in this formalism as open graphs, or diagrams, that can be transformed locally according to a set of axioms that preserve the result of the computation. One of the most important aspects of language is its completeness: Given two diagrams that represent the same quantum evolution, can I transform one into the other using only the graphical rules allowed by the language? If this is the case, it means that the graphical language captures quantum mechanics entirely. The language is known to be complete for a particular subclass (or fragment) of quantum evolutions, called Clifford. Unfortunately, this one is not universal: we cannot represent, or even approach, certain quantum evolutions. In this thesis, we propose to extend the set of axioms to obtain completeness for larger fragments of the language, which in particular are approximately universal, or even universal. To do this, we first use the completeness of another graphical language and transport this result to the ZX-Calculus. In order to simplify this tedious step, we introduce an intermediate language, interesting in itself as it captures a particular but universal fragment of quantum mechanics: Toffoli-Hadamard. We then define the notion of a linear diagram, which provides a uniform proof for some sets of equations. We also define the notion of singular value decomposition of a diagram, which allows us to avoid a large number of calculations. In a second step, we define a normal form that exists for an infinite number of fragments of the language, as well as for the language itself, without restriction. Thanks to this, we reprove the previous completeness results, but this time without using any third party language, and we derive new ones for other fragments. The controlled states, used for the definition of the normal form, are also useful for performing non-trivial operations such as sum, term-to-term product, or concatenation.