Data integration strategies for informing computational design in synthetic biology

PhD ThesisThe potential design space for biological systems is complex, vast and multidimensional. Therefore, effective large-scale synthetic biology requires computational design and simulation. By constraining this design space, the time- and cost-efficient design of biological systems can be facilitated. One way in which a tractable design space can be achieved is to use the extensive and growing amount of biological data available to inform the design process. By using existing knowledge design efforts can be focused on biologically plausible areas of design space. However, biological data is large, incomplete, heterogeneous, and noisy. Data must be integrated in a systematic fashion in order to maximise its benefit. To date, data integration has not been widely applied to design in synthetic biology. The aim of this project is to apply data integration techniques to facilitate the efficient design of novel biological systems. The specific focus is on the development and application of integration techniques for the design of genetic regulatory networks in the model bacterium Bacillus subtilis. A dataset was constructed by integrating data from a range of sources in order to capture existing knowledge about B. subtilis 168. The dataset is represented as a computationally-accessible, semantically-rich network which includes information concerning biological entities and their relationships. Also included are sequence-based features mined from the B. subtilis genome, which are a useful source of parts for synthetic biology. In addition, information about the interactions of these parts has been captured, in order to facilitate the construction of circuits with desired behaviours. This dataset was also modelled in the form of an ontology, providing a formal specification of parts and their interactions. The ontology is a major step towards the unification of the data required for modelling with a range of part catalogues specifically designed for synthetic biology. The data from the ontology is available to existing reasoners for implicit knowledge extraction. The ontology was applied to the automated identification of promoters, operators and coding sequences. Information from the ontology was also used to generate dynamic models of parts. The work described here contributed to the development of a formalism called Standard Virtual Parts (SVPs), which aims to represent models of biological parts in a standardised manner. SVPs comprise a mapping between biological parts and modular computational models. A genetic circuit designed at a part-level abstraction can be investigated in detail by analysing a circuit model composed of SVPs. The ontology was used to construct SVPs in the form of standard Systems Biology Markup Language models. These models are publicly available from a computationally-accessible repository, and include metadata which facilitates the computational composition of SVPs in order to create models of larger biological systems. To test a genetic circuit in vitro or in vivo, the genetics elements necessary to encode the enitites in the in silico model, and their associated behaviour, must be derived. Ultimately, this process results in the specification for synthesisable DNA sequence. For large models, particularly those that are produced computationally, the transformation process is challenging. To automate this process, a model-to-sequence conversion algorithm was developed. The algorithm was implemented as a Java application called MoSeC. Using MoSeC, both CellML and SBML models built with SVPs can be converted into DNA sequences ready to synthesise. Selection of the host bacterial cell for a synthetic genetic circuit is very important. In order not to interfere with the existing cellular machinery, orthogonal parts from other species are used since these parts are less likely to have undesired interactions with the host. In order to find orthogonal transcription factors (OTFs), and their target binding sequences, a subset of the data from the integrated B. subtilis dataset was used. B. subtilis gene regulatory networks were used to re-construct regulatory networks in closely related Bacillus species. The system, called BacillusRegNet, stores both experimental data for B. subtilis and homology predictions in other species. BacillusRegNet was mined to extract OTFs and their binding sequences, in order to facilitate the engineering of novel regulatory networks in other Bacillus species. Although the techniques presented here were demonstrated using B. subtilis, they can be applied to any other organism. The approaches and tools developed as part of this project demonstrate the utility of this novel integrated approach to synthetic biology.EPSRC: NSF: The Newcastle University School of Computing Science

Determination of the Change in Electrical Conductivity of Single, Bimetallic and Trimetallic Cylindrical Billets with Plastic Deformation Induced by Upsetting Process

In this study, measurement of the effect of singular, bimetallic and multimetallic materials exposed to cold plastic deformation on electrical conductivity properties was investigated. The main subject of this research is plastic deformation occurring in the upsetting process and changing the conductivity properties of the parts. In the experiments, steel, aluminium, copper, brass, bimetallic and multimetallic materials designed with different combinations of these materials were used as test materials. Experimental upsetting tests were performed as a height reduction ratio 10%, 20% and 30%. The electrical conductivity measurement results of the deformed samples were obtained with a conductivity measuring device. The results obtained from the experiments are presented in graphs with electrical conductivity axis that change due to deformation. As a result of the experiments and measurements, it was concluded that the electrical conductivity of the deformed materials generally decreased slightly due to the plastic deformation of the deformed materials, and the bimetallic and multimetallic materials were similar to the properties of the majority material

ASSESSMENT OF MOTOR DEVELOPMENT OF PRESCHOOL CHILDREN WITH SPECIAL EDUCATION NEEDS

Assessment of motor development in preschool children has become increasingly important with the recent acknowledgement that motor impairment/deficit is linked with cognitive, language, social, and emotional difficulties. As there is lack of evidence regarding motor development and early intervention in children with special education needs (SEN), the purpose of this study was to assess the motor development of preschool students with SEN within the educational context to allow their teachers to design appropriate physical education activities to improve students’ motor proficiency. In the present study, the Peabody Developmental Motor Scales – Second Edition test battery was used with five groups of students with different SEN: (a) Autism Spectrum Disorder, (b) Down syndrome, (c) cerebral palsy, (d) mental disability, and (e) specific learning difficulties. Students were grouped on the basis of specific characteristics, such as gender and SEN, and statistically significant differences between groups were sought. Differences in the difficulties encountered during the subtests by children in different SEN groups were found, suggesting that evidence of certain motor weaknesses are more likely for children with specific SEN. An unsatisfactory level in overall performance in gross, fine, and total motor quotients confirmed the delayed motor development of students with SEN. The paper concludes with recommendations for an appropriate evaluative measure and early intervention programmes for children with specific motor impairments. Article visualizations

libSBOLj 2.0: A Java Library to Support SBOL 2.0

The Synthetic Biology Open Language (SBOL) is an emerging data standard for representing synthetic biology designs. The goal of SBOL is to improve the reproducibility of these designs and their electronic exchange between researchers and/or genetic design automation tools. The latest version of the standard, SBOL 2.0, enables the annotation of a large variety of biological components (e.g., DNA, RNA, proteins, complexes, small molecules, etc.) and their interactions. SBOL 2.0 also allows researchers to organize components into hierarchical modules, to specify their intended functions, and to link modules to models that describe their behavior mathematically. To support the use of SBOL 2.0, we have developed the libSBOLj 2.0 Java library, which provides an easy to use Application Programming Interface (API) for developers, including manipulation of SBOL constructs, serialization to and from an RDF/XML file format, and migration support in the form of conversion from the prior SBOL 1.1 standard to SBOL 2.0. This letter describes the libSBOLj 2.0 library and key engineering decisions involved in its design

A Genetic Circuit Compiler: Generating Combinatorial Genetic Circuits with Web Semantics and Inference

A central strategy of synthetic biology is to understand the basic processes of living creatures through engineering organisms using the same building blocks. Biological machines described in terms of parts can be studied by computer simulation in any of several languages or robotically assembled in vitro. In this paper we present a language, the Genetic Circuit Description Language (GCDL) and a compiler, the Genetic Circuit Compiler (GCC). This language describes genetic circuits at a level of granularity appropriate both for automated assembly in the laboratory and deriving simulation code. The GCDL follows Semantic Web practice, and the compiler makes novel use of the logical inference facilities that are therefore available. We present the GCDL and compiler structure as a study of a tool for generating k-language simulations from semantic descriptions of genetic circuits

SBOL-OWL: An ontological approach for formal and semantic representation of synthetic biology information

Standard representation of data is key for the reproducibility of designs in synthetic biology. The Synthetic Biology Open Language (SBOL) has already emerged as a data standard to represent information about genetic circuits, and it is based on capturing data using graphs. The language provides the syntax using a free text document that is accessible to humans only. This paper describes SBOL-OWL, an ontology for a machine understandable definition of SBOL. This ontology acts as a semantic layer for genetic circuit designs. As a result, computational tools can understand the meaning of design entities in addition to parsing structured SBOL data. SBOL-OWL not only describes how genetic circuits can be constructed computationally, it also facilitates the use of several existing Semantic Web tools for synthetic biology. This paper demonstrates some of these features, for example, to validate designs and check for inconsistencies. Through the use of SBOL-OWL, queries can be simplified and become more intuitive. Moreover, existing reasoners can be used to infer information about genetic circuit designs that cannot be directly retrieved using existing querying mechanisms. This ontological representation of the SBOL standard provides a new perspective to the verification, representation, and querying of information about genetic circuits and is important to incorporate complex design information via the integration of biological ontologies

Synthetic Biology Open Language (SBOL) Version 2.2.0.

Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The synthetic biology open language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.2.0 of SBOL that builds upon version 2.1.0 published in last year's JIB special issue. In particular, SBOL 2.2.0 includes improved description and validation rules for genetic design provenance, an extension to support combinatorial genetic designs, a new class to add non-SBOL data as attachments, a new class for genetic design implementations, and a description of a methodology to describe the entire design-build-test-learn cycle within the SBOL data model