Control Engineering Inspired Design Tools for Synthetic Biology

Recent technological advances allow us to manipulate the circuitry inside cells and to modify their behaviour. Moreover, we can now design entirely new circuits within cells. This ability parallels the technological advances in Electrical Engineering in the mid-20th century and the potential of this new technology is being recognised throughout the world. This new field, which goes under the name of Synthetic Biology , has been described as the Engineering of Biology .This field is in its infancy and inevitably faces several challenges. For example, current practice concentrates on the design of very simple circuits by putting together several components/parts that are believed to be characterised adequately. When implemented, these circuits almost never work as expected not least because of the uncertainties/noise that are present inside cells, the level of cross-talk with other circuits inside cells as well as the limitations posed by measurement and implementation technologies. In fact the design/redesign process is still more of an art rather a technology, in that it is mainly based on intuition and moreover, uncertainties/noise and crosstalk are not taken into account at the design stage. For Synthetic Biology to fulfil its potential and be able to produce large-scale biocircuits with richer functionality, the design cycle needs to take into consideration all available biological 'knobs' that could be used to tune the circuit's behaviour, as well as the uncertainties of the environment in which these circuits will need to function.In this project we propose a systematic design approach that uses engineering principles for the analysis and design of biological networks. The objective is to develop a new design cycle, inspired from control engineering practice but adapted to the constraints and needs of synthetic biology for the design of biosystems that behave in a predictable fashion. This engineering cycle will be exemplified on three systems of fundamental importance, i.e., oscillators, filters and switches with the goal of optimising their performance in such a way that they work reliably within uncertain environments. This research will be undertaken at Engineering and Life sciences departments in the three institutions involved in this research (the University of Oxford, the University of Cambridge and Imperial College London) and will be supported externally with international project partners who will collaborate on this project (California Institute of Technology (CalTech), Eidgenossische Technische Hochschule (ETH) Zurich, and the Massachusetts Institute of Technology (MIT)).

Synthetic Biology is a new interdisciplinary area that has enormous potential for economic impact through the development of new biological systems to produce consumer products in medicine, smart materials, food, bioreactors and biofuels, to name a few. However, there is currently need for rigorous tools to make the design of biological systems more systematic so that the resulting biological networks behave in a reliable, efficient manner in the uncertain environment of the cell and optimise their performance. In the proposed research, we will develop a bio-inspired design cycle for Synthetic Biology which builds on methodologies and techniques that have been used extensively for years in engineering for the design of technological and other systems so that they work reliably in uncertain environments. As soon as these tools are developed, Synthetic Biology research will benefit directly and this will eventually mean that the design of several consumer and industrial products will perform efficiently and reliably with guaranteed performance. In effect, beneficiaries of this research will include Industry, policy-makers and the wider public, independent of the application area in which this framework will be used. For example, if the application is biomedical, e.g., the design of molecular medical devices, then society as a whole will benefit from the reliable production of such devices, as well as the pharmaceutical Industry and policy-makers. Similarly, if the aim is energy production (e.g., by developing photosynthetic pathways) then beneficiaries could include all these groups. The same holds if the aim is bioremediation (e.g., by developing biosensors for environmental cleanup) or indeed for any other application area. Overall the outcomes of this research will impact positively on UK's health and wealth as it will facilitate Synthetic Biology to fulfil its potential to generate a new set of wealth-creating industries, which will improve the economic competitiveness of the UK. Moreover, some of the application areas could have a direct impact on the quality of life and health of society. Even if some of these application areas have already had an impact this is small compared to the improved functionality that our design framework will provide to the designs. In that sense, our research is of transformative nature to these Industries. However, this could take more than 5 years to have a direct impact depending on the uptake of these tools by Industry. To facilitate uptake, the staff that will be working on this project will develop the necessary research and professional skills to use these tools independent of the specific application area. The integration of the project means that all 3 PDRAs will have the opportunity to interact and learn all techniques in the three parts of the project. They will also undergo media training and learn to appreciate the ethical, legal and societal issues surrounding Synthetic Biology. In terms of societal impact, if Synthetic Biology design is done in a proper manner then potential safety risks are reduced and hence society as a whole will benefit. To ensure that all the aforementioned groups benefit from this research, we have set up a detailed Impact plan which includes collaboration with three internationally leading institutions in Synthetic Biology (Caltech, MIT and ETHZ) who will be heavily engaged in this project. Through this collaboration we will aim to extend the impact of our methods to their own collaborators and industry in these countries by arranging visits/seminars to nearby universities etc. There will be several opportunities to disseminate our research to the wider community and Industry at several conferences. We have extensive experience to that end, collectively through RoSBNet but also through the research/industrial collaborators of each of the investigators on this proposal.