Engineering Fellowships For Growth: Designing Feedback Control in Biology for Robustness and Scalability

Synthetic Biology is the "Engineering of Biology": it aspires to use the Engineering design cycle to produce bio-circuits that behave predictably and reliably, usually with specific applications in mind. Synthetic Biology has the potential to create new industries and technologies in several sectors, from agriculture to the environment, and from energy to healthcare. Some of these applications require Synthetic Biology designs to be scalable, so that small circuits can be composed to form larger systems. Currently, however, even small bio-circuits seldom function as expected because of the high level of uncertainty in the cellular environment, the way poorly-characterized parts are assembled together and the lack of a systematic framework for integrating parts to form systems. This is a major challenge that needs to be overcome in order for the potential of Synthetic Biology to be fulfilled and for industry and society to reap the rewards.

Natural systems use several mechanisms to overcome this major challenge. The most important one involves careful use of feedback control. This is done at all levels of organization - from the genetic, metabolic, cellular to the systems level. The regulation of biochemical processes inside a cell is key for ensuring robust functionality despite the high levels of environmental uncertainty and intrinsic and extrinsic noise.

This Fellowship application will use a systems and control engineering approach, based on modelling, abstraction, standardization and the development of new bio-feedback modules to target specific uncertainties in the cell. I will create an interdisciplinary research team which will demonstrate that through careful design and implementation of feedback control components, the functionality of the rest of the designed circuitry can be made robust and allow scalability. The feedback designs will be done at multiple organizational scales and interactions (genetic, signalling and cell-cell), which will be implemented in the laboratory, demonstrating the effectiveness of the approach.

Synthetic Biology is expected to have significant impact on the economy and society, as outlined in the recent UK Synthetic Biology Roadmap for the UK. Currently, Synthetic Biology constructs do not operate as intended, as they suffer from the uncertainty of the cellular environment in which they have to operate. Moreover, our ability to interconnect them to form larger systems is limited.

The aim of this research fellowship is to develop bio-feedback control modules that can be used by Synthetic Biologists to improve the robustness of their constructs, but also to improve their composability. Allowing scalability and robustness of these modules will undoubtedly have a large impact on the economy and society.

In particular, using feedback control at various scales will bring significant industrial and economic benefits. Industries in which this research has a large potential for economic impact include pharmaceuticals, energy, and agriculture. In the medium to long term, possible applications of synthetic biological systems have been proposed in biosynthesis (including biofuels), biosensors, environmental clean-up, smart materials, etc. Another major long-term potential application of Synthetic Biology will bring wider benefits to society through the development of personalised medicine, with therapies delivered through the application of functionally engineered cells.

In order to realize the full potential of Synthetic Biology to perform the variety of tasks specific to this large number of industrial applications, it is rapidly becoming critical for simple isolated systems to be able to be combined to allow the design of the increasingly sophisticated functions envisioned. For industrial relevance, the design of biological systems needs to be specified at a high, functional level, which is currently not attainable due to the unreliability of the synthetic components at our disposal in the presence of uncertainty when implemented in the cell. This research will be crucial to providing the standardized framework needed to allow the design of biological systems to be scaled to the required level.

At the societal level, it is important that researchers and users of Synthetic Biology are engaged with the wider public as research progresses. There are widely-held concerns over the ethical and safety implications of many aspects of the manipulation and creation of biological systems. This research is intended to apply the principles of Control Engineering to Synthetic Biology. Robust control theory is expressly concerned with ensuring the reliability and safety of engineered systems in the presence of uncertainty. Therefore a key impact of this research will be to help to transform the public perception of Synthetic Biology from a collection of ad hoc methods into a formal engineering discipline.