21ENGBIO BBEB: Boosting the Bandwidth of Engineered Biology

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In natural biological systems many regulatory processes and functions operate with incredibly short timescales (within milliseconds). This enables organisms such as bacteria to rapidly change their behaviour in response to external triggers. In contrast, most engineered biological systems to date (e.g. bacterial cells containing synthetic networks of genes and proteins as circuits), operate with much longer timescales (tens of minutes). This is because they typically rely on the expression of genes, the production of proteins and the accumulation of sufficient concentrations of the fully folded active protein in the cell. We are defining this slow rate of sensing and production of a measurable response in engineered biological systems, as having "low bandwidth". To address this shortcoming of typical engineered biotechnologies, we aim to boost the bandwidth by combining cells containing completely novel, fast-acting, non-native biological circuits, with robotic measurement and actuation hardware, allowing rapid measurement and control of individual cells in an array. To realise this exciting and ambitious aim, we will divide the work into three components.The biological component of this work will focus on the construction of electron-conducting protein wires from the surface of a bacterial cell to specific protein targets inside the cell. Light-harvesting proteins will be introduced to harvest the energy of light at the cell membrane and drive electrons along these wires. Combinations of proteins that are able to receive and transfer electrons will be tested to propagate the signal along the wires. Finally, the electrons will be used to switch on and off important enzymes inside the cell, using a variety of processes that are highly-responsive to electron transfer. Once identified, we will fuse promising wire protein candidates to each other, using flexible amino-acid linkers, to optimise the switchability and specificity of the system. We believe this approach will allow us to realise engineered biological systems with the sub-second timescales that are crucial for complex biotechnologies.Supporting the biological engineering work, the team will develop an automated and massively parallelised experimental hardware platform that can interface with an off-the-shelf microscope. This platform will use a modified data projector to dynamically regulate the wavelength and intensity of light delivered to single-cells. This will be integrated with high-speed image processing and control algorithms to rapidly measure and regulate the behaviour of many cells simultaneously. Combining the above technologies, we will demonstrate an integrated platform for high-bandwidth engineered biology. This will be applied to realise rapid control of microbial pattern formation across hundreds of single-cells. Additionally, as a public engagement demonstrator, we will use the "bio-hybrid" platform to transmit real-time audio data, thereby acting as a "microbial telephone repeater". These demonstrations will form the basis of the longer-term vision of our project: to create the biological and robotic technologies required to dramatically increase the speed of action of engineered biotechnologies in disparate applications.