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Sensing the impossible, an engineering biology approach

Principal Supervisor: Professor Timothy Dafforn

Secondary Supervisor(s): TBC

University of Registration: University of Birmingham

BBSRC Research Themes:

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Deadline: 4 January, 2024


Project Outline

The Challenge

Engineering biology and its place in sensing

Imagine if we could tap into the natural magic of sensing! Creatures big and small respond to various signals, be it light, taste, odour, or even drugs. Think about sniffer dogs with their powerful noses – what if we could borrow that amazing power without actually needing the dog?

A long-term challenge of Engineering Biology (EB) (also known as synthetic biology) has been to harness natural systems to develop new and improved sensing systems. For example, one might be able to use cellular receptors to monitor hormones like insulin to control a disease, or detectors would be used to monitor different aspects of the food supply chain from detecting plant or animal diseases through to monitoring food spoilage. Alternatively, real neuronal receptors could be used to detect narcotics like fentanyl providing a detector that mimicked the human brain.

Our strategy to achieve this lofty ambition involves a “bottom up” approach where individual biological components, or small groups of components, are combined to produce a sensing element. This has the advantage of exploiting the unique capabilities of biological molecules without ethical issues associated with using GM organisms in the environment.

In our laboratory we have assembled an ensemble of methods and component systems that we have shown can be used to produce sensing systems of demonstrable global importance. These include pure samples of receptor proteins (including GPCRs) which bind and respond to specific chemical signals.

We have also developed a novel nanoencapsulation system (SMALPs) which stabillises these receptors and allows the development of sensing nano-particle that combines the GPCR with other elements required to generate a readable signal. We have also established connections with agricultural, medical and defence sectors who are interested in applying these sensors to real world problems.

The Scientific Background

The project proposed focuses on our development in 2009 of a novel method that allows us to make and stabilise membrane proteins that nature uses in sensing (1). The method (SMALPs) uses a polymer to encapsulate a sensing membrane protein complete with it’s surrounding lipid environment. We have shown that this is a generically applicable method that produces very stable and active samples of a wide range of membrane proteins. In this project our aim is exploit our previous work which shows that SMALPs can be used to make G-protein Coupled Receptors (2). GPCRs are “nature’s detector molecules” and have evolved to bind to an exceptionally wide range of ligands (including hormones, cell signalling molecules and neurotransmitters. Ligand binding induces these proteins to change shape. We have shown that we can detect this shape change (3) using fluorescence providing the route to a revolutionary new detection system based on GPCRs.

Work in the Project

The project will continue the work of a current MIBTP PhD student who has developed a production system for a range GPCR-SMALPs. These include hormone receptors, messenger receptors and a receptor for the active ingredient in cannabis. This new project will use these reagents to test different detection modalities including the use of fluorescence and electrochemical detection. The project will aim to develop a platform approach to harnessing these GPCR-SMALPs for an entirely new generation of molecular detectors.

References

  1. Knowles, T.J., et al., J Am Chem Soc, 2009. 131(22): p. 7484-5.
  2. Grime R.L. et al.,Nanoscale. 2021 Aug 21;13(31):13519-13528,
  3. Routledge S. J. et al., Biochim Biophys Acta Biomembr. 2020 Jun 1;1862(6):183235

Techniques

  • Engineering Biology “Design, Build, Test” approaches
  • Membrane protein expression, extraction and purification
  • Biophysics (including fluorescence, absorbance, circular dichroism, analytical ultracentrifugation, dynamic light scattering).
  • Imaging including electron and fluorescence microscopy
  • Polymer chemistry
  • Robotics automation and control
  • Assay design and development