Genetically ENgineered BIOsensors to detect BIological Threats (GENBIOBIT): Influenza A Virus

Lead Research Organisation: University of Edinburgh
Department Name: MRC Centre for Regenerative Medicine

Abstract

We want to pioneer a new class of genetically engineered biosensors that can rapidly, sensitively and efficiently detect and diagnose infectious diseases to address the fast-changing landscape of human and animal population biosurveillance. Infectious diseases and emerging biological threats (natural, accidental or deliberate) are a challenge to UK security. We aim to deliver a step-change in current technological capability to overcome the current barriers that prevent cell-based biosensors to work in the field without sample preparation at ambient temperature for a prolonged period of time.

This new technology could be part of a nationwide biosurveillance network of multiple biological threats with large economic and societal impact.

In particular, we want to establish proof-of-feasibility for the influenza A virus. IAVs have proven potential to damage livestock welfare and productivity, as well as to cause human pandemics. They thrive in wild animal populations and can transmit to farmed animals. As well as causing direct economic harm, this then provides a gateway for zoonotic infections (e.g. avian H5N1 and swine H1N1 subtypes). The worst recorded instance is the 1918 pandemic that resulted in the deaths of more than 50 million people. To reduce economic impacts as well as public health risk, there is a need to monitor and control the disease in the animal source.

Despite multiple IAVs biosensors have been developed in the lab, there is currently no practical applications. We wish to introduce a key innovation that will enable their use in the field, and in particular in animal drinkers. The key innovation is a synthetic membrane receptor that 1) has an extracellular domain that is highly selective to IAVs 2) has an intra-cellular domain that activates specific genes of interest controlling cell behavior upon virus binding 3) can be expressed in a resilient cell line originating from rainbow trout gills, that was demonstrated to survive over a range of temperature from more than a year in the field without maintenance to test water toxicity. Finally, by combining multielectrode arrays and multiple engineered cell lines (with the same selectivity to the virus but encoding different cell behavior) we will have a multiplexed electronic readout improving considerably the robustness and its potential to discriminate (diagnose) IAVs from others biological threats (toxins, bacteria, viruses) with faster response time and sensitivity than signals associated with pathogen associated cell death.

Phone-sized hybrid sensors (containing several gene-engineered cells interrogated in parallel by multi-electrode arrays) will be demonstrated in the lab (TRL3) to detect and discriminate between IAVs and other pathogens or toxins.

Our approach harnesses synthetic biology and data science to monitor existing infectious diseases and thus rapidly adapt to emerging biological threats. The extra-cellular part of the synthetic receptor can be quickly re-engineered to address other biological threats. Genetically engineered Biosensors will pave the way towards networks of biosensors that can be deployed in the field sampling water (drinkers, ponds, lakes) or volatiles (e.g. in air conditioning system) and could directly alert or feed real-time data to monitoring centres. This novel technology, demonstrated with a portable biosensor detecting IAV, will also provide a broader impact on the life science community for which novel tools for the detection of target binding are highly desirable (e.g. drug screening, infectious diseases). This will also provide a new tool for the emerging field of bio-computation. This is a highly interdisciplinary project with great potential for the PDRAs involved to work across the discipline of virology, synthetic biology and biosensing.

Technical Summary

We wish to introduce a key innovation that will enable the use of influenza A biosensors in the field, and in particular in animal drinkers. The key innovation is a biosensor with engineered cell lines that express a synthetic membrane receptor that: 1) has an extracellular domain that is highly selective to IAVs; 2) has an intra-cellular domain that activates specific genes of interest controlling cell behavior upon virus binding; 3) can be expressed in a resilient cell line originating from rainbow trout gills, that was demonstrated to survive over a range of temperature from more than a year to test water toxicity. Finally, by combining multielectrode arrays and multiple engineered cell lines (with the same selectivity to the virus but encoding different cell behavior) we will have a multiplexed electronic readout improving considerably the robustness and its potential to discriminate (diagnose) IAVs from others biological threats (toxins, bacteria, viruses) and with a faster response time and sensibility than signals associated with natural pathogen-induced cell death.
Phone-sized hybrid sensors (containing several gene-engineered cells interrogated in parallel by multi-electrode arrays) will be demonstrated in the lab (TRL3) to detect and discriminate between IAVs and other pathogens/toxins.

Publications

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