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Integrating CRISPR-Cas diagnostics into organic electronics for point-of-care genotyping

   Department of Materials

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  Dr L Wong, Dr Antony Adamson, Prof M Turner, Prof B Newman  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

To apply for this programme, please visit Informal enquiries are welcome, to [Email Address Removed].

ABM CDT Gentamicin is an aminoglycoside antibiotic commonly used to treat neonatal infections. Each year in the UK, approximately 90,000 babies are administered gentamicin on Neonatal Intensive Care Units (~7 million worldwide). National and international guidelines stress the importance of rapid antibiotic administration, ideally within an hour for cases of suspected sepsis.

In high doses, or with protracted regimens, aminoglycosides causes ototoxicity that can manifest as hearing or balance impairment. However, certain individuals have a genetic predisposition to aminoglycoside induced ototoxicity (AIO), whereby just a single dose causes profound and irreversible hearing loss. These individuals have a variant in the mitochondrial RNR1 gene (m.1555A→G), which has a prevalence of 0.2% (1 in 500) in the general population. A method to rapidly (within minutes) determine a patient’s genetic status from a buccal swab sample would therefore be of significant clinical value, by establishing if alternative antibiotics should be used instead to avoid AIO.

This project aims to develop a bioelectronic device to detect the m.1555 variant from human buccal samples. Currently, a patient’s genetic status is determined by PCR-based methods that require complex laboratory equipment, expensive reagents, specialist personnel, and are insufficiently rapid for this clinical scenario. The proposed device will biochemically detect the presence of the variant and deliver an easily interpretable digital read-out. Such an electronic output can then be transferred to a patient’s electronic records, without the need for manual interpretation and transcription of the results, thus saving time and reducing the risk of human error.

Main questions to be answered:

The proposed device will consist of electrolyte-gated organic field-effect transistors (EGOFETs) functionalised with RNA signal strands. This device will be used in conjunction with an enzyme called Cas13 (derived from CRISPR gene editing technology) that can be “programmed” to recognise specific gene sequences. Upon binding of the target sequence, the activated Cas13 will degrade the RNA strands on the EGOFET, resulting in a change in the output characteristics (e.g. current, threshold voltage, sub-threshold slope) that indicate a positive result.

The underlying technologies related to EGOFET-based devices and Cas13-based sequence recognition are already well-established. Thus, the main questions are (in order of the proposed research plan):

  1. What surface chemistries are required to immobilise the RNA on to a range of EGOFET devices in a stable and enzymatically-processable form?
  2. Can degradation of the RNA probes from (1) result in a detectible change in EGOFET output characteristics, and to what level of sensitivity?
  3. What amount of target DNA that is required to activate the Cas13 protein to confer sufficient RNA-degrading activity for (2)?
  4. Is sample DNA preamplification of the necessary to achieve (3)?
  5. What sample preparation is necessary for patient swabs to be used with the proposed device?

University of Manchester, Department of Materials - 19 PhD Projects Available

University of Sheffield, Department of Materials Science and Engineering, 7 PhD Projects Available

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