OxTB: Cambridge and Oxford, UK

This team successfully won a Discovery Award seed-funding grant to help further develop their ideas for their Longitude Prize application and create a diagnostic test  that helps solve the problem of global antibiotic resistance. Below we have asked them to explain their test and motivation for applying.

Please explain your test. 

Tuberculosis (TB) is a disease that has been with us for thousands of years. There are records of it having killed pharoahs in ancient Egypt, it was known as “consumption” in the 19th century as it causes weight loss. Other symptoms include fever, coughing blood and night sweats – it is a disease that kills slowly. Tuberculosis kills more people each year than any other pathogen. There were about 10 million new cases in 2015, and around half a million of those were “multi-drug resistant” – meaning that at least one standard drug meant to help make someone better does not work at all.

There is an urgent need for rapid, comprehensive, accessible diagnostics. Because the bug that causes TB can develop the ability to resist a drug, current treatment includes at least four different drugs. Traditional testing of TB is very slow (2-3 months). Our test involves getting the patient to spit up some sputum, isolating the bacteria, and decoding the DNA, which we can now process within 12 hours now – and we are pushing to drop this time frame down much further. The idea is to develop a completely portable solution – a handheld machine which can be used in a clinic.

Please share a more detailed description of this work from a medical professional’s perspective.

We are developing a bedside-test that uses whole-genome sequencing (WGS) technology to determine the presence of M. tuberculosis in a clinical sample, predict drug-susceptibility, and inform disease surveillance by demonstrating the genomic relationships to previously seen strains. The test uses the Oxford Nanopore (ONT) handheld MinION platform for which we are optimising cheap and simple methods of DNA extraction, and easy-to-use software for WGS-data analysis. Our group’s work has led to the country-wide roll-out of routine WGS from mycobacterial culture in England.

We have since established proof-of-principle for direct-from-sample (‘culture-free’) MinION sequencing that will form the basis of a Longitude Prize application. Turnaround times of around 12 hours were achieved in that paper with experimental mixtures of sputum and a form of TB – we are working to reduce that time, improve sensitivity, and do more realistic testing.

Why did you apply and what will the Discovery Award funding be used for in your work? 

We have done a lot of work on DNA testing of TB, using thousands of samples from all over the world to get a good measure of how well we can predict drug resistance. We are working with public health experts to understand the practical problems implementing our test.  Now we want to do a small pilot of our diagnostic in Ho Chi Minh City and Mumbai, two cities with large TB burdens and also a lot of multi-drug-resistant TB. Hence we applied for a Discovery Award – we think we can learn a lot about the real-life challenges of doing these tests in the field, and use those learnings to for future work.

What difference will your work make in the long term with regards to antimicrobial diagnostics? 

We showed in our recent paper that you can get extremely accurate results using these handheld sequencing devices. This is a first step towards a revolution in the management of TB. Rapid comprehensive tests, if available to all, could drastically cut down on undiagnosed drug resistance. Since they also provide information on spread of strains, diagnostics could provide information both for the patient, and for the world.

If there is a design for a prototype, please describe it and how it will work.

The MinION sequencer is a small handheld DNA sequencer. You pipette in your material to test, and plug it into the USB port of a laptop. It then outputs electrical signatures, which software on the laptop can interpret as DNA. We are still working on the step between the patient and the MinION, where the sputum is processed into a form that can be passed into the machine.

Who is on your team?

Dr Zamin Iqbal (EMBL-EBI)
Dr Tim Walker (Oxford)
Dr Nerges Mistry (Mumbai)
Dr Kayzad Nilgiriwala (Mumbai)
Dr Anirvan Chatterjee (Mumbai)
Dr Thuong Nguyen Thuy Thuong (Ho Chi Minh City)
Prof Guy Thwaites (Ho Chi Minh City)
Dr Tan le Van (Ho Chi Minh City)
Dr Sarah Hoosdally (Oxford)
Prof Derrick Crook (Oxford)
Dr Kate Dingle (Oxford)
Oxford Nanopore Technologies

If you are interested in collaborating with this team, please email us.