Rapid metagenomics could revolutionize how we diagnose infections—but getting it into hospitals took a decade of breakthroughs and setbacks. Professor Justin O’Grady was one of those leading that charge, by moving from PCR to sequencing at the University of East Anglia to crack a critical bottleneck. A 2015 conference conversation sparked an experiment that succeeded thanks to an unnoticed error—the turning point for rapid clinical metagenomics.
In this 3-part mini-series, Justin traces the journey from lab discovery to revolutionizing patient care. After proving his method at St Thomas's Hospital in London, Jonathan Edgeworth's team further refined it into a respiratory service now used across UK ICUs. Today at the Ellison Institute, Justin is pushing to make metagenomics the standard for pathogen detection.
If you’d like to hear how the method Justin introduced to the Edgeworth team was further refined into a validated approach now being implemented across UK hospitals, join our upcoming webinar.
Episode 1 — From PCR to Sequencing: Why Diagnostics Needed a New Path
In 2013,Justin O'Grady made a radical shift: abandoning targeted PCR testing forreal-time sequencing. This episode reveals why that leap became essential fordiagnosing infections in the ICU—and how it positioned him as a pioneer inrapid clinical metagenomics.
Episode 2 — The Host DNA Depletion Breakthrough: Solving Human DNA Overload
Human DNA was drowning out pathogen signals, stalling metagenomics for years. This episode reveals how Justin's team finally cracked the problem—through an experimental error nobody noticed until it delivered the breakthrough they'd been chasing.
Episode 3 — Turning Discovery Into Practice: Trials, Translation and the Push Toward Automation
A breakthrough in the lab is only half the battle. This episode tracks how Justin moved metagenomics into hospitals by demonstrating its clinical value through ICU cases and why automation is now the focus of his work.
If you’d like to hear how the method Justin introduced to the Edgeworth team was further refined into a validated approach now being implemented across UK hospitals, join our upcoming webinar.
Transcript
Episode 1 — From PCR to Sequencing
Tell us about your move into metagenomics
I started off in the area of, PCR and qPCR. And it wasn't until that I took my first significant academic role at the University of East Anglia in Norwich in the UK that I started to think about metagenomics. The person who hired me is a professor of medical microbiology called John Wayne. He hired me for my diagnostics expertise, but he was very interested in sequencing, and he was keen that I would apply sequencing to diagnostics. And he was aware of the work that was ongoing at Oxford Nanopore Technologies, shortly after that famous talk by Clive Brown at AGBT where he introduced the MinION sequencer.
And the exciting thing about that was that you were going to have a sequencer that was able to produce data in real time and move it on to a laptop in real time. And that was going to change how we gathered data and how quickly we could gather data from a sequencer. And that could open up a whole new field in infectious diseases diagnostics.
And that's what John Wayne saw as part of the future. And it didn't take him long to convince me that that was probably a great idea. So that's where we started thinking about how we might apply sequencing to the diagnostics of infection. And I had a good background in diagnostics to be able to apply that technology.
What does sequencing make possible that current techniques simply couldn't?
Microbiological culture is slow. It takes at least two days really to go from patient sample to an antimicrobial susceptibility test.
If you are very unwell in hospital, two days is too long to wait to know if you're on the appropriate antibiotics. As antimicrobial resistance rises, as we have more global travel, as people are more immunocompromised in hospitals, we get more unusual bugs and more antimicrobial resistance bugs, and more often the first line therapies just don't work.
So, we need to get the answer to the antimicrobial susceptibility test quicker than two days. In my opinion, microbiologic culture just is not fit for purpose anymore, particularly for severe disease.
What held back metagenomics adoption in a clinical setting?
I worked in the area of diagnostics and rapid diagnostics for a number of years, and I'd applied QPCR to that problem. And that was have starting to have impact back in 2013 with the introduction of sample to answer type machines like the Cepheid gene expert. And just around 2013 was the release of the BioFire Film Array, which was another approach to do multiplex testing in clinical samples. And these technologies, because they were automated from sample to answer, we're starting to have a clinical impact.
But the challenge with those technologies is they were targeted. So, they could not replace culture. They could only be used as an adjunct to culture. They couldn't test for enough antimicrobial resistance and susceptibility. And they only detected the top pathogens for certain diseases and indications.
So, we felt that there was a gap in space in the market for a technology that was as comprehensive or more comprehensive than culture, but that was faster and speed was key. So, we needed to get results from metagenomics as soon as we possibly could.
We started with blood and blood stream infections. And that was a bit naive because that's the hardest challenge. And what we understood after a short while is we did some maths and figured out that you can be septic with one pathogen in a mL of blood. In that same mL of blood, you will have a million leukocytes, the cells within blood that contain DNA.
So that's a million to one ratio straight away. But the challenge here is that there is also another thing to take into account, and that's the size of the genomes. So human genomes are a thousand-fold bigger than bacterial genomes on average. So, if you add those ratios together, you're talking about a billion to one ratio of human DNA to pathogen DNA in a blood sample, you know, at worst.
So that's not good. That's going to take days of sequencing to get a single pathogen read. So, we knew we had to remove human DNA, that's what led us to putting effort into developing host depletion methods.
