Q+A: Phage viruses – the next tool in the diagnostic box?

Med-Tech Innovation News spoke to Dr Tomas Richardson, a specialist in DNA replication and molecular diagnostics, who has joined PBD Biotech to set up a dedicated R&D laboratory and head up the research team, as the company looks to develop a series of diagnostics for tuberculosis (TB) and related diseases.

First, tell us about phage, and how they can be used in diagnostics?

Well, phage (or bacteriophage) are viruses that infect and replicate within bacteria as part of their natural lifecycle. During that process, the bacterial cell is destroyed, and its DNA is released. From a diagnostics perspective, that’s useful as the DNA can be used as a target for detection, for example by using PCR-based methods. What makes phage useful though is that they infect only viable bacteria. That means they can be used to identify only live, disease-causing bacteria from clinical samples. Traditional PCR-based methods do not discriminate between live and dead targets. As such, they can generate false positives due to the detection of genetic material that has been shed during clearance of an infection, or that may have originated from a vaccine, for example.

PBD Biotech has developed a technology that uses bacteriophage to improve the molecular diagnosis of TB. I’m not aware of any comparable approaches that are currently commercially available. 1.5 million people died worldwide from TB in 2020. Many of these deaths could have been prevented with better diagnostic tools.

Having recently joined PBD Biotech, how do you plan to use phage to develop future innovations?

One of the things that most impresses me about PBD Biotech is the high level of scientific expertise within the company. Two of the company founders, Professor Cath Rees and Dr Ben Swift, have successful academic research careers and conduct fundamental research on how phage and bacteria behave. By improving our understanding of the basic science that underlies how phage interact with their hosts, we’re in a much stronger position to be able to apply that knowledge in making better diagnostics.

When applying that knowledge in future innovations, I think defining and even adapting the host-range of different phage will enable the Actiphage assay to be applied in different contexts. Employing phage that can infect and lyse dormant mycobacteria, for example, would be very exciting, as it would potentially enable identification of latent TB infections. Although perhaps less exciting, I think there are also lots of small, stepwise improvements that could be made to the existing assay. For example, by continuing to optimise the storage conditions of the phage and other reagents, we should be able to improve the stability and shelf life of the product, which is important for deploying the assay to where it’s most needed.

How do you see phage being used in antimicrobials, and other areas?

It’s no secret that antibiotic resistance is one of the major threats to modern medicine and food security. It has been suggested that many common medical procedures, like organ transplants or caesarean sections, could one day become impractical, or at least extremely dangerous, if our current arsenal of antibiotics becomes ineffective. Bacteriophage represent a powerful, alternative weapon in that fight.

Due to the practicalities of identifying, preparing, and distributing phage for use as antibacterial treatments, I don’t necessarily envisage a future where they’re used in the same way that chemical antibiotics currently are. That kind of biological control approach to treating routine infections would ultimately lead to bacteriophage resistance, in the same way that we’ve seen with chemical antibiotics. What I think is more likely is that in very specific cases a suitable bacteriophage will be identified and adapted by specialists for use against chronic bacterial infections where chemical antibiotics have failed. Currently, that sort of approach isn’t licensed for use in most territories, but it has been shown to work and we’re starting to see permissions granted as an option of last resort.

Speaking more generally, I think phage- and virus-mediated technologies are having a bit of a ‘moment’ now as researchers start to realise their potential. Increasingly, they’re being used in a variety of different contexts. We’ve seen their application in COVID-19 vaccine development, as viral vectors. Viruses are also a rich source of components in the field of synthetic biology where they can be used to engineer orthologous circuits and systems in living cells. Phage have been proposed as a potential way for achieving tailored engineering of the gut microbiome.

You’ve described how bacteriophage are currently used in TB diagnosis – could it be used to detect other conditions?

Absolutely. The principals that underlie the Actiphage assay apply equally to the detection of other bacterial pathogens. The assay is already being used to detect another mycobacterial disease in cattle, known as Johne’s disease, which is caused by the bacterium, Mycobacterium aviumsubspecies paratuberculosis (MAP).