“Studies have shown clinical metagenomics can be effective at detecting infections in a huge array of human samples, such as tissue, fluids and wounds.

To understand what clinical metagenomics is, we first have to delve into the meaning of metagenomics. Genomics is the study of the genome, the complete DNA profile of an organism. Metagenomics refers to the study of all the genomes found in a single sample.

Clinical metagenomics uses metagenomic techniques to identify microorganisms that cause infections, as well as genes associated with antimicrobial resistance and virulence, from human clinical samples.

How does clinical metagenomics work?

The exact steps for clinical metagenomics will vary depending on your sample type. Samples containing cells packed with lots of human DNA, like blood, need more extensive steps than samples like cerebrospinal fluid in your brain, which contains fewer human cells.

To get a good amount of microbial DNA to analyse, we first perform a ‘host depletion’ step to remove human genetic material, using detergents that burst open human cells but leave bacteria intact. We then use a type of enzyme that breaks down DNA, called DNase, to remove the exposed human DNA.

After this, we use a piece of equipment called a ‘bead beater’ to vibrate a mixture of our bacteria and silicon beads with lots of force. This bursts open the bacterial cells to release their DNA.

We then do a quick proteinase K incubation, which breaks down any remaining proteins or enzymes, and extract our bacterial DNA on a machine called a Maxwell. At this point, we can do purification and quality checks on our DNA before  preparing it for sequencing.

Once we have our processed DNA sequences, we can run them through an in-house bioinformatic pipeline, which will tell us what bacteria are present, the quality (completeness and reliability) of our sequences, and also what antimicrobial resistance genes were detected in the sample.

Clinical metagenomics is a promising diagnostic tool to identify infections

Clinical metagenomics holds promise as an incredible diagnostic method for the future.

In a hospital or diagnostic testing laboratory, the current methods used to diagnose infection include culturing microbes from samples, molecular tests like Polymerase Chain Reaction (PCR) which look at known DNA sequences, serology which looks for antibodies in blood, and high-throughput techniques such as MALDI-TOF, which produces a unique protein signature linked to a specific bacterium.

Many of these current diagnostic methods are excellent, but have drawbacks such as lacking sensitivity, being time-consuming or expensive.

Clinical metagenomics gives a more comprehensive view of a patient’s sample as it can determine microbial taxonomy all the way down to the strain level, detect antimicrobial resistance and virulence genes, and can be performed faster than some of the current methods.

Another huge benefit of clinical metagenomics is the ability to identify organisms which are ‘non-culturable’, meaning they can’t be grown on agar plates. Environmental scientists estimate only 2% of organisms on earth can actually be cultured through traditional means.

By identifying more microbes through clinical metagenomics, we can better detect the microbial perpetrators of infection than we currently do, enabling more appropriate treatment.

Developing clinical metagenomics methods to identify bloodstream infections

In my work at the Quadram Institute, I investigate the use of clinical metagenomics as a diagnostic tool for bloodstream infections.

This can be very challenging because the number of bacteria in the blood can be incredibly low during bloodstream infections — there can be 1 to 10 bacterial cells per millilitre of blood.

I am building on previous work at the Institute to improve the capabilities of clinical metagenomics methods. This includes the management of a collaborative trial with the Norfolk and Norwich University Hopspital (NNUH) which tests this method on a type of blood sample. We hope these clinical metagenomics methods will be more effective than previous studies.

Before working at the Quadram Institute, I worked in several healthcare-related roles at the NNUH and on the Norwich Research Park.

Firstly, I worked at the Earlham Institute, using loop-mediated isothermal amplification technologies to test sputum samples from NHS staff for COVID-19 — a more rapid test than PCR and more accurate than lateral flows.

Following this, I worked in the virology department of NNUH, using molecular and serological tests to diagnose viral infections. These roles heightened my interest in healthcare, and more  specifically infection diagnostics.

Clinical metagenomics is the ideal area of speciality for me, as it combines my love for healthcare with my eagerness to learn more about sequencing and molecular biology!

The future of clinical metagenomics

My hope for the future of clinical metagenomics is that through more and more successful studies, the technique will prove to be as effective, if not more effective, than current gold standard diagnostic tests, like culturing microbes.

If this is achieved, clinical metagenomics could be used as a complementary or stand-alone tool in diagnostic laboratories to drastically improve patient care, thanks to its specificity in identifying microbial strains and detecting antimicrobial resistance. “