Portable genome sequencing: transforming infectious disease diagnosis?

Chris Rands

8 October 2015

Accurate and rapid identification and characterisation of pathogens is the bedrock of clinical microbiology. Diagnosing bacterial infections often relies on decades, even centuries, old techniques, such as microscope based methods that identify pathogens from bacterial colonies or immunoassays that detect specific antibody molecules. These methods have been invaluable, but are now looking outdated, can be slow - microscopy requires bacterial culturing that can take months - and offer limited resolution for outbreak investigation.

The methodological shortcomings of classical microbiological approaches can, to some extent, be overcome by the use of whole genome sequencing using next-generation sequencing technologies. Commercial provider Illumina has dominated this arena in recent years by offering technologies for accurate, high-throughput, and relatively cheap sequencing for many applications, including pathogen detection. However Oxford Nanpore Technologies (ONT) is currently creating a buzz in the research community with the launch of their MinION sequencer. This portable device, effectively a slightly bulky USB  stick, can read much longer DNA sequence fragments than most comparable  technologies, which can improve pathogen genome reconstruction and the detection of genetic variation.  Furthermore, the MinION can provide near real-time results, enabling analyses that can inform infection control measures during an outbreak.

Research studies have already begun to demonstrate the clinical and public health utility of the MinION in an infectious disease context. For example, the MinION was used to detect Salmonella and trace the spread of the foodborne pathogen around a hospital. In another recent study the MinION accurately detected acquired resistance genes in pathogens, suggesting potential for the device in tailoring antibiotic treatments. A further study used the MinION to detect Ebola and other viruses directly from human blood samples in less than six hours.

As with all technologies at the vanguard of their field, the MinION is work-in-progress. Current developments focus on making the DNA preparation step less labour intensive (Voltrax) and expanding the bioinformatics software for data analysis and visualisation (e.g. Poretools) to make interpretation easier. The sequencing error rate for the MinION is moderately high, but it is decreasing, and it was recently demonstrated that MinION data is in principle of sufficient quality to be used for pathogen genome reconstruction without accompanying data from other sequencing technologies.

In addition to these technical challenges, ONT will also need to work with clinicians, health systems and regulators to consider how their devices can be used as part of clinically accredited services. Even if these various hurdles are cleared, evidence will still be required that the use of portable sequencing in infectious disease management is cost-effective. A health economic evaluation will be necessary before wide spread adoption within the health system and subsequent larger scale patient benefits from this new technology can be realised. 

Will you spot a MinION in a hospital near you soon?

The MinION is shaking up pathogen genomics research.  Its portability gives it the power to democratise access to pathogen genome sequencing, as it can be used in the field as well as in established molecular laboratories. For example, equipment for a small MinION based sequencing laboratory was recently transported to Guinea in just a few suitcases to undertake Ebola sequencing, something which would be impossible with traditional sequencing machines. 

However, the impact of the MinION on the delivery of clinical and public health infectious disease management in the UK will probably be limited, in the short term at least. The device cannot match the workhorse throughput or capacity of the Illumina machines already installed in many national and regional microbiology laboratories, which are beginning to be used for outbreak investigation and drug resistance testing for HIV and tuberculosis. In fact, the ONT benchtop sequencing machine, the PromethION, or the newly announced PacBio Sequel, may be more suitable than the MinION in this context because both offer a combination of the ability to sequence long DNA fragments and high sequencing capacity (the later at the expense of portability).

Further into the future, as demand for more localised point-of-care genome sequencing models develops, the MinION (or similar devices) may facilitate the devolution of some microbiological testing from hospital laboratories to primary care facilities, which could provide faster test results for patients. Either way, the ability to rapidly diagnose and characterise infections with the MinION without the entire infrastructure required for benchtop sequencing permits nimble and dynamic infectious disease investigations. This provides a unique advantage over other sequencing technologies in contexts where larger sequencing machines are unfeasible and biological samples are difficult to transport. 

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