Coronavirus testing with a sledgehammer designed for universal genetic sequencing

The announcement today of a major boost to the UK capacity for Coronavirus (SARS-CoV-2) testing is good news as schools and universities get closer to the time when they will be open to students for ‘business’. The likelihood of another major spike in COVID-19 is mounting as the full magnitude of the challenge comes into view. The government has opted to deploy two relatively new technologies being developed in the UK rather that increase the capacity of existing testing facilities. The reasons for this are not clear and the move could be risky if resources are diverted away from more reliable ongoing efforts. The two types of device being rolled out are relatively compact but were designed for other uses and are being repurposed. One from genetic screening of point mutations called SNPs and the other from high throughput genome sequencing. The consequence is that a Dominic Cummings call last year for “Push button cheap DNA sequencers” that are as “ubiquitous as desktop printers” is much closer to fruition. The only problem is that they are not so cheap or inexpensive to run. They also significantly increase the capacity for achieving his stated aim of “free universal ‘SNP’ genetic sequencing” of UK citizens. The danger lies in creating gross inequalities by using such data to discriminate between those that get health and educational resources and those that do not. 

Today saw an announcement by the Department of Health and Social Care of a major increase in Coronavirus (SARS-CoV-2) testing capacity in anticipation of another rise in COVID-19 disease cases. The tests will determine if patients with symptoms are infected with Coronavirus. They will not be able to assess previous infection during the earlier spike in cases. The link between deploying the new tests and educational policy would seem to be very tenuous on the surface. However, there are likely to be profound, perhaps unintended, consequences if the technology proposed makes it into mainstream genetic monitoring of the population. The instruments being rolled out can be used for widespread genetic screening of humans as well as for virus detection. Some explanation and arguments are set out below so please bear with it for a few minutes. 

New technology introduced to virus detection. 

The tests are based upon new technology platforms for detection of the virus. They will add another angle to the armoury of tests that have already been established and the hope is that they will be more portable and yield quicker results. Testing to date has been reliant upon central laboratory-based assays using specific virus gene amplification by the polymerase chain reaction (in the case of this RNA virus, reverse transcriptase RT-PCR) and subsequent detection of the amplified genes. This technique requires an expensive laboratory temperature cycler and detector and is usually ‘multiplexed’ to handle many samples at the same time. Like the PCR tests already established, the new tests are designed to detect the presence of Coronavirus SARS in nose or mouth swabs. However, the basis of the detection is different in each case. 

Using a sledgehammer to crack a nut? 

There are two technologies about to be deployed in addition to the existing RT-PCR tests. The Oxford Nanopore Technologies test is called ‘LamPORE’ that they describe as “a new generation of COVID-19 test”. This differs in two ways. Firstly, it uses a type of PCR reaction that does not require a thermocycler that takes samples through a series of high and low temperature steps. Instead, this is all done at the same temperature using Loop-mediated isothermal amplification or LAMP. Although the biochemistry is more complex, it cuts out the need for more complicated instrumentation. The RT-LAMP biochemistry has been around for many years and similar tests were developed for virus detection after the outbreak of the Middle East respiratory syndrome Coronavirus (MERS-CoV) eight years ago (Kazuya Shirato et al. 2014 ‘Detection of Middle East respiratory syndrome coronavirus using reverse transcription loop-mediated isothermal amplification (RT-LAMP)’ Virol J. 11:139). 

The Oxford Nanopore company has simply ‘bolted’ this existing chemistry onto their very advanced high throughput DNA sequencing apparatus that is relatively small at benchtop size and ‘portable’. Although there are several competitors, the Oxford company is considered a world leader in the use of nanopore sequencing technology to decode large amounts of DNA in small samples. 

In very simple terms, single stranded DNA is sifted through a very small pore one base at a time by applying an electrical current either side of the pore. As the DNA passes rapidly through (under 5 microseconds per base), each of the four bases generate small differences in the current density that identifies which base it is (A,T,G or C). The beauty is that it is a direct sequencing method, with no intervening chemistry steps as a complication, and can rapidly determine the sequence of very long strands. This makes it ideal for quickly determining a whole human genome using portable or small benchtop equipment (see Nobuaki Kono and Kazuharu Arakaw 2019 ‘Nanopore sequencing: Review of potential applications in functional genomics’). In this case, the virus genes are sequenced and not simply detected. It seems to be analogous to using a large sledgehammer to crack a small nut. 

The other technology is produced by DnaNudge company that is a spin out from Imperial College. The DnaNudge test is composed of a small single use cassette unit that takes nose or throat swabs. It is inserted into the DnaNudge box instrument that is designed to detect multiple SNPs (Single nucleotide polymorphisms or single base pair variants in individual genes) in amplified DNA from small samples. It has the ability to carry out 72 independent DNA amplification reactions and then matches the resulting sequences to an array of SNPs (see Cambridge Network TTP Plc partners ‘TTP plc Desktop Biology enables development and manufacture of DnaNudge technology’) .The exact number of SNPs in the virus assay array is uncertain from the company www site, but it should able to detect several different viruses in the same single sample. 

The original purpose of this technology was to identify the key gene SNPs in human DNA samples that are linked to metabolism and nutrition. It is marketed as ‘Personalized Nutrition’ available in shops as a wrist band that holds personal data and indicates (or nudges towards) what people should include in their diet in relation to the combination of SNPs they possess (‘Eat right, move more – shop with your DNA’). It is easy to see how it can be adapted quickly to screen for SNP gene variants associated with other human characteristics linked to health or behaviour. It is another sledgehammer approach to cracking a small nut. 

A simpler approach using the Human Eyeball Mk 1. 

The idea of using the single temperature ‘isothermal’ RT-PCR chemistry to amplify genes is not a new one and it has been established for some time. Its ease of use is a clear advantage. When target genes, such as those in Coronavirus SARS-CoV-2, are amplified it is possible to detect them at high sensitivity by observing a colour reaction in a small test tube or 96-well microtitre plate. 

The detector technology has been around for over 200,000 years. It is called the ‘Human Eyeball Mk1’. It is coupled with a world beating logic processer called the human brain and is very portable. The irony is that other researchers in Oxford University with colleagues at the Oxford Suzhou Centre for Advanced Research (OSCAR) in China, reported successful tests using this technology on SARS-CoV-2 (see Wei Huang et al 2020 ‘RT‐LAMP for rapid diagnosis of coronavirus SARS‐CoV‐2’ Microbial Biotechnology, Volume13, Issue4, Pages 950-96. 25 April 2020). The team was led by Wei Huang, a former collaborator of mine. They were one of the first to add to new reports of the effectiveness of RT-LAMP for SARS-CoV-2 detection linked to a simple colour reaction. It is therefore hard to see how this could be beaten on price per test. See Figure 1 below. 

Costs and effectiveness. 

The publicity makes it clear that the new tests are ‘low cost’. However, no full costings are apparent in any of the information released. Although the DNA Nudge device has been tested recently in hospitals in London, it is difficult to find any results or data to support the real costs and effectiveness of the test. There is no doubt that RT-LAMP technology does work, but I cannot find data relating to its use in multiplexed nanopore sequencing of Coronavirus genes. 

It is hard to determine if there will be major cost benefits of the two new tests. A direct comparison between the current technology used by the NHS and the new technology would be required. This should be made fully transparent by the government. 

The total DnaNudge package for 5.8 million tests and 5,000 machines is reported by the company to be a £161m order. This comes to just over £27 per test. The current list price of the DnaNudge cassette for one test is £40 each. It would seem a reasonable deal. However, it has been reported that 5,000 machines (BBC News) will be supplied and this seems about right. However, it is not clear if the cost of these are included in the total. 

The cost of the LAMPore test is less clear. The Department of Health notes that “450,000 of the new LamPORE tests will be available from next week”. The  DNA 'barcoding' kits, that are needed to track samples in mixtures run through the sequencer, alone cost £1,360 for 96 x 10 tests, making an additional cost of around £1.50 per test. One USA supplier currently quotes £827.00 for 500 reactions for the simple LAMP colorimetric test at around £1.70 per test. Conventional RT-PCR is listed as £153 for 30 test reactions and just over £5 per test. On the face of it, the LamPORE test will come in at around £3.2 per test. 

But the real cost may lie in the additional instrumentation and staff time. There are two devices available from Oxford Nanopore Technologies. The smaller capacity Mk1C is £8,050 and the larger GridION Mk1 is £40,225. Both come with a 3 year annual software licence and warranty but a subsequent software licence and warranty is £10,000 per annum. 

At the moment, it is impossible to determine the pricing structure and real underlying costs. My own laboratory used RT-PCR and multiplexed 'barcoded' sample sequencing using previous generation technology. The costs were split between the sequencing and the extraction and PCT protocols. Staff time also had to be factored in at a greater cost and this involved a lot of training and practice. I would expect the new machines will arrive with a significant time burden for training. 

Unintended consequences? 

The question of why the government would risk considerable funds to procure two new testing systems, instead of expanding and speeding up the existing tests that are well established, remains unanswered. The promise of quicker results nearer to the point where the samples are taken, either on site or in a local 'pop up' laboratory, is one clear advantage. But there may be easier options.

It is significant that both the DnaNudge and Nanopore technologies were developed with different purposes in mind. This is where some unintended consequences could arise. The DnaNudge system was originally designed to screen human DNA for various permutations in SNPs. The Nanopore technology is highly advanced and is designed to carry out extensive DNA sequencing at the level of whole genomes. It is therefore apparent that, once the instruments are  deployed in considerable numbers across the UK, they could revert to being used for their original purposes. It might not be long before most people in the UK have their genetic profiles recorded and analysed. 

The Cummings agenda. 

Now to the main point of the argument about how testing for Coronavirus infection could eventually lead to changes in educational policy. The dangers of moving toward more discrimination, by linking the genetic sequence of individuals to determine suitable access to educational resources, is all too painfully apparent. The roll out of the new instruments offers a clear route to making this possible. It is then only a small step away from promoting further inequalities or worse, lay the foundation for eugenics. 

In February last year, Cummings posted a blog ‘Genetics, genomics, predictions & ‘the Gretzky game’ — a chance for Britain to help the world’ (See also TEFS 10th January 2020 ‘Genetics, Intelligence, Social Mobility and Chinese Whispers’ for a detailed appraisal). 

He concluded that a person’s genetic makeup is the main driver of success and most interventions would not work. This included providing disadvantaged children with books. He dismisses the argument that “Kids who can read well come from homes with lots of books so let’s give families with kids struggling to read more books” and replaces it with the “truth” that “children and parents share genes that make them good at and enjoy reading, so causation is operating completely differently to the assumptions”. 

His solution was to call for “free universal ‘SNP’ (single nucleotide polymorphism) genetic sequencing” for everyone and a polygenic score can then be calculated for various traits including intelligence. The logical outcome would be the use of genetic testing to determine what individuals might receive in terms of health care, social services, and education. But whilst such testing might inform the probability of a person in a population, for example, developing a disease in time, it does not predict that an individual will develop the disease. Similarly, it might suggest the probability of an IQ test result, but it does not mean that this is the actual IQ of any individual. The technology is useful in research into populations, and in recognising what genetic factors increase the probability of disease, but it is still imprecise. 

He went on to insist that “We should plan for free universal ‘SNP’ genetic sequencing as part of a shift to genuinely preventive medicine — a shift that will lessen suffering, save money, help British advanced technology companies in genomics and data science/AI”. The amount of data would be immense, so the recent expansion of data analysis planning through establishing a ‘Skunkworks’ at the heart of No10 makes more sense as another piece in his masterplan jigsaw (see TEFS 24th July 2020 'Skunkworks' at the heart of government’). 

Importantly, and in the context of the current developments, he notes that “Push button cheap DNA sequencers are around the corner. Might such devices become as ubiquitous as desktop printers?” It looks like he may be getting his way under the smokescreen of virus testing. 

The trouble is they are not so cheap and require intense servicing and skilled staff time to deploy them effectively. But this is nothing compared to the cost for future generations in inequality, lost hope, and misery.

Mike Larkin, retired from Queen's University Belfast after 37 years teaching Microbiology, Biochemistry and Genetics. He has served on the Senate and Finance and planning committee of a Russell Group University.