DNA sequencing is driving a revolution in healthcare

“Science will save us” was the rallying call by Sir Jeremy Farrar, head of the UK’s Wellcome Trust at the start of the Covid-19 pandemic. And indeed, it will. But not just in the ways that you might think. Behind the headlines of new vaccines and new therapeutics, scientists are innovating new technologies that are driving revolutions in healthcare – not just for today to address the Covid pandemic, but for tomorrow, for the pandemics to come, and to address major issues on the horizon like growing resistance to antibiotics. DNA sequencing is one of those technologies. It’s the newest frontier for medical exploration and is already transforming our ability to both detect and treat disease.

Scientists used it in Denmark to identify and track the outbreak of a mutation in the SARSCoV-2 virus in mink. Scientists in the UK, at the Quadram Institute are working with teams at the Wellcome Trust in what is called ‘viral epidemiology’ – to play ‘molecular detectives’ to follow the spread of the virus in order to inform public health interventions. And groups worldwide are trying to identify genetic differences in all of us that may make us more or less vulnerable to Covid-19.

Genomics research on COVID-19 is making giant strides. First the virus has been sequenced repeatedly as it mutates, secondly some genes found in patients have been shown to be associated with poorer outcomes and thirdly, genomics has identified some bacteria in the microbiome of the patient that are also associated with a poor prognosis. 

Firstly, the new variant of the COVID 19 virus that appears to be spreading faster than the original virus is a clear example of how repeated sequencing of the virus is helping to control the virus. It was also sequencing that gave the vaccine makers their first target and first approved effective vaccine.

Secondly, the genomes of the severely ill COVID patients have also been shown to have some common immune features that may give a insight into ways to successfully treat the disease other than the Dexamethazone anti-inflammatory drug. The following Nature article illustrates this linkage and shows how important it is to use long-read sequencing for this research as it often involves large variants in the genome of the patient. Long-read sequencing needs High Molecular Weight DNA extracted such as what Fire Monkey produces in order to properly read these large variants in the genome. Research to find these important associations between the genomes of patients who suffer from severe Covid-19 is ongoing and is a promising predictor of who will require intensive medical support. Some of these associations lead directly to potential therapeutic approaches to augment interferon signalling, antagonise monocyte activation and infiltration into the lungs, or specifically target harmful inflammatory pathway This has been well illustrated in this Nature article preprint; 

#covid19research  

https://www.dhirubhai.net/posts/stienstra_gene-analysis-important-for-covid-19-resilience-activity-6746819939874746368-u5pL

Thirdly, the microbiome of bacteria and other micro-organisms that live on the patient can have a major influence on the subsequent progress of the disease as this article shows; l Microbiol Biotechnol. 2020 Sep;104(18):7777-7785. doi: 10.1007/s00253-020-10814-6. Epub 2020 Aug 11.

The best way to identify the sea of bacteria that we all swim with and in is through sequencing all the bacteria and treating the important ones. This is where Fire Monkey really comes into its own as the long-read sequencing that it facilitates makes identifying all the separate bacteria in a single sample very accurate. Fire Monkey also permits large scale multiplexing of these samples which reduces the sample costs down to commercially viable levels. The big advantage of this system is that it delivers a whole world of more complete information about each bacteria such as the antibiotic resistance gene profile of each bacteria as well as the strain identity of each bacteria. 

The Quadram Institute is RevoluGen’s largest client that uses Fire Monkey for this bacterial identification. Quadram are using Fire Monkey for whole genome bacterial sequencing to extract High Molecular Weight – DNA followed by long-read sequencing. New research is also opening up showing that the mix of bacteria present in a patient (their microbiome) can alter the course of the COVID-19 disease considerably. This is an area of research that could have major implications for the rapid uptake of whole genome bacterial sequencing using Fire Monkey and multiplexed long-read sequencing to guide treatment of patients.

Quadram is already working at the bleeding edge frontline of pandemic research using genomic sequencing to track the virus. Now, COVID-19 is an RNA virus so sequencing it does not actually need Fire Monkey to extract the nucleic acid blueprint from the virus. However, Fire Monkey can help with spotting patients with the genetic susceptibility genes that some patients have and for spotting the microbiomes associated with poor outcomes that more specific treatment. For example, the COVID-19 Genomics UK (COG-UK) consortium has been created to deliver large-scale and rapid whole-genome virus sequencing to local NHS centres and the UK government. COG-UK is made up of an innovative partnership of NHS organisations, the four Public Health Agencies of the UK, the Wellcome Sanger Institute and over twelve academic partners providing sequencing and analysis capacity. COG-UK is supported by ￡20 million funding from the UK Department of Health and Social Care (DHSC), UK Research and Innovation (UKRI) and the Wellcome Sanger Institute, administered by UK Research and Innovation.

The Norwich based Quadram Institute, together with other collaborators in COG-UK, claim to be sequencing more SARS-CoV-2 than the rest of the world combined. This will give COG-UK a very powerful database to work from. It is known that this virus is relatively stable and does not mutate rapidly although all RNA viruses mutate constantly. As a virus makes copies of itself, occasionally a random change happens that propagates, sometimes the change or mutation is significant but often it’s not. Virus mutation is inevitable. With SARS-CoV-2 these mutations happen at a rate of around one to two mutations per month and, as a result of this on-going process, many thousands of mutations have already arisen in the SARS-CoV-2 genome since the virus first emerged in 2019. The vast majority of the mutations observed in SARS-CoV-2 have no apparent effect on the virus and only a very small minority are likely to be important and change the virus in a significant way (for example, a change in the ability to infect people; cause more severe disease; or make vaccines ineffective.)

However, other viruses, like seasonal influenza (‘flu), frequently undergo rapid changes and that is why new vaccines have to be developed every year for ‘flu. The good news is that SARS-CoV-2 is more stable. There is also currently no evidence to suggest that the new variant has any impact on disease severity or vaccine efficacy even if it may increase the ease of transmission between people. Using genomics, we can tell when two people have an identical, or very similar type of virus which we group into ‘lineages’, and we can see when people have different lineages. It’s like building up a family tree but for the virus.

In Norfolk, Quadram has built up a detailed knowledge of this coronavirus and it's lineages that are circulating in the region. These lineages change over time. Some disappear of their own accord. Others also emerge as they’re introduced from different parts of the country or from abroad. The new variant recently mentioned by Matt Hancock has been named ‘VUI – 202012/01’ (the first Variant Under Investigation in December 2020). As of 13 December, 1,108 cases with this variant have been identified, predominantly in the South and East of England. Quadram first saw this new variant appear in November when it made up 19 per cent of all cases in the county. The spike in COVID-19 cases seen around Wymondham last month was attributable to the new variant and over half of the new cases in London now appear to be caused by this new variant strain.

It is possible this mutation could make it easier for the virus to pass from one person to another and there is a wide range of factors that affect how widely the virus circulates. More needs to be done to answer that question and Public Health England is working on that. Quadram and its colleagues up and down the country are undertaking this type of genomic surveillance precisely so we can identify and track changes in the virus in real time and help understand how we adjust to tackle the virus, if we need to.

RevoluGen is at the bleeding edge of the NAIP extraction technology

The first step in DNA sequencing is to get the DNA out of the cell. RevoluGen has honed its Fire Monkey DNA extraction technology that is driving down the cost of genome sequencing so much, such that it may be possible to sequence a bacterial genome for less than a few Euros. It presented its ground-breaking data at a conference of sequencing scientist a few weeks ago.

RevoluGen is a genomic tools company straddling the UK and Germany that has developed and patented a disruptive new DNA extraction and purification technology. This technology so improves DNA sequencing that it could become the dominant product in this $4bn market for preparing DNA for the approaching genomic gold rush. RevoluGen’s Fire Monkey technology has this potential because it does what scientists have not been able to do up to now. Fire Monkey uses a standard laboratory spin column process to extract High Molecular Weight DNA, in other words long intact fragments of the very long DNA molecule, from cells. The Fire Monkey extracted DNA is not too short and not too long; it is just the right length that long-read sequencing technologies need to work efficiently. The standard spin column DNA extraction is simple, fast and cheap but normally so rough on the very long and delicate DNA molecule that only short fragments are normally extracted with this process that QIAGEN initially popularised worldwide and used to dominate the market with.

“RevoluGen has used an old spin column technology, which everyone is familiar with in the lab and upgraded it to the next level”

Dr Georgios Patsos CSO RevoluGen

All DNA work needs to extract the DNA from the cells first, so this is a rapidly growing market with multiple applications in areas such as infectious disease diagnostics, regenerative medicine manufacturing, laboratory research and vaccine development. Eventually it is thought that all the living species in the world will be sequenced and maybe all the individual people as well, so this market has high potential growth. RevoluGen’s recent results with Fire Monkey show that its use can improve sequencing efficiency significantly by extracting more DNA of the correct size for the sequencing technologies. Fire Monkey can reduce the overall long-read sequencing costs by some 30% whilst at the same time improving the final sequencing result. This makes the long-read technologies much more competitive in $/Gb price terms with the short-read technologies whilst sustaining their information delivering advantages.

"Increased yield can drive disposable costs for MinION to $35/Gb and for PacBio to <$10/Gb"

Dr Erling Refsum COO RevoluGen

Fire Monkey also offers the short read sequencing users the upgrade option of now being long-ready for further investigations if required. Fire Monkey’s longer DNA fragments therefore have the potential to disrupt this whole market for DNA extraction and as the COVID pandemic has shown, DNA and genetics is revolutionising the whole world very rapidly at the moment.

The growing worldwide problem of Antibiotic Microbial Resistance is massive and dangerous. Using Fire Monkey to automate the DNA extraction and multiplex the long-read sequencing of whole bacterial genomes will reduce the cost of precisely identifying each bacteria and rapidly reveal all the antibiotic resistance genes in each bacteria. The infectious disease diagnostic market is estimated to become over $25 billion by 2027 and this sort of sequencing could replace much of the ancient agar plate-based methods of identification. Being able to choose the correct antibiotic early in an infection will prove a major step forward in treatment whilst new antibiotics are developed to overcome this growing AMR problem. “Our technology offers experimental flexibility and sample-saving. Based on lower cost and superior performance, we believe we can become the DNA extraction technology of choice in the global $4bn/year DNA sequencing market and become a key part of the $25bn microbial identification market” concludes Pieter Haitsma Mulier, the CEO of RevoluGen from his base in Germany at schloss Buckeburg. To ensure its Fire Monkey technology is available globally to as many scientists as possible, RevoluGen has signed a distribution agreement with Merck KGaA.

For all life and disease, it is clear that the more you know about the DNA sequences involved, the more you can use that to a healthy advantage.

“Our technology unites short-read and long-read sequencing, enabling both from the same sample, offering experimental flexibility and sample-saving. Based on lower cost and superior performance, we believe we can become the DNA extraction technology of choice in the global $4bn/year DNA sequencing market”

Pieter Haitsma Mulier CEO RevoluGen

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Revolugen will be taking part at the JP Morgan digital healthcare conference in January 2021. If you are interested in a meeting please PM me on LinkedIn.