Rolling out the academic sequencing network
The distributed sequencing model
Various ideas were considered at COG-UK's first meeting for sequencing COVID-19 samples, including centralised, distributed and mixed models. Julian Parkhill recalls, 'There were plenty of loud voices saying, there are good local academic labs that know how to do sequencing; let them do it and collate the data. And there were other voices saying, "it's much more effective and cost-efficient to build two or three mega labs and shuffle everything through those"' (Parkhill transcript). Central to this discussion was the speed with which sequencing could happen. As Sharon Peacock outlines, there was a 'balance between what we use and where. If we were going to do centralised sequencing, then the transportation times to a central hub is actually quite significant.' Another factor was they felt that 'people were going to get sick around the country, that the time it takes for transportation to move samples from one place to another, would be a large draw or drag on turnaround time' (Peacock transcript).
In the end, Peacock says, the consensus of the meeting was 'the fast pace could only be achieved by using what was already there, rather than planning for three months down the line to buy equipment and put it in and train people. It was simply go and use what you have' (Peacock transcript). According to Parkhill 'it was just a question of making linkages and funding people who were already doing it.' From his perspective and everyone else at the meeting, 'It would have been criminal to have thrown away that expertise and that readiness. Not just readiness; viral sequencing was already happening in some places. And it seemed much more sensible to spread that expertise around than to try and build something from scratch in a central place'. Another important driver was that they 'knew that local sequencing could be much more responsive to local needs, especially in terms of looking at local outbreaks, and looking for local transmission, and looking for evidence of hospital-based transmission' (Parkhill transcript). This point was strongly emphasised by Judith Breuer in her presentation to the meeting where she outlined the advantages of going for a mixed model (Breuer transcript).
Alongside considering the best model for sequencing, the first COG-UK meeting in London spent a lot of time discussing how they would source COVID-19 samples. From their perspective, one of the easiest routes was to access the waste product from samples that tested positive in PCR diagnostic tests (Peacock transcript). At the time this meant samples collected within hospitals because the government had yet to roll out community testing sites across the country supported by what was known as Lighthouse Labs. Announced by the government on March 24 2020, the Lighthouse Labs took their name from the PCR technology that uses fluorescent light to detect the virus. Initially staffed by highly-skilled volunteers drawn from academia and industry, the Lighthouse Labs aimed to support the testing of tens of thousands of samples each day (DHSC). The first Lighthouse Lab was set up in Milton Keynes, and this was followed by others which are highlighted in figure 6.1.
Figure 6.1: Map showing location of Lighthouse Labs. Credit: Smith.
Figure 6.2: Photograph of sign for COVID-19 testing site in Sheffield. Credit: Dennell.
In the end, COG-UK sourced its samples from two diagnostic pathways known as 'pillars'.
Pillar 1 comprised hospital diagnostic laboratories which were primarily testing samples collected from patients hospitalised with severe symptoms.
Pillar 2 covered the community testing sites, including four Lighthouse Labs that were taking swabs from the wider population and from people in long-term care facilities including nursing homes. Some of the swabs were done at drive-in centres. Generally, the pillar 1 samples were sent for sequencing to COG-UK's regional laboratories, and pillar 2 samples, which came in much higher volumes, were allocated to the Wellcome Sanger Institute (Peacock Dec 2020).
On March 23 2020, within 12 days of its inaugural meeting, COG-UK was able to report that it had managed to assemble a national network of sequencing centres and analysis groups in Belfast, Birmingham, Cambridge, Cardiff, Edinburgh, Exeter, Glasgow, Liverpool, London, Norwich, Nottingham, Oxford and Sheffield and anticipated setting up others in the near future (COG-UK Report #1). Between May and August 2020 the number of active COG-UK sites rose from 15 to 19 (COG-UK Report #6; COG-UK Report #10). The COG-UK sequencing sites included academic centres, the Wellcome Sanger Institute, and laboratories under the auspices of the public health bodies in England, Wales, Scotland and Northern Ireland. Multiple diagnostic laboratories in the NHS hospitals also joined the effort over time.
Figure 6.3: Map showing location of COG-UK sequencing sites as of 7th May 2020. Source: COG-UK Report #5.
Getting all of the different sites on board took an enormous amount of work behind the scenes. Some idea of the effort that went into the process is recounted by Dr Catherine Ludden, a post-doctoral research fellow in Peacock's research group, who stepped in to help on 17th March 2020. A lot of the early work involved 'doing a lot of Zoom calls with NHS sites trying to say who we are, why we thought sequencing was important and what information was needed.' She admits that 'at the beginning it was quite challenging. A lot of labs, unless they were academic linked hospitals, and even some of the ones who were, simply said that they didn't have the bandwidth, staff or time to get the samples. The samples were in big freezers, and they didn't have the staff to go looking in the freezers'. However, the reception got easier once people began to recognise the significance of what COG-UK was doing (Ludden and Blane transcript).
Figure 6.4: Diagram showing the way samples were accessed. Credit: Ludden.
Ludden's efforts were aided by Beth Blane, Peacock's laboratory manager. One of the advantages Blane had was the fact that she had long experience of working in a clinical microbiology laboratory so 'had an understanding of their processes and the best people to contact'. Importantly, as she says, 'I had an understanding of how to approach laboratories and the expectations we could have of them, because obviously, they were all suddenly very busy. We couldn't just go stomping in there demanding samples, there was a way to go about these things' (Ludden and Blane transcript).
Two researchers from Kwaitkowski's malaria team at the Wellcome Sanger Institute, Dr Cristina Ariani and Dr Sonia Goncalves, also joined in on the enrollment process. Goncalves had spent the previous 12 months working out how patient and mosquito samples came into the Sanger Institute from around the world and then how to triage, sort and register them, ensure quality control and then how to push them through into sequencing and align them with metadata (Kwiatkowski transcript). The four of them divided the work up so that they each covered different areas. Working with a list of questions, each of them tried to engage with the hospitals to understand how they could send the samples (Ariani transcript; Goncalves transcript).
Sixteen academic institutions became partners of COG-UK (Marjanovic, Annexes). Many of them were helped in this process by the fact that they had strong links to hospitals. A number had already begun sequencing COVID-19 samples some weeks before COG-UK was set up so for them, the work was a continuation of what they had already started. In many cases the scientists saw it as a golden opportunity to 'apply their skills to something that could make a difference to society' (Marjanovic, Final Report). Just how keen people were to jump on board to help with the sequencing was expressed by Dr Alex Trotter who was part of the sequencing effort undertaken by the Quadram Institute. As soon as he heard about Quadram contributing to COG-UK he instantly said 'Please, please, let me out of the house, please let me come join in' (Trotter transcript). The same sentiment was articulated by Dr Louise Aigrain who quickly became embedded in rolling out the sequencing at the Wellcome Sanger Institute. She points out 'none of us thought that we would have a chance to help in a pandemic. We are scientists working normally at the back in labs, you know we are a bit remote because we are certainly not medics. So that was very exciting for us' (Ariani transcript). Every academic centre has their own story to tell about their involvement with COG-UK. This section presents case studies from eleven academic centres.
University of Glasgow
One of the earliest academic groups to become quickly involved in sequencing was the Centre for Virus Research (CVR) based at the University of Glasgow. On 3rd March they reported that they had sequenced the SARS-CoV-2 virus from the first COVID-19 patient confirmed in Scotland, which they uploaded to GISAID and Virological. The work was led by Professor Emma Thomson who prior to the pandemic had been active in sequencing a range of viruses including hepatitis C in countries including Uganda. Because of this work, she was one of the people Peacock invited to participate in the first meeting to set up COG-UK. She had also taken part in the STOP-HCV Consortium, a project funded in 2012 by the UK Medical Research Council which used epidemiological, clinical and genetic information to improve knowledge about hepatitis C. As part of this she had helped develop sequencing that 'was then handed over to Public Health England for national use'. With this experience she knew that CVR had the necessary capacity to contribute to COG-UK's efforts (Thomson transcript).
Figure 6.5: Photograph of Professor Emma Thomson, OBE. Credit: Bethany Lavin Photography. Educated at a comprehensive school in Glasgow, Thomson’s teachers never really encouraged her to study medicine. They quickly changed their minds when much to their surprise she got an A in physics in the final school exams. Thomson took an intercalated degree in Parasitology at the University of Glasgow and then qualified in medicine. On starting clinical practice, she soon realised that her true vocation lay in research so decided to return to university, first going to Imperial College London and then doing a PhD at the University of Oxford. Following this she returned to the University of Glasgow where she set up her first lab in the MRC Centre for Virus Research (COG-UK Jan 2023). Prior to COVID, her research took her to Uganda where she was looking at the relationship between the ecosystem and the emergence of new viruses. Paused by the pandemic, Thomson quickly switched to helping the COG-UK effort as well as assisting in running vaccine trials locally (Thomson transcript).
Figure 6.6: Tweets sent out reporting the successful sequencing of the first COVID-19 cases in Scotland by the Centre for Virus Research. Professor Emma Thomson together with Dr Ana Da Silva Filipe carried out the sequencing at CVR in partnership with NHS Greater Glasgow & Clyde West of Scotland.
University of Edinburgh
Alongside the early efforts in Glasgow, sequencing also quickly got underway at Edinburgh University where Professor Andrew Rambaut was based. This was not surprising given that Rambaut played a pivotal role in the release into the public domain of the first SARS-CoV-2 genome completed by Chinese scientists in Wuhan. Some idea of the importance he attached to sequencing was summed up by Áine O'Toole, then one his doctoral students. As she said, 'I think he knew we were at that crux point where it was a make-or-break moment of proving sequencing was going to be useful' (O'Toole transcript).
Sharing Rambaut's attitude, O'Toole quickly got involved in sequencing. In early March 2020, she worked closely with colleagues at the Royal Infirmary in Edinburgh to sequence some of the first cases of patients who had been hospitalised in the city. Her interview reveals just how makeshift the process was at this point. She recalls, 'At that time there was no special sequencing capacity to do this sort of thing, so I was getting the bus down to the Royal Infirmary with a laptop and my MinION sequencer.' On March 9th she managed to get the first genomes sequenced together with three colleagues. Their objective in sequencing the samples was not for diagnostic purposes because they were already known to be positive. Rather it was designed to provide 'a proof of principle to see if we could sequence it and also for genomic surveillance purposes to try and get a handle on what the diversity in Edinburgh was looking like at that point'. Critically, the sequencing showed they had the skills to contribute to COG-UK which was initiated a couple of days later (O'Toole transcript).
Very early on, the academics at the Universities of Glasgow and Edinburgh started to have regular meetings together because it made sense for them to work together. Dr Ana Da Silva, who was in Glasgow, recalls 'These meetings started in parallel really early on while COG-UK was being set up.' She says that they quickly realised when the number of cases began to increase that it was 'important to have an even geographic distribution of what we were sequencing in Scotland'. Together, the two hubs 'defined which health boards would be covered by which team (Glasgow and Edinburgh)' and they contacted different diagnostic labs to send them a specific number of samples.' This was done to 'keep the surveillance as unbiased as possible in terms of numbers' (da Silva transcript). The two groups ended up working a lot with Public Health Scotland (Holden transcript).
University of Sheffield
Around the same time as the Scotland teams began to get themselves organised, other academics were also beginning to do sequencing elsewhere in the UK. This included Professor Thushan de Silva, a senior clinical lecturer at the University of Sheffield and honorary consultant at Royal Hallamshire Hospital, who had spent a number of years working on infectious diseases at the MRC Unit in Gambia. Returning to the UK in December 2019, de Silva was still in the early stages of building up his laboratory and team when news came through of the outbreak of COVID-19 in Wuhan. Two months later, in February 2020, he admitted the first two coronavirus patients to Royal Hallamshire Hospital. Both patients had acquired the SARS-CoV-2 virus after travelling to China. One of the reasons they went to Royal Hallamshire Hospital was because it is one of the five hospitals in the UK that takes in patients with high consequence respiratory infection diseases. At the time, the hospital was taking measures to isolate and try to prevent onward transmission of COVID-19 (de Silva transcript).
Figure 6.7: Tweet put out by de Silva on 12th March 2020 announcing the successful sequencing of the SARS-CoV-2 virus in two patients hospitalised in Sheffield. One of the genomes they sequenced proved to be identical to the original Wuhan virus and the other did not show much genetic change from the original (Simpson).
Having previously done HIV and bacterial sequencing, it was a natural step for de Silva to consider applying his skills to COVID-19. At the time, he was highly aware of the possibility that as 'a virus travels we know it can mutate as it reacts to the genetics of localised populations, creating different strains which may behave in different ways to treatments, vaccines and our body's immune response. Generation of sequence data is vital to track this process'. de Silva argued, 'This data, used alongside published samples from our international partners will be crucial for us to see the trends in these mutations' (Ferguson).
De Silva did the sequencing in collaboration with Dr Matthew Parker, a clinical bioinformation at Sheffield University and Matthew Wyles, a research technician based at the Sheffield Institute for Translational Neuroscience. They were able to sequence the genomes in less than 24 hours with the help of the ARTIC Network protocol and a Nanopore Sequencer (Ferguson). De Silva recalls the pride they felt in sequencing the two genomes because, as he says 'at the time there were probably about 20-25 genomes from the UK that were in the international databases, so there weren't that many.' Sensing what they had done was big news, Thushan tweeted out their achievement on March 12th 2020. The post was then quickly picked up by Ewan Harrison, then in the midst of pulling together partners for COG-UK following the foundation meeting held in London on March 11th. This happened remarkably fast. As de Silva remembers, he put out the tweet on Thursday and on Sunday he received an email out of the blue from Harrison, following which they chatted about Sheffield joining COG-UK. Their first discussion is etched on de Silva's memory because it took place while he was taking his child swimming. One of the strengths Sheffield had in coming on board was the fact the university had strong links with the NHS diagnostic laboratory and extensive bioinformatics expertise. That meant they could 'go from patient to sequence seamlessly in terms of the sample flow, the data flow' and get organised very quickly to participate in the COG-UK effort (de Silva transcript).
University of Cambridge
De Silva was not the only one that had an advantage of being closely tied to a hospital to do such sequencing. So too was Ian Goodfellow, who worked in the Department of Pathology at Addenbrooke's Hospital and was professor of virology at the University of Cambridge. An expert in RNA viruses, Goodfellow had been one of 20 British scientists who went to Sierra Leone in the summer of 2014 to support efforts to bring the outbreak of the epidemic caused by the Ebola virus in West Africa under control (Crealock-Ashurst; Brierley). As part of this effort, he and his colleagues had helped to establish a diagnostic centre and shipped out sequencing equipment to study the virus in real-time. Successfully able to demonstrate the value of rapid sequencing for halting an outbreak, their work laid the foundation for the establishment of the ARTIC Network for helping to respond quickly to future disease outbreaks (Goodfellow transcript).
In December 2019, when news broke in Wuhan, Goodfellow was running a course with Nick Loman and Joshua Quick in the Democratic Republic of the Congo for a task force set up to combat another Ebola outbreak. Soon after this they returned to the UK, leaving behind most of their equipment and reagents. In early March 2020 Goodfellow began having discussions with ARTIC members and also Professor Gordon Dougan, who at that time was based in the Department of Medicine in Cambridge, about the value of setting up sequencing locally to help with the pandemic. Not having had time to replenish the supplies he had left in Africa, Goodfellow turned to various people to get what he needed. Within two days he had 'managed to pull together enough reagents to get going.' He was helped in the process because he and his laboratory had already done a lot of sequencing of viruses before and he had had a role in the establishment of the ARTIC protocols favoured by COG-UK for getting its effort off the ground (Goodfellow transcript).
Figure 6.8: Photo of Professor Ian Goofellow (front) with right to left Dr Charlotte Houldcroft, Dr Aminu Jahun, Dr Myra Hosmillo and Fahad Khokhar (back) during pre-lockdown training (prior to social distancing directives). This was just a fraction of the team right at the start of the pandemic - the team became much larger after a while and evolved over time. Credit: Cambridge University.
To get the sequencing started, Goodfellow was able to source samples from the diagnostic laboratory in Addenbrooke's Hospital. Part of Public Health England, the diagnostic laboratory is distinct from the University of Cambridge, but Goodfellow had the advantage that it was located just one floor above his own laboratory and had a good existing relationship with them. Goodfellow says that Martin Curran and the PHE staff based in the diagnostic lab were brilliant and were critical to the success of the work (Goodfellow email). The process was also made immeasurably easier by Drs Estee Török and William Hamilton, two clinicians who quickly joined the effort. Importantly, they were able to act as a bridge between Goodfellow's academic team and the clinical side of the operation (Török transcript; Hamilton transcript). This was vital for getting access to anonymised patient data relating to the samples. Having invested in doing sequencing prior to any reimbursement arrangements, Goodfellow points out they had to spend the money upfront to get moving (Goodfellow transcript).
Figure 6.9: Slide capturing how the sequencing process started in Goodfellow's laboratory. Credit: Török.
Figure 6.10: Professor Ian Goodfellow and some of his team at Cambridge. Fahad Khokha, Dr Sarah Caddy, Dr Laura Caller, Anna Yakovleva, Grant Hall, Dr Aminu Jahun, Myra Hosmillo, Luke Meredith, Dr Estee Török, Dr William Hamilton, Dr Charlotte Houldcroft, Dr Aminu Jahun. Credit: Török.
Able to get up and running very quickly, at one point Goodfellow had 14 people working in his laboratory to help with the COVID-19 sequencing. The work they were doing included accessing samples from the diagnostic lab, and then extracting genetic material from the samples before putting them through the sequencing process. All of this work Goodfellow initially supported using funds secured from previous grants, primarily from the Wellcome Trust which was highly supportive of the funds being used for the COVID-19 work. The funding was subsequently recouped with funding from the government through COG-UK (Goodfellow transcript; Goodfellow email).
University of Portsmouth
Figure 6.11: Photograph of Dr Sam Robson. Credit: Bethany Lavin Photography. Growing up in Portsmouth, Robson developed a passion for science early in life, and remembers spending many hours during his childhood conducting his own ‘science experiments’. After school, Robson studied mathematics at the University of Warwick and then joined a doctoral training programme in Molecular Organisation and Assembly in Cells at the same university. He says that the programme ‘ignited my love for working at the intersection of biology and mathematics and opened the door for me to read DNA and sequence the human genome’. While studying on the course his mother was diagnosed with breast cancer which led him to focus on the biology of cancer for his doctorate. Following this he took on a bioinformatics role as a postdoc at the Wellcome Trust Case-Control Consortium project, which involved investigating the role of copy number variants in common diseases. He then joined a cancer research group at the Gurdon Institute at the University of Cambridge before going on to take a senior research position at the University of Portsmouth. In 2019 he helped set up the Centre for Enzyme Innovation at the university to focus on finding solutions to global environmental challenges, including how to deal with recycling plastic (COG-UK Jan 2023).
Like Goodfellow, Dr Sam Robson, a bioinformatician based at the Centre for Enzyme Innovation at the University of Portsmouth, also got the ball rolling before COG-UK got fully operational. This was in part spurred on by trying to keep abreast with the science around COVID-19 to aid healthcare workers like his wife, a senior respiratory physiotherapist who was in the 'thick of it' supporting desperately ill COVID patients being treated in the high care wards to aid over-subscribed intensive care units. One of the articles he came across in this search led him to the ARTIC network which had recently 'released a protocol for how to use Nanopore sequencing for doing whole genome sequencing of the [SARS-CoV-2] virus from patient samples' (Robson and Beckett transcript).
After he read the article, Robson called Dr Sharon Glasyher who runs the Translational Research Laboratory for Portsmouth Hospitals University NHS Trust. Having worked with her previously on various projects he wondered whether he could help set up a mini sequencing lab with her to help track the transmission of the virus within the hospital and use it as part of its infection control procedures. He knew he was able to do this based on his experience in Nanopore sequencing and having the appropriate equipment in his own laboratory (Robson and Beckett transcript).
Glaysher was very enthusiastic about Robson's suggestion. Importantly, she saw it as a 'good opportunity' for both herself and 'the hospital team to be able to do something that wasn't currently being done' at the hospital. But then, as she says, 'I also knew the results could be very useful for the hospital and our patients, especially when we didn't know the mechanisms of how the virus was spreading, how quickly it was spreading, and the data we could therefore generate could be really useful for the hospital.'. Having a good relationship with the microbiology team, located just down the corridor from her laboratory, she knew she 'could work with them to get hold of those samples quite easily. In the beginning it was just a process of waiting for them to finish their diagnostic testing and highlight the positive samples to us, we could then step in and collect these for onward sequencing' (Glaysher transcript).
Within hours of telephoning Glaysher, Robson received an email from the university saying it was about to shut down everyone's laboratories because of the first lockdown, scheduled to start on March 26th. He says, 'If I remember rightly, I think the email came on a Thursday to tell us that the doors would be shut the following day on the Friday, and if you didn't have everything by 4pm the next day it would all be locked away and you wouldn't be able to get in.' Based on this, he quickly called Glaysher to say he was on his way and then, he says, he ran around the department with one of his colleagues 'grabbing everything that we could find relating to Nanopore sequencing'. He recalls, 'We had a couple of MinIONs, the smaller of the sequencers, various library prep kits and other reagents that we just shoved into cold boxes, computers, anything that we might need to run the protocol, and we thought if we just get it to the hospital, we can worry about the ins and outs of it later. I filled the back of my car up and drove it down to Sharon's lab at about 4pm.' He arrived there just as the doors were being locked behind him. As he says 'I won't forget that we were so close to the cut-off because there was one particular kit which we'd purchased and we couldn't find, so we were desperately trying to find it before we were told, “No, seriously guys, you've got five minutes and then we're just locking you out”. If we couldn't find this, we wouldn't be able to do anything. We found it in the end through various phone calls… And then we couldn't get in the lab because it had a code on the door and we didn't know what it was. It was lots of fun' (Robson and Beckett transcript).
Following the dash to transfer the equipment to the hospital, Robson spent the weekend writing a proposal to secure some funding from the university to enable him to sequence 500 samples for the hospital. It then took about a month to get the project approved, get the ethics granted, set up our staff at the hospital, and get the sequencing protocol running. By this point the number of patients being hospitalised in Portsmouth was rapidly increasing (Glaysher transcript).
Soon after getting sequencing operational in Portsmouth, Robson learnt about the national sequencing effort being launched by COG-UK. Hoping to find out more Robson and Glasher emailed colleagues in the hospital, including Kelly Bicknell, a clinical scientist specialising in virology, to see if they could connect them with anyone in the consortium. Two days later Bicknell emailed one of her former collaborators, Professor Judith Breuer, a clinical virologist at University College London, who she saw was involved in the consortium. In this email she highlighted the fact that the University of Portsmouth together with the R&D Laboratory at Portsmouth Hospitals NHS Trust were collaborating to set up a 'research project sequencing COVID-19 genomes.' Noting that the closest centres to Portsmouth in the consortium appeared to be in London and Oxford', she said that Portsmouth wanted 'to contribute to the national picture providing some data for the South. To date we have had 130 cases and 10 deaths, which may simply reflect the socioeconomics and age of the population, but may also be related to viral factors. It would be excellent to compare with the rest of the UK' (Bicknell email).
Following a chain of emails, by 30 March 2020 the team received their first contact with Ludden at COG-UK. Recounting the subsequent sequence of events, Robson says when he first reached out he had little idea how closely he would get involved in COG-UK. He states, 'I remember sending an email saying, we're doing something quite similar to what you're talking about doing, it'd be great to be kept up-to-date, to suddenly being in my first COG-UK weekly meeting on a Monday, discussing the network, getting everything set up, what we needed to do and, being in the same league as people like Sharon (Peacock) and Nick Loman, and Matt Loose and all the people that have been doing this kind of thing for a long period of time, who led the way for what became the COG-UK consortium.' He believes that a lot of it had to do with the timing of when he sent the email. As he argues, 'I think had I emailed a couple of months later, it would have all been up and running, and they wouldn't have brought me into the fold in the way that they did' (Robson and Beckett transcript).
Figure 6.12: Email sent out by Dr Glaysher to colleagues (redacted) to make contact with COG-UK. Credit: Glaysher.
Figure 6.13: Email from Catherine Ludden to Sam Robson, 30 March 2020 welcoming the Portsmouth team into COG-UK. Credit: Catherine Ludden, Sharon Glaysher.
Figure 6.14: Area covered by the sequencing overseen by the team at the University of Portsmouth and Portsmouth Hospitals University NHS Trust. As many NHS Trusts were brought on board as possible, with many working extensively with Robson and his team to regularly provide samples and metadata. Bournemouth University also helped provide samples from Poole Hospital. Credit: Robson.
Figure 6.15: Photo of the Portsmouth team involved in the COG-UK sequencing effort. The photographs were taken when physical distancing requirements were not in place. Credit: Sam Robson.
Figure 6.16 Number of samples sequenced by the Portsmouth team. Credit: Robson.
Portsmouth quickly became the hub for sequencing samples from across the South coast and the South East to 'save them having to go up to the North of England say, and therefore taking a lot longer to get there' (Robson and Beckett transcript). As part of this arrangement, early on Robson managed to get assistance from Drs Sarah Buchan and Anna Mantzouratou at Bournemouth University to supply them with RNA extracts from COVID-19 swab samples they were processing in a makeshift diagnostic laboratory they set up at Poole Hospital (Buchan transcript).
University of Exeter
Just as the group at Portsmouth was getting its operations rolling, another academic hub based at the University of Exeter was also beginning to talk about sequencing COVID-19 samples. Again, this took place before the formation of COG-UK. One of the drivers of this effort was David Studholme, a bioinformatician. Being academic director of the university's sequencing faculty, Studholme says that 'it occurred to me that the obvious thing to do with this emerging outbreak is to perform the genome sequencing on as many isolates as possible so you can figure out how it's spreading, how it's evolving during the pandemic.' In part this was influenced by a project around a big outbreak of E. coli initially centred around Germany where, Studholme explains, 'essentially what happened is people sequenced isolates of the pathogen, they made that data publicly available within a few days, and then, because that data was freely available, scientists from all over the world were able to jump on that data and get information from it much more quickly than if it had been left just to one individual group to do this'. Studholme had been involved in the crowdsource analysis for the project so he says 'I was thinking of just doing something similar to that, just putting the data out there, [so that] anyone can do what they want with it, trusting that somebody would do something constructive'. He was also interested in looking at the data himself to see if he could determine any differences in the sequences taken from different patients and figure out transmission points (Studholme transcript).
Based on this thinking, he and his colleagues started to talk to their contacts at the local hospital to see if they were willing to team up together. At the time they envisaged their work would be 'driven by whatever the hospital's needs would be'. In retrospect, Studholme argues their action was 'of course slightly naive' because 'lots of people were doing this on a small scale with each other like this and we hadn't realised that there was this national effort being put together.' But in the course of these conversations they found out about COG-UK which they decided to join (Studholme transcript). Exeter had the advantage that it would easily be able to get access to samples from the local hospital, but it also had a wide range of sequencing technologies, including equipment to do Nanopore sequencing (Temperton and Michell transcript).
University College London
University College London was another academic centre that joined the COG-UK sequencing effort early. It was academically led by the clinical and molecular virologist Professor Judith Breuer, the founder and Director of UCL's Pathogen Genomics Unit, a genomics research hub funded by the UCL/ University College London Hospital/Great Ormond Street Hospital Biomedical Research Centre, was present at the first COG-UK meeting in London. Founded in 2016 in the centre of London, the Unit was ideally placed to help with COG-UK's effort due to its location and expertise in state-of-the-art genomics technologies.
The Unit took on two functions as part of COG-UK. First, it aimed to do a lot of the heavy lifting in sequencing samples for the London area. Second, it provided support to other units in London to help them get sequencing up and running locally in their own places (Breuer transcript).
Figure 6.17: Tweet put out by Professor Sergei Castellano reporting first generation of SARS-CoV-2 genomes by UCL team, 3 April 2020.
Overseen by Dr Rachel Williams, the sequencing in the Unit was conducted by a large team of specialists, including from the UCL Genomics Centre, and a number of volunteers (Breuer transcript). The Unit got its sequencing operation for COVID-19 samples up and running within the space of just a month, starting on 23 March 2020. The effort this required was what one of the members of the team described as 'all hands to the deck'. Receiving the first patient samples on 4 April 2020, the UCL site uploaded its first set of sequences to the CLIMB database on 24 April 2020 (Williams).
Most of the first samples the Unit sequenced were just what people sent them, but it rapidly moved on to sequencing as many samples as it could for about 25 hospitals mainly in the London area and also from Birmingham. Alongside this, the Unit provided support to other hospitals to help them get their own sequencing operations up and running. Among the hospitals it helped were St Bartholomew's Hospital and St George's Hospital. It also lent some help to Guy's and St Thomas' Hospital and liaised with UCLH, who were already up and running with their sequencing capabilities. The Unit did all of the sequencing for Imperial and the Royal Free because they had not mobilised their expertise locally (Breuer transcript). In addition to hospital samples, the Unit also received some pillar 2 samples from Lighthouse labs and also from PHE (Williams).
Figure 6.18. Slide showing what the UCL Pathogen Genomics Unit achieved Credit: Williams.
Video showing the UCL team conducting COVID-19 work. Credit: Williams.
Sequenced with the help of the ARTIC protocol, the team had to first extract genetic material from the hospital samples before they could be put through sequencing. In addition to contributing to the national surveillance effort, the Unit was the sequencing centre for three NHS Trust sites taking part in the COG-UK Consortium Hospital-Onset COVID-19 Infections study (COG-UK HOCI), which took place between November 2020 and April 2021. This added a layer of complexity to the operation because it required a quick turnaround time of 48 hours to generate sequence data. At first, the Unit deployed Nanopore sequencers, but changed over to using Illumina machines from December 2020. As of October 2021, UCL had uploaded 15,187 samples to CLIMB. Looking back at the work, Williams says the work was 'challenging yet rewarding' (Williams).
Another early academic institution to partner with COG-UK was the Quadram Institute. Opened in Norwich in 2018 to support food and health research, the Institute has deep expertise in sequencing food-borne pathogens. The Quadram team first learnt about COG-UK two weeks before the consortium released its press statement announcing its establishment. But at this stage they had little idea of the scale envisaged. Dr Andrew Page, who became a principal investigator of COG-UK, remembers, 'We thought it was just a few people going to do some sequencing'. Page had previously worked with Peacock and Parkhill at Sanger so had some sense of what was involved.
Clip of BBC programme of COVID-19 work undertaken at the Quadram Institute as part of COG-UK. The voice at the beginning is that of Dr Andrew Page. Credit: Page.].
Figure 6:19: Photos of different team members at Quadram Institute. Credit: Page.
Figure 6.20: Photos of bioinformaticians and sequencing team at Quadram Institute. Credit: Page.
Figure 6.21: Norfolk Biorepository team who helped the Quadram Institute access the necessary patient metadata from local hospitals for COG-UK sequencing effort. Credit: Page.
The team at Quadram knew what they were going to do because they had been sequencing bacteria, viruses, and other pathogens for years. In addition, Quadram had all the necessary infrastructure to get started. Not only did it have the right sequencing equipment, it also had the containment level 3 laboratories necessary for working with high-risk pathogens. Another important factor was that it was closely tied to Norwich and Norfolk University Hospital, the University of East Anglia and the Norwich Research Park (NRP) Biorepository (Page transcript).
University of Nottingham
Efforts to sequence COVID-19 samples also got off the ground early at the University of Nottingham. This was initiated by Professor Matthew Loose, a developmental biologist and bioinformatician who heads up DeepSeq, the high-throughput genomics facility at the university. Originally working on non-model organisms, that is organisms not extensively studied because they lack features that make them easy to investigate, Loose had first developed an interest in pathogen genomics when he started to collaborate with Nick Loman and Joshua Quick Loman in 2015 to help optimise the nanopore sequencing approach they were using to sequence the Ebola virus in West Africa. Following this, he had gradually become more and more drawn into utility pathogen sequencing and was just on the verge of helping to get the first nanopore sequencers embedded in the diagnostic labs at the Queen's Medical Centre in Nottingham when the pandemic started (Loose transcript).
Alerted to the news from Wuhan early on, by early February 2020 Loose was beginning to become concerned about the challenges that could lay ahead. As soon as decisions began locally to shut down as much activity as possible within the university, including work in the laboratories, Loose began thinking it was not sensible for his group to do so because he had 'a lot of sequencing reagents that were sitting in fridges' which he believed could prove useful, As he says, 'I thought, right, rather than throwing these things away, let's try and generate some data' (Loose transcript).
Part of his motivation for doing this was driven by scientific curiosity. But he also felt it was important, because, as he points out 'I couldn't see how hospitals were going to track anything unless we offered to help them. They didn't have the time in their diagnostics labs to set up sequencing at the drop of the hat. They were too busy and overrun with the testing requirements…. and I didn't see anybody else who would be able to do it locally, quickly. So I thought we should do it ourselves.' Based on this he reached out to Quick to send him some primers and worked out a way for the virology group in the university, based in Queen's Medical Centre, to perform RNA extractions on samples so that he and his group could get sequencing safely off the ground locally. Fortunately, one member of his team, Dr Nadine Holmes, had previously done a lot of pathogen sequencing so she knew how to set up the laboratory in a way that would avoid issues like contamination (Loose transcript).
The group in Nottingham sequenced their first set of genomes on 26th March 2020, which at that point consisted of just a handful of samples. At first most of the samples came from the diagnostic laboratory based in Queen's Medical Centre, which was the main site that handled the testing. But over time Loose's group began to receive samples from other sites in Leicester and Lincolnshire. Loose recalls that 'really anywhere that could send us samples, we would take them and filter them and sequence them appropriately' (Loose transcript).
Figure 6.22 Tweet put out by Matt Loose, 26 March 2020, reporting first batch of sequences for COVID-19 samples.
Figure 6.23: Tweet put out by Matt Loose, 15 May 2020. Among those involved in the sequencing were three wet lab staff, two bioinformaticians and a lab manager working remotely. This sequencing was done following extractions done by a team in the virology lab led by Dr Patrick McClure.
Initially, Nottingham carried out its sequencing separately from COG-UK, but from the start shared its data with the consortium and quickly got integrated into its activities. A lot of the early work was financially supported by the university. On 15 May 2020, Loose reported that the group had contributed nearly 800 sequences to COG-UK (figure 6.22). By this point Nottingham was beginning to get reimbursed by COG-UK. Loose points out that 'without COG-UK, we could have done a few 100 samples, but then I doubt we would have found the funding to generate more. Having that centralised resource that was shared was what enabled everything to happen' (Loose transcript).
University of Northumbria
Based in Newcastle-upon Tyne, the COG-UK effort at the University of Northumbria was led by Dr Darren Smith, Associate Professor in Phage Biology and Director of NU-OMICs, the University's DNA sequencing facility. The group first became connected to COG-UK via Loman and a sales representative from Oxford Nanopore Technology. Setting up the sequencing operation was helped by the fact that two months before the pandemic, a brand new laboratory had been opened for a joint initiative between Newcastle and Northumbria University. Funded by Research England, the collaboration aimed to provide the world's first research Hub for Biotechnology in the Built Environment (HBBE). Not yet in use, the laboratory was equipped with some extra sequencers, which meant the team had a perfect place to start the work for COG-UK. It also had a minus 80 freezer which provided storage for the samples. Taking about a month to get all the health and safety approvals signed off by the university, Smith was able to take advantage of the contacts he already had from his work into respiratory infections to get the sequencing network set up for Northumbria University (Smith; Smith transcript).
Figure 6.24: Workflow of how a sample was sequenced at Northumbria University. Credit: Smith.
Figure 6.25: Northumbria University lab team. Credit: Smith. As well as Smith, the laboratory team included Dr Andrew Nelson, Dr Clare McCann, Dr Gregory Young, Dr John Henderson, Rui Nunes Dos Santos, Zack Richards, Dr William Stanley, Dr Wen Yew and Matt Crown with bioinformatics led by Matthew Bashton who had just taken up an appointment with HBBE.
Figure 6.26 Breakdown of pillar 1 (hospital) sequencing at Northumbria in GISAID table 2020-21. Credit: Smith.
Begun in April 2020, the sequencing in Northumbria was conducted with 'samples from several different hospital trusts across the whole of the Northeast and Cumbria' (Bashton transcript). Collection of the samples was aided by the fact that the university allowed the team to drive to the different sites with vans usually used by security staff (Smith transcript). Northumbria submitted its first batch of sequences to the COG-UK effort on 12th May 2020. At first, the number of samples sequenced remained fairly small, averaging about two samples per site per day, but this number ramped up to 14 samples per day and then increased from there. This included not just hospital samples, but also some samples from a Lighthouse Lab based in Gateshead. Figure 6.26 provides a breakdown of the number of samples sequenced by the group in Northumbria between 2020 and 2021 which totalled 25,357. By the time Northumbria stood down its sequencing for COG-UK it had sequenced between 40,000 to 50,000 samples (Smith; Smith transcript).
Queen's University Belfast
Dr Derek Fairley and Dr David Simpson, both research scientists specialising in pathogen genomics led the sequencing of samples for COG-UK at Queen's University Belfast. Also linked to the Regional Virology Laboratory (RVL) under the Belfast Health and Social Care Trust, Fairley had led Northern Ireland's molecular typing services for Clostridium difficile and Pseudomonas aeruginosa and was looking for ways to expand pathogen genomics services within Northern Ireland (COG-UK Fairley). The Academic lead of Queen's Genomics Core Technology Unit, Simpson matched Fairley's experience with his strong expertise in nanopore sequencing (COG-UK Simpson). Together with Dr Tanya Curran, also based at the RVL, the two scientists led the sequencing hub for COG-UK in Northern Ireland (Queen's University Belfast). The initial work was supported by funds from the university.
Queen's University of Belfast took time to get its sequencing operations off the ground for COG-UK. Some of the teething problems it had is captured in the interview with Dr Julia Miskelly, the manager of the Genomics Core Technology Unit. When called on to help COG-UK, Miskelly remembers she and her team were still snowed under helping to develop and validate COVID-19 diagnostic tests for Royal Victoria Hospital and the public testing in pillar 1 and 2. They were beset with problems getting hold of the right reagents which were in short supply across the world, but were especially hard to get hold of in Northern Ireland. Miskelly explains, 'I know there were issues across the UK, but trying to get anything into Northern Ireland was absolutely horrific. It really was bad. Everything was stopped at the borders, and even from Ireland into Northern Ireland'. Miskelly articulates some of the frustration this caused. As she says 'We didn't actually get ourselves put on the COG-UK map for a long time, and it was purely because of the lack of consumables. I don't think it was really visible to the rest of the UK that that's where the issue was, it wasn't because we couldn't do the work, it was because we couldn't get hold of the reagents' (Miskelly transcript; QUB Pulse).
Figure 6.27: Nextera XT library preparation being done by on Clara Radulescu the Echo being done in the Genomics Core Technology Unit, Queen's University Belfast. Credit: Julia Miskelly.
Figure 6.28: RT-PCR being performed by Deborah Lavin and Marina Reyne to amplify the SAS-CoV-2 genome in the Genomics Core Technology Unit, Queen's University Belfast. Credit: Julia Miskelly.
The challenge of getting reagents forced Miskelly's team to look for ways to cut down on the amount needed for the PCR tests. Such work was not only important in terms of the diagnostic tests but also for sequencing. Two technicians in the group worked on the project for eight weeks and came up with what they called a Mini-XT assay (Fuchs). While time-consuming, Miskelly points out they had no other option but do the work 'because we knew that we had to miniaturise the amount of reagents tenfold in order for us to be able to deliver and keep up with the sequencing, and know that we could actually do it within the unit.' Subsequently used across COG-UK and other places, the Mini-XT assay provided an important first step for Miskelly's team to start sequencing (Miskelly transcript).
Figure 6:29: Pooling and bead cleanup of the A and B amplicons performed by Fiona Rogan and Umbreen Syed in the Genomics Core Technology Unit, Queen's University Belfast. Credit: Julia Miskelly.
Figure 6.30: This photograph captures the moment the Genomics Core Technology Unit, Queen's University Belfast, reached the point of sequencing 384 samples. Credit: Julia Miskelly.
The Genomics Core Technology Unit initially planned to go live with COG-UK sequencing in September/October 2020, and were more or less ready but could not deliver until after Christmas because of the difficulties getting reagents. Initially the unit started off doing 384 samples a week, but they got to over four or five times that amount by March 2021, after which it stayed at that plateau. Miskelly says the reason it stayed at that plateau was because they were working at maximum capacity with the equipment they had in the laboratory. One of the pivotal moments for Miskelly's team was when they began being able to sequence 2000 samples a week. At that point it felt like they had 'a well oiled machine'. In the long term this work proved highly beneficial to the Genomics Core Technology Unit. Importantly, the Unit was able to purchase more sequencing equipment and to hire more staff (Miskelly transcript).
Academy of Medical Sciences, Professor Judith Breuer.Back
Anon (n.d.) 'The Covid detectives helping to track the spread of the virus'.Back
Beckett, A (14 Oct 2021) Presentation: COG-UK UCL, COG-UK Together Event.Back
Bicknell, Kelly email (unpublished) to Judith Breuer J (26 March 2020).Back
Brierley, C (n.d.) 'Track and trace in Sierra Leone', University of Cambridge.Back
COG-UK (29 June 2021) 'In conversation with the "Queen of Virology", Professor Judy Breuer'.Back
COG-UK Women (Jan 2023) Snapshots of Women in COG: Scientific excellence during the COVID-19 pandemic.Back
COG-UK Dr Derek Fairley.Back
COG-UK Dr David Simpson.Back
COG-UK (23 March 2020) Weekly Report #1.Back
COG-UK (23 March 2020) Weekly Report #5.Back
COG-UK (14 May 2020) Report #6.Back
COG-UK (11 Aug 2020) Report #10.Back
Crealock-Ashurst, B (8 April 2019) 'Professor Ian Goodfellow Working in Sierra Leone to combat Ebola'.Back
DHSC Press Release (9 April 2020) 'Health Secretary launches biggest diagnostic lab network in British history to test for coronavirus'.Back
Ferguson, R (13 March 2020) 'Whole genomes of coronavirus from UK patients sequenced by Sheffield scientists', University of Sheffield News.Back
Fuchs, M, Radulescu, C, Tang, M, et al (3 March 2022) 'Mini-XT, a miniaturized tagmentation-based protocol for efficient sequencing of SARS-CoV-2', Journal of Translational Medicine, 105.Back
Bicknell, Kelly email Goodfellow, Ian email (unpublished) to Lara Marks, 13 Jan 2022.Back
Ludden (14 Oct 2021). Presentation to COG-UK: UCL, COG-UK Together Event.Back
Marjanovic, S, Romanelli, R, Claire-Ali, et al (2022) Evaluation of the COVID-19 Genomics UK (COG-UK) Consortium, Final Report, RAND Europe.Back
Marjanovic, S, Romanelli, R, Claire-Ali, et al (2022)Evaluation of the COVID-19 Genomics UK (COG-UK) Consortium, Annexes, RAND Europe.Back
Murgia, M (8 Nov 2021) 'Pandemic puts Oxford Nanopore 'on the map', Financial Times.Back
Page, A (14 Oct 2021) Presentation: COG-UK UCL, COG-UK Together Event.Back
Peacock, S (17 Dec 2020) 'A short history of the COVID-19 Genomics UK (COG-UK) Consortium', COG-UK blog.Back
Robson, S (14 Oct 2021) Presentation: COG-UK UCL, COG-UK Together Event.Back
Quick, J, Grubaugh, ND, Pullan, ST, et al (24 May 2017) 'Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples', Nature Protocols.Back
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Williams, R (14 Oct 2021) Presentation: COG-UK UCL, COG-UK Together Event.Back
Note: The position listed by the people below is the one that they held when interviewed and may have subsequently changed.
Interview with Dr Cristina Ariani, Lead Genomic Surveillance Operations, Wellcome Sanger Institute.Back
Interview with Dr Louise Aigrain, Former head of Research Operations, Wellcome Sanger Institute and now part of the MRC Epidemiology Unit at Addenbrooke’s Hospital. Back
Interview with Dr Matthew Bashton, Computational Biologist, Northumbria University.Back
Interview with Judith Breuer, professor of virology, University College London.Back
Interview with Dr Sarah Buchan, Lecturer in immunology, Bournemouth University.Back
Interview with Dr Ana Da Silva Filipe, Research fellow, NGS Facility Manager, Centre for Virus Research, University of Glasgow.Back
Interview with Dr Thushan de Silva, Principal Investigator of COG-UK, Senior Clinical Lecturer at the University of Sheffield.Back
Interview with Dr Sharon Glaysher, Specialist Biomedical Scientist who manages Portsmouth Hospitals University NHS Trust's Research Laboratory.Back
Interview with Ian Goodfellow, professor of virology, University of Cambridge (interviewed 15 Dec 2022, unpublished).Back
Interview with Dr Sonia Goncalves, Head of Service Delivery, Genomic Surveillance in the Genomic Surveillance Unit, Wellcome Sanger Institute.Back
Interview with Dr William Hamilton, academic clinician working in infectious disease and microbiology at Cambridge University Hospitals NHS Foundation Trust.Back
Interview with Professor Matthew Holden, Director of Impact at St Andrew’s University.Back
Interview with Dr Beatrix Kele (Clinical Scientist), Dr Maria Teresa Cutino (Virology Clinical Lead), Barts Health NHS Trust.Back
Interview with Professor Dominic Kwiatkowski, Head of Parasites and Microbes Programme at the Wellcome Sanger Institute in Cambridge and Professor of Genomics at University of Oxford.Back
Interview with Matthew Loose, Professor of Developmental and Computational Biology, University of Nottingham).Back
Interview with Dr Catherine Ludden, Director of Operations, COG-UK and Beth Blane, Logistics Manager for COG-UK, Research Assistant in the Department of Medicine, University of Cambridge.Back
Interview with Dr Julia Miskelly, Manager of the Genomics Core Technology Unit, Queen's University Belfast.Back
Interview with Eleni Nastouli Clinical virologist at University College London Hospitals NHS Foundation Trust and Great Ormond Street Hospital (interviewed 27 Jan 2022, unpublished).Back
Interview with Dr Áine O’Toole, Postdoctoral research associate, University of Edinburgh.Back
Interview with Dr Andrew Page, Head of Informatics, Quadram Institute, Principal Investigator, COG-UK.Back
Interview with Professor Julian Parkhill, Department of Veterinary Medicine, University of Cambridge.Back
Interview with Sharon Peacock, Professor of Public Health and Microbiology in the Department of Medicine, Cambridge University and Executive Director of the COVID-19 Genomics UK (COG-UK) Consortium.Back
Interview with Dr Sam Robson, Principal Research Fellow (Bioinformatics), Angela Beckett, Specialist Technician (Research), Faculty of Science & Health, School of Biological Sciences, Centre for Enzyme Innovation, University of Portsmouth.Back
Interview with Darren Smith, Professor of Bacteriophage Biology, Northumbria University.Back
Interview with Dr David Studholme, Associate Professor in Bioinformatics, University of Exeter.Back
Interview with Ben Temperton, Associate Professor of Microbiology, University of Exeter; Dr Steve Michell, Senior Lecturer in Molecular Microbiology, University of Exeter and COG-UK Principal Investigator.Back
Interview with Emma Thomson, Professor in Infectious Diseases, Centre for Virus Research, Glasgow University.Back
Interview with Dr Estée Török, Consultant at Cambridge University Hospitals NHS Foundation Trust and Senior Visiting Fellow University of Cambridge.Back
Interview with Dr Alex Trotter, Bioscience researcher, Quadram Institute.Back
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