Images by Dan Ross

Categories: COVID-19, Sanger Science22 October 202013.7 min read

Sequencing COVID-19 at the Sanger Institute

On 23 March 2020, the UK entered a state of lockdown in response to the emerging COVID-19 pandemic. The previous week, the Sanger Institute had shut down all but critical and essential operations and sent most staff home. But amid all the uncertainty, disruption and anxiety brought on by the pandemic, some colleagues were just beginning a months-long mission to help tackle it. This photo essay goes behind the scenes of the effort to sequence the genome of the COVID-19 virus at the Wellcome Sanger Institute.

Sequencing large numbers of viral genomes provides invaluable information about where a virus has come from, how it is spreading and what related versions are in circulation. This data can help public health bodies to identify and contain outbreaks, allowing decisions to be made on solid data. Though the Sanger Institute has a wealth of experience in these areas, such as helping to stop an outbreak of MRSA at Addenbrooke’s hospital or sequencing hundreds of thousands of human genomes for the UK Biobank, now it was being asked to develop a complex, large-scale scientific operation from scratch in a matter of weeks. The operation was named Project Heron and would form part of the COVID-19 Genomics UK (COG-UK) consortium.

As colleagues scrambled to develop lab protocols or develop software, Sonia Goncalves and her team had arguably one of the most important jobs – getting something to sequence.

Sonia Goncalves, Head of Service Delivery-Genomic Surveillance

“Since Project Heron began, we’ve received COVID-19 samples from 28 NHS and Lighthouse Lab sites across the country. But in the beginning there was a lot of work just to get the samples flowing into Sanger. Defining processes for sample preparation and shipment, finding out about sample types at each site, number of samples coming in, organizing couriers, coordinating with the lab and stores teams and supporting the metadata to be transferred…… as well as fitting in home schooling. It was a challenging time.”

Sonia Goncalves

At first the number of samples arriving was small. Sandra McHugh and her team from Stores were the first to handle them. They’d receive a 15-minute warning that samples were inbound, collect them from the courier and get them to where they needed to be. The task was made harder by the fact that Sandra’s team were having to navigate life in a pandemic.

The Stores team (L-R): Sean Smith, Sandra McHugh, Suzanne Szluha, Charles Olney, Neil Flack, Nicholas Hough, Ralph Anderson

Sandra says it has brought out the best in the team. “We had team members with partners working in the NHS and children to look after, another who had to shield at home due to family members being extremely vulnerable. There was a lot of disruption, but I’m really proud of the way the team pulled together, supported each other and got on with the job.”

Soon the volume of samples coming in went from hundreds to thousands each day. The scale of the operation required new sample storage infrastructure, which would normally take months to set up. Now, Sameena Iqbal and the Capital Projects team had to work quickly to install a workable solution in a matter of weeks.

“At first we had to plan for a lot of unknowns in terms of storage. We knew the scale of the effort, but not the particulars of the samples themselves. We weren’t even sure that the freezers and equipment needed could be sourced at the beginning of the pandemic. People were struggling to get essential items during lockdown – would we be able to get everything we needed to store the samples on time?”

Sameena Iqbal

Fortunately, five huge freezer containers were acquired and installed in one of the campus’ vacant car parks in record time. Outdoor storage presented new challenges, however. Physically getting samples to and from the labs in the Bridget Ogilvie Building would be labour-intensive and too big a job for the Stores team alone. But without people to do the heavy lifting, this complex scientific operation would grind to a halt.

Gaurang Patel working in the deep freeze unit; Petra Korlevic scans in samples

Of the volunteer effort, Sameena said: “The people who volunteered to help us move samples around campus have been amazing. Most were at home, unable to continue their own research. But they chose to come out in all weathers, working in tough conditions, to help keep things moving. We really couldn’t have done it without them.”

In the first few months of Project Heron, Sanger was receiving live viral samples from NHS sites. These had to be inactivated to make them safe for handling by scientists in the sequencing labs. But before this could happen, Rachel Nelson and her team in the Containment Level 3 (CL3) lab had to figure out how to do this. COVID-19 was such a new virus, there was little in the scientific literature to guide them.

“We had the benefit of access to CL3 labs and could take receipt of primary COVID samples, but none of the team had ever worked on an aerosol virus which was killing people in this country. Sometimes it was hard driving into work, hearing about deaths on the news, knowing you were going to work on the same virus. The gravity of the situation was almost overwhelming at times. Everything was confidential, so we couldn’t talk about it. We were pinching PPE from other labs, not able to explain to other colleagues why we needed it.”

Rachel Nelson

But Rachel and her team found a way. “It was a delicate balance, keeping the team safe while working towards our goal. We scoured the literature, got advice from virologists at EMBL-EBI and Addenbrooke’s, and experimented to develop a process that we were confident made the samples safe. I’m immensely proud of the team and I think it has been good for us in many ways – we’ve learned new skills, worked with new people and felt part of the collective effort.”

Laura Letchford, Sally Kay and Katie Bellis outside the CL3 lab

In order to be sequenced, the samples must undergo a number of processes in several different labs – what is known as a DNA pipeline.

Joe Dawson, Mia Williams and Catarina Caetano of the DNAP Operations Team

The first of these is sample management, where positive samples are separated from negative samples and collated into 96-well plates. Part of the process is automated, but still involves scientists doing certain tasks by hand. Viral RNA then needs to be converted into DNA through a process called reverse transcription. Then the plates of positive samples can move to library preparation to get the biological material ready to be loaded into the sequencing machines.

Members of the DNAP Operations Team (L-R): Irfaan Mamun, Marcella Ferrero, Howerd Fordham, Tristram Bellerby, Shaun Wright

Richard Rance, who co-leads the DNAP Operations team with Emma Gray, said: ‘At our busiest we were sequencing almost 5,000 genomes a week. Some staff have continued in a familiar role, others have come in to support while their usual work is on hold and learned new processes. All have volunteered to do so and it has been an incredible effort to shift focus and create new pipelines so quickly, especially under such trying circumstances – whether that has meant coping with the world being a bit of a scary place, or trying to work from home with two young children on the loose.’

Although various DNA pipelines already existed at Sanger, shifting focus to COVID-19 wasn’t a straightforward task. Naomi Park and Lesley Shirley were part of the R&D team responsible for adapting existing pipelines to sequence the virus.

Lesley Shirley and Naomi Park

“To prepare samples for sequencing, one of the things we need to do is isolate and amplify the virus’s genetic material. The process of doing this for COVID-19 is similar to processes we already do at Sanger, but we needed a way to do this more quickly. But our initial attempts failed, because the viral load of each sample varied so much. We had to think outside of the box – and my last ditch attempt, scribbled on a notepad at home, was thankfully successful!”

Naomi Park

For, Lesley, the whole experience has been something of an emotional rollercoaster: “The initial weeks of the project were very intense, there was no time to think of much else. But it was often a welcome distraction from what was going on in the outside world. My personal highlight was watching the live quality control of our first set of patient samples. There was relief and joy all round! Working on this project has been a career highlight for me – it’s been a privilege to work alongside such talented individuals.”

Moving between so many labs, the samples required a system to help keep track of them and the processes they’ve undergone – known as a Laboratory Information Management System (LIMS). That task fell to Rich Livett and his team of software developers, who had all been exiled to their homes.

"Our way of working completely changed. Normally, we would visit the lab to observe the challenge that our scientists are facing and design software from there. But since lockdown, we've had to do this remotely. In the beginning, the fear was it would be too difficult to understand what needed to be built without seeing it. But the working relationships with scientists have paid dividends and we’ve used remote working tools to be effective. I’m really proud of what we’ve achieved – seeing the team in full flow and delivering under trying circumstances, it’s been a privilege to be a part of.”

Rich Livett

Rich and his team have made the most of Zoom (and empty wall space) to deliver software for the Project

The genomic data streaming out of the Institute’s sequencers is the result of the efforts of hundreds of people, from wet lab scientists to the staff who keep the campus running. But that is far from the end of the story. The data needs to be safely stored, organised and made available to researchers and public health bodies. The Sanger Institute’s data centre holds around 30 petabytes of information – that’s around 60 million average laptop computers – which needs to be well looked after. Throughout Project Heron, Simon Binley and his team of four have been making sure everything is running smoothly, both from home and on site. Alex Gedny joined Simon's team as an apprentice in 2018.

"Hardware-wise, Project Heron is similar to other large-scale projects. What’s different is the urgency – you need to respond right away because people are relying on that data. I feel very proud to be helping the world face this pandemic. It’s been difficult working from home at times, I’ve missed the social aspect of being on site. But the workflow and keeping in touch with colleagues remotely have kept me going."

Alex Gedny

In order to keep campus COVID-secure, many of those working to make genomic data available are doing so from home. David Jackson, who leads the Sequencing Informatics team, says the transition has been surprisingly smooth. "For my team the job has been business-as-usual in many ways, just faster. A big part of this has been interacting with COG-UK's CLIMB platform, which is where other universities and institutes access the data."

“Perhaps the biggest thing is the loss of my dining table, which is now home to three monitors. While schools were closed it became a combined workspace for me and my 9-year-old daughter. Which worked fine, until I had a group meeting at the same time as she had a recorder lesson.”

David Jackson

For David, the importance of the work has been a source of motivation. "I’m proud of the efforts of the team and I’m glad to be doing something of immediate benefit to the world. It spurs you on to keep working at a high pace, because it really matters how quickly you get the data out.’

Rob Amato, Head of Data Analysis & Translation in Malaria Genetics, has swapped malaria for coronavirus and his office for his bedroom. He is helping to ensure the metadata from hospitals, such as when and where the virus was collected, is integrated with the genomic data so that public health bodies can understand how the virus was introduced, track how it is spreading and monitor local outbreaks.

Rob says one of the hardest things to get used to has been how quickly things could change on the project. "We’ve been working quickly, but the pace of change has been the biggest difference to my usual research. There’ve been a lot of meetings and if you miss one, you can feel like you’re three months behind. The definition of medium- or long-term changed – long-term became next week."

“Unfortunately, I don’t have the luxury of another workspace so I’ve been seeing a lot of the same room. The transition has been OK, as a manager you notice that different people have different challenges and do your best to navigate them as a team. It helps to know you’re creating resources that are producing actionable knowledge, which is used by everyone from government agencies to individual researchers.”

Rob Amato

Of course, considerable effort has gone into planning and coordinating Project Heron. One of those in the thick of things from the beginning has been Tanya Brooklyn. As a project manager, Tanya usually supports Sanger’s Finance team to implement their improvement programme.

“A few days before Project Heron began, I was invited to have a ‘quick chat’ about managing a new project. Little did I know then how big an endeavour this would be. As with any major undertaking unfolding at breakneck speed, there has been a lot of mess and a lot of stress since March. But there has also been excellence, which is the culmination of highly skilled and dedicated teams working together. I think we’ve proved the value of genomic data to public health and proved that nothing is insurmountable. The COVID-19 pandemic is a terrible thing, but it’s been an honour to be a part of the effort to do something about it.”

Tanya Brooklyn

At the time of writing, there are over ten million COVID-19 samples on campus, with hundreds of thousands arriving each day. The UK has sequenced more COVID-19 genomes than any other country, with the Sanger Institute the single largest contributor. The genomic data created has already helped Public Health England and health authorities to save lives, such as by improving infection control in dialysis units where vulnerable individuals were at greater risk.

Head of Sequencing Operations, Ian Johnston, surrounded by planning notes in his office; the only person actually in the room, Tanya chairs a Project Heron meeting

The ambition now is to accelerate the production of genomic data even further to make near real-time genomic surveillance possible. This will allow public health bodies to identify outbreaks as they emerge and take measures to stop them in their tracks – and, hopefully, help the world return to some form of normality.

Inevitably, far more people contributed to Project Heron than can be acknowledged here. The stories and experiences featured are mere snapshots of a massive collective effort. This photo essay is dedicated to everyone who played their part and to acknowledge their sacrifices, hard work and commitment.

Check out what happens to samples when they arrive on campus in this short film

Find out more

This photo essay was a collaboration between the Wellcome Sanger Institute and Connecting Science's Public Engagement team. Look out for more Project Heron stories on our social media channels @sangerinstitute and @ConnectingSci