19 Jan Why has the UK been successful at sequencing SARS-CoV-2?
Professor Sharon Peacock, Director of the COVID-19 Genomics UK Consortium, reflects on SARS-CoV-2 sequencing in the UK
In the last few months, a topic rarely before featured in conversations between anyone other than scientists has become a major talking point – sequencing pathogens, and specifically, the SARS-CoV-2 virus. This has entered into the mainstream after a growing realisation that scrutiny of viral sequence data is going to help us stay one step ahead of the problems that virus evolution could have in store for us. The information it provides will increasingly become part of life as we know it.
Drivers for sequencing SARS-CoV-2
There are four step changes in the narrative of the virus-human interaction that we need to concentrate on. These are changes in virus transmissibility, the severity of the disease, immunity (from ‘natural’ infection or after being vaccinated), and the way that some diagnostic tests for COVID-19 perform.
Detecting mutations (increasingly in different combinations) that are worrying enough to study them in detail – and make decisions around matters such as lockdown and travel – depend on routinely sequencing viruses that are infecting us. Mutations in the virus genome are happening all around the world – this is an unstoppable force of nature.
But increasingly apparent is that some countries are sequencing the virus much more than others. Like many other aspects of the response to the pandemic, different countries have responded differently, often based on history, experience, available resources, funding, and advice that is both proffered and acted upon.
The UK can already count virus sequencing as one of their major contributions to the global pandemic response. They have contributed just under half of the global count of SARS-CoV-2 sequence data deposited in GISAID, a major open-access database that is used by people around the world. UK sequencing has been delivered by the COVID-19 Genomics UK (COG-UK) Consortium.
How did the UK achieve it?
There isn’t a single answer. In part, our forward-thinking comes down to our recent history.
For example, the UK were one of the first adopters of pathogen sequencing for public health – in the form of TB sequencing. All TB isolates (Mycobacterium tuberculosis) are now sequenced as routine, and the information is used to rapidly predict drug resistance (vital if we are to detect and treat people infected with multidrug-resistant isolates).
The same information can be used to look for TB outbreaks based on the extent to which isolates from different people are related. The UK also has a large number of leading experts in pathogen genomics, several of whom have used sequencing during previous global emergency responses, including the Ebola outbreak in West Africa. But several clues lead directly to COG-UK.
Ten building blocks of COG-UK
It’s possible to identify ten different factors that we drew upon to develop COG-UK, half of which are generic and available to many countries.
1. Instruments are needed that generate the sequence data in volume. These have been in existence now for a decade or more and are not complicated to run.
2. Methods are needed to turn clinical samples from people with confirmed COVID-19 into material that can be sequenced. Most often, this uses the leftover material from a PCR diagnostic test. Such methods have been widely available since the very early days of the pandemic, many of which were developed by COG-UK members.
3. Automated analysis tools are needed that translate the individual ‘letters’ of sequence data into something rapidly meaningful for the pandemic response. For example, are there specific mutations emerging in the genome that could be of concern? Are there clusters of very related viruses that could be linked to an outbreak? A range of tools are readily accessible and open access, several of which were developed by COG-UK members.
4. Scientists are needed to help interpret the genome outputs, further analyse the genomes, and provide public health insights. Bioinformaticians are trained in numerous countries worldwide as a recognised scientific discipline.
5. Funding, and a prioritisation of funding, is needed to make the first 4 things happen.
The other half of the explanation rests with circumstances that may vary from place to place.
6. People need to work together in a cooperative and collective way, setting aside individual priorities and managing contrasting approaches and underlying goals of different partner members. Efforts to sequence the virus across an entire country involves an army of people, and this requires a sense of shared purpose and commitment, forged together by leadership that is crafted to that setting.
7. There needs to be a spirit of open science and data sharing. Science is competitive by its very nature but concealing data and only focusing on science publications is not appropriate. Instead, open access and a willingness to make sequence data freely available as it is generated is essential. This requires scientific integrity, in which data generated and released is not used for individual gain and without relevant permission where required.
8. A trinity needs to exist (or be created) between patient samples and the health services in which they are treated, scientists and academic institutions who can support sequencing and its analysis, and public health specialists who can bring together the genome and patient information. It is only when information on people with COVID-19 comes together with the genome data that the benefit starts to be realised.
9. Data architecture needs to be strong enough to allow data from numerous different places and sources to come together into one place.
For example, COG-UK take samples from numerous Lighthouse labs (UK mega-labs) and from up to 90 different hospital labs, and then sequence these in 16 regional labs (including the four Public Health Agencies of the UK) and the Wellcome Sanger Institute. Data then need to be shared with the Public Health Agencies.
This got a huge boost from being given rapid access to MRC CLIMB (Cloud Infrastructure for Microbial Bioinformatics). We also need to know how to target samples for sequencing that are most likely to provide the sort of information we are looking for. Data flow has been our greatest challenge and is more difficult than it sounds.
10. And finally – we need the legal, ethical, governance, and management wrap-around to make this complex landscape work effortlessly.
The human story behind the success of COG-UK
This represents a relatively straightforward list of why we have achieved what we have. But anyone who follows a recipe will know that different chefs given the same ten ingredients can create radically different dishes. So, what actually happened in the UK? This is a very human story.
The idea for COG-UK was kick-started on 4th March 2020 with a series of phone calls between a handful of pathogen genome experts who were enthusiasts for the application of genome sequencing to real-world problems. This was a day when there were 84 confirmed COVID-19 cases in the UK. The true scale of the global pandemic was yet to declare itself, as was the value of viral sequencing in its control.
Two days later, an email trail to 17 people built on this interest and outlined plans for a round-table meeting. By 11th March 2020, around 20 people were assembled in a meeting room in the Wellcome Building in London, where they spend the entire day developing a blueprint for COG-UK. By the close of play, it was clear how this could be done.
Over the next four days, a proposal was written that set out the plans for COG-UK. It was short but compelling, and within a matter of days, the funding needed to develop a sequencing consortium was agreed.
This came from the COVID-19 rapid-research-response “fighting fund” from Her Majesty’s Treasury established by Professor Chris Whitty and Sir Patrick Vallance, as well as UK Research and Innovation and the Wellcome Sanger Institute. Around £20M allowed us to get started and set up the consortium.
More members and institutions rapidly joined as we started to plan. Our aim was to be welcoming rather than exclusive. And the rest is history.
COG-UK has become one of the most successful SARS-CoV-2 sequencing operations in the world. Furthermore, this will provide the foundations for the future of a sustainable pathogen sequencing network across the UK that becomes fully embedded in public health agencies. COG-UK provides a legacy for a future where sequencing is on tap and can be used to detect and control future threats from known and new infectious diseases.
Bold plans have paid off
The plans were a combination of bold, optimistic and risky.
We acknowledged criticism from several prominent voices but did not waver as a result. Some detractors thought that there would not be sufficient viral variation to make it worthwhile – as coronaviruses mutated relatively slowly, we would find ourselves sequencing the same virus, over and over again – which would benefit no-one.
It is true that early on, we sequenced many genomes that were very similar. But the value of developing our thinking, methods, tools, logistics and operation, networks, and ways of working is rapidly becoming apparent.
This strategic, forward-thinking approach has allowed us to be fully prepared and at the ready to sequence viruses and detect important mutations at a time when this really matters for human health.
Looking back, probably the worst that could have happened is that we generated a mountain of scientifically interesting data, on which to base a stack of published papers. But in reality, we are poised and ready to be of use to the UK and beyond.
Furthermore, much of what we have achieved was done at no extra cost to the public purse. Funding has been vital, but nearly all of the COG-UK funds have been channelled into the costs of viral sequencing. Most people working in COG-UK are not paid by COG-UK funds.
Many people volunteered, and others were already employed where the sequencing data is generated – numerous universities, and the Wellcome Sanger Institute. All embraced the opportunity to contribute.
This is not a sustainable funding model for the future, but COG-UK has generated almost half the world’s sequence data on a budget that represents excellent value for money.
It is also the case that COG-UK represents a human pyramid of endeavour. A large number of people working in laboratories across the UK are essential to what we do. This includes those in diagnostic laboratories that perform the tests for COVID-19 and COG-UK members that take this material and generate sequence data. The majority go unrecognised, and this is an opportunity to say a heartfelt thank you.