The Woman Who Made the UK a World-Beater in Genomics

[ad_1]

[Sam Fazeli co-authored this column.]

The term “world beating” gets bandied about a lot in Britain, most often by Prime Minister Boris Johnson. In many cases, it’s self-serving hyperbole. But not when it comes to the deployment of viral genomics during the pandemic.

A virus’s genome, composed of nucleotide base “letters,” is essentially its instruction manual. The UK’s ability to rapidly sequence SARS-CoV-2 samples allowed the country to identify how quickly the virus was spreading, to identify new variants and to gauge the impact of public-health measures.

Indeed, if you were to sum up the hopes vested in the “Global Britain” moniker — a place where innovation, collaboration and global outreach thrives — then the Covid-19 Genomics UK program, known as COG-UK, ticks all those boxes. A collaboration that included the National Health Service, four public-health agencies, 16 academic partners and the Wellcome Sanger Institute, the program offers a useful example of how to break down bureaucratic barriers and steer public health decision-making.

COG-UK could not have happened without the leadership of Sharon Peacock, a microbiologist at the University of Cambridge. Peacock had to tackle doubts about the utility of doing mass sequencing early on. But she has a lot of experience in overcoming obstacles.

Therese Raphael and Sam Fazeli spoke with Peacock about how to monitor the virus’s development now, how the UK’s much-increased sequencing capabilities can be harnessed for other causes and her formula for success. The transcript has been edited for length and clarity.

Therese Raphael: How would you describe the impact, in the UK and globally, of building out a genomic-sequencing infrastructure in pretty much real time?

Sharon Peacock: Coming into the pandemic, we knew how to do sequencing. But like many countries, we didn’t have the extensive national network capability we would need to sequence the SARS-CoV-2 virus.

The question on day one was can we do sequencing so rapidly that we can influence policy and decisions. In the UK, from the beginning of March 2020 onwards, sequencing provided information on the variants that were circulating. And that was key because we started to sequence in ways that were strategic. We would not only do sequencing from random samples, so we could just see what was circulating, but also do targeted sequencing of samples from people who had been traveling to see what was being introduced into the country and for outbreaks to see whether that outbreak was associated with a new variant or a possible super-spreader event.

As vaccines were introduced, we sequenced samples from people with vaccine failure. We were able to spot new variants and we were able to categorize whether people had (hypothetical) variant A or variant B. That allowed the UK to have the capability to do some of the key studies around the variants and their degree of transmissibility, their degree of immune evasion and their degree of lethality.

Now other people, of course, contributed greatly. In Denmark and in Israel and elsewhere. In global terms, all of our sequencing methods, our analytical tools and our sequence data from COG-UK was accessible to the world. At one point during the pandemic, we sequenced 50% of the global total of SARS-CoV-2. That situation isn’t the case anymore as many more people are contributing genomes, though pathogen sequencing is vital even looking ahead to what SARS-Cov-2 does next.

Sam Fazeli: Are we no longer at 50%? Is anyone still really sequencing at high levels?

SP: Our sequencing data no longer makes 50% of the total because actually that was fairly early in the pandemic when we were perhaps ahead of the curve and sequencing at a high volume. The latest strategy report from the WHO notes that two-thirds of member states can do sequencing now. And so I see the fact that our percentage has gone down as a proportion of the global total as a good thing because it means that other people are doing sequencing and contributing.

I don’t see it in competitive terms because a small amount of sequencing done strategically in a specific country where they haven’t had any sequence data before could be incredibly important. That’s why COG-UK developed a training arm (COG-Train).

TR: Is there an ideal number of cases you’d want to sequence for a robust sequencing program?

SP: There isn’t a perfect sweet spot as far as I can see. It depends how you sequence. If you’re doing a combination of targeted sequencing and unbiased sequencing, you’re getting a picture of what’s happening. We’ve covered 10% of positive cases, which we thought was realistic and feasible. We have gone up to 50% or further when numbers of cases were very low.

You need sequencing to spot changes in the virus. And you need a significant number of people to be involved. The 10% actually served us very well in terms of the answers that we got out. Now that we’re using lateral flow devices, which you can’t sequence from, getting up to a very high proportion is not realistic. Between 5% to 10% appears to be a reasonable estimate for what you’d need to cover. And the sequencing capability is on stand-by if we need it. Remember it’s not like a diagnostic test — say, for example, for diabetes — where you need to know information for patient care.

SF: What is the value of continued genomic testing if vaccines don’t prevent infection, as we have seen? As soon as someone gets to hospital, they get a test anyhow.

SP: Something that I’ve learned over the pandemic is that you can’t predict the future very easily. We’ve known for some while that vaccinations don’t prevent infection. We cannot exclude the possibility of another variant emerging at some point, which actually has a different biological characteristic. The thing that would be a particular concern is if, through a kind of evolutionary lottery if you like, it caused more severe disease than the previous variant.

Either you’re going to get an indication from sequencing or you detect a growing epidemiological signal first and then investigate, for example in the reports from South Africa with BA.4 and BA.5. So is there a role for sequencing in the future? Absolutely.

TR: What role do you see for wastewater surveillance going forward?

SP: Wastewater sequencing was really useful for detecting variants emerging or circulating in populations at different levels. I think the future of wastewater sequencing is such that you can actually use it at different scales — at population level or at a community scale, in a school or hospital.

Of course, if you have a single case of a new variant, you’re unlikely to be able to detect that very easily, because of the scale of the waste you have the effect of having to pick a needle out of a haystack. But I think the wastewater sequencing can be really powerful, particularly in areas that don’t have any sequencing capability at all. For example, in low and middle-income countries where you don’t have much sense of what might be circulating.

TR: Covid catalyzed a huge jump in awareness of genomic sequencing. What are some of the other applications we should look forward to from a public-health perspective?

SP: I think the next frontier is adding genome sequencing to the human genome data. We’ve done a lot of human genome sequencing in the UK and that’s underpinned a lot of the work about how genetics makes you more susceptible to severe disease. What we’re attempting to do now is to bring together that with the viral data.

Another area is being ready to sequence for the next potential pandemic. Sequencing also has a role to play in antimicrobial resistance. The exact applications for AMR that are being hotly debated at the moment.

A big and important question will be should we use sequencing in hospitals for infection prevention and control. If you bring together the sequence data of say MRSA with epidemiological data, the sequence data gives you much more clarity about whether you have an outbreak or not compared with just your shoe-leather epidemiology.

SF: What are you trying to learn from viral sequences of mutations in patients when you try to link it to their genes?

SP: A critical outcome would be to know whether a patient is going to do worse with their infection compared with somebody else. Because then you’re forewarned and you could potentially treat them in a different way.

You may already know, for example, that somebody would do poorly from condition X, because they have particular risk factors. But the question is what extra can you get in terms of predictive analytics when you bring the pathogen genome together with the host genome [of an individual who tests positive for SARS-CoV-2], and we’re starting to do that now.

TR: I’d like to ask about your remarkable personal story. You were not given the opportunity to go to university or take science classes in your high school. You left school at 16 and then went from working at a shop to a dental nurse and found your way into a nursing degree and then into medicine, via night school and various rejections along the way. I’m compressing a lot, obviously. You had the doggedness to persevere. I wonder what needs to happen for more Sharon Peacocks to emerge in Britain.

SP: Wouldn’t it be nice if you had a single answer to that question! There isn’t one. I don’t think that we can leave any stone unturned to provide opportunities and education to children and early on. My parents didn’t go to university. We didn’t know anyone at university and at my school nobody went to university. We all left at 16 to get a job.

If you don’t have that academic environment at home, you have to get it at school. So leaving an impression on young people that they can really aspire in what they want to do, and not take no for an answer, is really important. Perhaps we’re better at this now than we used to be. But talent and capability comes in very different shapes and sizes and starts to mature at different times in your life.

Being an academic at a university now, I’m really particularly focused on access to higher education. I got myself through further education initially by going to night school, but the door that opened that really changed my life was getting into university.

TR: Would you say we need more of a culture that allows failure and encourages young people to take risks?

SP: Anybody who is successful will have failed many times. Every time you fail, you learn and do something differently. And so I guess you have to allow people to fail. And it’s quite interesting because when you see CVs, they never talk about failure, they only talk about success. I think encouraging a culture where people are allowed to talk about their failures and what they learned is very important.