Lucy van Dorp: Tracking SARS-CoV-2 around the world, from animals to humans and back again
Image courtesy of Lucy van Dorp
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Dr Lucy van Dorp is a UCL Excellence Fellow and a group leader at the UCL Genetics Institute in London. If you’re a regular listener, you might remember her from episode 16 in season 3, Sickness and Susceptibility, when we chatted about her work sequencing DNA from historic pathogens to learn more about our ongoing evolutionary relationship with the infections that plague us.
At the beginning of 2020, Lucy got an opportunity to switch from studying ancient diseases to a brand new one, as COVID-19 swept around the world. She set to work using her skills to track the SARS-CoV-2 virus as it spread and mutated in animals as well as humans, providing vital insights to help us understand and tackle the pandemic.
I bundled her into a broom cupboard at the drinks reception after the symposium to find out more - so apologies for the background noise - and started by asking her how she felt when she realised that she had a unique opportunity to track the evolution of a new virus unfolding in real time:
Kat: I think the initial response was just compelled to help. I think many people felt that during the pandemic, they wanted to do something important and I was in a luxurious position that I had this toolkit and ways that I could analyse genomic material.
Lucy: Actually before the pandemic, I'd really only worked on bacteria, so I had to co-op my skillset. But I was firstly wanting to contribute by analysing the genomic material. But also, given the very large sequencing effort, the amount of genomic data that was being shared from a purely scientific point of view, it was really irresistible to try and understand how the virus was evolving and watch that in very close to real time because of the enormous sequencing effort.
Kat: So tell me about the kinds of samples. How do you, on a practical level, get hold of COVID and sequence it and figure out what's going on?
Lucy: Very many of the nasal pharyngeal swabs that many of us were doing to check whether we were PCR positive for COVID were being sent to sequencing labs to generate genomic material from the RNA from which you could assemble and reconstruct a genome. This wasn't something that I was doing. This was something that many labs around the world were doing. And then making the decision to share that data on public genome sharing repositories so that other people could analyse it.
Lucy: It was really quite an extraordinary effort from very many labs around the world, really with the emphasis on data sharing and reusability, which allowed people like myself, who are predominantly on the computational side of of this kind of sphere of work to take forward and analyse the data.
Kat: As all these sequences are pouring in, thousands of sequences from all over the world, as the pandemic spreads, what were the sorts of things you were looking for? What were the patterns you were looking for? What were you hoping to see?
Lucy: I think the initial question was just how much diversity is there? Is it the case that we have a very genetic homogeneous system, which would imply a young virus? Or is it very cosmopolitan suggesting something that's been circulating for a really long time? We tend to think that the former based on the kind of analysis that we've conducted.
Lucy: Then the next big question was are we seeing changes in the virus in terms of the genomic content? So we have in the case of coronaviruses, and particularly for SARS‑CoV‑2, the accumulation of around about two mutations or so a month. So are those mutations doing anything? Are they completely neutral to the virus or are they changing it in some way? And if they are, is that important? So we spent a really long time tracking individual mutations. I've worked on many microbial systems but I've never fixated on individual mutations in quite the way that we used with SARS‑CoV‑2. But trying to identify where we might see properties that might indicate changes or adaptation in the virus to human infection and trying to understand if those were concerning.
Lucy: Some of our early work was looking particularly for mutations that kept appearing in different lineages, which we thought might offer useful signpost to potential convergent evolution. It follows that as we had the emergence of different variants of concern, despite these being quite unrelated lineages, so emerging from very distinct parts of the phylogenetic tree or history of the virus, we were seeing the same mutations appearing again and again, and that's because they were useful.
Lucy: We've all heard about the spike protein. Of course, that's a real epicentre of mutations in SARS‑CoV‑2 and an area we're particularly concerned about in terms of evolution to evade say the immune response or the vaccine targets we've many of us have been vaccinated with.
Kat: I'm just curious on a sort of technical level, who makes the decision when something's basically a new variant? Because we had Alpha, the OG COVID, we had Delta, we had Omicron, the one that got me. What's a variant and what's just there's a couple of bases different.
Lucy: It's actually exceedingly difficult and even the terminology is poor. So in some realms of genomics, a variant would be used to describe a single mutation change rather than say a new lineage. There is a set of criteria set out by the World Health Organization, which actually doesn't really relate to the genomics of the virus, but instead relates to the properties of how we experience it. So do we see lineages that are causing us problems in terms of our need for mitigation methods? Certainly in thinking about vaccine efficacy or very high transmissibility to higher growth rates than we would expect. But the actual kind of concrete evidence that this is a viral lineage which is of concern compared to just different, is difficult and takes time. I think many of us will remember over the course of the COVID 19 pandemic scare stories about potential variants that were gonna be the new big problem.
Kat: Ooh, hybrid ones!
Lucy: Absolutely. But being able to confirm that we may well see viral images that are going up to high frequency, but that could simply be because of behaviour or founder effects or many other processes, rather than the intrinsic behaviour of the virus. So it is one of those cases that it actually takes a bit of time and functional follow up on mutations to really be able to say, this one is something we should be concerned about.
Lucy: The nomenclature has changed as of quite recently, but there was a state that variants were often considered as under investigation before they would get to the point of being called a VOC or variant of concern.
Kat: You showed in your talk today how the different big variants, the variants of concern, swept through. So we had Alpha, Delta, and then Omicron. My question now is is there any Alpha still around in the UK, or is it all Omicron all the time?
Lucy: We of course don't sequence everywhere, so it's quite plausible that there are lineages that we've not sequenced or surveyed and we're not seeing. But given our current surveillance efforts, really Omicron is maybe 98/99% of sequences. As far as I know, Alpha is largely extinct. Though for some of the other variants, there have been some observations. For example, the Beta variant has been picked up in some regions of the world, but really we are seeing a regime where we are dominated by Omicron.
Lucy: One area that I think is important is looking at animal reservoirs. So the Alpha variants, as we mentioned, are still circulating within whitetail deer, for example. Perhaps we don't see them in human infections, but some of these variants, it's a bit of a mystery as to why perhaps there's a different immunological pressure or for some reason some of the variants that are extinct within humans are actually persisting within animal reservoirs.
Kat: That is what I wanted to come onto because it's not just humans that get SARS‑CoV‑2. What do we know so far about the kinds of species that can catch this virus?
Lucy: I think the best thing I can say is a huge number. Pretty much everywhere you look across the mammalian orders you'll find some observation of either natural infections or infections that are possible within experimental systems for different animals.
Lucy: So I think this really suggests, and it's a property that is known of Coronaviruses, is that this is a multi-host virus. It doesn't struggle to infect many different species and certainly we see a very large number of infections across a large number of animals. I think a point that is probably fairly underappreciated is how many animals actually have been exposed and successfully infected by SARS‑CoV‑2.
Lucy: There are some quite intriguing examples where we don't tend to see infections. Dogs for example get infected but they don't seem particularly transmissible. There's not really been any reported infections in pigs despite obviously the pig industry and humans being in close contact. So there's definitely work to be done there to understand susceptibility to infection in different hosts. But as a broad tenet of what we see in SARS‑CoV‑2, it's pretty good at infecting a very large number of mammals.
Kat: This is really important because certainly from what I know about the other Coronaviruses and one of the main theories about where SARS‑CoV‑2 came from is that it came from animals to us. Maybe it can go back from us to animals. How do we keep a handle on this? Why is it so important to figure out what's going on and where this virus is going?
Lucy: I think as a broader property that there is a lot of microbial flow and that's difficult to quantify because of course not all exposures lead to infections, not that more infections lead to nasty symptoms that we pick up. But I think in general we do have a system where there is quite a lot of flow of SARS‑CoV‑2. The effected population size is massive, humans are interacting with animals all the time. The question is how concerned we should be. And I think the major concern is where we have cases of very established animal to animal transmission following a spillover event. So not just incidental infections.
Lucy: One example of this is SARS‑CoV‑2 spilling over into cats. You tend to see that those are a little bit dead end infections and whether that's something about the cat biology or whether it's just simply the case that we don't tend to farm cats. It's difficult to say at this stage. But I think when we see animal to animal transmission, those are cases where we could then see viral adaptation and changes.
Lucy: The reason that might be a problem is because the virus is then exposed to a different set of immunological properties in the new host. It may evolve and adapt and acquire new mutations it wouldn't otherwise have in human infections. And then we've seen that coronaviruses are quite good at infecting many species. So there's real potential to spill back into humans providing a new set of mutations, which might create a combination which would be unfavourable In terms of the way that we're currently handling the COVID 19 pandemic.
Kat: So SARS‑CoV‑2 is here. COVID is a thing. It's going to be a disease now we live with as a human species, not going away. But how do we use this genomic surveillance technology in humans, in animals, in the environment? How can we stop the next pandemic? What should we be looking for?
Lucy: I think SARS‑CoV‑2 has been a useful experience in that regard. We need to think about the best strategies going forward. As attractive as it would be to me as a genomicist, we simply can't sequence absolutely everything everywhere, all the time. So I think lessons learned from SARS‑CoV‑2 is firstly that genomic surveillance can be or will be a mainstay of our response to future epidemics and pandemics. I think it's here to stay. But we need to think about what systems to target.
Lucy: Some suggestions are, for example, wastewater surveillance. This is a way of monitoring what might be circulating in the community, trying to detect novel pathogens that might be changing in frequency. Other possibilities, for example, travel surveillance. Sequencing potential infections at an airport, you can actually get quite a good representation of what might be circulating around the world by working in say, just one place. But also thinking about where we might have cases where we would detect viruses that might be of concern, in particular species that might be of concern, and what we do about that in terms of follow up.
Lucy: Some strategies are, for example, to assess the ability of those candidate viruses that we might have streamlined and pointed down to as being potentially concerning to assess their ability to infect human cells in a laboratory. And then there could be scope, for instance, to preemptively design panels of monoclonal antibodies or vaccine targets in the hope that we won't need them, but to be ready to act quickly if the worst were to happen.
Kat: So what I'm really hearing is that the outflow from the toilets at Heathrow Airport, we need to be sequencing that.
Lucy: I'd be very interested in that!
