When the COVID-19 pandemic hit in early 2020, Sam Wilson and his colleagues quickly realized that they lacked the fundamental tools to study the disease-causing virus, SARS-CoV-2. “That’s when we started to produce these research tools,” including antibodies and a system for modifying the virus, says Wilson, a molecular virologist at the MRC University of Glasgow Centre for Virus Research. At the same time, Wilson noticed many non-coronavirus labs were pivoting their research to focus on COVID-19. “We were producing reagents for ourselves, so it seemed sensible to produce them for the wider research community as well,” he says.
In a paper published February 25 in PLOS Biology, Wilson and his collaborators describe a molecular toolkit for SARS-CoV-2 research, including viral isolates, a reverse genetics system for genetically manipulating the virus, and a suite of antibodies that target almost all its proteins. “The publication has just come out, but actually the tools that are described have been available to the scientific community as soon as they were produced,” says Wilson. The resources described in the paper are available for purchase on their nonprofit website.
The Scientist speaks with Wilson to learn more about how these tools could help advance research on the emergence of SARS-CoV-2, immunity to viral “scariants,” and COVID-19 treatments.
The Scientist: Tell me a little bit about the tools in this kit.
Sam Wilson: There are a lot of tools, but there are really two main tools that are the most useful features of the toolkit. The first one of those is the newly comprehensive panel of antibodies to proteins in SARS-CoV-2, the virus that causes COVID-19. The second most important tool is the very easy to use reverse genetics system, which is a simple way that we can genetically modify the SARS-CoV-2 virus to conduct experiments.
TS: What kind of research are you hoping to facilitate with the reverse genetics system?
When you produce tools, in a way you send them out into the world and they’re going to take on a life of their own.
SW: It’s important to point out that when you produce tools, in a way you send them out into the world and they’re going to take on a life of their own. So in some ways, it’s limited by the imaginations of the investigators and legal restraints that are placed upon genetic modification of viruses. There are a number of simple and predictable things that these systems can be used for. One of the things we’ve done, for example, is take fluorescent proteins and put those into viruses so that they can be followed in real-time in infection experiments. For the day-to-day job of a molecular virologist, this takes an experiment that can take hours and it means you can do it in real-time with no additional labor.
The world is obsessed with the emerging coronavirus variants of concern or ‘scariants’ as I’ve heard them called on social media. You can take a variant of concern out of a person and culture it in the laboratory and you can study it. It’s very hard to know which individual change is conferring the different phenotypes or different behaviors that you’re monitoring in the lab. So if we take the Kent variant [B.1.1.7], one of the first famous variants to emerge, there’s about 17 major coding changes in the virus—over half of those are not in the spike gene. It’s very easy to study the spike gene in isolation because you can decorate another virus with the spike and study its properties. But if you think of that as the outer shell, if you lift up the bonnet, there’s a lot of other proteins contributing to how the virus behaves and you need to be able to modify those to really work out what contribution they’re having to how the virus behaves.
TS: What about the antibody panel you describe in the paper. How do you see those being used?
There are a number of reverse genetics systems that are available for coronaviruses, but we’ve tried to create a system that can be used by labs that are not coronavirus labs.
SW: People are going to come up with really good ideas of what these antibodies can be used for that are going to be part of much bigger studies, to validate how they’re doing experiments. I think they’re going to have a really big role in lots of things in the scientific community. But if we think of specific things that antibodies tend to be used for in the laboratory, I can think of two main uses. We might take a step back and remember what antibodies are: they’re a way that animals have to very specifically recognize a component of an invading pathogen. . . . And we can use that by making antibodies in animals to all the virus components and then we can use those antibodies to pull a virus protein out of an infected cell and see what that viral protein is stuck to. That can tell us a lot about how that virus protein functions and it can also identify interfaces between host and pathogen. And these are very often druggable, so by learning about these interfaces it can give you new ideas for therapeutic interventions.
The other thing that people do very commonly is use antibodies to find out where the virus is—say, in an infected tissue, or you can use the antibodies to find out where exactly in a cell this viral protein is. And again, that can help you understand what that viral protein does.
TS: In the paper, you mention that part of the reason for developing these tools was to facilitate research in labs that maybe hadn’t worked on coronaviruses in the past. Can you tell me about that?
SW: I think now there’s a huge number of labs around the world working on SARS-CoV-2 and COVID-19. But at the beginning [of the pandemic] there was a real hunger for bespoke reagents—there are certain scientific tools that need to be tailored towards the virus. If you think about the reverse genetic tools and the antibodies, both of those can help research in laboratories unaccustomed to working with coronaviruses. There are a number of reverse genetics systems that are available for coronaviruses, but we’ve tried to create a system that can be used by labs that are not coronavirus labs—molecular virology labs but with no prior coronavirus expertise. It’s a very stable and simple genetic system that you can recover virus from what scientists would call a miniprep, a very simple way of preparing DNA. So there’s no complicated upstream steps before, what we call, the rescue of infectious virus.
TS: Have you seen a lot of labs moving towards coronavirus research during the pandemic? How has this helped push forward research on SARS-CoV-2 and COVID-19?
SW: I think it’s both amazing and a tremendous risk. I think that probably at no time in human history has there been such a universal move around the world in science to focus one specific global problem. So that’s meant that the pace of research has been faster than I’ve ever seen in my life. I’ve never seen so much collaboration, so many preprints, and the sharing of research data before publication. I’ve heard the term ‘covidization’ of global research, which is used to describe that. And obviously there’s a risk to that as well—all the research that people were doing before that was presumably very important [has halted]. Just as hospitals have suffered as they’ve moved over to treating COVID-19 because patients are no longer being treated for other illnesses, it’s the same for research—there’s been a huge investment of time and effort in SARS-CoV-2 and COVID-19 research, which has been amazing, but I wonder what we’ve lost in place of that.
TS: What do you see as the big research questions around COVID-19 that still remain?
Another big question mark that is probably the most important one facing humanity right now is, just how long and how robust is immunity to SARS-CoV-2 from the vaccines that are currently being used?
SW: There are many, many big questions. So I’m going to answer that from a very personal point of view. My research interests are in cross-species transmission and the emergence of viruses. I’m very interested in the events that led to the emergence of SARS-CoV-2. At the moment there is still some debate as to the exact bat that the SARS-CoV-2 virus originated from and whether there were intermediate species involved in cross-species transmission to humans. I think that’s really important if we’re to understand how this might happen again.
I think that another big question mark that is probably the most important one facing humanity right now is, just how long and how robust is immunity to SARS-CoV-2 from the vaccines that are currently being used? Are we going to have to move to a model where we repeatedly vaccinate people to create lifelong sterilizing immunity with a vaccine to SARS-CoV-2? I think that’s quite an open question.
TS: What is the current understanding around the emergence of SARS-CoV-2?
I think that probably at no time in human history has there been such a universal move around the world in science to focus one specific global problem.
SW: If we look in bats, specifically horseshoe bats, Rhinolophidae, you can find very closely related viruses to SARS-CoV-2. So we assume that there is a bat species or multiple species that are harboring viruses that are very closely related to SASR-CoV-2. What are the specific circumstances that favor cross-species transmission to humans, perhaps through an intermediate species? Was it happening before but not taking off for some reason? Or was there a specific event that led to this virus emergence? I think that these are the questions that a lot of people are looking into now, and there’ll be a lot of sampling required.
TS: How do you hope this study is received by the research community?
SW: I think this is quite different from most science in that it’s not a discovery piece. . . . I think when you produce reagents like these, the main hope is that somebody, somewhere will use them to do something either useful or very interesting. And then I think that our job will have been done.
S.J. Rihn et al., “A plasmid DNA-launched SARS-CoV-2 reverse genetics system and coronavirus toolkit for COVID-19 research,” PLOS Biol, 19:e3001901, 2021.
Editor’s note: This interview was edited for brevity.