How can viruses escape labs?

As the search continues for the ancestors of SARS CoV-2 in the wild, another hypothesis has circulated -  the virus leaked from a lab. When first proposed, many dismissed the idea out of hand on the grounds there already seemed to be a reasonable explanation for how the virus emerged. But, the possibility that SARS CoV-2 is an escaped laboratory experiment has gone back up the agenda with the discovery in recent months of new evidence of the kinds of experiments that were being conducted, or at least proposed, at the Wuhan Institute of Virology…

Julia - This kind of work is vital to understand the pandemic potential of some infectious diseases, but, as David Matthews who studies MERS at his Bristol lab explains, this kind of work needs to be conducted very carefully.

David - We have a high containment facility here: containment level three. It's airtight, it's sealed, it has an air handling system that sterilizes the air inside the room Only sterile air leaves the room, so nothing escapes, and then within that room we have another cabinet which is called a "class three cabinet", which is the sort of thing you see in Hollywood movies where you've got a sealed box with giant rubber gloves that you stick in and there's airlocks and techniques for passing things in and out. Anything that leaves that contained box has to be sprayed down with a bleach solution and left for 15 minutes and, even before we do all that, we have to do a series of experiments to prove that our techniques for sterilizing things actually do kill viruses. It's a series of layered defense between yourself and the dangerous virus.

Chris - But where there are humans, there are, of course, potential or real errors. Lab leaks have happened before as in the case, for example, of foot and mouth. Alina Chan, who's a scientific advisor at the Broad Institute of MIT and Harvard, and co-author with Matt Ridley of 'Viral, the search for the origin of COVID 19', explains -

Alina - We know that lab leaks occur quite frequently, and accidents happen to even the most highly trained people; as long as there's human error, there's a chance for a virus to escape from a lab. This was demonstrated in the recent lab leak of SARS CoV-2 in Taiwan in late 2021. That was a researcher in her twenties, she was fully vaccinated with Moderna, but she had been bitten by a mouse at least twice in that lab. She was diagnosed on December 9th, 2021 and Taiwan immediately launched an investigation into the lab, as well as all of her contacts. Within 12 days, they had already publicly announced that they had concluded the investigation into the lab. They said it was definitely from the lab. They went into that bio safety level three lab where the animal work had been done. They found contamination all over the place and then also identified several flaws in protocol where there were human error. So, we know that it can happen.

Julia - Wuhan house is one of the leading laboratories in the world for studying SARS like viruses, which is important to take into account.

Alina - With SARS CoV-2, the virus that causes COVID 19, we know that it occurred on the doorstep of a lab in Wuhan city that had a long history of collecting SARS like viruses. So, the question is, did it come from the laboratory in that city?

Chris - Are there any other explanations, though, because one must be cautious about the difference between cause and association: if one asks "do fire engines cause fires because I always see fire engines where I see fires", I could draw the wrong conclusion. Are there other possibilities?

Alina - COVID 19 was detected in the city where they had the world's best expertise at tracking SARS like viruses. They had spent the last decade, at least, searching through south China and Southeast Asia where these viruses were known to be found. The spillover zone for SARS-like viruses is down South, like thousands of kilometres South, so it's not impossible that an animal was infected and was somehow transported all the way up, thousands of kilometres up into Wuhan, and only caused an outbreak there, but I'd say that the odds are pretty low.

Chris - Were the agents, meaning the samples, the possible viruses? Were they similar enough to what we see now causing COVID 19, the SARS CoV-2 virus, for that to be a reasonable prospect? Or were they studying viruses that were so different that the chances of what they were collecting turning into the causative agent behind COVID 19 so remote as to be impossibly likely?

Alina - We now know, based on the work of independent analysts and scientists, that when COVID 19 was detected in Wuhan had in their hands at least nine of the closest relatives to SARS CoV-2 at that time. So, there is a lot of circumstantial evidence, I would say, that warrants a deep investigation into the origin of COVID 19.

Chris - In terms of the research they were then doing on these viruses to further study them, what were they actually doing?

Alina - Their purpose was to predict future outbreaks. To do so, their aim was to collect and study as many viruses from the wild as possible. After they collect these samples, tens of thousands of samples, they are sent back to Wuhan city and in the lab they take these samples and they sequence it. They're trying to see what viruses are in here and, if possible, they try to grow them so as to extract the virus out of the sample.

Julia - Speculation has circulated around the exact work which was going on to grow these viruses. Certain viruses are notoriously hard to culture in a lab. By altering the genetic sequence, this can then enhance its ability to grow, making it easier to study. One theory was that SARS CoV-2 emerged as a hybrid of other coronaviruses being grown. But, Jesse bloom suggests this is unlikely -

Jesse - I don't think that's possible because if SARS CoV-2 looked like two known viruses, where part of it looked like one, and part of it looked like the other, then we could imagine the scenario you're positing. But compared to the closest known viruses, SARS CoV-2 has the mutations scattered across the whole genome, so this combinational mixing - I can't explain it. Whatever SARS CoV-2 is directly descended from is a virus for which we don't yet know the sequence.

Chris - Another point of contention when trying to deduce if SARS CoV-2 arose naturally or was synthetically manipulated comes from certain sequences inside its genetic material. Specifically, SARS CoV-2 contains a structure called a furin cleavage site. This is a bit like a pin in a grenade -  when this furin pin is pulled, the virus is primed to infect. Some coronaviruses naturally have these, and they do boost infectivity enormously, but, critically, none of the closest relatives of SARS CoV-2 that we have found have them. And this is what initially made people very suspicious. Alina Chan, again -

Alina - Without this furin cleavage site, the virus could have never caused a pandemic, and we know that now from studying the virus -  if you take out this cleavage site, it's completely attenuated - it can barely cause disease and is barely transmissible. So, the question is, how did it appear in SARS CoV-2? The reason why some people find the furin cleavage site very suspicious is that, if you look at all SARS-like viruses that have arisen to date, only SARS CoV-2 has this furin cleavage site. So, the question is, was it natural? Was it just a freak accident in nature? Or was it put there in a lab?

Chris - Now, as furin cleavage sites are found in the wider coronavirus family, they do naturally occur in these viruses, it's not beyond the realms of possibility that this powerful genetic infectivity boost could have cropped up in the COVID 19 virus by chance. But, a leaked grant proposal that surfaced only recently and which involved The Wuhan Institute of Virology and collaborators in the US, is very grave cause for concern.

Jesse - In late 2021, a grant proposal called the DARPA diffuse proposal was released, which showed that a group of scientists were proposing to introduce furin cleavage sites into SARS related coronaviruses. That particular proposal was not funded, and it's unknown if that work ever happened, but I think at this point we certainly know that furin cleavage sites can arise in coronaviruses and that there are scientists out there who are interested in engineering them into coronaviruses.

Chris - Now we don't know if this kind of work was actually being carried out on SARS-like coronaviruses, which is why Alina Chan points out investigation is urgently warranted -

Alina - This group of researchers say that they're gonna put horns on horses and, about two years later, a unicorn strolls up in their city. So, based on that striking coincidence, there's a need to investigate.