That spillover most probably occurred at a market in the city of Wuhan, China, an environment that presented the virus with ample opportunity to rapidly mutate and spread from one organism to another. It’s also a possibility that COVID-19, whether a bioengineered chimera or not, leaked from a laboratory environment due to some combination of the hubris and carelessness of the researchers who were studying it. Much of the scientific world has spent the last year playing down the possibility of a lab leak, due to its unfortunate proximity to the xenophobic wailings of political opportunists and conspiracy-loving provocateurs, and in that respect, hesitation to address the prospect head-on has made some sense. But as the number of credible scientific and political figures highlighting the need to seriously examine the possibility has grown in recent months, it is clear that ignoring the theory would be both intellectually dishonest and ethically irresponsible. Lab leak likelihood When you begin looking at the tenebrous forest of information connected to the virus’s origins, one thing quickly becomes clear: there is as yet no direct evidence for either a natural spillover event (as investigators have yet to find the animal from which the pathogen jumped to humans) or a lab leak. That doesn’t mean the two possibilities are equally likely. A zoonotic spillover, according to a number of sources, including the World Health Organization (WHO), is the more conceivable of the two scenarios. Horseshoe bats (Rhinolophus sinicus) are known hosts of a family of SARS viruses closely related to SARS-CoV-2, and it’s not unheard of for those pathogens to mutate to be able to infect humans. But the circumstantial evidence surrounding the lab leak hypothesis is more robust than might be immediately obvious, and it’s certainly not doing the animal spillover hypothesis any favours. The Wuhan Institute of Virology (WIV), one of a handful of coronavirus research centres in the world, happens to be located a dozen kilometres from the market where epidemiologists believe the virus began infecting people. The Wuhan Center for Disease Control and Prevention, another facility known to have conducted work on bat coronaviruses, sits within a single kilometre of it. Such proximity would be less notable if it weren’t for the fact that, historically, viruses and other pathogens escape labs where they’re being studied with unsettling frequency. In 1972, a strain of smallpox found its way out of two English labs on three separate occasions, infecting 80 people and killing three. After seemingly disappearing in the aftermath of the 1918 pandemic it caused, the H1N1 influenza virus reappeared in Russia in 1977, the result of a lab leak, and continued circulating until as late as 2009. More recently, the original SARS virus escaped virology labs in Taiwan, Singapore, and Beijing on six separate occasions. Investigations into these leaks showed that they occurred in lab environments whose biosecurity measures were either insufficient or poorly enforced. All the more discomforting, then, is the fact that in 2018, the US Embassy in Beijing sent officials to the WIV several times, reporting back that safety protocols at the research centre were starkly inadequate. The Washington Post was recently able to obtain the first of two cables sent to Washington detailing these visits. In it, officials explicitly warn that the facility’s bat coronaviruses constitute a risk of human transmission and even of a potential pandemic. The virus in the room A good deal of the conversation surrounding the origins of the pandemic has to do with what’s known as 'gain-of-function' research and the biosecurity levels at which it’s carried out. Organisms in nature have the ability to acquire new functions or features that are the result of natural selective pressures. But scientists can also replicate the process in a lab, creating conditions favourable to the changes they wish to study and better understand. Using technologies like CRISPR, they can even make such changes at the level of an organism's genetic code. It’s just such gain-of-function research that has led to scientists engineering drought-resistant plants. This research could one day help create mosquitoes unable to carry malaria, and other beneficial advances. Viruses are by no means exempt from this kind of research, which usually involves experiments – often carried out specifically in the name of pandemic prevention – to make the virus either more or less transmissible. The value of experimenting with modified strains of pathogens to make them more virulent has been the subject of pointed debate within the scientific community for years, and answering the question of how much risk is acceptable has never been straightforward. Ralph Baric, a well-known virologist at the University of North Carolina, is among those who believe the research is well worth the risk. Baric’s work with coronaviruses began in the late 1990s and expanded significantly after he witnessed the emergence of SARS in 2002 and MERS in 2012. Gain-of-function research with these viruses, he believed, must become a societal priority. Engineering virus chimeras in the lab meant the possibility of developing an all-purpose vaccine against them, something that could save countless lives in the future. His work eventually connected him with Shi Zhengli, the top coronavirus researcher at the WIV. Over the course of her career, Shi’s work at the institute, which was born out of attempts to find the origins of the virus that caused the 2002 pandemic, revealed numerous virus species in nature that are just a few mutations away from being able to jump to humans. One key virus her lab discovered, SHC014, was found to be a close genetic relative to SARS. Baric and Zhengli began collaborating with one another after meeting in 2013, with Baric sending genetically modified mice with human lung receptors to Wuhan and Zhengli sharing SHC014’s genetic sequencing with researchers at UNC. During this time, however, the National Institutes of Health (NIH) had begun scaling back its funding for gain-of-function research both in the US and abroad. Due to the convincing arguments of researchers like Baric, who defended the need for continuing such work, the NIH decided to fund studies at the WIV; research that, according to the MIT Technology Review, included reverse-engineering coronavirus chimeras of their own. As investigators have yet to find the host animal that made the COVID-19 jump to humans possible, Zhengli and her lab’s work has come under increasing scrutiny. Shi denies the possibility that her lab played any role in the start or spread of SARS-CoV-2 outright, but also admitted in an interview with Scientific American in June 2020 that she initially wondered if the virus could have come from her lab. In a more recent interview with the New York Times, however, Zhengli stoutly rejected the likelihood of her lab’s involvement, saying, “My lab has never conducted or cooperated in conducting gain-of-function experiments that enhance the virulence of viruses”. It’s possible that she’s telling the truth. Even if her lab did play a role in the virus’s emergence, such work may have taken place outside of her direct supervision. Unluckily for Zhengli and her team, at least some of the coronavirus research that did take place at the WIV has since been found to have been conducted at biosafety level 2 (BSL-2), a level that Richard Ebright of Rutgers University recently described to Financial Times as being, “roughly equivalent to a standard dentist office”. This is far below the level of safety needed to work with such viruses, even according to gain-of-function proponents like Baric, who carried out his research at BSL-3 or above. More and more scientists have begun raising their voices about this revelation, calling it scandalous, even if the Wuhan lab had nothing to do with the pandemic. Zhengli is in the unenviable position of being pressured by international organisations and media outlets to be forthcoming and honest while simultaneously having every word she utters labelled as suspicious. The fact that she has displayed some degree of inconsistency in her remarks about the virus may not be entirely her fault or necessarily suspect. The Chinese government has a tendency to stifle information that doesn’t serve it – even if Zhengli did possess knowledge of a leak, she might not be free to speak about it. Pathogenic politics The English-language report of the US diplomats’ final visit to the WIV in 2018 has since been taken down from the virology institute’s website. It’s one indication of many that China intends to keep a tight and uniform lid on information connected to the virus from the run-up to the outbreak, an unhelpful trend that doesn’t exactly inspire confidence that the government is being candid with what they know (or don’t know). In February, during an official WHO investigation into the virus’s origins, Chinese officials turned down requests from WHO members to provide raw data on 174 cases of COVID from the very early stages of the pandemic. Authorities instead provided investigators with comprehensive summaries and aggregate data from their own investigations, saying they found no evidence of the virus in the Wuhan region in the months leading up to its emergence. Information on these early cases is vital to being able to determine if the Wuhan market was the source of the outbreak or simply a place where it began to proliferate. Compounding matters is the fact that a full year had passed before WHO officials were allowed into the country to begin what was, by all accounts, a closely supervised investigation. Without detailed information on these cases, and with a year of time lost in the interim, assembling a complete picture may not be possible. Many observers doubt the integrity of the final WHO report that resulted from that visit, including the organisation’s director, Dr Tedros Adhanom Ghebreyesus, who recently said in a press release that, “As far as WHO is concerned, all hypotheses remain on the table.” The furin cleavage site conundrum The presence of an enzyme that makes COVID-19 particularly good at infecting humans is called the furin cleavage site, and depending on who you ask, it’s either evidence for or against a potential lab leak. “The reason that some say it might be laboratory-derived is because it has this furin cleavage site that is relatively rare in adjacent species of coronaviruses, but does show up in other viruses,” says Dr Christopher Mason. A professor of genomics, physiology, and biophysics at Weill Cornell Medicine in New York, Dr Mason has spent the last year sequencing the virus’s RNA profile and learning how the pathogen interacts with the human body on multiple levels. “The thing that’s amazing is that we can see genes for haemoglobin regulation and olfactory reception go down. Olfactory, of course, is your sense of smell. You can see it in the data. We’re using more and more assets to give us a really broad view of the host-microbial and immunological state at the site of infection.” The presence of the furin cleavage site and its relative rarity in related coronavirus species has led some to think that it was genetically engineered into existence, something that isn’t an extreme consideration, according to Dr Mason. “It’s not impossible for this to occur naturally,” he says, “it’s just uncommon in this clade of viruses. The other thing is that there was gain-of-function research going on at the Wuhan institute which played with the same cleavage site.” Speaking with Foreign Policy this June, Stephen Goldstein, a postdoctoral research associate in evolutionary virology at the University of Utah, claimed that the cleavage site is an important signal that the virus’s origins are natural rather than designed. “You cannot, in a normal cell culture, maintain the furin cleavage site. It is possible to replicate the virus in a lab while preserving the cleavage site, [but that would] require doing things differently than everyone does them.” Sceptics also point to the fact that, since the pandemic began, Covid has infected hundreds of millions of people and only managed to mutate into a few different versions of itself in that time. Speeding things along in the lab to engineer new strains of a virus during gain-of-function research is certainly possible, they add, but would be unlikely and difficult to conceal if it were being done. Infect me once, shame on you Lessons from the pandemic are already shaping the discussions that will form the basis of the future of public health, social responsibility, biomedical research, for example. This is for the better. 'Gain-of-function experiments, when done appropriately, can be very safe and very informative.' For people like Nicole Hassoun, co-director of Binghamton University’s Institute for Justice and Well-Being, the pandemic has clearly highlighted the need for better oversight of pathogenic research. “Good governance of gain-of-function research is essential and, although a precautionary attitude seems warranted, we should also evaluate risks on a case by case basis if the US plans to fund such research,” she explained in an email to Interesting Engineering. “Moreover, international engagement is important to manage risks that may cross international borders. I think it is also worth considering whether international guidelines for engaging in such research should be created.” Dr Mason echoes this case-by-case sentiment, noting that not all viruses are alike. “Should you synthesise smallpox and study it in a lab? The answer is clearly no. It’s not circulating, it’s not dangerous. Operating on and modifying that organism is probably not worth the risk. There, you’re tinkering with something that you don’t really need to defend against, whereas coronaviruses have been and continue to emerge, so there's an ethical argument that doing some research is required, and the question then becomes how much and how do you do it? Gain-of-function experiments, when done appropriately, can be very safe and very informative.” Key technological and medical advances have made the need for risky study of this sort less of a necessity, however. The pandemic overhauled the world’s ability to produce vaccines at record speed and scale, and these changes undermine some of the justifications behind conducting gain-of-function studies. 'It’s an extraordinarily solvable problem.' "People have been asking, 'If we can’t do it in a way that’s perfectly safe, should we just not do it'?" says Dr Mason. “If you’d have asked me two years ago, I would’ve said yes. Today, I think it might not be worth it. We don’t need to have as much of a better understanding of the most aggressive version of a virus and see how it enters into human cells. All of that is because, until about 16 months ago, we had no rapid way to create a global vaccine and deploy it. But now we can do it within weeks – that has fundamentally changed the priorities of research.” Masking the data By most accounts, keeping an open mind regarding the virus’s origins is probably the most reasonable approach to take at this point. Likewise, keeping a healthy and critical attitude regarding the available evidence (and political sensitivities that set the conditions for how that evidence is gathered or accessed) seems to be the better half of wisdom. To expect greater transparency from Chinese officials and a sober discussion on the realities and ethics of biomedical research is not to automatically claim that the virus came from a lab. Neither is considering the likelihood that the virus came from nature an excuse to ignore the disregard for lab safety protocols sometimes involved in the study of dangerous pathogens. Whatever happened, it’s clear that understanding the origins of the virus could be more straightforward than it has been. Dr Mason sums up the situation well: “We can’t know from the data that we have whether [the virus] was from [the WIV] or naturally derived. It can happen in either [situation], but what did happen requires us to get the lab notebooks on the exact experiments that were being run. It would be really easy to solve if we just got some of the samples that were being tested and used in the past two, three years at the institute. It’s an extraordinarily solvable problem.” Unfortunately, investigators and researchers have so far been attempting to piece together a puzzle with ill-defined edges whose pieces seem to have been at least partially locked away from view. “It’s really easy to tell [where it came from],” says Dr Mason. “It takes a matter of days and we’d know the answer. All you need are the samples. If we had that, the mystery would be over, but so far, that has not happened.” Due to these blind spots, it’s possible we’ll never find a definitive answer to the question of how the COVID-19 pandemic originated. However, thanks to the insights already gained from simply trying, it’s an encouraging fact that we might not need an answer to stop it from happening again. In any case, Dr Mason implores people to get vaccinated. "Many of the vaccines, especially the Moderna and Pfizer ones, are extraordinarily effective. The efficacy is good. It’s not as good against the Delta variant, so it’s about 70% or 80% versus 95%, but it’s still pretty damn effective, frankly, compared to other medicines or vaccines. When else in medicine have you heard someone say, “This is 95% effective.” That almost never happens. People have to remember that that’s really good." This article was written by Eric James Beyer and first appeared in Interesting Engineering.