More than a year later, we still don’t know exactly what happened. Though governments and news organizations have focused more attention recently on the notion that the virus leaked from a lab, it’s unclear that we’ll ever identify a theory that satisfies everyone as to how SARS-CoV-2 emerged. Ironically, given the recent prominence of the lab escape theory, the questions the world wants answered about the virus — and the astonishingly fast development of the vaccines that can quash the pandemic — depend entirely on research conducted in labs like the Wuhan Institute of Virology and across the world over the past several decades. This fundamental research underpins our ability to prepare for and respond to pandemics. We need to know what’s out there and what kind of viral threats we face. The only way to do that is to go where the viruses are, with our colleagues who are already there.
In March 2020, a group of renowned evolutionary virologists analyzed the genome sequence of SARS-CoV-2 and found it was overwhelmingly likely that this virus had never been manipulated in any laboratory. Like the earlier coronaviruses SARS-CoV and MERS-CoV, they theorized, it “spilled over” from its natural reservoir host (bats) to a new one (humans). Viruses jump species frequently, with unpredictable consequences. Often a virus hits an evolutionary dead end if it cannot adapt to the new host rapidly enough to be transmitted again. Sometimes, however, it can. Clues that reveal this scenario can be found by analyzing the sequence of the virus genome, and that’s exactly what this study did.
The study carefully examined whether key elements of the virus, particularly the spike protein on its surface, appeared engineered. They did not. The spike didn’t optimally bind to its receptor, ACE-2, and the interaction between the two proteins was unpredictable even using the most advanced computer algorithms. Another key feature often cited as evidence of laboratory origin is the furin cleavage site, where the spike protein is cut in half to “activate” viral material for entry into cells. The viruses most closely related to SARS-CoV-2 don’t have this site, but many others do, including other human coronaviruses. The furin site of SARS-CoV-2 has odd features that no human would design. Its sequence is suboptimal, meaning its cleavage by the enzyme furin is relatively inefficient. Any skilled virologist hoping to give a virus new properties this way would insert a furin site known to be more efficient. The SARS-CoV-2 site has more of the hallmarks of sloppy natural evolution than a human hand. Indeed, a timely analysis last year showed convincingly that it is a product of genetic recombination, a natural feature of coronavirus replication and evolution.
Unfortunately, the pandemic has provided many opportunities to observe SARS-CoV-2 evolution in humans as it unfolds — and confidence in its natural origin has grown over time. The molecular handshake between SARS-CoV-2 and ACE-2, seemingly unique in early 2020, turns out to be found in several related viruses and has since evolved to be a better fit. Its ability to infect human cells also turns out to be unremarkable. A related virus discovered in pangolins infects human cells even more readily than SARS-CoV-2. The virus behind the pandemic may be special in its impact on our lives and the global economy, but the way it infects us isn’t unique at all.
The evolutionary trajectory of SARS-CoV-2 further undermines claims that the virus is obviously artificial and designed for human transmission. Early in the pandemic, a mutation called D614G took hold and spread rapidly around the world, showing that the virus was adapting to its host from the very beginning. Since then, mutations in the region of the spike protein that binds ACE-2, as well as near the furin cleavage site, show continued adaptation. Several of these are found repeatedly in different variants of concern and almost certainly contribute to increased transmissibility. SARS-CoV-2 continues to evolve. It wasn’t perfectly tuned for humans when it appeared, just good enough.
The epidemiological evidence in the World Health Organization’s origins mission report from this spring further bolsters the natural-origin hypothesis. Among early cases, 55 percent had had exposure to wildlife markets, and the growth of the outbreak over time, both in cases and excess deaths, clearly shows that the neighborhood surrounding the Huanan market was the initial center of the epidemic in Wuhan. It’s true that 45 percent of cases could not be linked to a market, but the silent spread of SARS-CoV-2 that has made it so hard to control also makes it difficult to rule out such connections. Yes, the WHO’s mission was imperfect and hampered by political forces in China and elsewhere; even the organization’s director general, Tedros Adhanom Ghebreyesus, has nodded to those limitations by calling for a more thorough examination of the possibility of a lab escape. We don’t disagree about the benefits of doing so, and perhaps the U.S. government’s 90-day intelligence review will turn up compelling new information. We must consider every possibility — but our priorities should be guided by what is most likely. There are still missing pieces of data, including those unlinked cases and inadequate animal sampling, but most of the data we do have points heavily toward natural origin.
Some of the public consideration of a lab escape has focused on a kind of research known as gain-of-function, and whether such experiments could have given rise to SARS-CoV-2. This work is defined by the National Institutes of Health as research on influenza, MERS-CoV or SARS coronaviruses with the potential to enhance transmissibility by aerosol droplet or pathogenicity in mammals. A subset of that research, done at the Wuhan Institute of Virology and some labs in the United States, has involved constructing “chimeric” coronaviruses, where the spike protein of one virus is inserted into the genetic backbone of another, typically the original SARS-CoV or a bat coronavirus called WIV1 used at the Wuhan lab. This allows scientists to study the properties of the spike protein within the context of a well-understood system and make direct comparisons about virulence with a known virus.
These experiments carry some risk, as noted by researchers who have engaged in them, and it’s appropriate to consider the balance between that risk and their benefits.
Understandably then, some people have wondered whether these types of experiments could have produced SARS-CoV-2. The answer is, in this case, not really. In theory, if you had the right viruses in your catalogue, sure. But there are no indications that anyone had ever seen this virus nor any viruses similar enough to serve as its genetic building blocks before SARS-CoV-2 emerged in the population.
The Wuhan institute’s most recent chimeric virus used a very different coronavirus as its genetic backbone. Looking at the body of research produced there, it’s clear that scientists were laser-focused on the bat viruses related to SARS-CoV, which spurred research on coronaviruses worldwide after it emerged in 2003 because of its pandemic potential. There’s just no trace of SARS-CoV-2 in the lab, and if the SARS-CoV-2 progenitor or its building blocks weren’t in the lab before the pandemic, the pandemic could not have started there — even accidentally. This precludes the possibility that SARS-CoV-2 evolved via serial passage in cell culture, or repeated rounds of infection of other cells in a lab, as do other observations about the virus. In standard cell culture, features like the furin cleavage site that are crucial for transmission and disease in humans are rapidly lost as the virus begins adapting to the vervet monkey kidney cells typically used to grow it. For the past 18 months, virologists around the world have been studying SARS-CoV-2 in the laboratory, and they have not seen any evidence that it becomes more dangerous to humans in the lab. The opposite is true: The virus loses features key to transmissibility and virulence, forcing researchers to innovate new culture methods to allow the study of antivirals or vaccines.
It does seem like quite a coincidence that the pandemic started in Wuhan, which has one of the world’s leading coronavirus research labs, and that’s surely helped raise questions about a possible leak. But in addition to being a coronavirus research center, Wuhan is a city of 11 million people, home to a major transportation hub that is connected to every other part of China, as well as wildlife markets supplied by farms throughout the country. The presence of the lab in the city where the pandemic emerged is simply not suspicious enough on its own to outweigh what we know about the virus.
We agree that researchers should continue to study whether the virus could have emerged from a lab, but this cannot come at the expense of the search for animal hosts that could have transmitted SARS-CoV-2 to humans. Getting better answers will take rigorous scientific work — and cooperation from China. As frustrating as obfuscation by the Chinese government is, the answers are there. If we make accusations and demands that aren’t firmly grounded in evidence, we run the real risk of having no origins investigations at all.
The only reason we can evaluate the genomic and virological evidence in a scientifically informed way, and the only reason we have vaccines so quickly, is decades of research on coronaviruses. We’d be years behind the curve without this fundamental knowledge, which resulted from gain-of-function studies and surveys of coronaviruses in bats and other wild animals. How many are there? Where are they? Can they infect us? How might they compare with the original SARS-CoV, which caused a global epidemic in 2003? An even bigger question looms now: Can we design vaccines that might protect us against all related coronaviruses? Research is progressing, but testing vaccine candidates will require finding out what viruses are out there. Again, we have to work with colleagues in China, where the viruses are, to do that.
As the vaccines start to bring the pandemic under control in the United States, the fundamental truth about how to identify and fight dangerous viruses hasn’t changed: Preparing for pandemics, global crises by definition, demands a global response. We must approach this collaboratively — and objectively recognize what the data shows. This virus is more likely to be a product of nature than a product of a laboratory. Letting politics lead us toward other conclusions won’t help keep anyone safer.