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Virologist Stuart Neil of King's College London says that, despite such allegations, "there is no evidence that Sars-CoV-2 is the product of laboratory engineering or any sort of experimental fiddling". The leading theory now backed by most scientists is that the virus arose in wild bats and found its way into animals (perhaps via a pangolin or a civet cat) sold at the Huanan Seafood Wholesale Market in Wuhan. The bat populations most likely to have harboured the virus are in southern China (probably Yunnan province), far from Wuhan--but that is no big mystery, for the market was, before being shut down in January 2020, partly supplied by wildlife farms in that region. Such long-distance transmission of a viral pathogen is nothing unusual, says Robert Garry of Tulane University Medical Center in New Orleans--it happened with the Ebola virus in Africa, for example. Zoonotic transmission from wild animals sold at Chinese markets is also how Sars is thought to have entered the human population.

Last July, a detailed study of the early epidemiology of Covid-19 offered compelling support for this picture. A team of scientists led by biologist Michael Worobey of the University of Arizona reported that most of the earliest human cases centred around the Huanan market. In the section where live wild animals were sold, samples containing the virus were taken from carts, drains and a metal animal cage. It was already known that 27 of the 41 people initially hospitalised in Wuhan had had direct exposure to the market, while 55 of 168 of the first known cases were also associated with it. Worobey and colleagues also found that the residential addresses of 155 of those first cases pointed to the market as the epicentre of infection. "There are no other epidemiological links to any other place in the city," said Kristian Andersen of the Scripps Research Institute in California, a co-author of the study. 

A parallel study of the Sars-CoV-2 genome suggested that there were at least two events, probably sometime in November 2019, when the virus jumped between species. Many experts feel that the conclusion is now rather clear. "The science is largely pointing in one direction, and that is that the pandemic began naturally," virologist Angela Rasmussen of the University of Saskatchewan told the BBC last November. 

What, then, sustains the lab-leak theory? Among scientists, the idea that Sars-CoV-2 was engineered has tended to rely on a different kind of evidence: claims that the biochemical nature of the virus bears signs of the kind of artificial tampering that might be expected in GOF experiments. One early line of argument concerned a part of the spike protein that attaches to human cells in the first stage of attack. Called the furin cleavage site (FCS), it acts like a kind of switch that flips the virus into infectious mode, and is thought to be a key factor in making Sars-CoV-2 highly transmissible. FCSs are found in other coronaviruses in the wild, but the original Sars virus does not have one--if somebody was trying to modify it, this would be the obvious change to make. In May 2021, Nobel laureate virologist David Baltimore was quoted as saying that the FCS looked like a "smoking gun" for an engineered origin--an imprudent suggestion that he later withdrew, in view of the fact that the FCS could have hopped to Sars-CoV-2 from some other virus in the wild. 

The somewhat unexpected FCS was noticed as soon as the genetic sequence of Sars-CoV-2 was known in early 2020. Fauci discussed what this might mean for the idea of an engineered origin on 1st February, in a confidential teleconference and subsequent emails with NIH director Francis Collins, head of the Wellcome Trust Jeremy Farrar, the UK government chief scientific adviser Patrick Vallance, and other experts. Although conspiracy theorists have asserted that these scientists then tried to bury the issue, emails released last November show a conventional story. The participants took seriously the idea that the FCS might imply a lab origin, sought expert advice, notified the WHO, and concluded that a lab origin was "largely incompatible with the data" but that more study was needed. In other words it was science as normal, conducted with open minds and commendable rapidity.

There was another flurry of lab-leak rumours last October, when a trio of scientists (none of them virologists) released a preprint--a paper not yet peer-reviewed--claiming that a certain kind of genetic sequence called a restriction site recurs in the Sars-CoV-2 genome at suspiciously regular intervals. This, the authors argued, suggests that the viral genome might have been artificially constructed by joining together short segments of roughly equal size. Several experts initially took the idea seriously. Systems biologist Francois Balloux of University College London told the Economist that "I couldn't identify any fatal flaw in the reasoning and methodology"--only to later withdraw that view. Others pointed out that there were statistical reasons why a sequence like this may arise naturally. Andersen called the pattern "random noise", while virologist Edward Holmes, who was part of the team that first announced the genome sequence of Sars-CoV-2, called the preprint's claims "nonsense".

Such false alarms ought to recommend caution about what a natural or engineered virus "must" look like, or what nature can and can't produce. "If you've been a virologist for any length of time, nothing surprises you about what a virus can do," says Neil. There is a frighteningly vast reservoir of wild coronaviruses; we know next to nothing about the overwhelming majority of them. The genomes of such viruses are immensely diverse, precisely because they are in a sense "randomly engineered" by natural selection in the wild. If two coronaviruses infect the same host, they can exchange their genetic material. This "recombination" helps the virus to increase its diversity and thereby its potential to spread: occasionally it will, by chance, make a much more effective virus. It is not at all hard to see how the FCS could have arisen this way. Recombination also explains why it is hard to identify a natural source for a virus like Sars-CoV-2: every segment of the genome will probably have come from a different progenitor.

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