Despite the "lab leak theory" taking flight again in the US media, global scientists still point out there's little evidence to suggest the SARS-CoV-2 virus originated in a Wuhan laboratory – and a large amount to suggest it came from nature. Otago University virologist Dr Jemma Geoghegan and Massey University infectious disease ecologist Professor David Hayman set out three reasons why a lab-made pandemic remains extremely unlikely.
It's happened before
There's a strong precedent for coronaviruses that have become "zoonotic", or jumped from animals to humans.
There have been seven that scientists are aware of – including SARS-CoV and MERS-CoV – and bats are thought to have been involved in most of these.
"And five of these human coronaviruses have emerged in the last 20 years," Geoghegan said.
While the source of the SARS-CoV-2 virus still hasn't been pinned down, she said that wasn't unusual.
"In fact, we don't know where most of the viruses that infect us have come from," she said.
"This is why we need to sample more viruses in nature and expand our knowledge of the diversity of viruses that exist."
Hayman added that, now that scientists were looking even harder, more cases of infections from newly-detected or "novel" coronaviruses were coming to light.
"One was identified in pneumonia patients in Malaysia where people were living in villages in close contact with domestic and wild animals."
While the pandemic found the world poorly prepared for it, scientists had been warning for years that the growing interaction between animals and nature – particularly through habitat destruction – had been raising the risk of a catastrophe like Covid-19.
Just like the first Sars coronavirus, the first cases of Sars-Cov-2 were associated with an animal market – this time in Wuhan, China.
The World Health Organisation's report identified that live animals like ferret-badgers and rabbits were being traded in these markets.
"These animals could provide an intermediate host for the virus to jump to humans," Geoghegan said.
"It's exactly the type of place you'd expect a zoonosis event to happen."
Hayman added that some of the farmed species had complex commodity chains.
That meant the farms could well be in places where there was a greater diversity of bat viruses than in Wuhan, where the pandemic appeared to have started.
"And we have seen how SARS-CoV-2 can be maintained in farmed fur animals, such as the very large outbreaks in farmed mink in Europe, which led to substantial mink to mink transmission as well as mink-to-human transmission."
Other evidence also shows that this type of coronavirus has existed in bats for decades – and the SARS-CoV-2 genome sequence happened to be 96 per cent identical to a coronavirus found in horseshoe bats.
There's no genetic sign of human meddling
In one of the earliest major studies into the virus, scientists analysed its genetic template for spike proteins – or armatures on the outside of the virus that it used to grab and penetrate the outer walls of human and animal cells.
More specifically, they focused on two important features of the spike protein.
Those were its receptor-binding domain (RBD) - a kind of grappling hook that grips on to host cells - and what's called the cleavage site, a molecular can opener that allows the virus to crack open and enter host cells.
They found the RBD portion of the SARS-CoV-2 spike proteins had evolved to effectively target a molecular feature on the outside of human cells called ACE2 - a receptor involved in regulating blood pressure.
The SARS-CoV-2 spike protein was so effective at binding the human cells, in fact, that the scientists concluded it was the result of natural selection, and not the product of genetic engineering that some theorists have suspected.
The idea of natural evolution was given further credence by data on the virus' backbone - its overall molecular structure.
If someone were seeking to engineer a new coronavirus as a pathogen, they would have constructed it from the backbone of a virus known to cause illness.
But the scientists found that the backbone differed greatly from those of already known coronaviruses.
It turned out to mostly resemble related viruses found in bats and pangolins - scaly-skinned mammals that are prized delicacies in China.
That led scientists to suspect one of two possible scenarios.
In one scenario, the virus evolved to its current state through natural selection in an animal host and then jumped to humans.
Yet there were no documented cases of direct bat-human transmission, suggesting that an intermediate host was likely involved between bats and humans.
In this scenario, both of the distinctive features of SARS-CoV-2's spike protein - the RBD portion that binds to cells and the cleavage site that opens the virus up - would have evolved to their current state before entering humans.
In this case, the current epidemic would probably have emerged rapidly as soon as humans were infected, as the virus would have already evolved the features that made it pathogenic, or able to spread between people.
In the other proposed scenario, a non-pathogenic version of the virus jumped from an animal host into humans and then evolved to its current state within the human population.
A coronavirus from a pangolin could possibly have been transmitted to a human, either directly or through an intermediary host such as civets or ferrets.
After that, the other distinct spike protein characteristic of SARS-CoV-2 - the cleavage site - could have evolved within a human host, or possibly among a group of people, before the outbreak kicked off.
Geoghegan said the idea that the cleavage site was so unusual that it must have been engineered was "totally false".
She said that assumed an amino acid sequence within the site called PRRAR had been created in a lab.
Yet these cleavage sites had been found in other coronaviruses - even with the exact same "PRRAR" insert.
"It's a totally bonkers argument," Hayman added.
"Similarly, people really need to understand that these viruses do recombine. For example, the novel virus from Malaysia that was recently detected seems to be a recombinant of a cat and dog viruses, which were also previously not known."
The slightly more plausible alternative lab leak theory was that scientists could simply have been growing a culture of the virus, and it escaped from there.
But that would've had to assume the virus could have leaked from a secure research facility – and also neglected the fact that the virus' feature of entry and infection markedly diminished in a lab culture setting.
And then, as Dr Jonathan Stoye, group leader of the Retrovirus-Host Interactions Laboratory at the UK's Francis Crick Institute, pointed out, the virus' spread around the world didn't gel with the lab-grown theory.
"The genome of SARS-CoV-2 shows more than 1000 individual differences from its closest known relative," he said.
"Given the rate of nucleotide change observed in virus spreading through the human population over the past year it seems extremely improbable, perhaps impossible, that changes spanning such an evolutionary distance could have occurred during virus growth in a lab.
"It therefore remains most likely that the immediate ancestor to SARS-CoV-2 exists in the wild and is still to be found."
The weight of evidence points in one direction
Scientists aren't saying the possibility of a lab leak should be entirely ruled out – on the contrary, many argue that it should be comprehensively investigated.
But more than a year after the outbreak, the weight of evidence overwhelmingly points to a natural source, while there's little to suggest the virus came from a lab.
Part of the lab leak theory is predicated on the fact that the Wuhan Institute of Virology has carried out extensive work on coronaviruses in bats.
While the institute didn't shared its lab records with a team of WHO investigators, there's as yet been no evidence that any samples of the virus were kept there before it was first reported, nor were there any viruses that could have combined to create it.
Much of the recent coverage has been fueled by a US intelligence report that stated several researchers had become sick with "symptoms consistent with both Covid-19 and common seasonal illness".
A top director at the institute has rejected this inference, reporting that all staff have tested negative for Covid-19 antibodies, and that there'd been no turnover of staff in the coronavirus team.
"Why would these scientists be working on a random secret bat virus and not have published anything on it previously?" Geoghegan said.
"Those that do gain-of-function experiments work on really well characterised viruses, and there would be really close genetic relatives of the virus published before.
"But for SARS-CoV-2, there isn't. Even the closest viruses in bats and pangolins are too divergent to be a starting point."
Hayman added that every expert in the area would have asked themselves, "what if it was that lab?"
"We ask ourselves, 'What would we see, what evidence would we need to support it?', and even, 'have we been lied to?'. We have, most of us, agonised over the possibilities.
"But right now the only way that this can be true is if there is a massive conspiracy, because while the lab pathway is a potential pathway, nothing published or reliably reported by China to date supports a lab escape at all, and there is a huge amount of data to support this being a natural event.
"This discussion would have gone away if it hadn't have happened in China. But unfortunately finding conclusive evidence of either is very unlikely."