What's more, Wuhan Institute of Virology scientists have for the past five years been engaged in so-called "gain of function" (GOF) research, which is designed to enhance certain properties of viruses for the purpose of anticipating future pandemics. Gain-of-function techniques have been used to turn viruses into human pathogens capable of causing a global pandemic......

The Institute began a program of gain-of-function research into bat coronaviruses in 2015. That involved taking selected strains and seeking to increase the ability of those viruses to transmit from one person to another. The gain-of-function research went hand-in-hand with the surveillance project. As scientists identified new classes of bat viruses that have the ability to infect human cells, that raised the question of what changes would have to arise in nature to make that virus transmissible in humans, which would pose a pandemic threat.

In 2015, the Wuhan lab performed a gain of function experiment using cut-and-paste genetic engineering, in which scientists take a natural virus and directly make substitutions in its RNA coding to make it more transmissible. They took a piece of the original SARS virus and inserted a snippet from a SARS-like bat coronavirus, resulting in a virus that is capable of infecting human cells. A natural virus altered with these methods would be easily flagged in a genetic analysis, like a contemporary addition to an old Victorian house.

A virus produced with animal passage methods would be much harder to spot. These viruses are not directly manipulated. When the virus passes from one animal to the next, it undergoes something similar to what would happen in the wild during the course of its evolution. A wild coronavirus passed through 10 ferrets would be difficult to identify as having been engineered or manipulated.

There is no published record of animal-passage work on coronaviruses in the Wuhan Institute. The lab got its first BSL-4 lab in 2018, which is now considered a requirement for this kind of work (though some work proceeds in BSL-3-enhanced labs). It's possible that researchers started animal passage work in the BSL-4 lab but didn't finish it in time to publish before the current pandemic, when China tightened up on publications. It's possible that the work was done in secret. It's possible that it never happened at all. But some scientists think it's unlikely that an expensive BSL-4 lab would not be doing animal-passage research, which by 2018 was not unusual.

Tracing the origins

To figure out where SARS-CoV-2 came from, Kristian Andersen of Scripps Research and his colleagues performed a genetic analysis: they published the work, which has been widely cited, on March 17 in Nature Medicine. The researchers focused on certain genetic features of the virus for telltale signs of "manipulation."

One feature was the spike of protein that the virus uses to attach so effectively to the human body's ACE2 receptors, a molecular feature of the cells in our lungs and other organs. The spike in SARS-Cov-2, the authors conclude, differs from that of the original SARS virus in ways that suggest it was "most likely the product of natural selection"—in other words, natural, not manipulated in a lab.

However, the paper's reasoning as to why animal passage, in particular, can be ruled out, is not clear. "In theory, it is possible that SARS-CoV-2 acquired the... mutations during adaptation to passage in cell culture," the authors write. The theory that the virus mutated in mammalian hosts such as pangolins "provides a much stronger... explanation." Whether or not that includes animal passage in a lab, they don't say. Andersen didn't respond to Newsweek requests for comment.

Rutger's Ebright, a longtime opponent of gain of function research, says that the Andersen analysis fails to rule out animal-passage as an origin of SARS-CoV-2. "The reasoning is unsound," he wrote in an email to Newsweek. "They favor the possibility 'that the virus mutated in an animal host such as a pangolins' yet, simultaneously, they disfavor the possibility that the virus mutated in 'animal passage.' Because the two possibilities are identical, apart from location, one can't logically favor one and disfavor the other."

Jonathan Eisen, an evolutionary biologist at UC Davis, says that the preponderance of evidence, while not definitive, suggests that the virus came from nature, not a lab. "There's no hint there that there's something unnatural, that is, genetically engineered or manipulated," he says. But "there is some wiggle room" in the findings that admits the possibility that the virus was concocted in a lab via animal passage. "Passaging is hard to test for. Escape from a lab is hard to test for," he says. "If [Wuhan researchers] collected something from the field and they were doing some experiments in the lab with it, and some person got infected and then it spread from there, that would be really hard to distinguish from it having spread in the field directly."

Wuhan is in possession of a virus, RATG13, that is thought to be the most similar to SARS-CoV-2 of any known virus—the two share 96 percent of their genetic material. That four-percent gap would still be a formidable gap for animal-passage research, says Ralph Baric, a virologist at the University of North Carolina who collaborated with Shi Zheng-Li on the 2015 gain-of-function research. "You keep running into problems that just don't make it likely," he says. Wuhan would probably have had to start with a virus closer to SARS-CoV-2 than RATG13, which is within the realm of possibilities.

"The only way to resolve it," says Baric, "is transparency and open science and have some real investigation into it. I don't think the Chinese are going to allow that. I don't know what any country would do in this situation. I would like to think that the U.S. would be transparent."