Controversial new research suggests that SARS-CoV-2 bears the hallmarks of genetic engineering

Two recent publications seem to have strengthened the case for the natural origin associated with “wet marketIn Wuhan. These markets sell live animals, often housed in poor conditions, and are known to be sites where new animal-to-human pathogens are transmitted. Early cases of covid-19 cluster around this market. But critics contest that there is too much Missing data about the early days of the pandemic This picture may be inaccurate.

The idea opposed to dropping out of the lab is not implausible. The accidental escape of viruses from laboratories is more common than many people realize. It is believed that the influenza epidemic of 1977 began in this way. But an escaped virus does not mean an engineered virus. And virology labs are full of the non-engineering kind.

Research like the one in Wuhan offers a number of ways for the virus to leak out. A researcher on a field trip could catch it in the wild and then return to Wuhan, thus spreading it to others there. Or, someone may have been infected with a virus collected from the wild in the same laboratory. But some argue that sars-cov-2 could have been synthesized in the laboratory from other viruses that were already there, and then leaked.

In this conflict comes analysis from an unexpected source. Alex Washburn is a mathematical biologist who runs Silva, a microbiome science startup based in New York. It’s weird, though, having worked in the past on viral modeling as a researcher at Montana State University. For this study, Dr. Washburn collaborated with two other scientists. One of them is Antonius van Dongen, associate professor of pharmacology at Duke University in North Carolina. The other, Valentin Brutel, is a molecular immunologist at the University of Würzburg, Germany. Dr. Washburn and Dr. Van Dongen were active proponents of the investigation of the leakage theory in the laboratory.

The trio base their claim on a new method for detecting reasonably engineered laboratory viruses. Their analysis, posted Oct. 20 on bioRxiv, a preprint server, indicates that sars-cov-2 has some genetic features that they say would emerge if the virus was pieced together by some form of genetic engineering. By examining how many putative sewing sites sars-cov-2 has, and how relatively short these pieces are, they are trying to assess how similar the virus is to others found in nature.

They started from the assumption that making a genome as long as the sars-cov-2 genome meant fusing together shorter fragments of existing viruses. For the assembly of the coronavirus genome, they say the ideal arrangement is to use between five and eight segments, all less than 8,000 characters long. These parts are created using restriction enzymes. These are molecular scissors that cut genomic material at a specific sequence of genetic letters. If the genome does not have such restriction sites in the appropriate places, researchers usually create new sites of their own.

They argue that the distribution of restriction sites for two common restriction enzymes – BsaI and BsmBI – is “abnormal” in the sars-cov-2 genome. And the length of the longer part is much shorter than expected. They determined this by taking 70 variant coronavirus genomes (not including sars-cov-2) and chopping them into pieces using 214 commonly used restriction enzymes. From the resulting set, they were able to calculate the expected lengths of fragments when cutting coronaviruses into varying numbers of pieces.

The paper, which, as a rough draft, has not received any formal peer review and has not been accepted for publication in a journal, will be picked up in the coming days – as it should be, because that is how science works. However, early reactions were deeply divided. François Balloux, professor of computational systems biology at University College London, said he found the results intriguing. “Unlike many of my colleagues, I could not identify any critical flaw in reasoning and methodology. The distribution of BsaI/BsmBI restriction sites in sars-cov-2 is atypical.” Dr Balloux said these sites need to be evaluated in good faith. But Edward Holmes, an evolutionary biologist and virologist at the University of Sydney, said every one of the features the paper identified were normal and already found in other bat viruses. If someone is engineering a virus, they will no doubt introduce some new viruses. He added, “There’s a whole host of technical reasons why this is just rubbish.”

Sylvester Marillonnet, a synthetic biologist at the Leibniz Institute for Plant Biochemistry, in Germany, agreed that the number and distribution of these restriction sites did not appear to be completely random, and that the number of silent mutations found at these sites indicated that SARS-CoV-2 may have been engineered. (Silent mutations are the result of engineers wanting to make changes to a sequence of genetic material without making changes to the proteins encoded by that sequence.) But Dr. Marillonette also said there are arguments against this hypothesis. One is the small length of one of the six parts, something that “doesn’t make sense to me”.

The other point Dr. Marilonette makes is that restriction sites don’t have to be present in the final sequence. He asked, “Why do people introduce sites in the genome and leave them when they are no longer needed?” Previous arguments supporting the possibility of a lab leak confirmed that a tampered virus would not need such anecdotes. Researchers have made coronaviruses before and left such sites in the genome, said Justin Kinney, a professor at Cold Spring Harbor Laboratory, in New York. He said the genetic signature indicated the virus was ready for further testing, and said it needed to be taken seriously, but warned that the paper needed careful peer review.

There are only small snippets of information out there and “it’s hard to extract anything definitive from that,” says Eric van Nimwegen of the University of Basel. He adds, “One cannot really rule out that such a group of sites might have happened by chance.” The paper’s authors acknowledge that this is the case. Christian Andersen, a professor of immunology and microbiology at the Scripps Research Institute in La Jolla, California, described the pattern on Twitter as “random noise.”

Any conclusion that sars-cov-2 was engineered would be highly contested. China denies that the virus came from a Chinese laboratory, and has demanded investigations into whether it originated in America. Dr. Washburn and his colleagues say their predictions are testable. If an ancestral genome of sars-cov-2 is found in the wild with homozygous or intermediate restriction sites, it will increase the likelihood that this haplotype evolved by chance.

Any widely supported conclusion that the virus was genetically engineered would have profound ramifications, both political and scientific. It would shed light on the behavior of the Chinese government in the early days of the outbreak, particularly its reluctance to share epidemiological data from those days. It would also raise questions about what was known, when and by whom about the supposed accidental escape of an engineered virus. Right now, this is the first draft of the flag, and you need to treat it as such. But the validators are already working.

Editor’s note: “Preprinted endonuclease fingerprint on a synthetic origin of sars-cov-2” by Bruttel, Washburne, and VanDongen, can be found at bioRxiv.

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