A string of about 30,000 genetic letters were all it took to start the nightmare of Covid-19, which is likely to have killed more than 20 million people. Exactly how this story began is hotly debated. Many think the origin of Covid-19 was zoonotic – a spread, like so many new pathogens, from wildlife because it resembles a group of coronaviruses found in bats. Others have pointed to the enthusiastic coronavirus development going on in laboratories around the world, but particularly in Wuhan – the Chinese city where the virus was first identified. In February 2021, a team of scientists (WHO), who visited Wuhan, said a lab leak was extremely unlikely. However, this conclusion was later challenged by the WHO‘s boss, who said ruling out that theory was premature.
Two recent publications seem to have strengthened the case for a natural origin in the context of a “wet market” in Wuhan. These markets sell live animals, often housed in poor conditions, and are known to be places where new pathogens jump from animals to humans. Early cases of Covid-19 clustered around this market. But critics counter that so much data is missing about the early days of the epidemic that this portrait may be inaccurate.
The opposite idea of a leak from a lab is not implausible. Accidental virus escapes from laboratories are more common than many people realize. This is how the 1977 flu epidemic is said to have started. However, an escaped virus does not mean that it is a manipulated virus. Virology labs are full of the unmanipulated variety, too.
Research like the one in Wuhan offers a number of ways a virus can escape. A researcher on a field trip could have picked it up in the wild and then returned to Wuhan and passed it on to others there. Or someone could have infected themselves in the lab with a wild-collected virus. But some argue so Sars–cOv-2 could have been assembled in a lab from other pre-existing viruses and then leaked out.
Into this fight comes analysis from an unlikely source. Alex Washburne is a mathematical biologist who runs Selva, a small microbiome science startup based in New York. He’s an outsider, though he has worked on virological modeling in the past as a researcher at Montana State University. For this study, Dr. Washburne with two other scientists. One is Antonius VanDongen, associate professor of pharmacology at Duke University in North Carolina. The other, Valentin Bruttel, is a molecular immunologist at the University of Würzburg, Germany. dr Washburne and Dr. VanDongen were active proponents of investigating the laboratory leak theory.
The trio base their claim on a novel method for detecting plausible, laboratory-made viruses. Their analysis, published Oct. 20 on bioRxiv, a preprint server, suggests Sars–cOv-2 has some genomic features that they say would appear if the virus had been put together through some form of genetic engineering. By examining how many of these putative seams Sars–cOv-2, and given how relatively short these pieces are, they try to gauge how closely the virus resembles others found in nature.
They start from the assumption that the creation of a genome is as long as that of Sars–cOv-2 would mean combining shorter fragments of existing viruses together. For a coronavirus genome assembly, she says, the ideal would be to use between five and eight fragments, all less than 8,000 letters long. Such fragments are generated using restriction enzymes. These are molecular scissors that cut genomic material at specific sequences of genetic letters. When a genome doesn’t have such restriction sites in appropriate places, researchers usually create new ones of their own.
They argue that the distribution of restriction sites for two popular restriction enzymes – BsaI and BsmBI – are “anomalous” in the Sars–cOv-2 genome. And the length of the longest fragment is much shorter than expected. They determined this by comparing 70 different coronavirus genomes (excluding Sars–cOv-2) and cut them into pieces with 214 commonly used restriction enzymes. From the resulting collection, they were able to calculate the expected lengths of fragments when coronaviruses are cut into different numbers.
The paper, which received no formal peer review as a preprint and was not accepted for publication in a journal, will be taken apart in the coming days – as it should be, because that’s how science works. Initial reactions, however, were deeply divided. Francois Balloux, professor of computational systems biology at University College London, said he found the results intriguing. “Unlike many of my colleagues, I could not find any serious flaws in the reasoning and methodology. The distribution of BsaI/BsmBI restriction sites in Sars–cOv-2 is atypical”. dr Balloux said these must be judged on good faith. But Edward Holmes, an evolutionary biologist and virologist at the University of Sydney, said each of the features identified in the paper is natural and has already been found in other bat viruses. If someone developed a virus, they would undoubtedly introduce some new ones. He added, “There’s a whole bunch of technical reasons why this is utter nonsense.”
Sylvestre Marillonnet, an expert in synthetic biology at the Leibniz Institute for Plant Biochemistry in Germany, agreed that the number and distribution of these restriction sites did not appear entirely random, and that the number of silent mutations found at these sites indicated this Sars–cOv-2 might have been tampered with. (Silent mutations are the result of engineers wanting to make changes in a sequence of genetic material without making changes to the proteins encoded by that sequence.) But Dr. Marillonnet also said that there are arguments against this hypothesis. One is the tiny length of one of the six fragments, something that “doesn’t seem logical to me”.
The other point that Dr. Marillonnet cites is that it is not necessary that the restriction sites were present in the final sequence. “Why should people enter and exit places in the genome when they are not needed?” he wondered. Previous arguments in support of the possibility of a lab leak have emphasized that a engineered virus need not have such signs. But Justin Kinney, a professor at the Cold Spring Harbor Laboratory in New York, said researchers had created coronaviruses before and left such spots in the genome. He said the genetic signature points to a virus ready for further experimentation and said it must be taken seriously, but warned the paper needs rigorous peer review.
Erik van Nimwegen from the University of Basel says there are only small scraps of information and it is “difficult to draw anything definitive from them”. He adds: “One cannot actually rule out that such a location constellation arose by chance”. The paper’s authors acknowledge that this is the case. Kristian 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 developed will be hotly contested. China denies the virus originated in a Chinese lab and has asked for research into whether it might have originated in America. dr Washburne and his colleagues say their predictions are testable. If a precursor genome to Sars–cOv-2 is found in the wild with the same or intermediate restriction sites, it would increase the likelihood that this pattern evolved by chance.
Any widely supported conclusion that the virus was genetically engineered would have profound consequences, both politically and scientifically. It would shed new light on the Chinese government’s behavior in the early days of the outbreak, particularly its reluctance to share epidemiological data from those days. It would also raise questions about what became known, when and by whom about the alleged accidental escape of a manipulated virus. At the moment this is a first draft of science and must be treated as such. But the commissars are already at work. ■
Editor’s Note: The preprint “Endonuclease fingerprint indicates synthetic origin Sars–cOv-2″ by Bruttel, Washburne and VanDongen, found at bioRxiv.
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