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On January 11, 2020, in Shanghai, just 11 days after the first reports of the outbreak in Wuhan first went global, a team of scientists led by Yong-Zhen Zhang of Fudan University released a draft genome sequence of the new virus via a website called Virological.org. The genome was provided by Edward C. Holmes, a British Australian evolutionary biologist based in Sydney and a colleague of Zhang on the genome assembly project. Holmes is famous among virologists for his work on the evolution of RNA viruses (including coronaviruses), his perfectly bald head and his biting candor. Everyone in the field knows him as Eddie. The posting was posted at 1.05am Scotland time, by which time the site’s curator in Edinburgh, a professor of molecular evolution named Andrew Rambaut, was alert and ready to speed things up. He and Holmes composed a brief introductory note to the genome“Feel free to download, share, use and analyze this data,” he said. They knew “data” is plural, but they were in a hurry.
Immediately, Holmes and a small group of colleagues set about analyzing the genome for clues to the evolutionary history of the virus. They relied on a background of known coronaviruses and their own understanding of how these viruses take shape in nature (as evidenced in Holmes’ 2009 book, “The Evolution and Emergence of RNA Viruses”). They knew that the evolution of coronaviruses can happen rapidly, driven by frequent mutations (single-letter changes in a genome of about 30,000 letters), recombination (a virus swapping sections of the genome with another virus, when the two replicate simultaneously in a single cell), and Darwinian natural selection acting on these random changes. Holmes exchanged ideas with Rambaut in Edinburgh, a friend of three decades, and with two other colleagues: Kristian Andersen of Scripps Research in La Jolla, California; and Robert Garry at Tulane University School of Medicine in New Orleans. Ian Lipkin, from Columbia University’s Mailman School of Public Health, joined the group later. These five people would form a sort of remote study group, aiming to publish a paper on the SARS-CoV-2 genome and its probable origin.
Holmes, Andersen and their colleagues recognized the virus’ similarity to bat viruses but, with more study, saw a pair of “notable features” that gave them pause. These features, two short genome moments, constituted a very small percentage of the whole, but with potentially high importance for the virus’s ability to grab onto and infect human cells. These were technical-sounding features, familiar to virologists, that are now part of the original Covid vernacular: a furin cleavage site (FCS), as well as an unexpected receptor-binding domain (RBD). All viruses have RBDs, which help them attach to cells; an FCS is a feature that helps some viruses get inside. The original SARS virus, which terrified scientists around the world but caused only around 800 deaths, was unlike the novel coronavirus in any way. How did SARS-CoV-2 come to take this form?
Andersen and Holmes genuinely feared, at first, that he might have been engineered. Were these two features deliberate additions, inserted into a coronavirus backbone through genetic manipulation, intentionally making the virus more transmissible and pathogenic in humans? We had to think about it. Holmes called Jeremy Farrar, a disease expert who was then director of the Wellcome Trust, a foundation in London that supports health research. Farrar saw the point and quickly arranged a conference call with an international group of scientists to discuss the puzzling aspects of the genome and possible scenarios of its origin. The group included Robert Garry at Tulane and a dozen others, mostly prominent European or British scientists with relevant expertise, such as Rambaut in Edinburgh, Marion Koopmans in the Netherlands, and Christian Drosten in Germany. Anthony Fauci, then director of the National Institute of Allergy and Infectious Diseases, and Francis Collins, then director of the National Institutes of Health and thus Fauci’s boss, were also on the call. This is the famous February 1 call in which – if you believe some critical voices – Fauci and Collins persuaded the others to suppress any idea that the virus might have been engineered.
“The story going around was that Fauci told us, let’s change our minds, yada, yada, yada, yada. We got paid,” Holmes told me. “It’s complete (expletive).”
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