Virus World

The episode underscores once again why a serious investigation is needed to get to the bottom of how the pandemic began.  The morning of Dec. 26, 2019, began as usual at Vision Medicals in Guangzhou in southern China. This commercial laboratory, a private start-up barely a year and a half old, was also known by its Chinese name, Weiyuan Gene Technology. It specialized in next-generation sequencing, called mNGS, and offered applications that can identify most infectious agents — viruses, bacteria and others — in a single test. A researcher browsed through the latest test results, as she did every day, before turning to her other work. She was proud of the laboratory’s metagenomic sequencing capabilities. Only a month before, her company played a key role in quickly detecting a plague outbreak in Beijing. The previous day, her laboratory had received a bronchoalveolar lavage fluid sample from Wuhan, a city of 11 million people and a major transportation hub, where a 65-year-old man was hospitalized with a pneumonia-like respiratory ailment. When she checked the test results that morning, they indicated the man was infected by a virus similar to the one that causes SARS, or severe acute respiratory syndrome, which was first identified in China in 2002 and ultimately killed 774 people worldwide. The researcher was alarmed. She wrote to a co-worker on WeChat, a messaging service, at 9:28 a.m., saying the sample was brimming with something that looked like SARS.

The co-worker wrote back, recalling the Beijing plague outbreak they had worked on together

This exchange took place 28 days before Wuhan was locked down because of human-to-human transmission of the novel coronavirus. In late December and early January, a number of researchers and the Chinese government were aware the virus could spread rapidly, but the truth was kept from the public. In those weeks, the virus exploded, leading to a pandemic that has killed more than 6 million people, by official tally. The actual toll is probably twice as many, or more. The researcher went by the online moniker Little Mountain Dog, with an avatar of a furry pup sitting alone in a field of lush grass. Her reflections and observations were posted in a blog on Jan. 28, 2020, which she took down two days later, saying it was written “for myself to read in the future, but it spread online and I didn’t want to get involved in anything, so I deleted it.” She asked that no one reprint it, and said the company’s leaders were “understanding and forgiving” after she posted it. “I don’t want to cause trouble to anyone, and I don’t want to stir up public opinion,” she added. At the time, her posts were quoted in news accounts online, including by the magazine Caixin, which published a detailed article, then took down parts of it. “I have to admire the reporters from Caixin.com, who dug up so much accurate information from the messy information in the early days,” she later wrote. Recently, the research group DRASTIC, which has been probing the pandemic’s origins, retrieved and translated her blog posts, including attached screenshots of WeChat messages.

The research group has withheld her real name, and we agreed to do so as well to protect her privacy. It provided her email and we sent a request for comment, but got no response. The company also did not respond. Her story points to a coverup with tragic consequences of historic proportion. A severe danger was concealed until it was too late. It came about because of a culture that prioritizes political stability at any cost, extraordinary state secrecy, and missteps by public health officials who did not speak out. The episode serves to underscore once again why a serious investigation is needed to get to the bottom of how the pandemic began. The virus’s origins might have been caused by a zoonotic spillover, a bat coronavirus jumping to humans, possibly with an intermediate host. Or it might have been an inadvertent leak from a laboratory in Wuhan studying bat coronaviruses. Only by learning what really transpired can we reach any conclusions about how to prevent it from happening again. China could go a long way toward finding the answers, but instead it has slammed the door on further inquiry....

The new coronavirus spread across much of the interior of the United States by tagging along with people moving from state to state, but US coastal regions were seeded with SARS-CoV-2 imported from other countries — perhaps in 2019, according to models. Alessandro Vespignani at Northeastern University in Boston, Massachusetts, and his colleagues studied air traffic, commuting patterns and other data to understand how and when the coronavirus took hold in the United States (J. T. Davis et al. Preprint at medRxiv http://doi.org/d3mf; 2020). The team found that in several coastal states, international travel drove introduction of the virus. In California and New York, SARS-CoV-2 might have begun circulating as early as December 2019.

But in many non-coastal states, domestic travelers rather than international visitors were the source of the first wave of infections. Infections spread across the country from late January to early March but were largely undetected, the authors say. The findings have not yet been peer reviewed.

Preprint of original study available at medRxiv (July 7, 2020):

https://doi.org/10.1101/2020.07.06.20140285

Scientist who found archived online files of removed NIH data says recovered information may clarify how coronavirus entered humans.  In a world starved for any fresh data to help clarify the origin of the COVID-19 pandemic, a study claiming to have unearthed early sequences of SARS-CoV-2 that were deliberately hidden was bound to ignite a sizzling debate. The unreviewed paper, by evolutionary biologist Jesse Bloom of the Fred Hutchinson Cancer Research Center, asserts that a team of Chinese researchers sampled viruses from some of the earliest COVID-19 patients in Wuhan, China, posted the viral sequences to a widely used U.S. database, and then a few months later had the genetic information removed to “obscure their existence.” To some scientists, the claims reinforce suspicions that China has something to hide about the origins of the pandemic. But critics of the preprint, posted yesterday on bioRxiv, say Bloom’s detective work is much ado about nothing, because the Chinese scientists later published the viral information in a different form, and the recovered sequences add little to what’s known about SARS-CoV-2’s origins. The sequences, Bloom says, do support other evidence that the pandemic did not originate in Wuhan’s Huanan Seafood Market, where SARS-CoV-2 initially came to light. Chinese health officials on 31 December 2019  tied the market to an outbreak of an “unexplained pneumonia,” but a month later, it had become clear that many of the earliest cases had no link to the location. The paper highlights three mutations found in SARS-CoV-2 collected from patients linked to the market that are not in the unearthed sequences of the coronavirus or its closest relative, which researchers from the Wuhan Institute of Virology discovered in bats in 2013. 

Bloom’s more explosive assertion, that the Chinese researchers deleted data, is bound to intensify the debate about whether the virus originally jumped to humans from an unknown animal or somehow leaked from a laboratory. Bloom says he has no bias toward a particular origin hypothesis for SARS-CoV-2, and he agrees that the viral sequences he highlighted are a small piece of a large unfinished puzzle. “I don't think this bolsters either the lab origin or zoonosis hypothesis,” he says. “I think it provides additional evidence that this virus was probably circulating in Wuhan before December, certainly, and that probably, we have a less than complete picture of the sequences of the early viruses.” Bloom, who studies viral evolution, launched his study after a controversial report on the pandemic’s origin issued in March by a joint commission of Chinese and foreign researchers organized by the World Health Organization (WHO).  Bloom helped organize a much discussed letter, co-signed by 17 other scientists, that criticized the WHO report for deeming it “extremely unlikely” that SARS-CoV-2 escaped from a laboratory. In the letter, published on 14 May in Science, the authors argued for “a dispassionate science-based discourse on this difficult but important issue.”

The WHO report relied heavily on sequences of SARS-CoV-2 found in COVID-19 patients tied to the market, Bloom notes. “I was just going through and trying to repeat a number of the analyses in the joint WHO-China report,” Bloom says. This led him to a study that listed all SARS-CoV-2 sequences submitted before 31 March 2020 to the Sequence Read Archive (SRA), a database overseen by the National Center for Biotechnology Information, a division of the U.S. National Institutes of Health (NIH). But when he checked SRA for one of the listed projects, he couldn’t find its sequences.

Googling some of the project’s information, he found another study, led by Ming Wang from Wuhan University’s Renmin Hospital, that was posted as a preprint on 6 March on medRxiv, and later published, on 24 June, in Small, a journal more focused on materials and chemistry than virology. That paper lists some of the earliest Wuhan COVID-19 patients and the specific mutations in their viruses, but doesn’t give the full sequence data. Further internet sleuthing led Bloom to discover that SRA backs up its information in Google’s Cloud platform, and a search there turned up files containing some of the earlier data submissions from Wang's team. The paper in Small makes no mention of any corrections to viral sequences that might explain why they were removed from SRA, which led Bloom to conclude in his preprint that “the trusting structures of science have been abused to obscure sequences relevant to the early spread of SARS-CoV-2 in Wuhan.” Bloom asserts that because the deleted sequences lack the three mutations seen in the SARS-CoV-2 from the seafood market, the viruses Wang’s team found more likely represent a progenitor. But the sequence of that bat virus found in 2013 differs from SARS-CoV-2 by about 1100 nucleotides, which means decades must have passed before it evolved into the pandemic coronavirus—and other species may well have been infected with the bat virus before it made the final jump into people. This great difference in sequences, says evolutionary biologist Andrew Rambaut at the University of Edinburgh, means researchers cannot use a few mutations like the ones Bloom highlights to look back in time to see the “roots” of the family tree of SARS-CoV-2 tree.

Bloom says he contacted the Chinese researchers to ask why they removed the SRA data, but they did not reply. (Science also received no reply after emailing the lead authors.) NIH issued a statement today saying it removed the sequences at the request of the submitting investigator, who the agency says holds the rights to the data. The scientist “indicated the sequence information had been updated, was being submitted to another database, and wanted the data removed from SRA to avoid version control issues,” NIH said.  (Bloom says he cannot find the sequences in any other virology database he knows.) Researchers are sharply divided about the value of Bloom’s resurrection of the SRA data. “This is a creative and rigorous approach to investigating the provenance of SARS-CoV-2,” says Ian Lipkin, a microbiologist at Columbia University’s Mailman School of Public Health. “The two take-home points are that the virus was circulating before the outbreak linked to the Wuhan seafood market and that there may have been active suppression of epidemiological and sequence data needed to track its origin.”

Leaving aside the meaning of the sequences Bloom found, the demonstration that researchers can potentially find “new” data in the cloud is an exciting advance, adds Sudhir Kumar, who does genomics research at Temple University and has published his own analysis of early SARS-CoV-2 sequences, “Many people feel that there is a lot more Chinese data out there, and they don't have access to it,” he says. Others are underwhelmed. “Jesse is resurfacing info that’s been online for over a year and claiming it proves a cover-up,” says Stephen Goldstein, an evolutionary virologist at the University of Utah. “I don’t understand [his reasoning].”  The Small paper is simply a good study that “unfortunately flew below the radar,” he adds. Rambaut notes that the Chinese researchers submitted their Small paper before requesting SRA remove the data. “The idea that the group was trying to hide something is farcical,” Rambaut says. “If they were covering something [up] they surely would have not submitted the paper. … I don't like the insinuations about malfeasance where [Bloom] has zero knowledge of the reasons the authors of the paper had for removing their data.”

A member of the WHO origin commission, Marion Koopmans from the Erasmus University Medical Center, notes that its report stresses the need to find more data about the earliest viruses in circulation. “It’s good to see additional data, but I’m not sure what point this makes,” Koopmans says, adding that the preprint’s accusations could harm future collaborations on origin studies with Chinese researchers. “The tone of the intro is in my view rather suggestive and I wish science would stay away from this.” Bloom acknowledges that researchers can piece together the coronavirus sequences from the data found in the Small paper, but he says that’s not the way most in the field conduct evolutionary analyses of SARS-CoV-2. “No one knew about these sequences because the way that people find sequences is to go to the sequence databases and download the sequences and look at them,” Bloom says.   Stepping into the divisive discussion of SARS-CoV-2’s origin comes at a price, he acknowledges. “So many people have agendas and preconceived notions on this topic that if you open your mouth on the topic, someone's going to take what you've said to support or reject some particular narrative,” he says. “So the choices are either not to say anything at all, which I don't think is useful or productive, or just to try to draw the conclusions you can and make it as transparent as possible. No matter how much people like [my new study] or don't like it, or agree with the interpretation or disagree with the interpretation, they can at least go download it and repeat it themselves.”

Published in Science (June 23, 2021):

https://doi.org/10.1126/science.abk1383 

Preprint of the research cited available in bioRxiv (June 22, 2021):

https://doi.org/10.1101/2021.06.18.449051 

Scientists at the University of Arizona were able to extract from the tissue a nearly complete genetic sequence of an HIV virus. For more than 50 years, the DNA remained hidden in a lymph node that had been snipped out of a 38-year-old man in what is now the Democratic Republic of the Congo. That nub of tissue, the size of a nail on a pinky finger, had been sealed up in a protective block of paraffin.

The sample that was examined dates from 1966. The sequence extracted from it is older by a decade than the previous oldest full-length sequence. It provides a snapshot of what the virus looked like when it was circulating undetected in central Africa 15 years before a cluster of strange infections among gay men in the United States led to recognition of a new disease that was eventually called AIDS. 

Worobey, whose lab has repeatedly performed virologic archeology on old tissue and blood samples, said the paper has not yet been submitted to a scientific journal for publication. As such, it has not been through the peer review process where independent scientists kick its tires, so to speak. Genetic codes of viruses that infected people in earlier days of the AIDS epidemic can be used by scientists to try to date when the HIV virus moved from primates into people. By studying differences in the viral sequences, scientists estimate how long it has been since the known sequences could have diverged from a common source. It doesn’t tell them when the event happened, but it can suggest that it had to have been prior to a particular time, Worobey said, adding that the new data suggest the jump likely did not happen in the 1920s.

Findings were  pre-printed in the bioRxiv website:

https://www.biorxiv.org/content/10.1101/687863v1