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Revision as of 02:15, 31 May 2021 by Korny O'Near (talk | contribs) (What the heck is an "unsourced removal"?)(diff) ← Previous revision | Latest revision (diff) | Newer revision → (diff)Scientific inquiries into the origins of the SARS-CoV-2 virus
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There are several ongoing efforts by scientists, governments, international organisations, and others to determine the origin of SARS-CoV-2, the virus responsible for the COVID-19 pandemic. The scientific consensus is that the virus is most likely of zoonotic origin in a natural setting, from bats or another closely-related mammal.
SARS-CoV-2 has close genetic similarity to multiple previously identified bat coronaviruses, suggesting it may have crossed over into humans from bats. Research is ongoing as to whether SARS-CoV-2 came directly from bats or indirectly through any intermediate hosts. Initial genome sequences of the virus showed little genetic diversity, although subsequently a number of stable variants emerged (some spreading more vigorously), indicating that the spillover event introducing SARS-CoV-2 to humans is likely to have occurred in late 2019.
Health authorities and scientists internationally state that efforts to trace the specific geographic and taxonomic origins of SARS-CoV-2 could take years, and the results could be inconclusive. A number of conspiracy theories have been promoted about the origins of the virus. Echoing the views of scientists internationally, a World Health Organization (WHO) mission said that a laboratory leak origin for the virus was "extremely unlikely", supporting what most experts already expected about the likely natural origins of the virus and its early transmission. The WHO director-general Tedros Adhanom Ghebreyesus said he was ready to deploy additional missions for further investigation.
Scientific consensus on origins
Main article: Severe acute respiratory syndrome coronavirus 2 § VirologyCOVID-19 is caused by infection with a virus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 appears to have originated in bats and was spread to humans by zoonotic transfer. Its exact evolutionary history, the identity and provenance of its most recent ancestors, and the place, time, and mechanism of transmission of the first human infection, remain unknown. The biology and regional distribution of other coronaviruses in southeast Asia, including SARS-CoV, help scientists understand more about the origins of SARS-CoV-2.
Taxonomically, SARS-CoV-2 is a virus of the species severe acute respiratory syndrome–related coronavirus (SARSr-CoV). It is believed to have zoonotic origins and has close genetic similarity to bat coronaviruses, suggesting it emerged from a bat-borne virus. Research is ongoing as to whether SARS-CoV-2 came directly from bats or indirectly through any intermediate hosts. The virus shows little genetic diversity, indicating that the spillover event introducing SARS-CoV-2 to humans is likely to have occurred in late 2019. Ultimately, the specific evolutionary history of SARS-CoV-2 in relation to other coronaviruses will be critical to understanding how, where and when the virus spilled over into a human population.
Reservoir and origin
No natural reservoir for SARS-CoV-2 has been identified. Prior to the emergence of SARS-CoV-2 as a pathogen infecting humans, there had been two previous zoonosis-based coronavirus epidemics, those caused by SARS-CoV-1 and MERS-CoV.
The first known infections from SARS‑CoV‑2 were discovered in Wuhan, China. The original source of viral transmission to humans remains unclear, as does whether the virus became pathogenic before or after the spillover event. Because many of the early infectees were workers at the Huanan Seafood Market, it has been suggested that the virus might have originated from the market. However, other research indicates that visitors may have introduced the virus to the market, which then facilitated rapid expansion of the infections. A March 2021 WHO-convened report stated that human spillover via an intermediate animal host was the most likely explanation, with direct spillover from bats next most likely. Introduction through the food supply chain and the Huanan Seafood Market was considered another possible, but less likely, explanation. An analysis in November 2021, however, said that the earliest-known case had been misidentified and that the preponderance of early cases linked to the Huanan Market argued for it being the source.
For a virus recently acquired through a cross-species transmission, rapid evolution is expected. The mutation rate estimated from early cases of SARS-CoV-2 was of 6.54×10 per site per year. Coronaviruses in general have high genetic plasticity, but SARS-CoV-2's viral evolution is slowed by the RNA proofreading capability of its replication machinery. For comparison, the viral mutation rate in vivo of SARS-CoV-2 has been found to be lower than that of influenza.
Research into the natural reservoir of the virus that caused the 2002–2004 SARS outbreak has resulted in the discovery of many SARS-like bat coronaviruses, most originating in horseshoe bats. The closest match by far, published in Nature (journal) in February 2022, were viruses BANAL-52 (96.8% resemblance to SARS‑CoV‑2), BANAL-103 and BANAL-236, collected in three different species of bats in Feuang, Laos. An earlier source published in February 2020 identified the virus RaTG13, collected in bats in Mojiang, Yunnan, China to be the closest to SARS‑CoV‑2, with 96.1% resemblance. None of the above are its direct ancestor.
Bats are considered the most likely natural reservoir of SARS‑CoV‑2. Differences between the bat coronavirus and SARS‑CoV‑2 suggest that humans may have been infected via an intermediate host; although the source of introduction into humans remains unknown.
Although the role of pangolins as an intermediate host was initially posited (a study published in July 2020 suggested that pangolins are an intermediate host of SARS‑CoV‑2-like coronaviruses), subsequent studies have not substantiated their contribution to the spillover. Evidence against this hypothesis includes the fact that pangolin virus samples are too distant to SARS-CoV-2: isolates obtained from pangolins seized in Guangdong were only 92% identical in sequence to the SARS‑CoV‑2 genome (matches above 90 percent may sound high, but in genomic terms it is a wide evolutionary gap). In addition, despite similarities in a few critical amino acids, pangolin virus samples exhibit poor binding to the human ACE2 receptor.
Phylogenetics and taxonomy
 Genomic organisation of isolate Wuhan-Hu-1, the earliest sequenced sample of SARS-CoV-2 | |
| NCBI genome ID | 86693 |
|---|---|
| Genome size | 29,903 bases |
| Year of completion | 2020 |
| Genome browser (UCSC) | |
SARS‑CoV‑2 belongs to the broad family of viruses known as coronaviruses. It is a positive-sense single-stranded RNA (+ssRNA) virus, with a single linear RNA segment. Coronaviruses infect humans, other mammals, including livestock and companion animals, and avian species. Human coronaviruses are capable of causing illnesses ranging from the common cold to more severe diseases such as Middle East respiratory syndrome (MERS, fatality rate ~34%). SARS-CoV-2 is the seventh known coronavirus to infect people, after 229E, NL63, OC43, HKU1, MERS-CoV, and the original SARS-CoV.
Like the SARS-related coronavirus implicated in the 2003 SARS outbreak, SARS‑CoV‑2 is a member of the subgenus Sarbecovirus (beta-CoV lineage B). Coronaviruses undergo frequent recombination. The mechanism of recombination in unsegmented RNA viruses such as SARS-CoV-2 is generally by copy-choice replication, in which gene material switches from one RNA template molecule to another during replication. The SARS-CoV-2 RNA sequence is approximately 30,000 bases in length, relatively long for a coronavirus—which in turn carry the largest genomes among all RNA families. Its genome consists nearly entirely of protein-coding sequences, a trait shared with other coronaviruses.
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A distinguishing feature of SARS‑CoV‑2 is its incorporation of a polybasic site cleaved by furin, which appears to be an important element enhancing its virulence. In SARS-CoV-2 the recognition site is formed by the incorporated 12 codon nucleotide sequence CCT CGG CGG GCA which corresponds to the amino acid sequence P RR A. This sequence is upstream of an arginine and serine which forms the S1/S2 cleavage site (P RR A R↓S) of the spike protein. Although such sites are a common naturally-occurring feature of other viruses within the Subfamily Orthocoronavirinae, it appears in few other viruses from the Beta-CoV genus, and it is unique among members of its subgenus for such a site. The furin cleavage site PRRAR↓ is highly similar to that of the feline coronavirus, an alphacoronavirus 1 strain.
Viral genetic sequence data can provide critical information about whether viruses separated by time and space are likely to be epidemiologically linked. With a sufficient number of sequenced genomes, it is possible to reconstruct a phylogenetic tree of the mutation history of a family of viruses. By 12 January 2020, five genomes of SARS‑CoV‑2 had been isolated from Wuhan and reported by the Chinese Center for Disease Control and Prevention (CCDC) and other institutions; the number of genomes increased to 42 by 30 January 2020. A phylogenetic analysis of those samples showed they were "highly related with at most seven mutations relative to a common ancestor", implying that the first human infection occurred in November or December 2019. Examination of the topology of the phylogenetic tree at the start of the pandemic also found high similarities between human isolates. As of 21 August 2021, 3,422 SARS‑CoV‑2 genomes, belonging to 19 strains, sampled on all continents except Antarctica were publicly available.
On 11 February 2020, the International Committee on Taxonomy of Viruses announced that according to existing rules that compute hierarchical relationships among coronaviruses based on five conserved sequences of nucleic acids, the differences between what was then called 2019-nCoV and the virus from the 2003 SARS outbreak were insufficient to make them separate viral species. Therefore, they identified 2019-nCoV as a virus of Severe acute respiratory syndrome–related coronavirus.
Investigations
There are multiple proposed explanations for how SARS-CoV-2 was introduced into, and evolved adaptations suited to, the human population. There is significant evidence and agreement that the most likely original viral reservoir for SARS-CoV-2 is horseshoe bats, with the closest known viral relative being RaTG13. The evolutionary distance between SARS-CoV-2 and RaTG13 is estimated to be between 20 and 90 years. The earliest human cases of SARS-CoV-2 were identified in Wuhan, but the index case remains unknown. RaTG13 was sampled from bats in Yunnan (located roughly 1,300 km (810 mi) away from Wuhan), and there are relatively few bat coronaviruses from Hubei province. Each origin hypothesis attempts to explain this gap in virus evolution and location a different way. These scenarios continue to be investigated in order to identify the definitive origin of the virus.
The most direct pathway of introduction is direct zoonotic transmission (also known as spillover) from the reservoir species to humans. Human contact with bats has increased as bat habitats and human population centers encroach on one another, creating additional opportunities for spillover. Bats are a significant reservoir species for a diverse range of coronaviruses, and humans have been found with antibodies for them suggesting that this form of direct infection by bats is common. In this scenario, the direct ancestor of SARS-CoV-2 remains undiscovered in bats.
In addition to direct spillover, another pathway is that of transmission through an intermediate host. Specifically, this implies that a cross species transmission occurred prior to the human outbreak and that it had pathogenic results on the animal. This pathway has the potential to allow for greater adaptation to human transmission via animals with more similar protein shapes to humans, though this is not required for the scenario to occur. The evolutionary separation from bat viruses is explained in this case by the virus' presence in an unknown species with less viral surveillance than bats. The virus' ability to easily infect and adapt to additional species (including mink) provides evidence that such a route of transmission is possible.
Another proposed introduction to humans is through fresh or frozen food products, referred to as the cold/food chain. This scenario's source animal could be either a direct or intermediary species as described above. Many investigations centered around the Huanan Seafood Wholesale Market in Wuhan, which had an early cluster of cases. While there have been food-borne outbreaks of human viruses in the past, and evidence of re-introduction of SARS-CoV-2 into China through imported frozen foods, investigations found no conclusive evidence of viral contamination in products at the Huanan Market.
The final scenario is the introduction of the virus to humans through a laboratory incident. The Wuhan Institute of Virology has performed research into bat coronaviruses since 2005, and identified the RaTG13 virus which is the closest known relative of SARS-CoV-2. Research topics included investigations into the source of the 2002–2004 SARS outbreak and 2012 MERS outbreak, some of which involved conducting gain of function research on viruses. The proximity of the laboratory to the initial outbreak has led some to speculate that it may be the entry point. Deliberate bioengineering of the virus for release has been ruled out, with remaining investigations considering the possibility of a collected natural virus inadvertently infecting laboratory staff during the course of study.
World Health Organization
In May 2020, the World Health Assembly, which governs the World Health Organization (WHO), passed a motion calling for a "comprehensive, independent and impartial" investigation into the COVID-19 pandemic. A record 137 countries, including China, co-sponsored the motion, giving overwhelming international endorsement to the investigation. In mid 2020, the World Health Organization (WHO) began negotiations with the government of China on conducting an investigation into the origins of COVID-19.
In November 2020, the WHO published a two-phase study plan. The purpose of the first phase was to better understand how the virus "might have started circulating in Wuhan", and a second phase involves longer-term studies based on the findings of the first phase. WHO director-general Tedros Adhanom Ghebreyesus said "We need to know the origin of this virus because it can help us to prevent future outbreaks," adding, "There is nothing to hide. We want to know the origin, and that's it." He also urged countries not to politicise the origin tracing process, saying that would only create barriers to learning the truth.
For the first phase, the WHO formed a team of ten researchers with expertise in virology, public health and animals to conduct investigations. The WHO's phase one investigation team arrived and quarantined in Wuhan, Hubei, China in January 2021.
Members of the investigative team included Thea Fisher, John Watson, Marion Koopmans, Dominic Dwyer, Vladimir Dedkov, Hung Nguyen-Viet, Fabian Leendertz, Peter Daszak, Farag El Moubasher, and Ken Maeda. The team also included five WHO experts led by Peter Ben Embarek, two Food and Agriculture Organization representatives, and two representatives from the World Organisation for Animal Health. The inclusion of Peter Daszak in the team stirred controversy. Daszak is the head of EcoHealth Alliance, a nonprofit that studies spillover events, and has been a longtime collaborator of over 15 years with Shi Zhengli, Wuhan Institute of Virology's director of the Center for Emerging Infectious Diseases. While Daszak is highly knowledgeable about Chinese laboratories and the emergence of diseases in the area, his close connection with the WIV was seen by many as a conflict of interest in the WHO's investigation. When a BBC News journalist asked about his relationship with the WIV, Daszak said, "We file our papers, it's all there for everyone to see."
In February 2021, after conducting part of their investigation, the WHO stated that the likely origin of COVID-19 was bats, and that the likely time of transmission to humans was towards the end of 2019. While the WHO investigation's objectives were not about fully determining the origins of the virus, which may take years, it seemed to confirm the existing consensus among experts. The most likely origin remains bats, likely through another animal carrier.
The Chinese and the international experts who carried out the joint investigation stated that it was "extremely unlikely" that COVID-19 leaked from a lab. No evidence of a lab leak from the Wuhan Institute of Virology was found, and WHO team leader Peter Ben Embarek stated that it was "very unlikely" due to the safety protocols in place.
The investigation also stated that transfer from animals to humans was unlikely to have occurred at the Huanan Seafood Market, since infections without a known epidemiological link were confirmed before the outbreak around the market. Early transmission is also unlikely to have occurred via the "cold chain" of frozen products.
In March 2021, the WHO published the written report with the results of the joint study. The joint team stated that there are four scenarios for introduction:
- direct zoonotic transmission to humans (spillover), assessed as possible to likely
- introduction through an intermediate host followed by a spillover, assessed as likely to very likely
- introduction through the (cold) food chain, assessed as possible
- introduction through a laboratory incident, assessed as extremely unlikely.
An argument in favor of direct zoonotic transmission to humans is the precedent that most of the current human coronaviruses have originated in animals. This path is also supported by the fact that RaTG13 does bind to hACE2, although the fit is not optimal.
The investigative team noted the requirement for further studies, noting that these would "potentially increase knowledge and understanding globally". The WHO director-general Tedros Adhanom Ghebreyesus said he was ready to dispatch additional missions involving specialist experts. He said in a statement, "We have not yet found the source of the virus, and we must continue to follow the science and leave no stone unturned as we do." He also called on China to provide "more timely and comprehensive data sharing" as part of future investigations. This call for more rigorous studies was accompanied by reactions from governments, across the EU and in a joint statement by 14 other countries (including the USA), for more transparency and access to raw data. Some diplomats noted that Chinese officials viewed this as an attempt to politicise the study. Scientists involved in the report, including Liang Wannian, John Watson and Peter Daszak, objected to the criticism and instead said that the report was an example of the collaboration and dialogue required to successfully continue investigations into the matter. In a letter published in Science, other scientists, including Ralph Baric, argued that the laboratory incident hypothesis had not been sufficiently investigated and remained possible, echoing the call for greater clarity and additional data.
The Lancet COVID-19 Commission task force
On 23 November 2020, an international task force led by Peter Daszak, president of EcoHealth Alliance, was formed as part of The Lancet COVID-19 Commission, chaired by economist Jeffrey Sachs of Columbia University and backed by the medical journal The Lancet. Daszak stated that the task force was formed to "conduct a thorough and rigorous investigation into the origins and early spread of SARS-CoV-2". The task force has twelve members with backgrounds in One Health, outbreak investigation, virology, lab biosecurity and disease ecology. The task force plans to analyze scientific findings and does not plan to visit China.
Chinese government
The first investigation conducted in China was by the Wuhan Municipal Health Commission, responding to hospitals reporting cases of pneumonia of unknown etiology, resulting in the closure of the Huanan Seafood Wholesale Market on 1 January 2020 for sanitation and disinfection. The market was originally suspected of being the source of the virus; however, the Chinese government and the WHO determined later that it was not.
In April 2020, China imposed restrictions on publishing academic research on the novel coronavirus. Investigations into the origin of the virus would receive extra scrutiny and must be approved by Central Government officials. The restrictions do not ban research or publication, including with non-Chinese researchers; Ian Lipkin, a US scientist, has been working with a team of Chinese researchers under the auspices of the Chinese Center for Disease Control and Prevention, a Chinese government agency, to investigate the origin of the virus. Lipkin has long-standing relationships with Chinese officials, including premier Li Keqiang, because of his contributions to rapid testing for SARS in 2003.
The Chinese government has said that COVID-19 may have first been transmitted to Wuhan from abroad, via frozen food imports. Scientists from the World Health Organization and other agencies have said there is no evidence for COVID-19 being transmitted through the food chain and that the risks are "negligible".
United States government
Trump administration
On 6 February 2020, the director of the White House's Office of Science and Technology Policy requested the National Academies of Sciences, Engineering, and Medicine to convene a meeting of "experts, world class geneticists, coronavirus experts, and evolutionary biologists", to "assess what data, information and samples are needed to address the unknowns, in order to understand the evolutionary origins of COVID-19 and more effectively respond to both the outbreak and any resulting information".
In April 2020, it was reported that the US intelligence community was investigating whether the virus came from an accidental leak from a Chinese lab. The hypothesis was one of several possibilities being pursued by the investigators. US secretary of defense Mark Esper said the results of the investigation were "inconclusive". By the end of April 2020, the Office of the Director of National Intelligence said the US intelligence community believed the coronavirus was not man-made or genetically modified.
US officials previously denounced the WHO investigation as a "Potemkin exercise" and criticised the "terms of reference" allowing Chinese scientists to do the first phase of preliminary research. On 15 January 2021, US Secretary of State Mike Pompeo said that to assist the WHO investigative team's work and ensure a transparent, thorough investigation of COVID-19's origin, the US was sharing new information and urging the WHO to press the Chinese government to address three specific issues, including the illnesses of several researchers inside the WIV in autumn 2019, the WIV's research on "RaTG13" and "gain of function", and the WIV's links to the Chinese military. On 18 January, the US called on China to allow the WHO's expert team to interview "care givers, former patients and lab workers" in the city of Wuhan, drawing a rebuke from the Chinese government. Australia also called for the WHO team to have access to "relevant data, information and key locations".
In March 2021, the US State Department's former head investigator into the origins of COVID-19, David Asher, who worked under Republican and Democrat administrations, explained in more detail that based on US intelligence that a cluster of workers from Wuhan Institute of Virology fell sick in early to mid-November 2019. Multiple staff had to go to the hospital. Their symptoms were consistent with both COVID-19 and influenza. He stated that "you don't normally go to the hospital with influenza, especially a cluster of people. This is the most probable source of the outbreak." The Wall Street Journal, however, notes that it is not unusual for people in China to go to the hospital with influenza. In contrast to the United States, primary care in China is often provided in a hospital setting.
Biden administration
On 13 February 2021, the White House said it has "deep concerns" about both the way the WHO's findings were communicated and the process used to reach them. Mirroring concerns raised by the Trump Administration, National Security Adviser Jake Sullivan stated it is essential that the report be independent and "free from alteration by the Chinese Government". On 14 April 2021, the Director of National Intelligence Avril Haines, and other officials of the Biden Administration, said that they had not ruled out the possibility of a laboratory accident as the origin of the COVID-19 virus. On 26 May 2021, President Joe Biden directed the U.S. intelligence community to "redouble its efforts" in determining whether the origin of the COVID-19 virus came from a human contact with an infected animal or from an accidental lab leak, and to produce a report on the matter within 90 days.
International politicians' calls for investigations
In April 2020, Australian foreign minister Marise Payne and Australian prime minister Scott Morrison called for an independent international inquiry into the origins of the coronavirus pandemic. A few days later, German chancellor Angela Merkel also pressed China for transparency about the origin of the coronavirus, following similar concerns raised by the French president Emmanuel Macron. The UK also expressed support for an investigation, although both France and UK said the priority at the time was to first fight the virus. In May 2021, Prime Minister Justin Trudeau told reporters Canada would "support the call by the United states and others to better understand the origins of COVID-19".
See also
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