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The Origin Of SARS-CoV-2: Animal Transmission Or Lab Leak?
Editor's Note: The origin of the virus that causes COVID-19, which spread from China to the rest of the world and has killed millions of people, is a scientific mystery, the answer to which has strong political implications. Gigi Kwik Gronvall of Johns Hopkins goes through the publicly available evidence, finding that animal-to-human transmission is the most likely story of how the virus developed and spread.
Daniel Byman
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Modern biology has lots of tools. Researchers can sequence genomes of viruses, bacteria, fungi, and mammals, and can track the evolution of a virus as it infects one person and then another. They can analyze a patient's immune responses and can see the complex damage that an infection can cause to lungs, kidneys, and even the brain. But there's much that biologists and immunologists still don't know. While researchers can monitor the genetic changes in SARS-CoV-2 as the virus evolves, they cannot predict the clinical significance of those changes until patients arrive at the hospital. They know that bat populations are stressed by human activity, which leads to virus spillovers, but they don't know how that happens or why bats are at the root of diseases like COVID-19, Ebola, dengue, or Nipah. They know that viruses pass between animals all the time, and spillovers to people are not uncommon—it's not even that uncommon for a person to get infected by more than one virus—but not every case of the cold is the subject of a Ph.D. Project to find out why the person got sick. If it turns out that an illness was mild in one person but devastating in another, samples will eventually get analyzed, but researchers can't analyze what doesn't get collected, and routine collection is not done.
For these reasons, the beginnings of epidemics and pandemics are murky, including for HIV/AIDS, Ebola, and the H1N1 2009 flu.
By comparison to past deadly epidemics, what we know about the early days of SARS-CoV-2 is less obscure. Though the origin of the COVID-19 pandemic is now the focus of hearings in the U.S. House of Representatives and headlines focused on whether the virus emerged from nature or a laboratory, the most likely origin of SARS-CoV-2 is animal-to-human transmission, like most emerging diseases. More than half (66 percent) of the first 41 hospitalized COVID-19 patients had a direct tie to the Huanan Seafood Wholesale Market in Wuhan, China, a city of 11 million people. A spatial mapping analysis later showed that hundreds of early cases were also clustered around the market. This early market connection led Chinese government officials to shut down the Huanan market on Jan. 1, 2020, and take some environmental samples from vendors' stalls but supposedly none from live animals.
It may seem puzzling that a seafood market could be the source of a disease spillover—fish cause plenty of diseases, but not typically respiratory infections—but animals were sold at the market as well. Though China had strict laws on the books regarding animal markets, pre-pandemic estimates of the illegal wildlife trade in China ranged from $18 billion to more than $75 billion per year—on par with U.S. Cattle production. The wildlife trade boosted local economies, and local officials and police enforcement looked the other way.
The rampant illegal wildlife trade was a sensitive issue for the Chinese government. After a World Health Organization (WHO) expert team was finally allowed to visit China in January 2021 to examine the origins of the pandemic, this tortured paragraph made its way into their final report:
Market authorities have confirmed that all reported live and frozen animals sold in the Huanan market were from farms that were legally licensed for breeding and quarantine, and that no illegal trade in wildlife has been found. Although there is photographic evidence in a published paper that live animals were sold at the Huanan market in the past (2014) … and unverified media reports in 2020, no verified reports of live mammals being sold around 2019 were found.
A later report from the WHO team revealed that this painfully exact, but likely inaccurate, paragraph took more than 19 hours for the WHO team to negotiate with Chinese officials for inclusion in the report.
A fortuitously timed scientific research study looking for a tick-borne disease in animal markets filled some gaps and proved that illegal wildlife sales were going on in the market. The study produced photographic evidence of 31 protected species sold at Wuhan's markets between May 2017 and November 2019, including many animals susceptible to SARS-CoV-2: racoon dogs, marmots, civets, mink, and other species, crowded together in cages, stressed, and in poor health. An environmental sample taken from the drain near where animals were butchered tested positive for SARS-CoV-2, as did samples from a hair and feather removal machine and an animal cage in which a raccoon dog had been photographed in the past. Recently, additional genetic information from these three-year-old samples was deposited by the Chinese Center for Disease Control and Prevention (China CDC) in a virology database, GISAID, but then removed once other researchers noticed the significance of the addition. An analysis of what was deposited showed a variety of susceptible animal DNA, especially racoon dog DNA, associated with the positive SARS-CoV-2 samples, adding more weight to the animal market origin theory. Under pressure, China CDC finally released this data, which may give more information about the early days of the pandemic—but this three-year obfuscation raises the question of whether Chinese researchers in fact took samples from animals at the market before it was cleared, in addition to the environmental samples.
SARS-CoV-2 may have been making market animals sick, but the virus was evolving as it passed from one animal to another. In the samples of early human cases, there were two genetically distinct versions of SARS-CoV-2, which have been called the "A" and "B" lineages. It was the B version that took off, causing person-to-person infections and sparking the pandemic. But the fact that people were infected with different versions of the virus early on suggests that there were multiple spillover events from animals, indicative of an ongoing epidemic with an evolving virus. The genetic diversity of the virus in these early days argues against any notion that the origin was elsewhere (such as a government lab) and that the market was merely a superspreading event.
About 10 miles away from the Huanan market, across the Yangtze River, is the Wuhan Institute of Virology (WIV). From the earliest days of the pandemic, this geographic coincidence—a pandemic caused by a coronavirus in the same city as a research institute that studies coronaviruses—was seen as evidence enough that the virus came from a "lab leak." President Trump even said so. The theory of the laboratory's potential involvement has gone through many iterations in the popular press and official government documents and communications over the past three years; it has also included character assassinations of Chinese scientists, WHO experts, and U.S. Scientists, as well as outright lying, grifting, online hate, and debunked charges of biowarfare. Most recently, the U.S. Department of Energy changed its intelligence analysis of the coronavirus's origin from being undecided to having a low-confidence assessment that the virus came from a laboratory, sparking a fresh round of headlines about the virus's origin. Nonetheless, no direct evidence of the laboratory's involvement in the origin of SARS-CoV-2 has emerged.
Some lab-leak proponents point to a viral strain called RaTG13, known to be at the WIV, which has a 96.2 percent similarity to SARS-CoV-2. However, that 3.8 percent dissimilarity is not isolated in one chunk in the viral genome; it is differences sprinkled throughout, especially in the last base pair of the codons, indicating that there may be more than a decade of viral evolution separating the strains. There have been accusations that so-called gain of function (GOF) research (GOF) could have turned RaTG13 into SARS-CoV-2, but unfortunately virology research tools do not include magic wands and no plausible scientific pathway has been offered to explain how such a transformation could occur. No progenitor strain to SARS-CoV-2 has been associated with the laboratory.
Other arguments involve whether the lab-leak theory was taken seriously in the beginning (it was), whether the Chinese government was lying (it was, including about the seriousness of the virus and that the United States played a role in causing the pandemic), and whether there were safety problems at the lab (selectively edited State Department cables suggested yes, but the full cables suggest otherwise). Adherents of these theories often call for a full investigation, but this is not likely to happen after the WHO expert processes ended prematurely amid the political backlash to the report's conclusion that a lab leak was "very unlikely." Regardless, any new evidence that implicates the WIV also needs to make sense given what we already know from the other existing evidence—patient samples, geospatial analysis, genetic indications of animal infections, the multiple versions of SARS-CoV-2 in early samples, environmental samples—all of which point to an animal origin. For these theories to be credible, new evidence implicating the lab as being involved must complement what is known but shift the conclusion to origination at the laboratory. This evidence has not yet emerged, and it would be extraordinary if it does.
While the scientific evidence points to a "natural" emergence, it is decidedly not natural to have the conditions in place that led to this spillover event, or the very similar circumstances that led to the SARS epidemic in 2003. (In that epidemic, the market was not immediately cleared out, and samples could be taken from the civet cats and other animals sold there.) There is plenty of guidance available for how to sell and butcher animals safely, regulate markets, and crack down on the illegal wildlife trade—a global phenomenon that has a great deal of overlap with other criminal activities, including human trafficking, money laundering, and the illegal drug trade. Further research could also help improve these standards and better prepare for other viruses that could emerge in similar settings. There are many scientific knowledge gaps that need to be filled about viral evolution and bats, and more undetermined infections that might turn out to be the next pandemic need to be investigated so that researchers and policymakers can do more, earlier and better.
Not all lab-leak proponents believe the same things, and multiple motivations energize this belief. Some people are concerned about GOF research (which is poorly defined and hard to characterize) or virology research, generally, and would like to increase restrictions on research in the belief that this would prevent the creation of dangerous pathogens that may then leak from a lab. New recommendations put forth by an advisory committee to the U.S. Department of Health and Human Services could, if implemented, place limits not only on virology research and public health surveillance but even vaccine development.
It is vital that the United States not go down that road. Virology research will continue around the world regardless of what the United States does because it is important, because there is a lot we do not know, and because we are still experiencing a pandemic caused by a virus that has killed at least 6.8 million people globally. But if policymakers restrict virology research in the United States, U.S. Researchers will not be in a good position to lead the world in biosafety norms for how the work should be conducted safely, and they will be hindered in their efforts to develop better ways to detect, understand, and fight viral disease.
What happens next? There will be future virus spillovers, and this process will be accelerated by climate change. With this will come additional opportunities to learn the necessity of creating a better buffer between animals and humans to limit the risk of disease. We are just at the beginning stages of understanding the complexity of viruses in the natural world, and further study will be critical for health and prosperity. U.S. National security experts may eventually need to become as familiar with the biology of pandemics as they are with the nuclear triad. But this won't be possible as long as politics and rhetoric take precedence over reason and necessary research.
Zoonotic Diseases
Psittacosis is caused by the bacteria Chlamydia psittaci. C. Psittaci is common in wild birds and can occur in laboratory bird colonies. Infected birds are highly contagious to other birds and to humans. The organism is spread to humans by aerosolization of respiratory secretions or feces from the infected birds. Typical symptoms in the bird are diarrhea, ocular discharge, and nasal discharge.
The infection in humans by C.Psittaci, can cause fever, headache, myalgia chills, and upper and lower respiratory disease. Serious complications can occur and include pneumonia, hepatitis, myocarditis, thrombophlebitis and encephalitis. It is responsive to antibiotic therapy but relapses can occur in untreated infections.
Prevention: Only disease-free flocks should be allowed into the research facility. Wild-caught birds or birds of unknown status should be treated prophylactically for 45 days with chlortetracycline.
Animal Biosafety Level 2 practices are recommended for personnel working with naturally infected birds or experimentally infected birds.
Wearing NIOSH certified dust masks should be considered in rooms housing birds of unknown health status.
One Health Genomics - Why Animal Diseases Matter For Human Health
In humans, pathogen genomics is beginning to improve diagnosis of infections, tracking of outbreaks and identification of antimicrobial resistance. Could a cross-species ('one health') approach, to include similar efforts with animals, benefit both animal and human populations?
The Animal and Plant Health Agency (APHA), together with Scotland's Rural College (SRUC), are responsible for performing testing for animal pathogens in Great Britain, through a network of national laboratories. The diagnostic methods currently used include pathology, serology (examining antibodies in the blood) and a relatively small number of specific molecular tests.
Only a handful of known pathogens are monitored by prospective (or routine) surveillance of livestock and the number of animals tested is a small proportion. However the economic burden of such testing may be considerable.
Retrospective surveillance, i.E. Detection of trends in data from samples submitted following suspicion of disease, or having died from a disease, is most common. Animal to human transmission of infection is determined retrospectively through the combination of surveillance information from animal and human samples. Although less costly to do, the outcomes of retrospective surveillance often come too late to intervene.
Case study 1Retrospective sequencing and analysis of influenza A (H1N1) samples from the 2009 swine flu outbreak suggested that the virus had been circulating unnoticed in a pathogenic form for years in pigs prior to the human outbreak. If prospective genomic surveillance was in place in pigs then this information could have helped prevent the human outbreak.
Case study 2While camels were implicated as potential vectors for transmission of the MERS virus to humans prior to genomic analysis, it was only once the virus isolated from camels could be shown to be genetically identical to that found in people who had been in contact with camels that the health authorities, such as the WHO, were able to issue clear advice on staying away from the camels. Asking camel farmers to do this has significant social and economic cost, and so accurate information is important.
How can genomics contribute to the surveillance of animal pathogens?Pathogen whole genome sequencing (WGS) using next generation sequencing, with downstream bioinformatics analyses, has several advantages over conventional methods for diagnosing animal pathogen infections and characterising outbreaks:
Rapid diagnosis
Genomic analysis could turn around diagnostic results faster than other approaches once a routine service has been setup, potentially taking less than 48 hours from clinical sample to whole genome sequence. However, culturing samples, which is required for genomic current methods that do not employ a metagenomic approach, takes considerably longer (sometimes over one month).
High sensitivity
Epidemiological information can be inferred from WGS analyses about the relationship between different individual pathogens, allowing outbreak clusters to be accurately identified. By contrast, traditional microbiological approaches are limited in the sensitivity and specificity with which they can detect transmission events.
Flexible analysis
Once setup, the protocols are fairly generically applicable regardless of the specific type of pathogen being investigated and can incorporate additional analyses such as testing for antibiotic resistance. Under traditional workflows, separate tests need to be conducted to determine drug susceptibility.
Implementing genomic cross-species surveillance - what needs to be considered?There are several considerations that need to be addressed in order to achieve effective and efficient implementation of genomic cross-species surveillance:
Investment
Animal pathogen genomic surveillance services need to be established. With sequencing infrastructure already at APHA, the main additional costs would be setting up new workflows and recruiting additional bioinformatics expertise. Closer collaboration with Public Health England (PHE), the governmental body responsible for human pathogen surveillance, could help mitigate these costs.
Collaboration and evaluation
Research between medical and veterinary practices, and academic institutes, such as the cGPS, GMI, COMPARE, and other initiatives, should be encouraged to facilitate the development of more standardised analytical methods and better databases for human-animal pathogen surveillance. Systematic health economic analyses is needed to determine when implementing WGS is cost-effective for the public health utility it provides.
Accreditation
Accreditation is required at national and international levels for both laboratories and diagnostic tests. NGS methods for detecting animal pathogens have not yet been approved. Until they are, NGS cannot replace existing accredited methods.
Coordination
APHA and PHE are working on parallel methodological protocols for conducting genomic analyses and guidelines for sharing their data and sensitive metadata. Further strategic coordination and knowledge sharing across government departments is desirable, building on the HAIRS initiative. Ultimately surveillance should be coordinated at an international level.
Prospective surveillance?
Prospective molecular surveillance, if well coordinated with related human pathogen surveillance, could detect disease outbreaks sooner, acting as an early warning system to reduce the risk of transmission to humans, decreasing the mortality and morbidity costs. Such surveillance could minimise the economic costs of controlling the outbreaks within the livestock. However, for very rare animal diseases it may not be cost effective. Context specific cost-benefit analysis is required to determine when prospective surveillance is feasible and desirable.
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