We “See” the Virus, But Don’t Know Its Origin or How It Emerged

Since the end of 2019, the seventh human coronavirus, SARS-CoV-2 (Novel Coronavirus), has infected more than 80 million people worldwide and killed more than 1.77 million people.
At the beginning of the outbreak, even trained virologists could not immediately determine the situation, and for a period of time the shadow of “unexplained pneumonia” hung over human society.

In the face of such a new outbreak of infectious diseases, scientists lead the charge, shoulder the responsibility to find out the “real culprit”.
“Competent scientists are needed to make judgments, draw conclusions and report them to the relevant authorities.”
In an interview with the Paper (www.thepaper.cn), a Chinese virologist stressed that the availability of competent and responsible scientists is particularly important in the early stages of the epidemic.

This is not an easy thing to do.
In April 2020 after the outbreak, Susan R. Weiss, an American microbiologist who has been researching coronavirus for 40 years, published an article in the American Journal of Experimental Medicine (JEM), laments that when she first entered the field of coronavirus, there were far fewer coronavirus researchers than there are now.

In the fall of 1980, the first international conference on coronavirus was held in Wurzburg, Germany, and Weiss was invited to the conference, which was attended by about 60 people, almost all global researchers in the field at the time.
“Every pandemic like SARS or COVID-19 pushes researchers into the field.
And as the virus disappears, the number of researchers decreases.
There are still many unknowns about human coronavirus in the scientific community.”

Compared with SARS (Severe acute respiratory Syndrome) in 2003, the time it takes for scientists to find the culprit is much shorter this time.
In the first few days of January this year, the Research team in China created a partial or complete novel Coronavirus genome sequence by sequencing bronchoalveolar lavage fluid (BALF) samples from patients.
To inform the World Health Organization of the identification results on 9 January;
On January 12, China registered the novel Coronavirus genome sequence information in the global influenza shared database, and notified the international community of the situation of genome virus data.

Wu Zunyou, chief epidemiologist with the Chinese Center for Disease Control and Prevention, said in November 2020 that in the early days of the COVID-19 outbreak, China identified the pathogen in only seven days and developed diagnostic reagents in two days, setting a record for the shortest time for humans to understand a new infectious disease.

Wu zunyou believes that the genetic sequence of the virus is the most core “neck clamping” technology for the treatment and prevention and control of the epidemic.
After Defining the coronavirus gene sequence, China did not apply for patent protection, but shared it with the whole world for free. “This is a public product that China provides to the whole world for free, and it is also China’s greatest contribution to the prevention and control of NOVEL CORonavirus.

In addition to deciphering the genome sequence of the virus, scientists have described the pathogen under an electron microscope.
Like several other known human coronaviruses, this enveloped RNA virus has a special Spike Protien protein in its envelope that makes it look like a “covid,” hence its name.

The current scientific understanding is that coronaviruses belong to the order neviridae, the family Coronaviruses and the genus Coronaviruses. They are enveloped normal single-stranded RNA viruses with a diameter of 80-120 nanometers and about 30,000 bases. Their genetic material is the largest among known RNA viruses.
Novel Coronavirus is a member of the coronavirus genus, belonging to a subgenus Sarbecovirus.

1965 Scientists isolated the first human coronavirus.
Until SARS, the coronavirus was designed to cause mild flu-like symptoms in humans.
But SARS-COV, MERS-CoV and, in this case, SARS-COV-2 pose a serious threat to humans.

A year after the outbreak spread across the globe, scientific forces around the world have rallied, but many mysteries remain to be solved.
Beyond traditional coping mechanisms, including social distancing, humans have not yet grasped the tools to destroy covids.

Where did the virus come from?
This could be the first to cause confusion and the hardest to solve.

Photo: Qu Jiuhui, distinguished Professor of School of Environment, Tsinghua University, researcher of Ecological Environment Research Center, Chinese Academy of Sciences, academician of Chinese Academy of Engineering, et al., “Natural Host — Environmental Media — Human: A New Potential Pathway of COVID-19 Outbreak”.
As of December 29, the latest data showed that more than 81.19 million people worldwide had been diagnosed with novel Coronavirus infection, and more than 1.772 million of them died.

The underlying data suggest that novel Coronavirus is fully adapted to humans.
In comparison, sarS-COV and MERs-CoV did not cause a global pandemic.
Mers-cov, in particular, has mostly been caused by the virus originating from camels in the Arabian Peninsula and spreading only sporadically from person to person.

As mentioned earlier, the covid is its special label, and functionally, spike proteins are responsible for binding to the receptor to invade host cells, with both being likened to “keys” and “locks”, respectively.
It is therefore seen as an important target for drug development.

During infection, S protein is cleaved by host proteases (such as TMPRSS2) into N-terminal S1 subunit and C-terminal S2 subunit, which mediate receptor binding and membrane fusion respectively.
Among them, S1 contains the N-terminal domain (NTD) and the receptor-binding domain (RBD), which are crucial in determining tissue tropism and host scope.

RBD binds to human receptor ACE2 (angiotensin converting enzyme 2) during virus invasion.
The function of NTD was not previously clear, but a study published in June by Chen Wei, a member of the Academy of Military Medical Sciences, and Zhou Qiang Laboratory of West Lake University, among others, indicated that NTD could serve as a key epitome of antibody neutralization and be a promising target for therapeutic monoclonal antibodies against the covid.

It is worth noting that by the time humans were aware of the virulent nature of the virus, it was already “at home” in humans, suggesting that its “key” matches very well, in what is known as “host adaptation”.

According to a Harvard Medical School paper published in April in Science, a top academic journal, the fatality rate for COVID-19 is statistically significantly higher than that for seasonal influenza, but lower than the two closely related coronavirus strains sarS-COV and Mers-CoV.
In addition, there is also evidence that novel Coronavirus is more contagious than SARS-CoV and MERs-CoV, and that an individual can transmit avirus while asymptomatic or in the incubation period before symptoms appear.

Surging news (www.thepaper.cn) reporter attended a conference in November, a researcher at the Chinese academy of agricultural sciences, Harbin veterinary research institute, member of national avian influenza reference laboratory director Chen mentioned: in general the virus spread from animals to humans need time to adapt to, and SARS – CoV – 2 after the onset of the transmitted particularly strong, this is likely to be its biggest characteristics.

Preliminary analysis showed that the similarity between novel Coronavirus and SARS-COV was 79% on nucleotide level.
However, novel Coronavirus and SARS-COV showed only 72% nucleotide sequence similarity in spike proteins.
The similarity between RaTG13 and novel Coronavirus samples collected in 2013 in Yunnan, China, by Shi Zhengli, researcher of Wuhan Institute of Viruses, Chinese Academy of Sciences, and others, was 96% in nucleotide sequence.

Despite this sequence similarity, novel Coronavirus and RaTG13 differ in many key genomic features.
One of the most important is that novel Coronavirus contains a multi-base (furin) restriction site insertion (PRRA residue) at the junction of S protein S1 and S2 subunits.

This insertion may have increased the infectivity of the virus, which is not present in other related -coronavirus species.
Similar polybase insertions have been found in other human coronaviruses, including HCOV-HKU1, and in highly pathogenic strains of avian influenza viruses.
It is worth noting that a new bat coronavirus (RmYN02) was discovered in 2019 in feces samples collected from Horseshit horsesus Malay in Yunnan by Xishuangbanna Tropical Botanical Garden of the Chinese Academy of Sciences. Independent insertion of PAA amino acid at S1/S2 cleavage site was also observed in this virus.

The scientists analyzed that these insertion events reflect the ongoing natural evolution of the coronavirus.
Although RmYN02 was quite different from novel Coronavirus in terms of spike proteins (sequence similarity approximately 72%), it was most closely related to the longest coding gene to 1AB (nucleotide sequence similarity approximately 97%).
And although SARS-Cov and Mers-Cov are closely related to novel Coronavirus and are both considered to have bat hosts, the biological differences between these viruses are striking.

Novel Coronavirus is significantly more infectious, which makes it very different from the epidemiological dynamics of SARS-COV and MERs-CoV.
Thus, for the scientific community, the identification of virological characteristics that support this transmissibility is clearly a priority.

Such transmissibility has alarmed scientists about the relatively virulent respiratory pathogen’s unusual ability to cross species boundaries.
A Chinese virologist told thepaper (www.thepaper.cn) that the virus has evolved in an intermediate host, and had evolved key mutations in the “secret transmission” stage among people as early as December 2019.

In March 2020, the Chinese academy of medical sciences, Peking union medical college hospital, Chinese center for disease control and prevention, the university of California, Los Angeles, Pittsburgh university, hunan university researchers in five partners blockbuster papers published, display will be coronavirus in spike protein (S) between S1 and S2 domain structure unique insert (PRRA) four amino acids, it may be a Flynn (Fruin) or TMPRSS2 (2) transmembrane serine protease enzyme loci.
Previous studies have suggested that coronaviruses may undergo protease lysis, which triggers virus-cell membrane fusion.
This flexibility in initiating and triggering fusion mechanisms greatly regulates the pathogenicity and tendency of different coronaviruses.

The paper suggests that the potential recombination of RBD and the presence of a unique Flynn irus cleavage site could explain the novel Coronavirus infectious increase significantly.

“Characteristics of SARS-COV-2 and COVID-19” by Shi Zhengli et al.
The Hunters are still on the hunt: From the bat?
Who was the “civet” novel Coronavirus first introduced into human society?
How did they evolve before that?
In all the history of human infectious diseases, not all pathogens were eventually traced back to success.

Reveal the H5N1 and H7N9 avian flu virus spread across a kind of the molecular mechanisms of microbial institute of Chinese Academy of Sciences applied a surge in news (www.thepaper.cn) reporter, said in an interview will be coronavirus where actually came from is not an easy question, “is actually the virus source not only simple in a study, it requires combining epidemiological, and epidemiological evidence is will annihilate in history, at some stage may be evidence of some biological samples, after half a year or more, the evidence could not continue to exist.”

At the end of October, held in wuhan, hubei Shi Zhengli the 15th international conference on genomics (ICG – 15) delivered a keynote speech, she talked about traceability problem, although the wuhan early most of the patients with a history of south China seafood market access, and in the market environment of samples detected virus RNA, however its team in the market for frozen meat and surrounding farmed animals were not found in the detection of viral RNA.

According to Shi, the available evidence only indicates that human-to-human transmission of the virus occurred in the seafood markets in southern China, but it may not be the source of the epidemic from animal to human.
Shi zhengli told thepaper (www.thepaper.cn) during the above meeting that her team has made no progress in tracing the source of the virus.

Shi is known as the “Batwoman” and her team was the source of China’s SARS virus.
In 2017, after 13 years of searching and research, Shi zhengli and others finally found all the genetic components of THE SARS virus in bats in a small cave in Kunming, Yunnan province, basically completing the tracing work of the SARS virus.

In the outbreak, the Chinese Academy of Sciences researcher at the Pasteur institute in Shanghai Hao Pei and military medical research national emergency prevention and control engineering research center for drug researcher Zhong Wu, molecular plant scientific excellence innovation center, a researcher at the Chinese Academy of Sciences team li and others, and like those led by Shi Zhengli team, respectively in January 21 and 23 January announced research conclusion, both reveals will be coronavirus and the correlation between the bats.
This is the earliest information about the source of the virus.

However, faced with the problem of tracing the virus from novel Coronavirus, the more intractable problem for scientists is that the intermediate host link is still missing.
During the SARS period, civets were the intermediate host.
Dromedaries played this role in the MERS outbreak.
Although a team of researchers now believe that pangolins may be intermediate hosts;
In addition, a team of researchers found that ferrets, cats and other animals are also susceptible to SARS-COV-2.
But who exactly is the novel Coronavirus “Civet”?
It’s all in speculation.

An article in The Lancet Infectious Diseases in September focused on The origins of SARS-COV-2.
“Tracking bats gives you only partial information, and the viruses you’re studying may or may not get the further mutations they need to spread in humans.”
“There’s almost always an intermediate host involved,” explains Stanley Perlman, a professor of microbiology and immunology at the University of Iowa in the United States. “If you don’t know what the intermediate host is and what’s going to happen to the virus, it’s hard to make any predictions.”

But David Robertson, director of bioinformatics at the Medical Research Council’s Centre for Viruses at the University of Glasgow, United Kingdom, said it was too early to rule out direct bat-to-human transmission.

In late July, Robertson et al published a paper online in Nature Microbiology, in which they used genomic data on Sarbecoviruses and three methods to identify sarS-COV-2 viral domains that had not been reassembled and could be used to reconstruct the evolutionary history of the virus.
All the methods showed that RaTG13 and SARS-COV-2 possessed a common single ancestral line. Sars-cov-2 appeared to be differentiated from related bat viruses in 1948, 1969 and 1982, respectively.

The finding suggests that the virus lineage that produced SARS-COV-2 may have been circulating in bats for decades.
Robertson et al. suggest that the long differentiation time of SARS-COV-2 indicates the possible existence of an unsampled and potentially contagious bat virus lineage derived from genetic sites adapted to contact residues in ancestral SARS-COV-2 RBD humans.
But better sampling is needed to assess this.

They conclude that the existing diversity and dynamic processes of viral recombination in the bat virus lineage demonstrate how difficult it is to identify viruses with the potential to cause major human outbreaks in advance.

In a novel Coronavirus review published in October, Shi Zhengli et al pointed out that our understanding of the origin of SARS-COV-2 animals is far from complete, and the host of the virus has not been clearly confirmed.
It is not clear whether SARS-COV-2 is transmitted to humans through an intermediate host, or which animals may act as an intermediate host.

The rumor is fading and the truth is still to be found

The virus is a long way from its source, but conspiracy theories soon hit.

Around February 2020, comments such as “laboratory virus leakage” and “artificial creation of new viruses” were gradually fermented on the Internet, and the shadow began to fall on some scientists.
Peter Daszak, a disease ecologist at the nonprofit EcoHealth Alliance, told Science that every time a new disease or virus emerges, there are “conspiracy theories” like lab leaks or bioengineered manufacturing. “It’s a shame!”
Shi Zhengli even had to respond in her circle of friends, “Novel Coronavirus 2019 is a punishment from nature for human uncivilized life habits. I Shi Zhengli guarantee my life and have nothing to do with lab.”

On December 24, When Party secretary Wang Xianguang and vice president Huang Chaolin of Wuhan Jinyantan Hospital visited the Institute of Virology of the Chinese Academy of Sciences, Shi zhengli still expressed her excitement.
She said that when Faced with pneumonia of unknown cause, Jinyintan Hospital sent the hard-won seven pieces of alveolar lavage fluid to The Wuhan Virus Center at the first time, which showed its full trust in us.
Without this trust, there would be no wuhan virus institute a series of scientific and technological achievements against the epidemic.
“In the follow-up research work, Wuhan Virology Institute has also encountered difficulties and setbacks, but it has always been firm in its original intention and determination to make contributions to the fight against the epidemic with science and technology.”

In the face of a lot of speculation at that time, a biologist interviewed by thepaper.cn said, “My view is based on reasonable speculation and academic research based on existing data. If there is, there is; if there is no, there is no. Scientific research cannot be based on assumptions”.

Xue Yu, professor of biomedical Engineering, School of Life Science and Technology, Huazhong University of Science and Technology, said directly in an interview with Thepaper.cn (www.thepaper.cn) that he did not think the novel Coronavirus came from a laboratory.
Xue also emphasized that if a novel Coronavirus originated from a RaTG13 laboratory leak, the leak should have occurred at least 6.6 years ago, and the field must be able to find a large number of virus strains that are between a Coronavirus and RaTG13 and have a higher degree of similarity to a Coronavirus.

It has also been suggested that the rate of virus mutation may be accelerated under laboratory culture conditions.
Xue stressed to Thepaper.cn, “As for the mutation rate of novel Coronavirus, it has been strictly estimated that the mutation rate of novel Coronavirus is about 1/3 that of the mutation rate I used, so I have tried to overestimate the mutation rate of novel coronavirus as much as possible to prevent others from making an issue in this place.”

“It should be noted that the current analysis shows that the evolution rate of virus from the novel Coronavirus is relatively low. Some researchers estimated the mutation rate of virus from the novel Coronavirus to be 2.067×10^-4 bases/site/year. After conversion, it would be about 6 base mutations per year in the whole genome, which is far lower than the mutation rate I assumed.
In addition, some scholars used different models and estimated the mutation rate of novel Coronavirus to be about 0.42 x 10^-3-1.89 x 10^-3, which was smaller than that of the virus I used.
Therefore, we estimate that novel Coronavirus will mutate about 90 base sites per year, which can be considered as the upper limit.

Yan Xiang, tenancies professor of microbiology and immunology at the University of Texas At SAN Antonio Medical Center, United States, also noted in a commentary that RaTG13 and Novel Coronavirus may have had a common ancestor 25 to 65 years ago, combined with assumed mutation rate estimates from other coronaviruses.

Xiang also pointed out in his commentary that RaTG13 was detected by Shi Zhengli and his team in bats in Yunnan province a few years ago, but they did not have a live virus or full sequence of RaTG13 before that.
In his opinion, the novel Coronavirus is a new virus that has never been seen before, and there is no living virus RaTG13 bat coronavirus that is closest to the coronavirus in the laboratory at present. It is grounless to say that the virus from the novel Coronavirus was leaked from the laboratory.

It is worth noting that one of the “bases” on which conspiracy theorists built their laboratories was a paper co-published in Nature Medicine in November 2015.
In this paper, the team adapted the bat coronavirus SHC014 strain, which is closest in sequence to the SARS coronavirus, for a series of studies.
Using a reverse genetic system for SARS coronavirus, the team generated and identified a murine chimeric virus expressing SHC014 spike protein in the sarS-coronavirus skeleton.
Reverse genetics is a genetic approach to determine the function of a gene by site-directed mutations and studying its phenotype.

In fact, Vineet D. Menachery, a professor of microbiology and immunology at the University of Texas Medical Branch, is the first author of the paper. He is responsible for designing, coordinating and executing the experiment, as well as analyzing and writing the manuscript. The experiment is also designed and implemented in the laboratory of the University of North Carolina at Chapel Hill.
Shi Zhengli ranks 14th among the 15 authors of this paper and is not the corresponding author.

Current virus designed by the artificial modification of the rumors, the rutgers university molecular biologist, tile waxman, institute of microbiology lab director Richard Ebright in surging news (www.thepaper.cn) reporter interview made it clear that opposition, “the virus has complete genome sequencing, no reliable evidence that the virus is the artificial design.”

In addition to scientists voice against The laboratory virus leakage “, The end of February, by an international team of six scientists jointly published an article on The virological.org website will be coronavirus Origin related articles “The Proximal Origin of SARS – CoV – 2”, The article has not yet been formally published at The time, but has been The industry known as The most professional, “The strongest technical analysis”.

Reporters from the Paper (www.thepaper.cn) were the first to report on thepaper, which is considered the “strongest technical analysis” in the industry.
Virus into the famous chemist America kerry’s institute for immunology and microbiology department Kristian g. Andersen (for the first time and the corresponding author), an associate professor, university of Edinburgh institute of evolutionary biology, Andrew Rambaut, Columbia University mailman school of public health, director of the center for infection and immunity, w. Ian Lipkin (one of the most famous virus hunters), the university of Sydney Marie bashir infectious diseases and biological safety institute professor Edward C.
Holmes and Robert F. Garry, professor of microbiology and immunology, Tulane University School of Medicine, United States, “unravels” the novel Coronavirus. They jointly refute the conspiracy theory and show through rigorous analysis that “RNA does not lie”.

Strongest in The “technical analysis” published a few days before, The top international medical journal The Lancet, The Lancet published an article on communication online, 27 from eight countries well-known public health scientists signed statement: support for China’s fight will be coronavirus disease (COVID – 19) 2019 outbreak of scientific research, public health and medical workers.

The statement pointed to various conspiracy theories that emerged during the outbreak.
The 27 scientists noted that the rapid, open and transparent sharing of data in this outbreak is now threatened by rumors and misinformation about the disease’s origins.
“We hereby join in strongly condemning the conspiracy theory that the Novel Coronavirus disease COVID-19 is not of natural origin.”

It is worth noting that on November 17, Shi zhengli’s team also formally submitted to Nature the detailed source of RaTG13, a virus that was sampled from a mine in Guanguan Town, Mojiang County, Yunnan Province, between 2012 and 2015.
This addition is in response to a paper the team published in Nature in early February, which reports that novel Coronavirus came from bats and also confirms that the virus entered the cell the same way that the SARS coronavirus did, through its ACE2 cell receptor.
The paper was also the first to be published in Nature.

Novel Coronavirus has been active in humans for more than a year, and the rumor gradually cooled.
But up to now, the origin of the covid is still an open question.

Virus back on some of the latest information from the nature at the end of November issued a press release, a Cambodian team in a refrigerator storage of chrysanthemum found a bat and will be coronavirus relatives coronavirus, the virus was discovered in 2010 in northern Cambodia capture Shamel chrysanthemum bat (Rhinolophus shameli).
However, the full genome of the virus has not been obtained so far.

Meanwhile, a team of researchers in Japan reported the discovery of another related coronavirus in frozen bat droppings.
The virus, named RC-O319, was found in a small Rhinolophus Cornutus captured in 2013 and matched 81.47% of the sarS-CoV-2 genome sequence, according to a study published by the research team in the November 2 issue of “Emerging Infectious Diseases.”

But that information is still a long way from final conclusions.
In theory, a new virus found in an animal host must have at least 99 percent resemblance to a novel Coronavirus before it can be proved to be a direct ancestor.