The Evolution of the SARS-COV-2 virus

[ChinleShale]

TL;DR Summary

SARS-COV-2 virus is said to have originated in bats but has evolved into a highly successful pathogen in humans. How might it have evolved to be able to bind to human cells and also infect them? How did it become so contagious and gain the ability to affect different human tissues?

The sudden appearance of SARS-COV-2 as a virulent pathogen in humans raises the question of how it gained the ability to attack human cells and why it is highly contagious. If I understand this right, an article in Virology Blog

https://www.virology.ws/2020/02/13/furin-cleavage-site-in-the-sars-cov-2-coronavirus-glycoprotein/

and a follow up

https://www.virology.ws/2020/05/14/sars-cov-2-furin-cleavage-site-revisited/

says that the spike protein contains two components, one which binds to human cells the other which allows the virus to enter the cell. To activate the second component the spike protein must be cleaved and SARS_COV-2 contains a "potential furin cleavage site" which is not found in similar viruses, in particular the bat virus that most closely resembles it. The thought is that human enzymes might be able to cleave the spike protein at this site thus allowing the virus to infect human cells. If I understand this, it says that the virus originated in bats but had to change before to being able to infect humans.

My question is two fold: How exactly do these spike proteins work and how might the virus have evolved to obtain them? More generally how do viruses evolve to be able to "jump" species?

Another article:
https://www.sciencedirect.com/science/article/pii/S0166354220300528?via=ihub

Disclaimer: As I am not a biologist I may have misunderstood these papers. But the general question still stands I hope.

 

[jim mcnamara]

I do not know a good answer. Bat populations are sampled for Coronavirus variants. Someone may know the full chain of infection through species.

However. Consider influenza pandemics. Wild ducks like mallards are the reservoir for many variants of the flu virus. The wild populations of mallards are sampled worldwide. Here is how it becomes a human virus in traditional farms in China or a family farm in North America.

Dabbling wild ducks, Anas spp., swim in farm ponds leaving feces with virus on the bottom.
Domestic ducks dabble (feed off the bottom) in  the same pond. They become infected.
The ducks spend the night in animal pens.  It rains or the pen gets hosed out.
If neighboring pens harbor pigs, some overflow from the the duck pen can be picked up by the pigs
Humans butcher the pig and expose themselves to the virus.
The virus then takes off into the human world.

You can consider that as a possible model for SARS-CoV-2.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419510/
The ecology of avian influenza viruses in wild dabbling ducks (Anas spp.) in Canada

 

[aheight]

How exactly do these spike proteins work . . .

Perhaps can start by researching receptor binding, membrane fusion and phagocytosis. Here's three references:

Wikipedia link to phagocytosis

Link to Nature article

The spike (S) protein of SARS-CoV-2, which plays a key role in the receptor recognition and cell membrane fusion process, is composed of two subunits, S1 and S2. The S1 subunit contains a receptor-binding domain that recognizes and binds to the host receptor angiotensin-converting enzyme 2, while the S2 subunit mediates viral cell membrane fusion by forming a six-helical bundle via the two-heptad repeat domain.

As I interpret this, S1 recognized the ACE 2 receptor (common on many human cells) and binds to it. Once it does this, S2 initiates membrane fusion: The cell membrane envelops the virus, closes in on itself, then open up on the inside to release it to the cytoplasm. Here's one reference:

Virus entry

Viral entry is a multistep process that follows attachment of the virion to the cell surface and results in delivery of the viral genome to the site of replication, either in the cytosol or nucleus. The key step in virus entry is penetration of a cellular membrane. For enveloped viruses, delivery of the viral genome across the lipid bilayer of the virus and a cellular membrane is accomplished by a membrane fusion reaction. For nonenveloped viruses, the viral genome is usually delivered across a cellular membrane by a pore that is formed by protein components of the viral capsid. Virus fusion and penetration proteins exist in metastable states that must be triggered in some way to undergo the needed conformational changes.

 

[ChinleShale]

I do not know a good answer. Bat populations are sampled for Coronavirus variants. Someone may know the full chain of infection through species.

However. Consider influenza pandemics. Wild ducks like mallards are the reservoir for many variants of the flu virus. The wild populations of mallards are sampled worldwide. Here is how it becomes a human virus in traditional farms in China or a family farm in North America.

Dabbling wild ducks, Anas spp., swim in farm ponds leaving feces with virus on the bottom.
Domestic ducks dabble (feed off the bottom) in  the same pond. They become infected.
The ducks spend the night in animal pens.  It rains or the pen gets hosed out.
If neighboring pens harbor pigs, some overflow from the the duck pen can be picked up by the pigs
Humans butcher the pig and expose themselves to the virus.
The virus then takes off into the human world.

You can consider that as a possible model for SARS-CoV-2.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5419510/
The ecology of avian influenza viruses in wild dabbling ducks (Anas spp.) in Canada

So is the mallard version of the virus able to infect people without traversing the intermediate sequence of hosts?

 

[jim mcnamara]

No it is not. The virus changes a little as it hops across species boundaries. So it may well be that SARS-CoV-2 transmission to humans follows a similar path. HIV originated from pet green monkeys to humans back in the 1950's, in West Africa. So there are different models for this chain of transmission.

Bat species are like $mallards^4$ when it comes to harboring viral variants. Apparently some populations of bats in small areas may harbor hundreds of strains/species of Coronavirus. Even at the individual level, there may be many multiple strains.

Also the evolution of the virus is poorly understood:
https://www.nature.com/articles/s41467-020-17687-3
"Origin and cross-species transmission of bat coronaviruses in China"

 

[ChinleShale]

No it is not. The virus changes a little as it hops across species boundaries. So it may well be that SARS-CoV-2 transmission to humans follows a similar path. HIV originated from pet green monkeys to humans back in the 1950's, in West Africa. So there are different models for this chain of transmission.

Bat species are like $mallards^4$ when it comes to harboring viral variants. Apparently some populations of bats in small areas may harbor hundreds of strains/species of Coronavirus. Even at the individual level, there may be many multiple strains.

Also the evolution of the virus is poorly understood:
https://www.nature.com/articles/s41467-020-17687-3
"Origin and cross-species transmission of bat coronaviruses in China"

So what is a general model for these changes? Is it natural selection? The virus finds itself in a new host. Some are able to bind to new host cells. Among these some are able to replicate and these proliferate in the virus population in the new host species. So the new components that allow this are already there or perhaps appear randomly with mutation?

In the path from mallards to humans why would any changes along the way, say in pigs ,allow the virus to infect humans? Wouldn't the changes adapt the virus to pigs not people?

Are there partially modified viruses that can bind to host cells but not reproduce in them?

 

[jim mcnamara]

Look up zoonosis. That is what we are discussing. Almost all of our diseases, smallpox, Black Plague, and so on, originated in animals. Domestication made it work faster. Smallpox <- Cowpox, for example.

Start here:
https://en.wikipedia.org/wiki/Zoonosis

The impact on all of history:
Hans Zinsser 'Rats, Lice, and History'
Jared Diamond 'Guns, Germs, and Steel'

North America was primarily conquered by Europeans with a series of zoonotic diseases, not necessarily technology. Or innate anything. It is a hypothesis, the Norse were repulsed from l'anse aux meadows in Caanada by the 'skralings'. Norse for Native American.

 

[Ygggdrasil]

So what is a general model for these changes? Is it natural selection? The virus finds itself in a new host. Some are able to bind to new host cells. Among these some are able to replicate and these proliferate in the virus population in the new host species. So the new components that allow this are already there or perhaps appear randomly with mutation?

In the path from mallards to humans why would any changes along the way, say in pigs ,allow the virus to infect humans? Wouldn't the changes adapt the virus to pigs not people?

Are there partially modified viruses that can bind to host cells but not reproduce in them?

Yes, the general model for these types of diseases is natural selection. Here's how I like to think of the process.

First, remember that animals are all fairly similar at the molecular level. SARS-CoV-2 binds to the ACE2 receptor in humans and the bat version of the ACE2 receptor protein is 80% identical to the human version. These similarities between animals allows viruses to hop between species fairly commonly. Indeed, people in rural South China who live near regions with bats commonly show antibodies against SARS-like coronaviruses, indicating that they commonly contract SARS-like coronaviruses from bats. Furthermore, viral exchange goes two ways: as SARS-CoV-2 has become widespread in human populations, researchers have seen the virus transmit from humans to a variety of human-adjacent animals such as cats, dogs, ferrets, and more recently minks.

Usually, when a virus hops between species, however, the virus is not optimized to replicate in the new host, so the virus usually dies off without causing serious illness or being able to transmit to other people. So, while zoonotic transmission of viruses from say bats to humans is fairly common, most cases would likely go unnoticed as mild colds that do not easily transmit to other people.

In rare instances, a virus may have some set of mutations that allows it to better replicate in humans and the viruses can cause disease. We know of three instances of coronaviruses like this in the past twenty years: the original SARS Coronavirus (first seen in 2002), the MERS Coronavirus (first seen in 2012), and SARS-CoV-2 (first seen in 2019). SARS-CoV and MERS-CoV, however, were both not very well adapted for transmission in humans (they caused very severe disease, so people who were infected were too sick to be around many other people to transmit the disease). SARS-CoV-2, on the other hand, has the fortuitous (for the virus) property of causing mild disease in most people, allowing asymptomatic people to spread the disease, resulting in the current pandemic.

How are the SARS, MERS, and SARS-CoV-2 coronaviruses different from the many other SARS-like bat coronaviruses? In all three cases, there is some evidence that these viruses passed from bats to humans via an intermediary species (civet cats for SARS, camels from MERS, and pangolins for SARS-CoV-2). Transmission of the virus in these intermediary species could have selected for variants that may have increased potential to transmit in humans. We may be seeing a similar phenomenon now: researchers have seen SARS-CoV-2 transmit from humans to mink farms in Europe, and while the virus has been circulating in these mink farms, it has acquired new mutations in the spike protein. While the spike protein mutations likely help the virus propagate in minks, the mutations could also help the virus evade immunity when the virus transmits back from minks to humans. (Similar dynamics are likely also at play in the emergence of new strains of influenza every year).

 

[Astronuc]

Back in March - https://www.theatlantic.com/science/archive/2020/03/biography-new-coronavirus/608338/

Coronaviruses are ubiquitous, but most are relatively benign, while few like SARS-CoV-2 are more severe.

To be clear, SARS-CoV-2 is not the flu. It causes a disease with different symptoms, spreads and kills more readily, and belongs to a completely different family of viruses. This family, the coronaviruses, includes just six other members that infect humans. Four of them—OC43, HKU1, NL63, and 229E—have been gently annoying humans for more than a century, causing a third of common colds. The other two—MERS and SARS (or “SARS-classic,” as some virologists have started calling it)—both cause far more severe disease. Why was this seventh Coronavirus the one to go pandemic? Suddenly, what we do know about coronaviruses becomes a matter of international concern.

The structure of the virus provides some clues about its success. In shape, it’s essentially a spiky ball. Those spikes recognize and stick to a protein called ACE2, which is found on the surface of our cells: This is the first step to an infection. The exact contours of SARS-CoV-2’s spikes allow it to stick far more strongly to ACE2 than SARS-classic did, and “it’s likely that this is really crucial for person-to-person transmission,” says Angela Rasmussen of Columbia University. In general terms, the tighter the bond, the less virus required to start an infection.

There’s another important feature. Coronavirus spikes consist of two connected halves, and the spike activates when those halves are separated; only then can the virus enter a host cell. In SARS-classic, this separation happens with some difficulty. But in SARS-CoV-2, the bridge that connects the two halves can be easily cut by an enzyme called furin, which is made by human cells and—crucially—is found across many tissues.

https://en.wikipedia.org/wiki/Furin
https://onlinelibrary.wiley.com/doi/full/10.1002/cti2.1073
https://www.ncbi.nlm.nih.gov/gene/5045

 

[Laroxe]

There is always a problem when we talk about virus as discrete entities with common features, the reality is that virus represent the largest number of entities ? / organisms ?/ bundles of bad news, on the planet. Considering what appears to be their relative simplicity they can engage in some very complex activities and their skills in genetic engineering does muddy the water when it comes to natural selection. Some have even inserted their own DNA into ours, were it coexists, we don't even know if the originating organisms still exist in the wild, so their fitness is totally dependent on our own.

Its only recently that there has been any real attempt to try and classify the viruses all around us and its still the case that the focus remains on the groups that cause us problems and so we are discovering huge numbers of viruses with the potential to cause harm. The word potential is important in this, there are a large number of factors that can influence how a disease develops. Its becoming increasingly obvious that many of what we consider to be new diseases might have been around for many years, perhaps at a level that simply didn't attract attention and its still the case that some remain very difficult to identify.

In the case of corona virus its becoming increasingly clear that this is a huge family which causes infections in a very wide range of animals. We also know that given the right circumstances a virus optimised for one animal host can infect other animals, often with different degrees of success. Its now thought that MERS originally a bird virus, infected camels sometime in the last hundred years and camels may have become their primary natural host. There have been multiple outbreaks of MERS in humans, probably for a lot longer than we realized, but the virus has never really mastered transmission in humans, so each new outbreak originates from transmission from camels.

With SARS CoV-2 this came to our attention after an outbreak in Wutan, where it was presumed to have originated, the closest match to the virus so far was found in bats, a natural reservoir for a large number of Coronavirus, and suspicion grew that this virus jumped species from bats to humans in a food market. In fact cross species transmission of virus is surprisingly common and this will lead to some changes in an attempt to adapt to the new host. However another trick some virus engage in is that if the animal is already carrying a similar virus, they can exchange some genetic information adding to the differences. The flu virus is particularly adept at this and the changes can radically effect its immunologic profile. Its almost certain that in what is likely to have been a chain of cross species transmissions that other animals have been involved, its just not clear which. There is now the added complication that there have been small outbreaks of infections in rural china that sound suspiciously like Covid 19, so again it might have its origins further back than we think.
You might find this discussion interesting which covers in some depressing detail at least some of the issues.



among the panel of researchers is Tony Schountz who spends his life investigating pathogens in bats, a lot of his papers are at;

https://www.researchgate.net/scientific-contributions/Tony-Schountz-38378938

 

[ChinleShale]

@Laroxe

I listened to the video but a lot was over my head. So what is the take away? It seems they are saying that there is a risk that this Corona virus will adapt to other species and create new risk through human contact with them. Right now we worry only about human to human contact. Deer mice are likely suspects since that are abundant in human environments and are known to carry Hanta virus which BTW scared the daylights out of me when I first moved here to New Mexico.

Another take away is that the virus will keep spreading until there is a vaccine and lock downs will only slow its progress. So is this because a complete quarantine as was done with small pox is logistically impossible? O is it because asymptomatic carriers will spread the disease with or without a quarantine?

The scientists in the discussion also seemed to be calling for way more basic research on viruses not only for knowlege's sake but also if we want to be free someday of pandemics such as this. They seemed to be sounding an alarm.

 

[Laroxe]

@Laroxe

I listened to the video but a lot was over my head. So what is the take away? It seems they are saying that there is a risk that this Corona virus will adapt to other species and create new risk through human contact with them. Right now we worry only about human to human contact. Deer mice are likely suspects since that are abundant in human environments and are known to carry Hanta virus which BTW scared the daylights out of me when I first moved here to New Mexico.

Another take away is that the virus will keep spreading until there is a vaccine and lock downs will only slow its progress. So is this because a complete quarantine as was done with small pox is logistically impossible? O is it because asymptomatic carriers will spread the disease with or without a quarantine?

The scientists in the discussion also seemed to be calling for way more basic research on viruses not only for knowlege's sake but also if we want to be free someday of pandemics such as this. They seemed to be sounding an alarm.

Virus in particular, generally have specific hosts, sometimes even specific cells in that host, but cross species transmission, particularly to animals similar or related to its preferred host, is common. Most of these episodes occur in very particular situations, animals that are experiencing problems effecting their immune system may become susceptible particularly if exposed to a large dose. The virus still requires the machinery to successfully infect and multiply in the new hosts cells and with enough time natural selection will favour the virus with the best biological match. The next obstacle is in then passing from the infected animal, to others of the same species, this is in fact where most fail, there are huge barriers.

One of the reasons they are so concerned about a virus like SARS-Cov2 passing from humans to other animals is that in this case the virus has already overcome these barriers. That's why they slaughtered all those mink, as the virus adapted to the mink, it could possibly pick up new traits and jump back to humans.
I've linked to a paper that describes the issues, which is readable, but yes as human Covid 19 spreads into the rodent population, it alters the disease dynamics and the availability of other natural hosts makes elimination almost impossible, its not just asymptomatic humans, it means we can catch it from close contact to these rodents.
To be honest I'm not sure that its likely that we will avoid new pandemics for quite some time, scientists have been fully aware of the risks and there have been a number of initiatives to try and reduce them. The problem is that the task is huge, there are vast numbers of unclassified virus and its still unclear how these new pandemics evolve over time. The pandemic everyone was waiting for was flu, consider how outbreaks of bird flu are treated and this is still a major threat, but the pandemic we got was from a virus that few people had heard of before SARs-Cov1, and even that had disappeared. We are always going to come into contact with other animals and of course virus do change.

You mention Hanta Virus, which is in fact a family of virus though we are not really sure how many of them there are, their natural hosts are rodents (and possibly bats) and they cause disease in humans that range from mild to deadly.
I thought you might be interested in a disease that appeared in England in the 16th century (2nd link) the cause of which remains unknown. One theory is that it was caused by a strain of Hanta, and its effects terrified people. You tube has some good vids about it.

https://pedersen.bio.ed.ac.uk/page4/assets/Pedersen_Davies_2010.pdf
https://www.pharmaceutical-journal.com/news-and-analysis/opinion/blogs/just-what-was-english-sweating-sickness/20067690.blog?firstPass=false

 

[ChinleShale]

I thought you might be interested in a disease that appeared in England in the 16th century (2nd link) the cause of which remains unknown. One theory is that it was caused by a strain of Hanta, and its effects terrified people. You tube has some good vids about it.

It seems like the sweating disease did not perfectly match Hnta virus to other known diseases. I wonder if after over 500 years that the virus could have changed and its current symptoms are not congruent to those of its ancestors.

A little reading on flu viruses indicates that while flu viruses differ most prominently in the severity of infection and contagiousness. H5N1 for instance is 60% lethal but does not spread easily. Here is the link

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4001451/

It seems that health officials worried that H5N1 could gain the ability to spread easily and with a 60% mortality rate would be maybe the worst virus since Small Pox. Here is a video in which Dr. Fauci expresses this worry



One could ask about SARS-COV-2 which spreads easily whether it can evolve to become more lethal.

 

[Monsterboy]

https://thebulletin.org/2021/05/the-origin-of-covid-did-people-or-nature-open-pandoras-box-at-wuhan/

I read the above article recently, it seems to suggest that the natural origin of SARS-CoV-2 is not fully confirmed and leaves the probability of a lab escape to non-zero or significantly more than zero according to the author.

For people without specialized knowledge in this area it is really difficult to guess who is telling the truth.

I would like some informed opinions.

Some extracts from the article linked above.

The decoding of the virus’s genome showed it belonged a viral family known as beta-coronaviruses, to which the SARS1 and MERS viruses also belong. The relationship supported the idea that, like them, it was a natural virus that had managed to jump from bats, via another animal host, to people. The wet market connection, the major point of similarity with the SARS1 and MERS epidemics, was soon broken: Chinese researchers found earlier cases in Wuhan with no link to the wet market.

“We stand together to strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin,” a group of virologists and others wrote in the Lancet on February 19, 2020

. . .
It later turned out that the Lancet letter had been organized and drafted by Peter Daszak, president of the EcoHealth Alliance of New York. Daszak’s organization funded Coronavirus research at the Wuhan Institute of Virology. If the SARS2 virus had indeed escaped from research he funded, Daszak would be potentially culpable. This acute conflict of interest was not declared to the Lancet’s readers. To the contrary, the letter concluded, “We declare no competing interests.”

What became clear was that the Chinese had no evidence to offer the commission in support of the natural emergence theory.

. . .

This was surprising because both the SARS1 and MERS viruses had left copious traces in the environment. The intermediary host species of SARS1 was identified within four months of the epidemic’s outbreak, and the host of MERS within nine months. Yet some 15 months after the SARS2 pandemic began, and after a presumably intensive search, Chinese researchers had failed to find either the original bat population, or the intermediate species to which SARS2 might have jumped, or any serological evidence that any Chinese population, including that of Wuhan, had ever been exposed to the virus prior to December 2019.

But I read pangolins were the intermediate species... was it not confirmed ?

It cannot yet be stated that Shi did or did not generate SARS2 in her lab because her records have been sealed, but it seems she was certainly on the right track to have done so. “It is clear that the Wuhan Institute of Virology was systematically constructing novel chimeric coronaviruses and was assessing their ability to infect human cells and human-ACE2-expressing mice,” says Richard H. Ebright, a molecular biologist at Rutgers University and leading expert on biosafety.

“It is clear that some or all of this work was being performed using a biosafety standard — biosafety level 2, the biosafety level of a standard US dentist’s office — that would pose an unacceptably high risk of infection of laboratory staff upon contact with a virus having the transmission properties of SARS-CoV-2,” Ebright says

“It also is clear,” he adds, “that this work never should have been funded and never should have been performed.”

This is a view he holds regardless of whether or not the SARS2 virus ever saw the inside of a lab.

Concern about safety conditions at the Wuhan lab was not, it seems, misplaced. According to a fact sheet issued by the State Department on January 15, 2021, “The U.S. government has reason to believe that several researchers inside the WIV became sick in autumn 2019, before the first identified case of the outbreak, with symptoms consistent with both COVID-19 and common seasonal illnesses.”

For lack of access to such records, another approach is to take certain salient facts about the SARS2 virus and ask how well each is explained by the two rival scenarios of origin, those of natural emergence and lab escape. Here are four tests of the two hypotheses. A couple have some technical detail, but these are among the most persuasive for those who may care to follow the argument.

1) The place of origin. Start with geography. The two closest known relatives of the SARS2 virus were collected from bats living in caves in Yunnan, a province of southern China. If the SARS2 virus had first infected people living around the Yunnan caves, that would strongly support the idea that the virus had spilled over to people naturally. But this isn’t what happened. The pandemic broke out 1,500 kilometers away, in Wuhan.

2) Natural history and evolution. The initial location of the pandemic is a small part of a larger problem, that of its natural history. Viruses don’t just make one time jumps from one species to another. The Coronavirus spike protein, adapted to attack bat cells, needs repeated jumps to another species, most of which fail, before it gains a lucky mutation. Mutation — a change in one of its RNA units — causes a different amino acid unit to be incorporated into its spike protein and makes the spike protein better able to attack the cells of some other species.

Through several more such mutation-driven adjustments, the virus adapts to its new host, say some animal with which bats are in frequent contact. The whole process then resumes as the virus moves from this intermediate host to people.

In the case of SARS1, researchers have documented the successive changes in its spike protein as the virus evolved step by step into a dangerous pathogen. After it had gotten from bats into civets, there were six further changes in its spike protein before it became a mild pathogen in people. After a further 14 changes, the virus was much better adapted to humans, and with a further four, the epidemic took off.

But when you look for the fingerprints of a similar transition in SARS2, a strange surprise awaits. The virus has changed hardly at all, at least until recently. From its very first appearance, it was well adapted to human cells. Researchers led by Alina Chan of the Broad Institute compared SARS2 with late stage SARS1, which by then was well adapted to human cells, and found that the two viruses were similarly well adapted. “By the time SARS-CoV-2 was first detected in late 2019, it was already pre-adapted to human transmission to an extent similar to late epidemic SARS-CoV,” they wrote.

3) The furin cleavage site. The furin cleavage site is a minute part of the virus’s anatomy but one that exerts great influence on its infectivity. It sits in the middle of the SARS2 spike protein. It also lies at the heart of the puzzle of where the virus came from.

The spike protein has two sub-units with different roles. The first, called S1, recognizes the virus’s target, a protein called angiotensin converting enzyme-2 (or ACE2) which studs the surface of cells lining the human airways. The second, S2, helps the virus, once anchored to the cell, to fuse with the cell’s membrane. After the virus’s outer membrane has coalesced with that of the stricken cell, the viral genome is injected into the cell, hijacks its protein-making machinery and forces it to generate new viruses.

But this invasion cannot begin until the S1 and S2 subunits have been cut apart. And there, right at the S1/S2 junction, is the furin cleavage site that ensures the spike protein will be cleaved in exactly the right place.

The virus, a model of economic design, does not carry its own cleaver. It relies on the cell to do the cleaving for it. Human cells have a protein cutting tool on their surface known as furin. Furin will cut any protein chain that carries its signature target cutting site. This is the sequence of amino acid units proline-arginine-arginine-alanine, or PRRA in the code that refers to each amino acid by a letter of the alphabet. PRRA is the amino acid sequence at the core of SARS2’s furin cleavage site.

Viruses have all kinds of clever tricks, so why does the furin cleavage site stand out? Because of all known SARS-related beta-coronaviruses, only SARS2 possesses a furin cleavage site. All the other viruses have their S2 unit cleaved at a different site and by a different mechanism.

Where we are so far. Neither the natural emergence nor the lab escape hypothesis can yet be ruled out. There is still no direct evidence for either. So no definitive conclusion can be reached.

That said, the available evidence leans more strongly in one direction than the other. Readers will form their own opinion. But it seems to me that proponents of lab escape can explain all the available facts about SARS2 considerably more easily than can those who favor natural emergence.

 

[atyy]

https://thebulletin.org/2021/05/the-origin-of-covid-did-people-or-nature-open-pandoras-box-at-wuhan/

The article by Wade has quite a bit of nonsense, even if it is attributed to an extremely distinguished source. The comments attributed to Baltimore on the furin cleavage site are nonsense, as detailed by Krystian Andersen in a Twitter thread.

The only point the article really has is that while we don't know for sure the origin of the virus, the lab release theory cannot be definitively ruled out. However, it is wrong in playing up the lab release theory. It is hard to rule out the lab release theory because it is hard to prove a negative. However, the main obvious routes from lab release as well as many exotic ones are improbable due to a combination of theoretical and experimental arguments found in Andersen et al https://www.nature.com/articles/s41591-020-0820-9 and the comments by Shi Zhengli of the Wuhan Institute on checks done by the institute itself on the possibility of lab release https://science.sciencemag.org/content/369/6503/487.summary. Wade's article is aware of and disagrees with the Anderson et al, but appears not to be aware of Shi Zhengli's comments at all. It is noteworthy that Shi Zhengli has commented that a visit probing the lab leak theory would be welcome https://www.bbc.com/news/world-asia-china-55364445.

 

[pinball1970]

Summary:: SARS-COV-2 virus is said to have originated in bats but has evolved into a highly successful pathogen in humans. How might it have evolved to be able to bind to human cells and also infect them? How did it become so contagious and gain the ability to affect different human tissues?

The sudden appearance of SARS-COV-2 as a virulent pathogen in humans raises the question of how it gained the ability to attack human cells and why it is highly contagious. If I understand this right, an article in Virology Blog

https://www.virology.ws/2020/02/13/furin-cleavage-site-in-the-sars-cov-2-coronavirus-glycoprotein/

and a follow up

https://www.virology.ws/2020/05/14/sars-cov-2-furin-cleavage-site-revisited/

says that the spike protein contains two components, one which binds to human cells the other which allows the virus to enter the cell. To activate the second component the spike protein must be cleaved and SARS_COV-2 contains a "potential furin cleavage site" which is not found in similar viruses, in particular the bat virus that most closely resembles it. The thought is that human enzymes might be able to cleave the spike protein at this site thus allowing the virus to infect human cells. If I understand this, it says that the virus originated in bats but had to change before to being able to infect humans.

My question is two fold: How exactly do these spike proteins work and how might the virus have evolved to obtain them? More generally how do viruses evolve to be able to "jump" species?

Another article:
https://www.sciencedirect.com/science/article/pii/S0166354220300528?via=ihub

Disclaimer: As I am not a biologist I may have misunderstood these papers. But the general question still stands I hope.

I have seen a few of these.

https://images.app.goo.gl/jGK8zNKLGbN34YNx8

Researchers use techniques to find the most likely most parsimonious relationship

 

[BillTre]

You should show your references for what sound to like weird claims.

 

[Ygggdrasil]

Both of your assertions are demonstrably false.

How did the medical community determine the disease COVID-19 is caused by the SARS COV II virus? Are there any quantified virus isolates available? According to the CDC there is not.

According to the CDC, there is: https://www.cdc.gov/coronavirus/2019-ncov/lab/grows-virus-cell-culture.html

Is there an electron micrograph of the isolate for SARS COV II ? To date, there is none available.

Again, this is demonstrably false: https://www.niaid.nih.gov/news-events/novel-coronavirus-sarscov2-images

 

[BillTre]

you should read the comment and reply accordingly.

You posted no link to a commentary to read.
I think your making this all up out of your head and dodging the responsibility of providing support for you wacky claims.
Are you some kind of troll?

 

[BillTre]

Extraordinary claims require at least some kind of support to be taken seriously.

You are providing none. Why would anyone want to waste their time on such drivel?

 

[berkeman]

[Mentor Note -- There has been some cleanup of the thread after a drive-by troll has been banned. Have a nice day.]

 

[Laroxe]

I did notice the statement that "the Chinese had no evidence to offer the commission in support of the natural emergence theory", isn't this the default position? It's a virus. Pandemics/epidemics/outbreaks happen all the time, they don't just effect humans, there are several new viral infections doing the rounds even now, one in plants and one in amphibians. Our own history is littered with examples of new diseases that needed no help from China.
What would be the point of creating a virus like this? no one with any sense tries to weaponise viruses anymore, bullets are cheaper and you can aim them. This would be the most useless bioweapon ever.

 

[pinball1970]

https://www.nature.com/articles/s41598-020-79484-8

Are MERS strains called MARS? I cannot find what the acronym is for this

I googled the Bat species.

R. affinis – Intermediate horseshoe bat
R. sinicus Chinese rufous horseshoe bat
R. macrotis Big-eared horseshoe bat
R. pusillus Least horseshoe bat

Civet is mentioned in the SARS-CoV line

This is from July 2020 so this is pre some of the later variants towards the end of last year and the Indian variant.

 

[Laroxe]

Some people might find this episode of TWiV interesting as they have 3 members of the WHO team that went to China to investigate this outbreak.

 

[Astronuc]

Claim: A classified US intelligence report - saying three researchers at the Wuhan laboratory were treated [edit: for what?] in hospital in November 2019, just before the virus began infecting humans in the city - began circulating in US media this week.

https://www.msn.com/en-us/news/world/why-the-lab-leak-theory-is-being-taken-seriously/ar-AAKrVdq?li=BBnb7Kz

Apparently, the 'lab-leak theory' has gained some traction, but the investigation is about the origin.

"That possibility certainly exists, and I am totally in favour of a full investigation of whether that could have happened," Anthony Fauci, President Biden's chief medical adviser, told the US senate committee on 11 May.

President Biden now says he asked for a report on the origins of Covid-19 after taking office, "including whether it emerged from human contact with an infected animal or from a laboratory accident".

It could be coincidental that the origin was in Wuhan where the Wuhan Institute of Virology is located. It could be that workers from the institute were exposed in the general population, as much as they could have been exposed in the field. Asymptomatic transmission could have been going on for a week or more for the original source.

Could it go from bat > civet > bat > pangolin > bat > human?

or

bat > civit ------------v
bat > pangoling > bat

 

[atyy]

Claim: A classified US intelligence report - saying three researchers at the Wuhan laboratory were treated in hospital in November 2019, just before the virus began infecting humans in the city - began circulating in US media this week.

https://www.msn.com/en-us/news/world/why-the-lab-leak-theory-is-being-taken-seriously/ar-AAKrVdq?li=BBnb7Kz

Apparently, the 'lab-leak theory' has gained some traction, but the investigation is about the origin.

In the interview (summary: https://science.sciencemag.org/content/369/6503/487.full full: https://www.sciencemag.org/sites/default/files/Shi%20Zhengli%20Q&A.pdf), Shi Zhengli says all staff had sera tested negative. If that meant an antibody test, that would exclude the possibility that the staff referred to in the report about a classified US intelligence report were a source of COVID-19.

 

[Astronuc]

Claim: A classified US intelligence report - saying three researchers at the Wuhan laboratory were treated [edit: for what?] in hospital in November 2019, . . . .

Shi Zhengli says all staff had sera tested negative.

I added [edit: for what?] to indicate that there was no mention for what they were treated. A undetermined respiratory or flu-like, or pneumonia-like, illness?

 

[Phil Core]

I read the article by Andersen et al - https://www.nature.com/articles/s41591-020-0820-9. It is very scholarly but somewhat misleading.

He starts the article by stating – “Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.”

I certainly did not find the article to be QED.

What the article did demonstrate well is that although diverse, appearing in difference organisms, there are similar organic structures to parts of the SARS – CoV – 2 ex ante.

The case then becomes similar structures appear in Nature therefore somehow they must have fused via random mutation and natural selection.

To my knowledge there is no study that takes an existing structure and then illustrated how via random mutation and natural selection you get the SARS – CoV – 2 genome.

With respect to the Sars Cov -2 ACE2 receptor I find it to be very important. There is a significant difference between this receptor and that found in Sars Cov – 1 - https://www.frontiersin.org/articles/10.3389/fmolb.2020.591873/full

Andersen notes – “SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2” (via random mutation and natural selection.)

Has anyone be able to demonstrate that starting with an existing source it is impossible to manifest the SARS – C oV – 2 in a lab?

The most honest answer to the source of the SARS – CoV -2 virus is it unknown. It may have originated in the wild or it is possible that it was influenced in a lab. At this time we are very far from having a definitive answer.

 

[Jarvis323]

I read the article by Andersen et al - https://www.nature.com/articles/s41591-020-0820-9. It is very scholarly but somewhat misleading.

He starts the article by stating – “Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.”

I certainly did not find the article to be QED.

What the article did demonstrate well is that although diverse, appearing in difference organisms, there are similar organic structures to parts of the SARS – CoV – 2 ex ante.

The case then becomes similar structures appear in Nature therefore somehow they must have fused via random mutation and natural selection.

To my knowledge there is no study that takes an existing structure and then illustrated how via random mutation and natural selection you get the SARS – CoV – 2 genome.

With respect to the Sars Cov -2 ACE2 receptor I find it to be very important. There is a significant difference between this receptor and that found in Sars Cov – 1 - https://www.frontiersin.org/articles/10.3389/fmolb.2020.591873/full

Andersen notes – “SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2” (via random mutation and natural selection.)

Has anyone be able to demonstrate that starting with an existing source it is impossible to manifest the SARS – C oV – 2 in a lab?

The most honest answer to the source of the SARS – CoV -2 virus is it unknown. It may have originated in the wild or it is possible that it was influenced in a lab. At this time we are very far from having a definitive answer.

It's important to understand that the article is a letter to the editor, not a peer reviewed scientific research article.

 

[Phil Core]

The Andersen et al - letter to the editor - has been quoted several times in threads on this site. It summarizes well the opinion held by many.

You can not just say the source you quoted was not peer reviewed therefore everything is wrong.

What fault do you find with the Andersen "letter"?

I think it is important to note that the letter is over a year old and no advancement at all has been made with respect to the Nature- random mutation and natural selection- origin of the virus. None!

 

[Jarvis323]

The Andersen et al - letter to the editor - has been quoted several times in threads on this site. It summarizes well the opinion held by many.

You can not just say the source you quoted was not peer reviewed therefore everything is wrong.

What fault do you find with the Andersen "letter"?

I think it is important to note that the letter is over a year old and no advancement at all has been made with respect to the Nature- random mutation and natural selection- origin of the virus. None!

I didn't say anything about it except that it is not a peer reviewed scientific article. It would be better to read the criticisms from virologists than for me to try and scrutinize it.

But just as a note: The natural zoonotic hypothesis has been that it came about after a jump between bats and an intermediate species and then to humans. Originally it was thought to have occurred at the wet market because live animals of different species are near to each other.

If this could happen so easily and quickly naturally by placing animals near to each other, how could it be impossible to reproduce in a lab, where animals are placed near to each other and also infected with viruses?

Nobody is arguing we shouldn't investigate the wet market.

The truth is that you can't rule out a lab origin. There are many possible mechanisms, including ones that are indistinguishable from natural origins outside the lab.

It would be wrong to hype the lab origin hypothesis, but also wrong to hype the non-lab origin hypothesis in my opinion. If we don't thoroughly and transparently pursue lab leak possibilities, then I don't think people should be allowed to pursue lab research with dangerous viruses.

 

[Phil Core]

With respect to the Sars Cov -2 ACE2 receptor I find it to be very important. There is a significant difference between this receptor and that found in Sars Cov – 1 - https://www.frontiersin.org/articles/10.3389/fmolb.2020.591873/full

The above article originally piqued my interest.

Now - https://www.dailymail.co.uk/news/ar...-lab-tried-cover-tracks-new-study-claims.html

Do not just disregard because of source Daily Mail. There are some very interesting diagrams about 1/2 the way through the article of the structure of the Cov - 2 virus and where it may have been altered.

Dalgleish is a London oncology professor known for breakthrough work on a vaccine for HIV. Sørensen is a virologist and chair of the pharmaceutical company Immunor, which developed a Coronavirus vaccine candidate called Biovacc-19. Dalgleish also has a financial stake in that company.

It was during their COVID-19 vaccine research that the pair came across "unique fingerprints" indicating the virus didn’t come from nature, they said. The telltale clue: a rare finding in the COVID-carrying virus of a row of four amino acids, which give off a positive charge and bond to negative human cells.

"The laws of physics mean that you cannot have four positively charged amino acids in a row," Dalgleish told the Daily Mail. "The only way you can get this is if you artificially manufacture it."

 

[atyy]

The truth is that you can't rule out a lab origin. There are many possible mechanisms, including ones that are indistinguishable from natural origins outside the lab.

It would be wrong to hype the lab origin hypothesis, but also wrong to hype the non-lab origin hypothesis in my opinion. If we don't thoroughly and transparently pursue lab leak possibilities, then I don't think people should be allowed to pursue lab research with dangerous viruses.

It is true that one cannot rule out a lab origin. However, there is evidence against the lab origin as provided by the Andersen article and the Shi Zhengli https://www.sciencemag.org/sites/default/files/Shi%20Zhengli%20Q%26A.pdf. Recently there have been prominent arguments for the lab origin. Among these are an article by Nicholas Wade that attrbutes comments to David Baltimore, but as explained by Kristian Andersen, the comments are nonsense. There have been reports about staff of the Wuhan Institute having been hospitalized before the outbreak, and so may have been its source, but Shi Zhengli (of the Wuhan Institute) has said that sera testing has been done of all staff; it is a little unclear what and who was tested, but if it was an antibody test, it would mean that none of the staff tested had been infected by SARS-CoV-2, and so could not have been a source. Then there is speculation by Nick Paton Walsh on CNN that experiments on RaTG13 (a bat virus whose sequence is currently the closest to SARS-CoV-2) were the source of the leak, but that route would also be ruled by information provided by the Shi Zhengli that while they do have "isolated live" coronaviruses, RaTG13 was not among them (we know about the RaTG13 sequence from samples collected by and sequenced by the Wuhan Institute). So at this stage, unless Shi Zhengli was lying, even many exotic and improbable ways the virus may have leaked from the lab origin are excluded. Nonetheless, it is noteworthy that Shi Zhengli had commented that she would welcome a visit to investigate the lab.

 

[Ygggdrasil]

It's important to understand that the article is a letter to the editor, not a peer reviewed scientific research article.

The Andersen et al. publication may have been peer reviewed, but even if it was not, it at least passed screening by the editorial team at the journal, Nature Medicine. Here's the journal's policy on correspondences:

"Correspondence​

The Correspondence section provides a forum for discussion or to present a point of view on issues that are of interest to the readership of Nature Medicine. Correspondences should not contain new research data, nor should serve as a venue for technical comments on peer-reviewed research papers, which would be considered Matters Arising. A Correspondence is generally 800-1000 words; it is limited to one display item and up to 10 references. Article titles are omitted from the reference list.​

​

Correspondences are initially screened for general interest, and may be returned to the authors if the topic, angle or content is deemed not to be of high interest to the journal’s readership or when the topic has already been covered in other pieces. Nature Medicine receives a very high volume of correspondence and the editorial team reserves the right to return submissions to authors without further feedback. After screening, correspondences are edited for concision and clarity, and additional changes may be requested from the authors. Correspondences may be peer-reviewed at editorial discretion."​

https://www.nature.com/nm/about/content

He starts the article by stating – “Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.”

I certainly did not find the article to be QED.

What the article did demonstrate well is that although diverse, appearing in difference organisms, there are similar organic structures to parts of the SARS – CoV – 2 ex ante.

The case then becomes similar structures appear in Nature therefore somehow they must have fused via random mutation and natural selection.

To my knowledge there is no study that takes an existing structure and then illustrated how via random mutation and natural selection you get the SARS – CoV – 2 genome.

With respect to the Sars Cov -2 ACE2 receptor I find it to be very important. There is a significant difference between this receptor and that found in Sars Cov – 1 - https://www.frontiersin.org/articles/10.3389/fmolb.2020.591873/full

Andersen notes – “SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2” (via random mutation and natural selection.)

The Andersen et al. article presents evidence that 1) the receptor was not purposefully engineered in the lab, and that 2) the virus does not show signs of selection inside of a laboratory (if the virus was being cultured for study). Essentially, the virus evolved in the wild.

These possibilities do not necessarily exclude all possibilities related to an accidental lab release (e.g. researchers encountered the virus in the wild while collecting virus samples and infected others or got infected while miss-handling samples). However, whether a wild virus transmitted from the wild to the general populous or whether a wild virus got to the general populous via the lab is difficult to distinguish solely from looking at the genetics of the virus and would be nearly impossible to distinguish.

Has anyone be able to demonstrate that starting with an existing source it is impossible to manifest the SARS – C oV – 2 in a lab?

The most honest answer to the source of the SARS – CoV -2 virus is it unknown. It may have originated in the wild or it is possible that it was influenced in a lab. At this time we are very far from having a definitive answer.

But just as a note: The natural zoonotic hypothesis has been that it came about after a jump between bats and an intermediate species and then to humans. Originally it was thought to have occurred at the wet market because live animals of different species are near to each other.

If this could happen so easily and quickly naturally by placing animals near to each other, how could it be impossible to reproduce in a lab, where animals are placed near to each other and also infected with viruses?

Nobody is arguing we shouldn't investigate the wet market.

The truth is that you can't rule out a lab origin. There are many possible mechanisms, including ones that are indistinguishable from natural origins outside the lab.

It would be wrong to hype the lab origin hypothesis, but also wrong to hype the non-lab origin hypothesis in my opinion. If we don't thoroughly and transparently pursue lab leak possibilities, then I don't think people should be allowed to pursue lab research with dangerous viruses.

Research that tries to turn wild coronaviruses into viruses capable of causing pandemic disease is exactly the kind of dangerous research that people are claiming caused the pandemic. That sort of research is very dangerous and maybe should not even be pursued.

However, we have plenty of examples of the SARS-CoV-2 gaining naturally mutations that increase its transmissibility and decrease its succeptibility to antibodies as it spreads among humans (e.g. the variants from the UK, South Africa, Brazil, New York, California, India, etc.), and we have also observed new variants as it jumps species (e.g. to minks in Europe), showing that mutation of the virus and transmission across species is something that occurs pretty frequently with these types of viruses.

Also, while the wet market may have just been a superspreader event that transmitted the virus from an infected individual to others and not the source of the original animal to human transmission. It is likely that the jump from bats to intermediate species happened much earlier. Because people at the wet market handle wild animals, it is possible that one became infected while collecting, transporting or handling the wild animals and then spread the virus at the market (a large social gathering which would be conducive to spreading the disease to many people).

With respect to the Sars Cov -2 ACE2 receptor I find it to be very important. There is a significant difference between this receptor and that found in Sars Cov – 1 - https://www.frontiersin.org/articles/10.3389/fmolb.2020.591873/full

The above article originally piqued my interest.

Now - https://www.dailymail.co.uk/news/ar...-lab-tried-cover-tracks-new-study-claims.html

Do not just disregard because of source Daily Mail. There are some very interesting diagrams about 1/2 the way through the article of the structure of the Cov - 2 virus and where it may have been altered.

Dalgleish is a London oncology professor known for breakthrough work on a vaccine for HIV. Sørensen is a virologist and chair of the pharmaceutical company Immunor, which developed a Coronavirus vaccine candidate called Biovacc-19. Dalgleish also has a financial stake in that company.

It was during their COVID-19 vaccine research that the pair came across "unique fingerprints" indicating the virus didn’t come from nature, they said. The telltale clue: a rare finding in the COVID-carrying virus of a row of four amino acids, which give off a positive charge and bond to negative human cells.

"The laws of physics mean that you cannot have four positively charged amino acids in a row," Dalgleish told the Daily Mail. "The only way you can get this is if you artificially manufacture it."

I have a PhD in biophysics, and you can absolutely have four positively charged amino acids in a row, and this can occur naturally. As noted by Kristian Andersen, similar sequences are found in many other Coronavirus found in nature (e.g. feline coronaviruses).

 

[atyy]

These possibilities do not necessarily exclude all possibilities related to an accidental lab release (e.g. researchers encountered the virus in the wild while collecting virus samples and infected others or got infected while miss-handling samples). However, whether a wild virus transmitted from the wild to the general populous or whether a wild virus got to the general populous via the lab is difficult to distinguish solely from looking at the genetics of the virus and would be nearly impossible to distinguish.

With the usual caveat that it is hard to prove a negative, there is some evidence against the possibility of accidental release during collection and handling of samples. In the addendum to the paper reporting RaTG13, https://www.nature.com/articles/s41586-020-2951-z, it seems that Shi Zhengli and colleagues briefly describes several samplings of bat caves, and to date the closest sequence is RaTG13, still quite far from SARS-CoV-2

Interestingly, the reason they sampled those particular caves was that there had been in 2012 a few people who visited the caves as preparation for copper mining, and they had pneumonia whose cause was not identified. The Wuhan researchers suspected the patients had been infected by an unknown virus, and therefore took samples from the cave to study that possibility. They have since retested the serum of those patients, and confirmed that they were not infected by SARS-CoV-2.