On May 14, a group of scientists from universities such as Harvard, Chicago, Toronto, Cambridge, Yale, Stanford, Berkeley and others, published a letter in the journal Science in which they requested to continue studying the origin of SARS-CoV-2 :
“We must take the hypotheses about both natural and laboratory origin seriously until we have enough data. The investigation must be transparent, objective, data-driven, encompassing extensive experience, subject to independent oversight, and managed responsibly to minimize the impact of conflicts of interest. Public health agencies and research laboratories must open their records to the public. “
What’s up, now everyone has turned denial and conspiratorial?
- If you ask me, is it possible today to create a new artificial virus in the laboratory?
The answer is yes. Take, for example, this article posted on PNAS.
- Is it possible for a virus to escape from a security lab?
The answer is also yes. Take, for example, this SARS outbreak, this Brucellosis outbreak, and the discovery of the Marburg virus.
- So SARS-CoV-2 has been artificially created and escaped from a lab?
We can’t rule it out, but most likely not. It is one thing that it is possible, another thing is that it is most probable.
Coronaviruses are animal viruses
Animal coronaviruses (CoVs) have been known since the late 1930s, and are classified into four genera (alpha, beta, gamma, and delta-CoV). Beta-CoV contains most of those that infect humans and is further subdivided into four lineages (A, B, C and D). The origin of most alpha and beta-CoVs is in bats and rodents, while birds are the largest natural reservoir of gamma and delta-CoVs.
For thousands of years, CoVs have been constantly crossing the species barrier. One of the characteristics of coronaviruses is their tremendous ability to jump from one animal species to another.
They mainly cause respiratory and gastrointestinal diseases in many farm and domestic animals: infectious bronchitis virus of birds, canine respiratory coronavirus, murine hepatitis, bovine coronavirus, transmissible gastroenteritis virus in pigs, peritonitis infectious feline and a long etcetera. One of the animals that harbors the most different types of coronavirus and that, therefore, acts as a store or natural reservoir is … the bat.
More than 200 different types of CoV have been identified in bats and 35% of the virome (the set of virus genomes) of the bat are CoV. By the way, bats are not rodents, they are the only flying mammals, of which there are more than 1,200 different species, they represent approximately 20% of all mammalian species, and they are present on all continents except Antarctica . Some of its colonies can host hundreds of thousands of individuals.
Human coronaviruses
In humans, in addition to SARS-CoV-2, six other coronaviruses are known to cause disease. Four of them cause a mild infection and are named followed by a code: HCoV-229E, HCoV-OC43, HCoV-NL63, and HCoV-HKU1. 30% of common colds are caused by these four coronaviruses, in some cases they also cause digestive disorders, and in immunocompromised children and elderly people they can become serious. Their distribution is global and they tend to be seasonal.
The first to be discovered was HCoV-229E, which was isolated from the respiratory tract of a patient in 1966. The following year, HCoV-OC43 was isolated. In late 2004, HCoV-NL63 was discovered isolated from a seven-month-old baby in the Netherlands, and the same year HCoV-HKU1 was isolated from a 71-year-old patient hospitalized for pneumonia and bronchiolitis in Hong Kong.
In 2002, SARS-CoV (8,096 cases and 774 deaths) was described as causing acute and severe pneumonia. It spread to 27 countries.
Ten years later, in 2012, MERS-CoV appeared, a new coronavirus that caused the Middle East respiratory syndrome, and that, although it infected fewer people, about 2,500, its fatality was much higher, up to 35%. The MERS-CoV is still sporadically isolated.
All of these HCoV are of animal origin. HCoV-NL63, HCoV-229E, SARS-CoV and MERS-CoV have originated in CoV of bats, while the origin of HCoV-OC43 and HCoV-HKU1 is in rodents. These types of viruses that infect humans but have an animal origin are called zoonotic.
In this leap from the bat or the rodent to the human being, there have been other animals that have acted as intermediaries, in which viruses have adapted to infect humans: civets and raccoons in the case of SARS-CoV, dromedaries in MERS-CoV, or cattle in HCoV-OC43. Bats and rodents would therefore act as a natural reservoir or place where the ancestors of these HCoVs live and multiply and are the common source of infections in other animals. In intermediate hosts, the CoVs would become human adapted.
Currently, HCoV-229E, HCoV-OC43, HCoV-NL63 and HCoV-HKU1 are highly adapted to humans, are easily transmissible and cause mild infections. On the contrary, SARS-CoV and MERS-CoV are much more pathogenic, they are not so well adapted and therefore their transmission between humans is not so frequent (since 2004 no case of SARS-CoV has been detected again, and the MERS-CoV outbreaks continue to be associated with contact with dromedaries that act as an intermediate reservoir of the virus).
The coronavirus family is very diverse, they mix with each other and jump from one animal species to another. We cannot rule out, therefore, that another new coronavirus such as SARS-CoV and MERS-CoV will appear again and give us problems.
The origin of SARS-CoV-2
One of the most interesting areas of the SARS-CoV-2 genome to investigate its origin is the one that codes for protein S, because it is the most variable and because its function is essential for entry into the cell, by binding to the receptor for the cell membrane, ACE2.
The 3D models show that protein S is divided into two subunits, S1 and S2, which are separated by the action of a cell enzyme with protease activity, furin. The structural, genomic and biochemical analyzes of this protein S allow us to study this process in detail and show that SARS-CoV-2 has two important characteristics, which can be related to its origin.
The RBD domain of protein S has a high affinity for the ACE2 receptor. Protein S has a sequence called RBD (receptor-binding domain), the most variable part of the virus genome, in which there are six amino acids that are essential to bind to the ACE2 receptor. If we compare that sequence between SARS-CoV-2 and SARS-CoV, only one amino acid out of those six is common.
However, computational analyzes indicate that this domain is not the best possible to bind to the receptor, theoretically there may be other combinations that are even more efficient to bind to the receptor. This suggests that this sequence has arisen by a process of natural selection throughout the passage of the virus between people or animals.
If someone had designed this new virus to be a pathogen, they would have done better.
Protein S has a furin cleavage sequence between the S1 and S2 subunits of the protein. Although some HCoVs, such as HKU1, also have this characteristic, the furin cleavage site is not very frequent in all coronaviruses, and less in those of the beta group, to which SARS-CoV-2 belongs. Could this peculiar sequence be the result of genetic manipulation of the virus? If we compare it with what happens in the influenza virus, it is very likely also generated by natural selection.
In some avian influenza viruses, it has been seen that in situations of high density of bird populations, this type of cut sequence is selected naturally in the hemagglutinin of the envelope (similar to the protein S of the coronavirus). This makes the virus replicate faster and is more transmissible.
This is how some low pathogenic avian influenza viruses turn into high pathogenic viruses. Acquisition of these cleavage sites in hemagglutinin has also been observed after repeated passages of the virus in cell culture or in animals. Therefore, this new property of the influenza virus is the result of natural selection, and the same could have happened in the coronavirus.
If the origin of the SARS-CoV-2 genome were genetic engineering, it is very likely that some genetic systems already present in other beta-CoVs would have been used and the data does not demonstrate any of this. On the contrary, it is most likely that these two characteristics of the virus are the result of natural selection.
One possibility is that these characteristics were selected in an animal before being transferred to humans. When the genomes of CoVs are compared, the most similar to SARS-CoV-2 is the one isolated from a bat in Yunnan (China) in 2013, the RaTG13 genome of Rhinolophus affinis , with more than 96% identity.
However, when comparing the RBD region of protein S they differ significantly. Although the bat virus continues to have greater genome-wide homology, the similarity between SARS-CoV-2 and pangolin coronaviruses is especially high in that RBD domain of protein S. This reinforces the idea that optimization of Protein S to bind to the human ACE2 receptor is the result of natural selection and not of genetic engineering or successive passage of the virus in a laboratory.
However, neither bat nor pangolin coronaviruses have the furin cleavage site in protein S. Coronaviruses are very common among these and other animals and it is very likely that we have not yet found the animal precursor to SARS -CoV-2. We cannot rule out that mutation, insertion and deletion phenomena have occurred naturally in the S gene in some other animal, probably with a high population density and with a human-like ACE2 receptor.
Another possibility that cannot be ruled out is that SARS-CoV-2 has acquired these characteristics while being transmitted undetectable between humans. All SARS-CoV-2 genomes sequenced so far show that they have a clonal origin from a common ancestor in Wuhan, most likely early November 2019. The presence in pangolins of the same RBD domain in protein S suggests that this characteristic was already in the virus before its jump to humans. Perhaps, then, the furin cleavage site was the one selected during human-to-human transmission.
This assumes that the virus was present before November 2019 and that it was transmitted between us undetectable for some time. We don’t know that now, but it would be very interesting if we were able to do retrospective studies and see if the virus actually circulated among humans before its outbreak in Wuhan at the end of 2019.
As we can see, the peculiar characteristics of SARS-CoV-2 were already in nature and it is not necessary to imagine laboratory experiments to explain its origin. We know less than 1% of the viruses out there and more than 70% of the new emerging viruses originate in animals.
Viruses are millions of millions of particles, which multiply at an enormous speed and with an extraordinary frequency of mutation and recombination. Viruses do not mutate, they live by mutating. In them, evolution is fast-paced.
Another interesting fact is that there are a large number of animals that are susceptible to an experimental infection with SARS-CoV-2: cats, dogs, ferrets, minks, hamsters, some species of rats and mice, macaques, African green monkey, shrews, fruit bats, raccoons, laboratory rabbits, cattle … On the other hand, naturally acquired infections of SARS-CoV-2 have been demonstrated in dogs, cats and ferrets in domestic environments, in tigers, lions, pumas and leopards in zoological collections, in gorillas and American mink farms. At the moment, mink farms are the only evidence of maintenance of a naturally acquired infection in an animal population and leap to humans.
Most likely it is a natural origin, but is another hypothesis possible?
Despite all that we have just said, it is true that there are reasonable doubts about what was done and how it was worked at the Wuhan Institute of Virology.
China took a year! in allowing an international team from the WHO to visit Wuhan to investigate the origin of the virus. His conclusion was that SARS-CoV-2 was “very likely” to have an animal origin, although it is not known which one. Unfortunately, it was the Chinese government that collected the data and samples and collected all the information, while the international team was only able to work on those data and reports.
On the other hand, it was known that since before 2008, genetic manipulation experiments of the SARS and MERS coronaviruses, called “function gains”, had been carried out to improve their capacity for infection and transmission. And since 2014, the US government had established a moratorium on funding this type of experiment due to its dangerousness and potential pandemic.
In March 2020, the top officials of the Institute indicated that no worker of the same had tested positive for SARS-CoV-2. But it has recently been made public that at least three scientists from the Institute fell ill with compatible symptoms of COVID-19 a month before the official announcement of the existence of a new coronavirus, so there remain serious doubts about the level of biosafety of the Institute.
A 2018 report by US State Department technicians to verify the biosafety of the Institute’s facilities raised concerns about lack of security, laboratory management weaknesses, and lack of specialized personnel, describing that many of the work was not done within the BSL4 facilities.
Conclusion: with the data we have at this time, the most probable hypothesis is that SARS-CoV-2, like the rest of human CoVs, is of natural origin, from a natural reservoir of CoV of bats and through some intermediate species (still unidentified) where it adapted to humans. Nature has enough resources to generate this and any other virus.
However, the tremendous opacity and lack of transparency of the Chinese Government means that an origin in the laboratory cannot be ruled out as a hypothesis, less probable but possible. Only a transparent, objective, data-driven and independent investigation will tell us the truth.
Ignacio López-Goñi, Professor of Microbiology, University of Navarra
This article was originally published on The Conversation. Read the original.
