A horseshoe bat (Rhinolophus sinicus), which was found in a cave in Yunnan province, China
While it has been close to six months since the global coronavirus outbreak started to afflict the humans, there are still several unanswered questions which have hampered scientists' understanding of the micro-organism. The most crucial question, to which the global scientific community is yet to reach a consensus, is about the virus' real fountainhead.
"... there are some recent claims both for and against the Wuhan wet market being the source of origin. Some retrospective data shows that the earlier cases had no contact with the market. But there is no doubt that it was the 'epicenter' because the viruses circulating in the world right now are all descendants of the earliest samples found in the patients from Wuhan (city)," says Rohit Chakravarty, a bat researcher and scholar at Leibniz Institute for Zoo and Wildlife Research in Berlin.
Another issue troubling scientists is about the route which the virus might have taken before it reached the human respiratory system. Interestingly, the receptor-binding domain of the coronavirus of Malayan pangolins is closely related to SARS-CoV2, but it does not match the entire genome. Scientists have not found sufficiently similar coronavirus in pangolins that can potentially be the progenitor of SARS-CoV2," reckons Kasturi Saha, another bat conservationist and currently a researcher at Indian Institute of Science (IISc) in Bengaluru.
Further, the scientific community seems to be divided over the question of SARS-CoV2 having its origins at a lab in Wuhan. While China and the World Health Organisation have denied the proposition outright, the United States says that it has "enormous evidence" to prove that the virus was, in fact engineered. "Scientific community always follows where the data and evidence takes and currently we have strong support that it would most probably have taken a bat - pangolin - human route," Baheerathan Murugavel at the Indian Institute of Science Education and Research in Thiruvananthapuram (IISER TVM) weighs in on the hotly-contested question.
"...there are some recent claims both for and against the Wuhan wet market being the source of origin. Some retrospective data shows that the earlier cases had no contact with the market. But there is no doubt that it was the 'epicenter' because the viruses circulating in the world right now are all descendants of the earliest samples found in the patients from Wuhan."
Bat researchers Chakravarty, Saha and Murugavel answered some of the questions for India TV Digital: Edited excerpts:
1. The World Health Organisation has stated that there can’t be any debate on the origin of coronavirus and that a ‘wet market’ in Wuhan was the epicentre of the outbreak. You, along with a group of other researchers, have however raised some doubts over the theory. So, are you backing the claim that SARS-COV2 was manufactured, say in a lab?
A. Rohit Chakravarty: We haven't disputed this theory at all. Our main goal was to explain that there is no evidence for direct bat to human transmission of this virus. We have, in fact, stated wildlife trade as one of the most possible hypotheses behind the outbreak.
It makes a lot of sense because, in wildlife markets, animals from different parts of the world are brought in together in unsanitary conditions. Their bodily fluids keep mixing and that creates an ideal situation for a virus from one animal to jump into another and mutate in order to become virulent to humans.
However, there are some recent claims both for and against the Wuhan wet market being the source of origin. Some retrospective data shows that the earlier cases had no contact with the market. But there is no doubt that it was the 'epicenter' because the viruses circulating in the world right now are all descendants of the earliest samples found in the patients from Wuhan. So that's where the virus started to spread from.
Other possible hypotheses about the origin include industrial-scale livestock farming of, for example, pigs. Such livestock farms again have animals in close contact and the animals are inbred. If any of these animals come in contact with a potential reservoir host of the virus then they can get infected and then transmit the virus to humans.
We strongly believe that such human activities are responsible for the outbreak of a virus that appears to be naturally-occurring.
Kasturi Saha: In addition to RC’s points, the virus shows some clear signs of natural selection like the similarity with already existing (but previously unknown) natural viruses and also its genetic structure, especially the binding efficiency. Scientists have not found any evidence of genetic engineering or computer-based modelling or a lab experiment gone wrong. So, we do not see any reason to back up the claim that it was manufactured in a lab.
"So, assuming this is the route the virus took, it would mean that the virus has gone through all stages of natural selection like any other wild virus which is close to impossible in a lab set up. Engineering such a complex genome from scratch is extremely difficult."
Q. Can a virus be manufactured in a lab? Have there been precedents?
A. KS: Yes, synthetic viruses do exist. As far as we know, they are only used for research purposes, for example to make better vaccines or medicines for other diseases like cancer. For example, synthetic horsepox virus was manufactured in a lab in Canada (2018) to develop a more effective vaccine against smallpox.
RC: From my understanding of basic biology, manufacturing SARS-CoV-2 in a lab seems extremely unlikely. I say this because the closest match of SARS-CoV-2 genome has been found in a natural source, an Intermediate Horseshoe Bat which has a virus called RaTG13. RaTG13 and SARS-CoV-2 are 96 per cent similar but they differ drastically in the receptor-binding area (which is why RaTG13 cannot directly infect human lungs and hence bats cannot spread the virus to us!).
Secondly, the most likely transmission route so far is the RaTG13 went from a bat to a pangolin and then recombined to become SARS-CoV-2 infecting humans. Pangolin is suspected because the pangolin coronavirus genome shows a very high match to the receptor-binding sites of the SARS-CoV-2 (but differs otherwise).
So, assuming this is the route the virus took, it would mean that the virus has gone through all stages of natural selection like any other wild virus which is close to impossible in a lab set up. Engineering such a complex genome from scratch is extremely difficult. Even if these natural coronaviruses were used to develop SARS-CoV-2, lab cultures do not have that level of genetic diversity required to mutate and form different strains (as we are seeing) in the human host. As shown by this study published in Nature, the mutations suggested by computer models don't work to achieve the binding efficiency of SARS-CoV-2.
Q. The new virus also has an exceptionally large genome, of about 30,000 nucleobases. Can such a large genome be present in a natural virus?
A. RC: I had no idea about the length of the SARS-CoV-2 genome and 30k seemed pretty large. That prompted me to look at publicly-available genomes of the two previous coronavirus outbreaks Bat SARS-CoV (that was linked to the original SARS outbreak in 2003) and MERS CoV (that caused MERS). Both of these also have genomes of ~30k base pairs (bp). Based on this, it doesn't seem unlikely that the SARS-CoV-2 has 30k bp too. Viruses that belong to the same family can have the same genome lengths (among other similarities).
KS: It’s not really exceptional. The biggest known viruses are Mimivirus which has 1.2 million base pair DNA and among RNA viruses too, there is a virus called Planarian Secretory Cell Nidovirus, which has a genome larger than 40,000 nucleotides. So yes, large genomes can be present in natural viruses.
"...the key point to note is that the bat virus RaTG13 is different from SARS-CoV-2. It cannot bind to human lungs (and hence cannot cause COVID-19) because it doesn't have the right surface proteins receptors. Which is why scientists believe that this virus went through an intermediate host to become the novel coronavirus."
Q. You have said that ‘surface proteins of all SARS-like viruses found in bats cannot bind efficiently to the corresponding receptors of the human lung epithelium which makes direct transmission even more unlikely. Does this directly challenge the view that the virus, known to cripple the respiratory system, has come from bats?
A. RC: It does challenge the claim that the virus comes directly from bats but not the possibility that a bat coronavirus could be the precursor of SARS-CoV-2.
In fact, all evidence seems to suggest that SARS-CoV-2 has a zoonotic origin probably from bats, as did SARS-CoV and MERS-CoV. However, the key point to note is that the bat virus RaTG13 is different from SARS-CoV-2. It cannot bind to human lungs (and hence cannot cause COVID-19) because it doesn't have the right surface proteins receptors. Which is why scientists believe that this virus went through an intermediate host to become the novel coronavirus. We also saw this pattern with SARS-CoV and MERS-CoV which went through intermediate hosts. Hence, we have nothing to fear from bats when it comes to contracting SARS-like viruses (or most other viruses!).
KS: It is also important to note the evolutionary difference between the bat coronavirus (RaTG13, isolated from horseshoe bat samples of 2013) and the SARS-CoV-2. A recent study suggests that they might have a common ancestor about 40-70 years ago, which is a very long time in terms of viruses, and they evolved separately after that. This indicates that the virus circulating in horseshoe bats in 2013 is not the precursor of SARS-CoV-2. They probably share a great-great-great-grandmother, but that’s all.
Q. What’s the sure-shot way of reaching the conclusion about the origin of coronavirus? With no consensus around the ‘Person Zero’, can’t samples from persons infected with the virus be employed to understand the real origin of the virus. What all options do we have on the table to find out the truth?
A. Baheerathan Murugavel: I can say scientists are currently trying to understand the origin of the virus by using samples from infected persons. The genome of SARS-CoV-2 was isolated from infected patients and that was later used to compare with existing viral genomes in bats and pangolins. The current hypothesis of a bat - pangolin- human SARS-CoV-2 is a product of available data and we could find more on this once we have more data.
More data on the history of the virus could be obtained by more surveillance for SARS-CoV-2 like viruses in other possible host animals and also by having the genomes of virus from infected patients.
"Scientists have not found sufficiently similar coronavirus in pangolins that can potentially be the progenitor of SARS-CoV2."
Q. Bats are known to be reservoirs of different viruses. But you say that none of them can infect humans directly. So, there is a likelihood that SARS-CoV2 could have been transmitted through pangolins to humans.
A. KS: We specifically mentioned that the bat coronaviruses cannot infect humans directly. We do not say that none of the bat viruses can infect humans. Bats can infect us with rabies, but the chances are very low, because we don’t come in contact with bats, like we do with dogs. Although the bat coronavirus shares similarity with SARS-CoV2, the receptor-binding domain in the protein spikes is different from SARS-CoV2 and so it cannot bind to human cells.
Interestingly, the receptor-binding domain of the coronavirus of Malayan pangolins is closely related to SARS-CoV2, but it does not match the entire genome. Scientists have not found sufficiently similar coronavirus in pangolins that can potentially be the progenitor of SARS-CoV2.
One such claim is that a combination via a natural process called homologous recombination between the bat coronavirus and pangolin coronavirus could possibly result into SARS-CoV2, but until we find that intact virus in nature we just have to keep looking! It is premature to blame pangolins, and also dangerous for their safety.
We know that they are already on the verge of extinction and suffering enough as the most trafficked mammal in global wildlife trade. There are many possibilities and speculations based on what scientists have found till now, but they need to be tested before coming up with any conclusion.
Q. How was the case of Nipah outbreak different?
A. BM: Nipah comes from a different virus family so the transmission is naturally a little different. According to WHO factsheets, Nipah can be transmitted to humans from animals such as bats or pigs and also directly from infected people.
In the case of Nipah outbreak in Kerala, 2018, the exact mode of transmission from animals to humans is not known yet. However, the Nipah virus isolated during that outbreak had genomic similarities to those found in some fruit bats of Pteropus genus. Once the route of transmission is known, it is possible to contain a disease.
In Bangladesh, Nipah broke out because bats fed on date palm sap that the villagers were collecting from date palm trees. So, there was indirect salivary contact (via date palm sap) between bats and humans. The saliva of any animal can have pathogens that can affect humans.
On the positive side, when this transmission route was identified, it became easier to stop the disease transmission. These cases show that we should invest more on identifying transmission routes to prevent future outbreaks - and of course, follow basic hygiene rules! Just having bats around you will not give you a virus. In fact, we have been sharing space with bats for centuries. Killing bats just because they house viruses (which all animals do) is unjustified.
"...the biologists whom I have spoken to (off the record) are of the opinion that engineering such a virus is extremely challenging. I personally believe that biologists are abstaining from making public statements because this is a political proposition."
Q. US Secretary of State Mike Pompeo says that there is enormous evidence to show that coronavirus originated at a Chinese lab. How well are researchers in Germany receptive to the proposition? Is there any consensus in the scientific community, regardless of what the WHO and China have been saying all along?
A. BM: Based on available scientific information till date, we could be certain that the virus is following all stages of evolution and it is highly likely that it is a naturally evolved virus with a zoonotic origin. Scientific community always follows where the data and evidence takes and currently we have strong support that it would most probably have taken a bat - pangolin - human route. Current research is trying to pinpoint and trace the exact route of transmission from the animal hosts to humans with more precision and certainty.
RC: I haven’t come across any press release from scientists in Germany or other countries clarifying that the virus is not engineered or is an outcome of a lab accident. However, the biologists whom I have spoken to (off the record) are of the opinion that engineering such a virus is extremely challenging. I personally believe that biologists are abstaining from making public statements because this is a political proposition. The various scientific papers investigating the natural origin of this virus should be seen as an attempt to understand the biology of the virus in a truly biological sense.
