Below, I print the full article from Nature, March 17, 2020. I believe this is the full article -- actually, it is a correspondence in the journal -- whose summary triggered some contested discussions on this listserve about whether CORVID-19 virus could have been genetically engineered. This article says such an event would have been improbable.

However, as I'd previously written, the assumptions written here for why the virus could not have been engineered are flawed and rely on interpreting the choice of pathways technicians would have most expediently taken to get to the result they'd wanted.

But by arguing in that way, the authors assume a "most expedient" cause-and-effect route is what is required. But there are many instances in the government's contracting of scientific research for military or corporate ends in which the scientists involved do not know why their particular research is being solicited and funded, and without a political and historical overview, trying to reason from a molecular piecing together (like Humpty Dumpty) leads to flawed conclusions.

One example that I remember vividly from our fight against war-related research at Stony Brook that others on this list may also remember came about when the U.S. government funded new research into the use of lasers (which were new at the time) to detect cavities in teeth. Innocuous enough, right? Except what the government did with that was to secretly combine that research with others to detect underground tunnels from the air in Vietnam.

My point is that one could not have predicted that from the isolated research itself. One cannot argue from assumptions about why, or how direct, or from fundamentally humane reasoning when dealing with these kinds of issues. Certainly one should not assume that the most direct or cost-effective technique will be the one employed -- even if one wanted to lead to specific and predictable ends; just because that's how we might think, it should not be assumed that all others will think that way too. We on-the-ground cannot hope to figure out from that fragmentary perspective the reasons for why certain things are being done -- for that, we need political and historical analyses, as already mentioned. As others pointed out here a few weeks ago (remember that far back?), one way of proceeding could be to just set the thing in motion and let nature or some other force take over from that point.

That said, there is no scientific proof at this time that CORVID-19 was genetically engineered by anyone -- the U.S. government, nor China, nor Russia; nor is there molecular proof that it wasn't engineered, either. (What I meant when I used the term "agnostic" about this issue.)

One more question for why we need a holistic (or dialectical) analysis, for the medical personnel and molecular chemists and biologists on this list: Millions of people are taking ACE inhibitors, which block ACE receptors in the heart, lower blood pressure and are frequently prescribed for all sorts of heart-related conditions. Here's a good description:
When there is reduced blood pressure in the kidney, the body produces the enzyme renin, which leads to the production of a protein called angiotensin I. This protein doesn’t have any effect on the body, but when it’s converted by another enzyme – the Angiotensin Converting Enzyme, produced particularly in the lungs – into angiotensin II, this has potent vascular effects that increase blood pressure. ACE inhibitors block this enzyme and so prevent the rise in blood pressure.

[ Rupert Payne, Consultant Senior Lecturer in Primary Health Care, University of Bristol, "What we know about ACE inhibitors, high blood pressure and COVID-19," March 25, 2020 published in The Conversation. ]
The article goes on to hypothesize that CORVID-19 may enter the body through ACE2 receptors, to which they have a molecular afinity. The body's unexpected result of ACE inhibitors is to possibly increase the number of ACE2 receptors to compensate for their medically-induced suppression.

I think of it as similar to the body growing more lung capacity as "pressured" by working out.

In other words, the body needs the ACE2 receptors, and when they are blocked by a drug like Enalapril or Ramipril, administered for one purpose (to lower blood pressure), the body on the other hand needs those receptors to function normally and so grows more of them. Interestingly, one of the side effects of some ACE inhibitors that a good doctor watches out for is a dry cough -- similar to one of COVID-19's symptoms.

Although they are seen as generally benign in low doses, I stopped taking Ramipril against doctor's orders almost a year ago. I agree that we need particular medications in emergency situations, but I don't believe in being maintained on them continuously once the emergency has passed. In my case, it's as much a philosophical disagreement as a medical one.

Here is how the article describes the current problem with CORVID-19 and ACE receptors:
... A key trick employed by the coronavirus is to attach to a receptor on the surface of the cells which binds to an enzyme related to ACE, called ACE2. ACE2 has different functions to ACE, including inactivating angiotensin II.
ACE inhibitors do not appear to directly affect the action of ACE2. Nevertheless, they may have indirect effects that could lead to an increase in the number of ACE2 receptors. This has led to concerns that ACE inhibitors may facilitate COVID-19 disease, particularly as these drugs are used in older people with other health issues who we know are at risk of more severe respiratory complications.
However, the situation is not necessarily that simple. Previous work with the related condition SARS showed that reduced ACE2 (and with it, increased angiotensin II) was associated with severe lung injury. Based on this, ACE inhibitors and ARBs, by reducing angiotensin II, might actually be expected to be protective against severe lung problems. In an attempt to address these opposing theories, there is currently a clinical trial which is examining whether the ARB drug Losartan may have benefits in patients with COVID-19. ... The balance of these risks and benefits is currently unknown.


The proximal origin of SARS-CoV-2

Nature Medicine (2020)
Cite this article

March 17, 2020

To the Editor ­ Since the first reports of novel pneumonia (COVID-19) in Wuhan, Hubei province, China 1 ,2 , there has been considerable discussion on the origin of the causative virus, SARS-CoV-2 3 (also referred to as HCoV-19) 4. Infections with SARS-CoV-2 are now widespread, and as of 11 March 2020, 121,564 cases have been confirmed in more than 110 countries, with 4,373 deaths 5.

SARS-CoV-2 is the seventh coronavirus known to infect humans; SARS-CoV, MERS-CoV and SARS-CoV-2 can cause severe disease, whereas HKU1, NL63, OC43 and 229E are associated with mild symptoms 6. Here we review what can be deduced about the origin of SARS-CoV-2 from comparative analysis of genomic data. We offer a perspective on the notable features of the SARS-CoV-2 genome and discuss scenarios by which they could have arisen. Our analyses clearly show that SARS-CoV-2 is not a laboratory construct or a purposefully manipulated virus.

Notable features of the SARS-CoV-2 genome

Our comparison of alpha- and betacoronaviruses identifies two notable genomic features of SARS-CoV-2: (i) on the basis of structural studies 7 ,8 ,9 and biochemical experiments 1 ,9 , 10, SARS-CoV-2 appears to be optimized for binding to the human receptor ACE2; and (ii) the spike protein of SARS-CoV-2 has a functional polybasic (furin) cleavage site at the S1–S2 boundary through the insertion of 12 nucleotides 8, which additionally led to the predicted acquisition of three O-linked glycans around the site.

1. Mutations in the receptor-binding domain of SARS-CoV-2

The receptor-binding domain (RBD) in the spike protein is the most variable part of the coronavirus genome 1 ,2 . Six RBD amino acids have been shown to be critical for binding to ACE2 receptors and for determining the host range of SARS-CoV-like viruses 7. With coordinates based on SARS-CoV, they are Y442, L472, N479, D480, T487 and Y4911, which correspond to L455, F486, Q493, S494, N501 and Y505 in SARS-CoV-2 7. Five of these six residues differ between SARS-CoV-2 and SARS-CoV (Fig. 1a). On the basis of structural studies 7 ,8 ,9 and biochemical experiments 1 ,9 , 10, SARS-CoV-2 seems to have an RBD that binds with high affinity to ACE2 from humans, ferrets, cats and other species with high receptor homology 7.
Fig. 1: Features of the spike protein in human SARS-CoV-2 and related coronaviruses.

a, Mutations in contact residues of the SARS-CoV-2 spike protein. The spike protein of SARS-CoV-2 (red bar at top) was aligned against the most closely related SARS-CoV-like coronaviruses and SARS-CoV itself. Key residues in the spike protein that make contact to the ACE2 receptor are marked with blue boxes in both SARS-CoV-2 and related viruses, including SARS-CoV (Urbani strain). b, Acquisition of polybasic cleavage site and O-linked glycans. Both the polybasic cleavage site and the three adjacent predicted O-linked glycans are unique to SARS-CoV-2 and were not previously seen in lineage B betacoronaviruses. Sequences shown are from NCBI GenBank, accession codes MN908947, MN996532, AY278741, KY417146 and MK211376. The pangolin coronavirus sequences are a consensus generated from SRR10168377 and SRR10168378 (NCBI BioProject PRJNA573298 ) 29 , 30.
Full size image

While the analyses above suggest that SARS-CoV-2 may bind human ACE2 with high affinity, computational analyses predict that the interaction is not ideal 7 and that the RBD sequence is different from those shown in SARS-CoV to be optimal for receptor binding 7 , 11. Thus, the high-affinity binding of the SARS-CoV-2 spike protein to human ACE2 is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. This is strong evidence that SARS-CoV-2 is not the product of purposeful manipulation.

2. Polybasic furin cleavage site and O-linked glycans

The second notable feature of SARS-CoV-2 is a polybasic cleavage site (RRAR) at the junction of S1 and S2, the two subunits of the spike 8 (Fig. 1b). This allows effective cleavage by furin and other proteases and has a role in determining viral infectivity and host range 12. In addition, a leading proline is also inserted at this site in SARS-CoV-2; thus, the inserted sequence is PRRA (Fig. 1b). The turn created by the proline is predicted to result in the addition of O-linked glycans to S673, T678 and S686, which flank the cleavage site and are unique to SARS-CoV-2 (Fig. 1b). Polybasic cleavage sites have not been observed in related ‘lineage B’ betacoronaviruses, although other human betacoronaviruses, including HKU1 (lineage A), have those sites and predicted O-linked glycans 13. Given the level of genetic variation in the spike, it is likely that SARS-CoV-2-like viruses with partial or full polybasic cleavage sites will be discovered in other species.

The functional consequence of the polybasic cleavage site in SARS-CoV-2 is unknown, and it will be important to determine its impact on transmissibility and pathogenesis in animal models. Experiments with SARS-CoV have shown that insertion of a furin cleavage site at the S1–S2 junction enhances cell–cell fusion without affecting viral entry 14. In addition, efficient cleavage of the MERS-CoV spike enables MERS-like coronaviruses from bats to infect human cells 15. In avian influenza viruses, rapid replication and transmission in highly dense chicken populations selects for the acquisition of polybasic cleavage sites in the hemagglutinin (HA) protein 16, which serves a function similar to that of the coronavirus spike protein. Acquisition of polybasic cleavage sites in HA, by insertion or recombination, converts low-pathogenicity avian influenza viruses into highly pathogenic forms 16. The acquisition of polybasic cleavage sites by HA has also been observed after repeated passage in cell culture or through animals 17.

The function of the predicted O-linked glycans is unclear, but they could create a ‘mucin-like domain’ that shields epitopes or key residues on the SARS-CoV-2 spike protein 18. Several viruses utilize mucin-like domains as glycan shields involved immunoevasion 18. Although prediction of O-linked glycosylation is robust, experimental studies are needed to determine if these sites are used in SARS-CoV-2.

Theories of SARS-CoV-2 origins

It is improbable that SARS-CoV-2 emerged through laboratory manipulation of a related SARS-CoV-like coronavirus. As noted above, the RBD of SARS-CoV-2 is optimized for binding to human ACE2 with an efficient solution different from those previously predicted 7 , 11. Furthermore, if genetic manipulation had been performed, one of the several reverse-genetic systems available for betacoronaviruses would probably have been used 19. However, the genetic data irrefutably show that SARS-CoV-2 is not derived from any previously used virus backbone 20. Instead, we propose two scenarios that can plausibly explain the origin of SARS-CoV-2: (i) natural selection in an animal host before zoonotic transfer; and (ii) natural selection in humans following zoonotic transfer. We also discuss whether selection during passage could have given rise to SARS-CoV-2.

1. Natural selection in an animal host before zoonotic transfer

As many early cases of COVID-19 were linked to the Huanan market in Wuhan 1 ,2 , it is possible that an animal source was present at this location. Given the similarity of SARS-CoV-2 to bat SARS-CoV-like coronaviruses 2, it is likely that bats serve as reservoir hosts for its progenitor. Although RaTG13, sampled from a Rhinolophus affinis bat 1, is ~96% identical overall to SARS-CoV-2, its spike diverges in the RBD, which suggests that it may not bind efficiently to human ACE2 7 (Fig. 1a ).

Malayan pangolins (Manis javanica) illegally imported into Guangdong province contain coronaviruses similar to SARS-CoV-2 21. Although the RaTG13 bat virus remains the closest to SARS-CoV-2 across the genome 1, some pangolin coronaviruses exhibit strong similarity to SARS-CoV-2 in the RBD, including all six key RBD residues 21 (Fig. 1). This clearly shows that the SARS-CoV-2 spike protein optimized for binding to human-like ACE2 is the result of natural selection.

Neither the bat betacoronaviruses nor the pangolin betacoronaviruses sampled thus far have polybasic cleavage sites. Although no animal coronavirus has been identified that is sufficiently similar to have served as the direct progenitor of SARS-CoV-2, the diversity of coronaviruses in bats and other species is massively undersampled. Mutations, insertions and deletions can occur near the S1–S2 junction of coronaviruses 22, which shows that the polybasic cleavage site can arise by a natural evolutionary process. For a precursor virus to acquire both the polybasic cleavage site and mutations in the spike protein suitable for binding to human ACE2, an animal host would probably have to have a high population density (to allow natural selection to proceed efficiently) and an ACE2-encoding gene that is similar to the human ortholog.

2. Natural selection in humans following zoonotic transfer

It is possible that a progenitor of SARS-CoV-2 jumped into humans, acquiring the genomic features described above through adaptation during undetected human-to-human transmission. Once acquired, these adaptations would enable the pandemic to take off and produce a sufficiently large cluster of cases to trigger the surveillance system that detected it 1 ,2 .

All SARS-CoV-2 genomes sequenced so far have the genomic features described above and are thus derived from a common ancestor that had them too. The presence in pangolins of an RBD very similar to that of SARS-CoV-2 means that we can infer this was also probably in the virus that jumped to humans. This leaves the insertion of polybasic cleavage site to occur during human-to-human transmission.

Estimates of the timing of the most recent common ancestor of SARS-CoV-2 made with current sequence data point to emergence of the virus in late November 2019 to early December 2019 23, compatible with the earliest retrospectively confirmed cases 24. Hence, this scenario presumes a period of unrecognized transmission in humans between the initial zoonotic event and the acquisition of the polybasic cleavage site. Sufficient opportunity could have arisen if there had been many prior zoonotic events that produced short chains of human-to-human transmission over an extended period. This is essentially the situation for MERS-CoV, for which all human cases are the result of repeated jumps of the virus from dromedary camels, producing single infections or short transmission chains that eventually resolve, with no adaptation to sustained transmission 25.

Studies of banked human samples could provide information on whether such cryptic spread has occurred. Retrospective serological studies could also be informative, and a few such studies have been conducted showing low-level exposures to SARS-CoV-like coronaviruses in certain areas of China 26. Critically, however, these studies could not have distinguished whether exposures were due to prior infections with SARS-CoV, SARS-CoV-2 or other SARS-CoV-like coronaviruses. Further serological studies should be conducted to determine the extent of prior human exposure to SARS-CoV-2.

3. Selection during passage

Basic research involving passage of bat SARS-CoV-like coronaviruses in cell culture and/or animal models has been ongoing for many years in biosafety level 2 laboratories across the world 27, and there are documented instances of laboratory escapes of SARS-CoV 28. We must therefore examine the possibility of an inadvertent laboratory release of SARS-CoV-2.

In theory, it is possible that SARS-CoV-2 acquired RBD mutations (Fig. 1a) during adaptation to passage in cell culture, as has been observed in studies of SARS-CoV 11. The finding of SARS-CoV-like coronaviruses from pangolins with nearly identical RBDs, however, provides a much stronger and more parsimonious explanation of how SARS-CoV-2 acquired these via recombination or mutation 19.

The acquisition of both the polybasic cleavage site and predicted O-linked glycans also argues against culture-based scenarios. New polybasic cleavage sites have been observed only after prolonged passage of low-pathogenicity avian influenza virus in vitro or in vivo 17. Furthermore, a hypothetical generation of SARS-CoV-2 by cell culture or animal passage would have required prior isolation of a progenitor virus with very high genetic similarity, which has not been described. Subsequent generation of a polybasic cleavage site would have then required repeated passage in cell culture or animals with ACE2 receptors similar to those of humans, but such work has also not previously been described. Finally, the generation of the predicted O-linked glycans is also unlikely to have occurred due to cell-culture passage, as such features suggest the involvement of an immune system 18.


In the midst of the global COVID-19 public-health emergency, it is reasonable to wonder why the origins of the pandemic matter. Detailed understanding of how an animal virus jumped species boundaries to infect humans so productively will help in the prevention of future zoonotic events. For example, if SARS-CoV-2 pre-adapted in another animal species, then there is the risk of future re-emergence events. In contrast, if the adaptive process occurred in humans, then even if repeated zoonotic transfers occur, they are unlikely to take off without the same series of mutations. In addition, identifying the closest viral relatives of SARS-CoV-2 circulating in animals will greatly assist studies of viral function. Indeed, the availability of the RaTG13 bat sequence helped reveal key RBD mutations and the polybasic cleavage site.

The genomic features described here may explain in part the infectiousness and transmissibility of SARS-CoV-2 in humans. Although the evidence shows that SARS-CoV-2 is not a purposefully manipulated virus, it is currently impossible to prove or disprove the other theories of its origin described here. However, since we observed all notable SARS-CoV-2 features, including the optimized RBD and polybasic cleavage site, in related coronaviruses in nature, we do not believe that any type of laboratory-based scenario is plausible.

More scientific data could swing the balance of evidence to favor one hypothesis over another. Obtaining related viral sequences from animal sources would be the most definitive way of revealing viral origins. For example, a future observation of an intermediate or fully formed polybasic cleavage site in a SARS-CoV-2-like virus from animals would lend even further support to the natural-selection hypotheses. It would also be helpful to obtain more genetic and functional data about SARS-CoV-2, including animal studies. The identification of a potential intermediate host of SARS-CoV-2, as well as sequencing of the virus from very early cases, would similarly be highly informative. Irrespective of the exact mechanisms by which SARS-CoV-2 originated via natural selection, the ongoing surveillance of pneumonia in humans and other animals is clearly of utmost importance.


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    We thank all those who have contributed sequences to the GISAID database ( and analyses to ( We thank M. Farzan for discussions, and the Wellcome Trust for support. K.G.A. is a Pew Biomedical Scholar and is supported by NIH grant U19AI135995. A.R. is supported by the Wellcome Trust (Collaborators Award 206298/Z/17/Z ARTIC network) and the European Research Council (grant agreement no. 725422 ReservoirDOCS). E.C.H. is supported by an ARC Australian Laureate Fellowship (FL170100022). R.F.G. is supported by NIH grants U19AI135995, U54 HG007480 and U19AI142790.

    Author information


    1. Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA, USA
      • Kristian G. Andersen
    2. Scripps Research Translational Institute, La Jolla, CA, USA
      • Kristian G. Andersen
    3. Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK
      • Andrew Rambaut
    4. Center for Infection and Immunity, Mailman School of Public Health of Columbia University, New York, NY, USA
      • W. Ian Lipkin
    5. Marie Bashir Institute for Infectious Diseases and Biosecurity, School of Life and Environmental Sciences and School of Medical Sciences, The University of Sydney, Sydney, Australia
      • Edward C. Holmes
    6. Tulane University, School of Medicine, Department of Microbiology and Immunology, New Orleans, LA, USA
      • Robert F. Garry
    7. Zalgen Labs, Germantown, MD, USA
      • Robert F. Garry

      Corresponding author

      Correspondence to Kristian G. Andersen.

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      Competing interests

      R.F.G. is co-founder of Zalgen Labs, a biotechnology company that develops countermeasures to emerging viruses.