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.

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 
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, 
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 
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 
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 
have benefits in patients with COVID-19. ... The 
balance of these risks and benefits is currently unknown.


The proximal origin of SARS-CoV-2

G. Andersen,
<>Andrew Rambaut,
    * <>W. Ian Lipkin,
<>Edward C. Holmes &
<>Robert F. Garry
<>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, 
there has been considerable discussion on the 
origin of the causative virus, 
(also referred to as 
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 

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 
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 
and biochemical 
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 
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 
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 
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 
Five of these six residues differ between 
SARS-CoV-2 and SARS-CoV (Fig. 
On the basis of structural 
and biochemical 
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 
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 
The pangolin coronavirus sequences are a 
consensus generated from 
(NCBI BioProject 
<>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 
and that the RBD sequence is different from those 
shown in SARS-CoV to be optimal for receptor 
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 
This allows effective cleavage by furin and other 
proteases and has a role in determining viral 
infectivity and host 
In addition, a leading proline is also inserted 
at this site in SARS-CoV-2; thus, the inserted 
sequence is PRRA (Fig. 
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. 
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 
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 
In addition, efficient cleavage of the MERS-CoV 
spike enables MERS-like coronaviruses from bats 
to infect human 
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) 
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 
The acquisition of polybasic cleavage sites by HA 
has also been observed after repeated passage in 
cell culture or through 

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 
Several viruses utilize mucin-like domains as 
glycan shields involved 
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 
Furthermore, if genetic manipulation had been 
performed, one of the several reverse-genetic 
systems available for betacoronaviruses would 
probably have been 
However, the genetic data irrefutably show that 
SARS-CoV-2 is not derived from any previously 
used virus 
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 
it is possible that an animal source was present 
at this location. Given the similarity of 
SARS-CoV-2 to bat SARS-CoV-like 
it is likely that bats serve as reservoir hosts 
for its progenitor. Although RaTG13, sampled from 
a Rhinolophus affinis 
is ~96% identical overall to SARS-CoV-2, its 
spike diverges in the RBD, which suggests that it 
may not bind efficiently to human 
(Fig. <>1a).

Malayan pangolins (Manis javanica) illegally 
imported into Guangdong province contain 
coronaviruses similar to 
Although the RaTG13 bat virus remains the closest 
to SARS-CoV-2 across the 
some pangolin coronaviruses exhibit strong 
similarity to SARS-CoV-2 in the RBD, including 
all six key RBD 
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 
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 

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 
compatible with the earliest retrospectively 
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 

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 
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 
and there are documented instances of laboratory 
escapes of 
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. 
during adaptation to passage in cell culture, as 
has been observed in studies of 
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 

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 
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 


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


    * Department of Immunology and Microbiology, 
The Scripps Research Institute, La Jolla, CA, USA
        * Kristian G. Andersen
    * Scripps Research Translational Institute, La Jolla, CA, USA
        * Kristian G. Andersen
    * Institute of Evolutionary Biology, 
University of Edinburgh, Edinburgh, UK
        * Andrew Rambaut
    * Center for Infection and Immunity, Mailman 
School of Public Health of Columbia University, New York, NY, USA
        * W. Ian Lipkin
    * 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
    * Tulane University, School of Medicine, 
Department of Microbiology and Immunology, New Orleans, LA, USA
        * Robert F. Garry
    * Zalgen Labs, Germantown, MD, USA
        * Robert F. Garry

Corresponding author

Correspondence to 
G. Andersen.

Ethics declarations

Competing interests

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