An appeal for an open scientific debate about the proximal origin of SARS-CoV-2
Jacques van Helden1,2,*, Colin D Butler3, Bruno Canard4, Guillaume Achaz5,6, François Graner7,
Rossana Segreto8, Yuri Deigin9, Fabien Colombo10, Serge Morand11, Didier Casane12,13, Dan
Sirotkin14, Karl Sirotkin14, Etienne Decroly,4,* José Halloy15,*
1. CNRS, Institut Français de Bioinformatique, IFB-core, UMS 3601, Evry, France
2. Aix-Marseille Univ, Inserm, laboratoire Theory and approaches of genome complexity (TAGC),
Marseille, France; ORCID: 0000-0002-8799-8584
3. National Centre for Epidemiology and Population Health, Australian National University, Canberra,
4. Aix-Marseille Univ, CNRS, UMR 7257, AFMB, Case 925, 163 Avenue de Luminy, 13288 Marseille Cedex
09, France. ORCID: 0000-0002-6046-024X
5. Eco-Anthropologie (UMR7206 Université de Paris-CNRS-MNHN), Muséum National d’Histoire
Naturelle, Paris, France
6. Center for Interdisciplinary Research in Biology (UMR7142 Collège de France-CNRS-INSERM), Collège
de France, Paris, France
7. MSC, Université de Paris, CNRS UMR 7057, 10 rue Alice Domon et Léonie Duquet, 75205 Paris Cedex
8. Department of Microbiology, University of Innsbruck, Austria
9. Youthereum Genetics Inc., Toronto, Canada.
10. Université Bordeaux Montaigne, Mediation, Information, Communication, Art (MICA, EA 4426), 10
esplanade des Antilles, Pessac, France.
11. Montpellier Université, CNRS, Institut des Sciences de l'Évolution (ISEM), 34290 Montpellier, France,
12. Université Paris-Saclay, CNRS, IRD, UMR Évolution, Génomes, Comportement et Écologie, 91198,
13. Université de Paris, UFR Sciences du Vivant, F-75013 Paris, France
14. Karl Sirotkin LLC. ORCID: 0000-0002-9685-0338
15. Université de Paris, LIED, CNRS UMR 8236, 85 bd Saint-Germain, 75006 Paris, France.
* Corresponding authors
One year after the onset of the COVID-19 pandemic, the origin of SARS-CoV-2 still eludes humanity.
Early publications firmly stated that the virus was of natural origin, and the possibility that the virus
might have escaped from a lab was discarded in most subsequent publications. However, based on a
re-analysis of the initial arguments, highlighted by the current knowledge about the virus, we show
that the natural origin is not supported by conclusive arguments, and that a lab origin cannot be
formally discarded. We call for an opening of peer-reviewed journals to a rational, evidence-based
and prejudice-free evaluation of all the reasonable hypotheses about the virus’ origin. We advocate
that this debate should take place in the columns of renowned scientific journals, rather than being
left to social media and newspapers.
On February 19, 2020, three weeks after the publication of the SARS-CoV-2 genome,1
twenty-seven scientists signed a Statement in support of the scientists, public health professionals
and medical professionals of China combatting COVID-19
in The Lancet.
2They took an authoritative
position about the origin of the novel coronavirus behind the pandemic: “Scientists from multiple
countries have published and analysed genomes of the causative agent, SARS-CoV-2, and they
overwhelmingly conclude that this coronavirus originated in wildlife”
. This statement has since
attracted 23,000 additional signatures, and was used throughout the international press as proof
that SARS-CoV-2 emerged due to a natural zoonosis.
We share our colleagues’ annoyance about various unfounded theories spreading over social
networks which seemed to be aimed at increasing geopolitical tensions. However, on the basis of
the current scientific literature, complemented by our own analysis of coronavirus genomes and
proteins,3–5 we hold that there is currently no compelling evidence to definitively arbitrate between
a completely “natural” origin (i.e. a virus that has evolved and been transmitted to humans solely via
contact with wild or farmed animals) and a “laboratory” origin (which might involve one or more
steps such as transport of animal samples to Wuhan, viral evolution, an index case occurring through
viral exposure in a laboratory, accidental laboratory escape, faulty autoclaving equipment, or any
other possible escape pathway ...).
Of the nine references cited in the statement to support the natural origin hypothesis, eight
consist of trees showing phylogenetic relationships between SARS-CoV-2 and other coronaviruses. A
distinction has to be made between the general ancestry and the proximal
origin of the virus, i.e. the
last step of its transmission chain from its original animal reservoir (putatively bats) to humans. To
the best of our knowledge, the fact that the causative agent of COVID-19 descends from natural
viruses has not been questioned by anyone, but this distal origin does not explain how it came to be
able to infect humans. This step is still unknown, since the closest animal virus at our disposal
(RaTG13) shows a 4% difference with SARS-CoV-2, genetic distance which has been estimated to
reflect 4 to 7 decades of evolutionary divergence6. Pangolins are no longer considered a plausible
intermediate host based on the molecular evidence.7–10 We thus still need to trace the animal
intermediates between the bat reservoir, locate the places of transmissions, characterize the viral
strains, trace back the outbreak from the first COVID-19 patients, and then finally understand the
ultimate conditions of the transfer from animals to humans.
The proximal origin was explicitly addressed in one reference in the Lancet statement: a preprint
by Andersen et al.
, later published in Nature Medicine in April 202011. This article was highly
influential: within 9 months it was cited in 2,000 scientific publications, and the vast majority of
scientists, including many of us, initially took it for granted that this novel coronavirus was of natural
origin. However, upon re-analysis, we realised that a conclusive proof of the proximal origin is still
lacking. The initial method of reasoning, endorsed in many subsequent papers, was to contrast two
opposing possibilities: natural origin versus “laboratory construct or purposefully manufactured
virus”. Two main arguments were presented against the latter possibility: (i) the specific mutations
that confer their particular affinity to the SARS-CoV-2 spike protein were unknown before COVID-19
emergence, and thus could not have been designed ; (ii) the SARS-CoV-2 genome has no evidence
for reverse engineering (e.g. a previously used viral backbone). The lab construct hypothesis was
thus rejected, leaving a natural proximal origin as the only possibility. However, this reasoning
suffers from a logical fallacy. Proving a hypothesis by discarding its alternative is only valid if the two
hypotheses are mutually exclusive, and cover all conceivable possibilities. In this case, these
conditions are not met, since other mechanisms are plausible, for example serial passage
experiments, 12 which consist of testing and measuring the ability of a virus to infect different animal
models or cultured cells. Such experiments exert an artificial selection of the random mutations that
increase the fitness of the virus to the new host, thereby resulting in a fast evolution of genomic
sequences. As in many virology labs, passage experiments are routinely performed in the Wuhan
Institute of Virology (WIV)13–15, consistently with their mission to collect and monitor viral strains
having epidemic potential into humans. Selection during passage is dismissed by Andersen, based on
the argument that it would be less parsimonious than the pangolin origin. However, the pangolin
hypothesis has since been abandoned. 7–10 Regarding the hypothesis of a laboratory construct,
absence of evidence is not evidence of absence, and a viral genome might be engineered with a yet
unpublished backbone. Also, the expectation of finding traces of engineering in the sequences does
not account for the seamless technologies currently used to synthesise nucleic acids, which have
been around for about 20 years16.
Experiments involving pathogenic viruses require highly secure laboratory conditions.17,18 There
are, however, many well-documented cases of pathogen escapes from laboratories, including
viruses.12,19–22 This scenario was a priori discarded in the February statement: “We stand together to
strongly condemn conspiracy theories suggesting that COVID-19 does not have a natural origin
We, like The Lancet authors, condemn conspiracy theories. However, an accident is not a conspiracy,
and we think that scenarios involving a potential lab accident should be evaluated rigorously, along
with the other hypotheses. Even more, it is precisely because actual conspiracy theories are so
rapidly spreading on social media and via some politicians that we ought, as a scientific community,
to evaluate all hypotheses on a rational basis. We need to weigh their likelihood, based on facts and
evidence, devoid of speculation concerning alleged political intent. This approach seems consistent
with the views presented near the conclusion of the Lancet statement “to promote scientific
evidence and unity over misinformation and conjecture
”, but a little word makes a whole difference:
a scientific question has never been solved, and should never be approached, by asking scientists to
promote unity. Science, by definition, explores and embraces alternative hypotheses, contradictory
arguments, verification, refutability, and even controversy. Departing from this principle risks
establishing dogmas, and abandoning science.
Unfortunately, the unitary view promoted in the Lancet statement has, to date, been widely
adopted, with few exceptions.3,4,12,23–25 Scientific evaluations of alternative hypotheses for the origin
of COVID-19 are, as yet, absent from the most prominent scientific journals. This lacuna may even
fuel conspiracy theories. Instead, the scientific community should bring this debate to the place it
belongs: the columns of renowned scientific journals26. An evidence-based, independent and
prejudice-free evaluation of all the reasonable origin scenarios will require collecting samples and
data in all the potentially relevant places, including wildlife sites and farms (as scheduled for the
WHO mission) but also in hospitals and in laboratories. This effort is crucial, not only to solve many
currently unanswered questions and elucidate the cause of the current pandemic, but also to take
appropriate measures of prevention.
1 Zhou P, Yang X-L, Wang X-G, et al.
A pneumonia outbreak associated with a new coronavirus of
probable bat origin. Nature
2020; 579: 270–3.
2 Calisher C, Carroll D, Colwell R, et al.
Statement in support of the scientists, public health
professionals, and medical professionals of China combatting COVID-19. The Lancet
3 Segreto R, Deigin Y. The genetic structure of SARS-CoV-2 does not rule out a laboratory origin:
SARS-COV-2 chimeric structure and furin cleavage site might be the result of genetic manipulation.
2020; : 2000240.
4 Sallard E, Halloy J, Casane D, Decroly É, van Helden J. Tracing the origins of SARS-COV-2 in
coronavirus phylogenies. Environmental Chemistry Letters
2021; in press.
5 Sallard E, Halloy J, Casane D, Decroly E, van Helden J. Tracing the origins of SARS-CoV-2 in
coronavirus phylogenies. Med Sci (Paris)
2020; 36: 783–96.
6 Sironi M, Hasnain SE, Rosenthal B, et al.
SARS-CoV-2 and COVID-19: A genetic, epidemiological, and
evolutionary perspective. Infection, Genetics and Evolution
2020; 84: 104384.
7 Lee J, Hughes T, Lee M-H, et al.
No Evidence of Coronaviruses or Other Potentially Zoonotic Viruses
in Sunda pangolins (Manis javanica) Entering the Wildlife Trade via Malaysia. EcoHealth
published online Nov 23. DOI:10.1007/s10393-020-01503-x.
8 Choo SW, Zhou J, Tian X, et al.
Are pangolins scapegoats of the COVID-19 outbreak-CoV
transmission and pathology evidence? CONSERVATION LETTERS
2020; 13. DOI:10.1111/conl.12754.
9 Frutos R, Serra-Cobo J, Chen T, Devaux CA. COVID-19: Time to exonerate the pangolin from the
transmission of SARS-CoV-2 to humans. Infection, Genetics and Evolution
2020; 84: 104493.
10 WHO-convened Global Study of the Origins of SARS-CoV-2.
2 (accessed Dec 20, 2020).
11 Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of
SARS-CoV-2. Nature Medicine
2020; 26: 450–2.
12 Sirotkin K, Sirotkin D. Might SARS-CoV-2 Have Arisen via Serial Passage through an Animal
Host or Cell Culture?: A potential explanation for much of the novel coronavirus’ distinctive
2020; : 2000091.
13 Hu B, Zeng L-P, Yang X-L, et al.
Discovery of a rich gene pool of bat SARS-related
coronaviruses provides new insights into the origin of SARS coronavirus. PLoS Pathog
14 Ge X-Y, Li J-L, Yang X-L, et al.
Isolation and characterization of a bat SARS-like coronavirus
that uses the ACE2 receptor. Nature
2013; 503: 535–8.
15 Yang X-L, Hu B, Wang B, et al.
Isolation and Characterization of a Novel Bat Coronavirus
Closely Related to the Direct Progenitor of Severe Acute Respiratory Syndrome Coronavirus.
Journal of Virology
2016; 90: 3253–6.
16 Yount B, Denison MR, Weiss SR, Baric RS. Systematic assembly of a full-length infectious
cDNA of mouse hepatitis virus strain A59. J Virol
2002; 76: 11065–78.
17 Moritz RL, Berger KM, Owen BR, Gillum DR. Promoting biosecurity by professionalizing
2020; 367: 856–8.
18 Xia H, Huang Y, Ma H, et al.
Biosafety Level 4 Laboratory User Training Program, China.
Emerg Infect Dis
2019; 25. DOI:10.3201/eid2505.180220.
19 Sewell DL. Laboratory-associated infections and biosafety. Clinical Microbiology Reviews
1995; 8: 389–405.
20 Heymann DL, Aylward RB, Wolff C. Dangerous pathogens in the laboratory: from smallpox to
today’s SARS setbacks and tomorrow’s polio-free world. The Lancet
2004; 363: 1566–8.
21 Siengsanan-Lamont J, Blacksell SD. A Review of Laboratory-Acquired Infections in the
Asia-Pacific: Understanding Risk and the Need for Improved Biosafety for Veterinary and Zoonotic
Diseases. Tropical Medicine and Infectious Disease
2018; 3: 36.
22 Klotz LC, Sylvester EJ. The Consequences of a Lab Escape of a Potential Pandemic Pathogen.
Front Public Health
2014; 2. DOI:10.3389/fpubh.2014.00116.
23 Rahalkar MC, Bahulikar RA. Lethal Pneumonia Cases in Mojiang Miners (2012) and the
Mineshaft Could Provide Important Clues to the Origin of SARS-CoV-2. Front Public Health
24 Seyran M, Pizzol D, Adadi P, et al.
Questions concerning the proximal origin of SARS-CoV-2. J
2020; : jmv.26478.
25 Butler CD. Plagues, Pandemics, Health Security, and the War on Nature. Journal of Human
2020; 16: 53–7.
26 Relman DA. Opinion: To stop the next pandemic, we need to unravel the origins of
COVID-19. Proc Natl Acad Sci USA
2020; 117: 29246–8.