COVID-19: Theories on the proximal origin of SARS-CoV-2.

COVID-19: Theories on the proximal origin of SARS-CoV-2. Jefferson T, Heneghan C.

Published on July 13, 2020

Reference Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nature Medicine. 2020;26(4):450-2. 2020
Study type
Country N/A
Setting Laboratory based investigation
Funding Details Wellcome Trust, NIH, European Research Council, Australian Laureate Fellowship
Transmission mode Mixed
Exposures Genome analysis

Bottom Line

Three possible origin theories are proposed and discussed. Not enough data are available to accept or reject any of the hypotheses.

Evidence Summary

The receptor-binding domains (RBD) of the protein spike on the viral envelope has a high affinity for the ACE2 receptors of humans and several animal species. Five of the six RBD of SARS CoV-2 are similar to those of SARS CoV-1. 

However despite high affinity of the spike RBDs for the ACE2 receptors the fit is not perfect indicating that is most likely the result of natural selection on a human or human-like ACE2 that permits another optimal binding solution to arise. The authors point to this as strong evidence that SARS-CoV-2 is not the product of man-made manipulation.

Another unique feature of CoV-2 is a cleavage site in the spike which could determine infectivity and virulence as happens in other respiratory viruses such as influenza. The authors propose three theories to explain the origins of the virus: 

1.Natural selection in an animal host before zoonotic transfer. 

However, no CoV so far found in animals is sufficiently similar to SARS CoV 2.

2. Natural selection in humans following zoonotic transfer. 

This presumes a period of unrecognised human to human transmission to allow the cleavage site to develop, from a common viral progenitor which jumped species and then adapted. 

3.Selection during passage in cells. 

Cleavage sites are acquired only after repeated passage in cell culture, this could also happen from cultures SARS Co-V 1. No lab escape episodes are known and the authors consider the genetic engineering hypothesis implausible.

None of these three hypotheses can be rejected or sustained on the basis of our current knowledge and further studies, especially of possible intermediate animal hosts, are required 

What did they do?

The study is a letter to the editor reporting the authors’ comparative analysis of the genome and the hypothesised origins of the virus. SARS-CoV-2 is the seventh coronavirus known to infect humans. SARS-CoV, MERSCoV and now SARS-CoV-2 may cause severe disease, the other four CoV are associated with the common cold and cause less severe symptoms (HKU1, NL63, OC43 and 229E). 

Study reliability

The study presents evidence and puts forward well-argued hypotheses requiring confirmation.

Clearly defined setting Demographic characteristics described Follow-up length was sufficient Transmission outcomes assessed Main biases are taken into consideration
N/A N/A N/A Yes N/A

What else should I consider?

The results of the study require updating and confirmation.

About the authors

Carl Heneghan

Carl is Professor of EBM & Director of CEBM at the University of Oxford. He is also a GP and tweets @carlheneghan. He has an active interest in discovering the truth behind health research findings

Tom Jefferson

Tom Jefferson, epidemiologist.