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The role of dual-use gain-of-function research in SARS-CoV-2 origin
Domina Petric, MD
Gain-of-function research involves experimentation that aims or is expected to (or actually
does) increase the transmissibility and/or virulence of pathogens. Such research aims to
improve understanding of disease causing agents, their interaction with human hosts, and
their potential to cause pandemic, but can also pose risks regarding biosecurity and
biosafety. Despite claims from prominent scientists that SARS-CoV-2 emerged naturally,
there is still open question about the true origin of the virus because the intermediate host
necessary for completing a natural zoonotic jump is not indubitably identified and the dual-
use gain-of-function research practice that mimics natural zoonotic jump in laboratory can be
considered a viable route by which the novel coronavirus arose. Further independent and
unbiased research is mandatory.
Gain-of-function (GOF) research
involves experimentation that aims or is
expected to (and/or, perhaps, actually does)
increase the transmissibility and/or
virulence of pathogens. Such research,
when conducted by responsible scientists,
usually aims to improve understanding of
disease causing agents, their interaction
with human hosts, and/or their potential to
cause pandemics. The ultimate objective of
such research is to better inform public
health and preparedness efforts and/or
development of medical countermeasures.
Despite these important potential benefits,
GOF research can pose risks regarding
biosecurity and biosafety
1
.
Karl and Dan Sirotkin explained in their
article that despite claims from prominent
scientists that SARS‐CoV‐2 indubitably
emerged naturally, the etiology of this
novel coronavirus remains a pressing and
open question: without knowing the true
nature of a disease, it is impossible for
clinicians to appropriately shape their care,
for policy‐makers to correctly gauge the
nature and extent of the threat, and for the
public to appropriately modify their
behavior. Unless the intermediate host
necessary for completing a natural
zoonotic jump is identified, the dual‐use
gain‐of‐function research practice of
viral serial passage should be considered
a viable route by which the novel
coronavirus arose. The practice of serial
2
passage mimics a natural zoonotic jump,
and offers explanations for SARS‐CoV‐2's
distinctive spike‐protein region and its
unexpectedly high affinity for
angiotensin converting enzyme (ACE2),
as well as the notable polybasic furin
cleavage site within it
2
.
The long‐standing practice of serial
passage is a form of gain‐of‐function
research that forces zoonosis between
species, and requires the same molecular
adaptations necessary for a natural
zoonotic jump to occur within a laboratory,
leaving the same genetic signatures behind
as a natural jump but occurring in a much
shorter period of time.
Researchers further explain:
The genetic signatures in question includes
two distinctive features possessed by
SARS‐CoV‐2's spike‐protein: the unique
sequence in the receptor binding domain
(RBD), a region known to be critical for
SARS‐CoV‐2's utilization of human
angiotensin converting enzyme (ACE2),
which is the cell surface receptor used by
both SARS‐CoV and SARS‐CoV‐2 for
fusion with target cells and subsequent cell
entry. The second feature is the presence of
a polybasic furin cleavage site, which is
also known as a multibasic cleavage site
(MBS)—a four amino acid insertion with
limited sequence flexibility—within the
coronavirus's novel spike‐protein, that is
not found in SARS‐CoV or other lineage B
coronaviruses. This furin cleavage site,
which is poly or multibasic by definition
since its composed of multiple basic amino
acids, is an important virulence feature
observed to have been acquired by fusion
proteins of avian influenza viruses and
Newcastle Disease Virus either grown
under experimental conditions or isolated
from commercial animal farms—settings
that mimic the conditions of serial
laboratory passage (pseudo-natural origin).
Jean-Claude Perez wrote in his article
that the main result of his updated release
is the formal proof that 2019-nCoV
coronavirus is partially a SYNTHETIC
genome. Author proofs the concentration
in a small region of Wuhan New genome
(300bp) of 3 different regions from HIV1
ENVELOPPE gene and 3 others from
HIV2 and SIV (ENV and POL RT)
3
.
Similar opinion has French Nobel Prize-
winning virologist Luc Montagnier who
believes that the COVID-19 was developed
in a laboratory in the Chinese city of
Wuhan and that the presence of elements
of HIV in the genome of the coronavirus is
highly suspect
4
.
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CONCLUSION
Despite that the mainstream opinion in
science today is that SARS-CoV-2 is
indubitably natural virus, the role of dual-
use gain-of-function research in the origin
of this virus cannot be completely
excluded and further independent and
unbiased research is mandatory.
REFERENCES
1. Selgelid MJ. Gain-of-Function Research: Ethical
Analysis. Sci Eng Ethics. 2016;22(4):923-964.
2. Sirotkin K, Sirotkin D. Might SARS-CoV-2
Have Arisen via Serial Passage through an Animal
Host or Cell Culture? BioEssays. 2020. DOI:
10.1002/bies-202000091
3. Perez JC. Wuhan COVID-19 synthetic origins
and evolution. Science. 2020; 8(2): 285-324.
4. Pavlovska E. Nobel winning scientist says
COVID-19 originated in Wuhan lab. April 22,
2020. Retrieved from (August 13, 2020)
https://www.neweurope.eu/article/nobel-winning-
scientist-says-covid-19-originated-in-wuhan-lab/
