









































                                                                                                                         2021, Vol. 1 (S4) 4-5 
 https://doi.org/dhrp.v1iS4.14 

  
 

http://dhrproceedings.org 4 © DHR Health Institute for Research and Development 
 

 

COMMENTARY 

Engineering of Viruses and Pathogens 
for Gain-of-Function Research  
Sohail Rao, MD, MA, DPhil1, 2 and Manish Singh, MD, FACS3 

 1 Executive Vice President, DHR Health, 5501 S. McColl Road, Edinburg, Texas 78539 and President 
& Chief Executive Officer, DHR Health Institute for Research & Development, 5323 S. McColl Road, 
Edinburg, Texas 78539.  
ORCID: https://orcid.org/0000-0001-5027-9992  
2 Correspondence should be addressed to: Sohail Rao, MD, MA, DPhil., DHR Health Institute for 
Research & Development, 5323 S. McColl Road, Edinburg, Texas 78539. Tel: (956) 362-2387. E-mail: 
s.rao@dhr-rgv.com  
3 Chief Executive Officer, DHR Health, 5501 S. McColl Road, Edinburg Tx 78539 
ORCID: Manish Singh: https://orcid.org/0000-0003-4146-3282  
 
Received 05/18/2021 
Accepted for publication 06/08/2021 
Published 06/08/2021 

Keywords:  Ethics, Laboratory, Pathogens, Influenza, NIAID, Gain of Function

Ethical concerns related to engineering of viruses and 
pathogens for gain-of-function (GoF) research has been 
widely debated in the literature (1). Scientists are conflicted as 
to the value of GoF research which has been used in the past 
to enhance viral pathogenicity, transmissibility, antigenicity, 
and tropism (2-4). The primary objective of these experiments 
was to gain a better understanding of the pathogen, allowing 
investigators to develop a more reliable predictive models for 
emerging infectious diseases and to combat them with 
effective vaccines and other therapeutic agents. This issue was 
recently highlighted during a U.S. congressional hearing 
aimed at elucidating the origin of the SARS-CoV-2 pandemic 
that has infected over 173 million worldwide and has resulted 
in the death of over 3.7 million people (5, 6). In US alone, 
SARS-CoV-2 has infected over 33 million and caused the 
death of over 594,000 people (7). 

Perhaps the most controversial research related to GoF was the 
modification of H5NI avian flu virus (8). In these experiments, 
the investigators used reverse genetics that enhanced the 
lethality of the virus, confirming that H5N1 can jump from 
birds to mammals and could be efficiently transmitted 
between humans. These studies that were funded by the 
National Institute of Allergy and Infectious Disease (NIAID) 
raised numerous ethical and public health concerns (9). It was 
argued that the risk posed by the inadvertent escape of 
laboratory engineered H5N1 into the community far 
outweighs the benefit that would be gained from these highly 
perilous experiments. The controversy escalated when the 

National Science Advisory Board for Biosecurity (NSABB) 
issued its recommendation that the controversial H5N1 reports 
be published with significant redactions (10). NSABB 
recommended that methodology and other details that could 
enable replication of the experiments by those who seek to do 
harm are to be redacted. This controversial research and the 
NSABB recommendation divided the scientific community, 
which recognized that the easily transmitted laboratory 
engineered GoF H5N1 could be extraordinarily lethal. 

In 2014, a series of mishaps in which highly pathogenic 
microbes were mishandled by various laboratories in the U.S. 
Centers for Disease Control and Prevention (CDC) resulted in 
closure of two labs and halted some biological shipments (11). 
The cases included an accidental shipment of live anthrax; the 
discovery of forgotten, live smallpox samples; and a newly 
revealed incident in which a dangerous influenza strain was 
accidentally shipped from CDC to another laboratory. These 
and other similar mishaps involving GoF experiments 
resulted, in the issuance of a moratorium by the U.S. 
Government pausing deliberative process and research 
funding for selected GoF research involving Influenza, 
MERS, and SARS viruses in 2014 (12). 

Subsequent to implementation of this “pause,” both the 
National Research Council and the Institute of Medicine 
organized a number of symposiums to discuss the potential 
risks and benefits of GoF research. These deliberations 
ultimately resulted in the publication by NSABB 

https://orcid.org/0000-0001-5027-9992
mailto:s.rao@dhr-rgv.com
https://orcid.org/0000-0003-4146-3282


DHRP, 2021, Vol. 1 (S4) 4-5  Viral Gain-of-Function 

  
 

http://dhrproceedings.org 5 © DHR Health Institute for Research and Development 
    
 

"Recommendations for the Evaluation and Oversight of 
Proposed Gain-of-Function Research" (13). This was 
followed by the publication by the US Department of Health 
& Human Services "Recommended Policy Guidance for 
Departmental Development of Review Mechanisms for 
Potential Pandemic Pathogen Care and Oversight" (P3CO) 
(14). With these P3CO recommendations in place, in 2017, the 
NIH lifted the moratorium into GoF research because it was 
deemed to be important in helping identify, understand, and 
develop strategies and effective countermeasures against 
rapidly evolving pathogens that pose a threat to public health 
(15). 

With the lifting of this moratorium, NIAID through an 
intermediate organization, funded GoF research to be 
conducted on bat coronavirus in collaboration with the 
Institute of Virology, Wuhan, China (16). The primary 
objective of this funding was to conduct GoF research for the 
purpose of understanding how bat coronaviruses could mutate 
to attack humans. It is unclear what and/or how this GoF 
research on bat coronavirus may have contributed to the 
current COVID-19 pandemic that has devastated the social 
and economic fabric globally.  

Despite the importance of GoF research and the fact that this 
recent funding has now been suspended by the NIAID, one 
must recognize that accidental escape of engineered pathogens 
and viruses do pose a catastrophic existential risk for the 
global human community and every effort must be exercised 
to prevent (not minimize) this risk.  

Diclosures 

SR declares no conflicts of interest.  

MS declares no conflicts of interest. 

References 

1. Selgelid, M.J. Gain-of-Function Research: Ethical 
Analysis. Sci. Eng. Ethics (2016) 22:923-964. 

2. Kuo, L., Godeke, G. J., Raamsman, M. J., Masters, P. S., 
and Rottier, P. J. (2000). "Retargeting of coronavirus by 
substitution of the spike glycoprotein ectodomain: 
Crossing the host cell species barrier". Journal of 
Virology. 74 (3): 1393-406.  

3. Imai, M., Watanabe, T., Hatta, M., et al. (2012). 
"Experimental adaptation of an influenza H5 HA confers 
respiratory droplet transmission to a reassortant H5 
HA/H1N1 virus in ferrets". Nature. 486(7403): 420–428.  

4. Zhang, Y., Zhang, Q., Kong, H., et al. (2013). "H5N1 
Hybrid Viruses Bearing 2009/H1N1 Virus Genes 
Transmit in Guinea Pigs by Respiratory Droplet". 
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5. World Health Organization Coronavirus (COVID-19) 
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6. Watkins, M. Rand Paul and Anthony Fauci Argue Over 
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fauci-argue-190133625.html   

7. U.S Center for Disease Control and Prevention COVID-
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8. Martin Enserink. Controversial Studies Give a Deadly Flu 
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9. Pavia, A.T. Laboratory Creation of a Highly 
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10. News Media Branch.  Press Statement on the NSABB 
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11. Kaiser, J. Lab Incidents Lead to Safety Crackdown at 
CDC. Science: News. 2014 July 13. 
https://www.sciencemag.org/news/2014/07/lab-
incidents-lead-safety-crackdown-cdc 

12. U.S. Government Gain-of-Function Deliberative Process 
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13. Recommendations for the Evaluation and Oversight of 
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15. Collins, F.S. NIH Lifts Funding Pause on Gain-of-
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