Gain of function research

Short description: Field of medical research

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Gain of function research (GoFR) is a field of medical research focused on the serial passaging of microorganisms in vitro and in vivo. This places positive selective pressure on the microorganisms to effect mutations that would increase their pathogenicity, transmissibility, and antigenicity. These studies can also expand the host tropism of a pathogen to new host species or organ tissue. This research is intended to reveal targets to better predict emerging infectious diseases and to develop vaccines and therapeutics.

In virology, gain-of-function research is employed with the intention of better understanding current and future pandemics.[1] In vaccine development, gain-of-function research is conducted in the hope of gaining a head start on a virus and being able to develop a vaccine or therapeutic before it emerges.[1]

## Contents

* 1 History
* 2 Society and culture
* 3 Biorisk concern
* 4 See also
* 5 Weblinks and Reports
* 6 References

## History

In February 2000, a group at the Utrecht University led by Peter Rottier published a paper on their gain-of-function studies titled "Retargeting of Coronavirus by Substitution of the Spike Glycoprotein Ectodomain: Crossing the Host Cell Species Barrier" detailing how they constructed a mutant of the coronavirus mouse hepatitis virus, replacing the ectodomain of the spike glycoprotein (S) with the highly divergent ectodomain of the S protein of feline infectious peritonitis virus. According to the paper, "the resulting chimeric virus, designated fMHV, acquired the ability to infect feline cells and simultaneously lost the ability to infect murine cells in tissue culture".[2]

The World Health Organization in 2010 developed a "guidance document" for Dual Use Research of Concern (DURC) in the life sciences because "research that is intended [to] benefit, but which might easily be misapplied to do harm".[3]

In May 2012, a Japan ese group of scientists operating out of the University of Wisconsin with funding from the Bill & Melinda Gates Foundation, ERATO, National Institute of Allergy and Infectious Diseases and support gifts from the National Institutes of Health and the Vietnamese National Institute of Hygiene and Epidemiology published a paper in the journal Nature about airborne transmission of the H5N1 bird flu introduced via respiratory droplet transmission from one ferret to another. The group "had altered the virus’s amino acid profile, allowing it to reproduce in mammal lungs, which are a bit colder than bird lungs. That small change allowed the virus to be transmitted via coughing and sneezing, and it solved the riddle of how H5N1 could become airborne in humans... (Some) members of Congress, among other critics around the world, responded to the publication of the research with alarm and condemnation." A New York Times editorial described the event as "An Engineered Doomsday."[4][5]

In May 2013, Hualan Chen, who was then director of the China 's National Avian Influenza Reference Laboratory, and colleagues successfully created a new strain of influenza virus through a gain-of-function experiment at the BSL3 approved Harbin Veterinary Research Institute.[6] The Chinese scientists "deliberately mixed the H5N1 bird-flu virus, which is highly lethal [to birds] but not easily transmitted between [humans], with a 2009 strain of H1N1 flu virus, which is very infectious to humans."[7] This event caused consternation in European biotech circles, as Professor Simon Wain-Hobson of the Pasteur Institute the Chinese scientists "haven’t been thinking clearly about what they are doing. It’s very worrying... The virological basis of this work is not strong. It is of no use for vaccine development and the benefit in terms of surveillance for new flu viruses is oversold," while Lord May of Oxford said: "The record of containment in labs like this is not reassuring. They are taking it upon themselves to create human-to-human transmission of very dangerous viruses. It’s appallingly irresponsible."[7]

In May 2014, the Bundestag was presented a report written by the National Ethics Council on proposed guidance for governance of GoFR.[8] At the time, some in Germany were concerned over "GoFR pathogenic pandemic microbes raging out of control".[8] Epidemiologist Marc Lipsitch used "data of past biosafety breaches to calculate that" they occur with a probability "of 0.01 to 0.1 percent per lab per year."[8]

In October 2014, The White House under the Obama administration instituted a moratorium on gain-of-function research into influenza, MERS, and SARS, launched inquiries from the Office of Science and Technology Policy (OSTP); the National Science Advisory Board for Biosecurity (NSABB); and the symposia by National Research Council (NRC),[9] and paused funding for all projects for three years.[10][11][12][13] At least 18 GoFR projects were affected, "including work that had been continued ... in the labs of Fouchier and Kawaoka."[8]

In December 2014, Veronique Kiermer (at the time on the editorial board of Nature) discussed the considerations at her place of employment, that go into the publication of DURC. She came to the conclusion that "the journal's editorial and review boards should not (and could not) be the only gatekeepers who decide which research results should be published, either fully or redacted, 'because it is way too late in the process of GoFR.'"[8]

In December 2014, the National Research Council and the Institute of Medicine organized a two-day symposium to discuss the potential risks and benefits of Gain-of-Function Research. The event was attended by scientists from around the world, including George Gao, Gabriel Leung and Michael Selgelid, Baruch Fischhoff, Alta Charo, Harvey Fineberg, Jonathan Moreno, Ralph Cicerone, Margaret Hamburg, Jo Handelsman, Samuel Stanley, Kenneth Berns, Ralph Baric, Robert Lamb, Silja Vöneky, Keiji Fukuda, David Relman, and Marc Lipsitch.[14] One day later, the US government granted exceptions to the GoFR moratorium to seven out of 18 research projects that had been affected.[8]

In 2016, synthetic virology scientists and bioethics experts again raised concerns with the dual-use of gain-of-function research.[1][13]

By March 2016 the second symposium launched by the Obama administration reported that funding for gain-of-function research was provided by government agencies, pharmaceutical research companies, venture capital funds, colleges and universities, non-profit research institutions, foundations, and charities.[15]

In May 2016,[16] the NSABB published "Recommendations for the Evaluation and Oversight of Proposed Gain-of-Function Research".[17]

On 9 January 2017, the HHS published the "Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight" (P3CO).[16]

On 19 December 2017 under the Trump administration, the NIH lifted the Obama moratorium into GoFR because it was deemed to be "important in helping us identify, understand, and develop strategies and effective countermeasures against rapidly evolving pathogens that pose a threat to public health,"[18] because on the same day the HHS P3CO Framework restored it.[19][18]

## Society and culture

The 2014 Hannover symposium summary mentioned the 1962 play by Friedrich Dürrenmatt, Die Physiker, in which a character named Mobius (who is one of the titular physicists) feigned insanity when he realized that his basic research might have an alternative use, [and therefore] he committed himself to an asylum to protect the world from his knowledge.[8]

During the COVID-19 pandemic a number of theories spread about the origin of the SARS-CoV-2 virus, and were sometimes deployed as a form of political propaganda. Virologist Angela Rasmussen wrote that one version of the information invoked previous gain-of-function work on coronaviruses to promulgate the idea that the virus was of laboratory origin. Rasmussen stated that this was unlikely, due to the intense scrutiny and government oversight to which GoFR is subject, and it is improbable that research on hard-to obtain coronaviruses could occur under the radar.[20]

The Wuhan Institute of Virology has openly participated in gain of function research in partnership with US universities and institutions.[21]

## Biorisk concern

In December 2014, a three-day symposium was organized by the Volkswagen Foundation with the Max Planck Society at Hanover, Germany. Concerns were "raised that the GoFR strains themselves were a threat to public health in two ways: First, because the knowledge of how to tweak an influenza virus into a potential pandemic pathogen (PPP) could be used by bioterrorists or for biological warfare purposes. Second, because the tweaked viruses could escape (or could be stolen) from the laboratory and could cause a pandemic."[8]

Volker Stollorz maintained at the symposium that "the public knows that with the ever-increasing experimental power and the growing diversity of scientific disciplines nobody can claim to grasp precisely what may happen." Said Stollorz: "Researchers who want to perform experiments creating man-made, new, more virulent, and transmissible microbial life forms not existing in nature have to first and foremost acknowledge the existence of the society they experiment in." A reporter at the forum characterized the problem thusly: "Societies need time to understand and digest the new science because the regulation has to adapt constantly to the new realities made possible by scientists."[8]

## See also

* Biotechnology risk
* Dual-use technology
* Directed evolution

## Weblinks and Reports

* European Academies' Science Advisory Council: Gain of function: experimental applications relating to potentially pandemic pathogens (Report)

## References

1. ↑ 1.0 1.1 1.2 Selgelid, Michael J. (2016-07-06). "Gain-of-Function Research: Ethical Analysis". Science and Engineering Ethics 22 (4): 923–964. doi:10.1007/s11948-016-9810-1. PMID 27502512.
2. ↑ Kuo, L.; Godeke, G. J.; Raamsman, M. J.; Masters, P. S.; 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. doi:10.1128/jvi.74.3.1393-1406.2000. PMID 10627550. PMC 111474. https://pubmed.ncbi.nlm.nih.gov/10627550/.
3. ↑ "Dual Use Research of Concern (DURC)". World Health Organization. https://www.who.int/csr/durc/en/.
4. ↑ Imai, Masaki; Watanabe, Tokiko; Hatta, Masato; Das, Subash C.; Ozawa, Makoto; Shinya, Kyoko; Zhong, Gongxun; Hanson, Anthony 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. doi:10.1038/nature10831. PMID 22722205. Bibcode: 2012Natur.486..420I.
5. ↑ Tucker, Patrick (n.d.). "To Protect Ourselves From Bioweapons, We May Have to Reinvent Science Itself". Defense One. https://www.defenseone.com/feature/bioweapons/.
6. ↑ Zhang, Y.; Zhang, Q.; Kong, H.; Jiang, Y.; Gao, Y.; Deng, G.; Shi, J.; Tian, G. et al. (2013). "H5N1 Hybrid Viruses Bearing 2009/H1N1 Virus Genes Transmit in Guinea Pigs by Respiratory Droplet". Science 340 (6139): 1459–1463. doi:10.1126/science.1229455. PMID 23641061. Bibcode: 2013Sci...340.1459Z.
7. ↑ 7.0 7.1 Connor, Steve (2 May 2013). "'Appalling irresponsibility': Senior scientists attack Chinese researchers for creating new strains of influenza virus in veterinary laboratory". The Independent. https://www.independent.co.uk/news/science/appalling-irresponsibility-senior-scientists-attack-chinese-researchers-creating-new-strains-influenza-virus-veterinary-laboratory-8601658.html.
8. ↑ 8.0 8.1 8.2 8.3 8.4 8.5 8.6 8.7 8.8 "SUMMARY REPORT DUAL USE RESEARCH ON MICROBES: Biosafety, Biosecurity, Responsibility". Volkswagen Foundation. 12 December 2014. https://www.volkswagenstiftung.de/sites/default/files/downloads/Summary_Report_HS_Dual_Use_Research_on_Microbes.pdf.
9. ↑ Akst, Jef (21 October 2014). "Moratorium on Gain-of-Function Research". The Scientist. https://www.the-scientist.com/the-nutshell/moratorium-on-gain-of-function-research-36564.
10. ↑ "U.S. Government Gain-of-Function Deliberative Process and Research Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS, and SARS Viruses". Office of the Assistant Secretary for Preparedness and Response. U.S. Department of Health & Human Services. 17 October 2014. http://www.phe.gov/s3/dualuse/Documents/gain-of-function.pdf.
11. ↑ McNeil, Donald G. Jr. (17 October 2014). "White House to Cut Funding for Risky Biological Study". The New York Times Company. https://www.nytimes.com/2014/10/18/us/white-house-to-cut-funding-for-risky-biological-study.html.
12. ↑ Kaiser, Jocelyn; Malakoff, David (17 October 2014). "U.S. halts funding for new risky virus studies, calls for voluntary moratorium". Science. http://www.sciencemag.org/news/2014/10/us-halts-funding-new-risky-virus-studies-calls-voluntary-moratorium.
13. ↑ 13.0 13.1 Imperiale, Michael J.; Casadevall, Arturo (2016). "Zika Virus Focuses the Gain-of-Function Debate". mSphere 1 (2). doi:10.1128/mSphere.00069-16. PMID 27303723.
14. ↑ https://www.nationalacademies.org/our-work/gain-of-function-research-a-symposium
15. ↑ Board On Life, Sciences; Division on Earth Life Studies; Board on Health Sciences Policy; Health Medicine, Division; Committee On Science, Technology; Policy Global, Affairs; National Academies Of Sciences, Engineering (March 2016). Millett, Piers; Husbands, Jo; Sharples, Frances et al.. eds. Gain-of-Function Research: Summary of the Second Symposium. doi:10.17226/23484. ISBN 9780309440776. https://easac.eu/fileadmin/PDF_s/reports_statements/GOF_symposium_summary_March_2016.pdf. Retrieved January 29, 2021.
16. ↑ 16.0 16.1 "Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO)". Office of the Assistant Secretary for Preparedness and Response. Department of Health and Human Services. 9 January 2017. https://www.phe.gov/s3/dualuse/Documents/P3CO-FinalGuidanceStatement.pdf.
17. ↑ "RECOMMENDATIONS FOR THE EVALUATION AND OVERSIGHT OF PROPOSED GAIN-OF-FUNCTION RESEARCH". National Science Advisory Board for Biosecurity. United States Department of Health and Human Services. May 2016. https://osp.od.nih.gov/sites/default/files/resources/NSABB_Final_Report_Recommendations_Evaluation_Oversight_Proposed_Gain_of_Function_Research.pdf.
18. ↑ 18.0 18.1 Collins, Francis S. (19 December 2017). "NIH Lifts Funding Pause on Gain-of-Function Research". Director, National Institutes of Health. https://www.nih.gov/about-nih/who-we-are/nih-director/statements/nih-lifts-funding-pause-gain-function-research.
19. ↑ "Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens". Office of the Assistant Secretary for Preparedness and Response. Department of Health and Human Services. 19 December 2017. https://www.phe.gov/s3/dualuse/Documents/p3co.pdf.
20. ↑ "On the origins of SARS-CoV-2". Nature Medicine 27 (9): 9. 2021. doi:10.1038/s41591-020-01205-5. PMID 33442004.
21. ↑ Rogin, Josh (8 March 2021). "Chaos under heaven: Wuhan lab book excerpt". Politico. https://www.politico.com/news/magazine/2021/03/08/josh-rogin-chaos-under-heaven-wuhan-lab-book-excerpt-474322.

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