Gain of function research

Gain of function research (GoFR) is a field of medical research focused on the serial passaging of bacteria or viruses in vitro, accelerating mutation processes to adapt their transmissibility, virulence and antigenicity, to better predict emerging infectious diseases and develop vaccines.

Types of research

Virology

Gain-of-function research is employed to better understand current and future pandemics.[1]

Vaccine development

Gain-of-function research is conducted in order to gain a head start on a virus and to develop a vaccine or therapeutic before it emerges.[1]

History
See also: Biotechnology risk and Soviet biological weapons program

Raymond Zilinskas reports that "the GoFR-like experiments in the former Soviet Union from 1972 to 1992. In several labs like "Vektor" in Novosibirsk, up to 60,000 people were involved in research programs like "Ferment" (on Ebola) or "Faktor" (on Marburg) and bacteria like Anthrax and the Plague. The goal was to add new features to the microbes, making them more pathogenic and transmissible. The Chimera project, for example, introduced Ebola virus genes into the Vaccinia genome... the Russian President Boris Yeltsin declared that the Soviet Union violated the Biological and Toxin Weapons Treaty."[2]

The 1925 Protocol for the Prohibition of the Use in War of Asphyxiating, Poisonous or other Gases, and of Bacteriological Methods of Warfare (aka the Geneva Protocol) was imprecise on virii. In addition, it was unclear when the Biological Weapons Convention (BWC) was ratified in 1975 that virii were regulated by it, because viruses lie "at the edge of life", ie, they possess some but not all of the characteristics of life. Synthetic biology was a figment of imagination at the time. This backdoor allowed curious scientists with pliable ethics committees to study gain-of-function.[3] Prior to the 1972 formation of the BWC, over four years from 1965, the Johnston Atoll under the dominion of the US was subject to large-scale bioweapons testing. The American strategic tests of bioweapons were as expensive and elaborate as the tests of the first hydrogen bombs at Eniwetok Atoll. They involved enough ships to have made the world's fifth-largest independent navy. One experiment involved a number of barges loaded with hundreds of rhesus monkeys; the experiment was a success and over half the monkeys died. It is estimated that one jet with bioweapon spray "would probably be more efficient at causing human deaths than a ten-megaton hydrogen bomb." The American biowarfare system was terminated in 1969 by President Nixon.[4]

The 1992 defection of Kanatjan Alibekov, who was then deputy director of Biopreparat in the Russian Ministry of Health, revealed that with Mikhail Gorbachev's signature weaponization-based GoFR was being pursued at two locations in Russia: at NPO Biosintez in Obolensk the combination of DNA from Venezuelan equine encephalitis and smallpox, and at the Vector Institute the combination of Ebola virus and smallpox.[5][6]

The British government made significant progress to design of compliance measures for the bioweapons verification protocol that was being negotiated between 1995 and 2001 but this initiative came to an end in July 2001 because of American refusal to sign on to the draft verification protocol for the BWC conditioned by Pfizer and PhRMA and with the untimely 2002 death of David C. Kelly and 2003 invasion of Iraq.[7]

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".[8]

In May 2012, a Japanese 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."[9][10]

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.[11] 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."[12] 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."[12]

In May 2014, the Bundestag was presented a report written by the National Ethics Council on proposed guidance for governance of GoFR.[2] At the time, some in Germany were concerned over "GoFR pathogenic pandemic microbes raging out of control".[2] Biologist 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."[2]

In June 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),[13] and paused funding for all projects for three years.[14][15][16][17] At least 18 GoFR projects were affected, "including work that had been continued... in the labs of Fouchier and Kawaoka."[2]

In December 2014, the National Research Council and the Institute of Medicine organised 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, Alta Charo and Marc Lipsitch.[18] One day later, the US government granted exceptions to the GoFR moratorium to seven out of 18 research projects that had been affected.[2]

In 2016, synthetic virology scientists and bioethics experts again raised concerns with the dual-use of gain-of-function research.[1][17]

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, nonprofit research institutions, foundations, and charities.[19]

In May 2016,[20] the NSABB published "RECOMMENDATIONS FOR THE EVALUATION AND OVERSIGHT OF PROPOSED GAIN-OF-FUNCTION RESEARCH".[21]

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).[20]

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,"[22] because on the same day the HHS P3CO Framework restored it.[23][22]

Controversy
See also: The Cambridge Working Group

In December 2014, a three-day symposium was organized by the Volkswagen Foundation in conjunction 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 potentially 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."[2]

In December 2014 Veronique Kiermer, at the time on the editorial board of Nature, discussed "the considerations at the journal Nature, that go into the publication of DURC. She came to the conclusion that 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." Redaction is not the solution, she said, because redacting key data or methods disables subsequent research and peer review. Also, distributing the redacted information to a selected group of people on a need-to-know basis is practically unfeasible. It is also not clear who should be responsible for holding and securing these data, which criteria should be used to determine who is allowed to see the redacted information, and who should make these decisions. She called intead for international standards of biosafety and oversight as well as incentives for a robust laboratory culture of safety and transparency."[2]

Volker Stollorz maintains 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. "Researchers who want to perform experiments creating manmade, 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." 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.[2]

Since the Dutch and Japanese studies, an increasing number of scientists and bioethics experts have voiced concerns with the increased risk of gain of function research in the case accidental laboratory-acquired infection and the potentially vast consequences to public health.[24]

In about 2015, a writer on GoFR observed that "there is little international enforcement of limitations on bioweapons. For chemical materials like sarin gas, the Chemical Weapons Convention provides a treaty-based legal framework for stopping proliferation, and a watchdog group, the Organisation for the Prohibition of Chemical Weapons, [investigates] potential violations." While the Biological Weapons Convention exists, "No similar watchdog exists around biological weapons."[10]

Society and culture

The 2014 Hannover symposium summary has as leitmotif the 1962 play by Friedrich Dürrenmatt, Die Physiker, in which a character named Mobius (who is one of the titular physicists) feigns insanity when he realizes "that his basic research might have an alternative use, [and therefore] he committed himself to an asylum in order to protect the world from his knowledge."[2]

During the 2020 COVID-19 pandemic a number of conspiracy theories spread about the origin of the SARS-CoV-2 virus, sometimes deployed as a form of political propaganda. One popular version of the story invoked previous gain-of-function work on coronaviruses to promulgate the idea that the virus was of laboratory origin. Virologist Angela Rasmussen writes that this is ironic, since in reality such research had enabled scientists to gain a better understanding of the novel virus.[25]

See also

References
  1. 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. PMC 4996883. PMID 27502512.
  2. "SUMMARY REPORT DUAL USE RESEARCH ON MICROBES: Biosafety, Biosecurity, Responsibility" (PDF). Volkswagen Foundation. 12 December 2014.
  3. Johnson, Durward; Kraska, James (14 May 2020). "Some Synthetic Biology May Not be Covered by the Biological Weapons Convention". The Lawfare Institute.
  5. Smithson, Amy (1999). "A bio nightmare". Bulletin of the Atomic Scientists. 55 (4): 69–71. Bibcode:1999BuAtS..55d..69S. doi:10.2968/055004019.
  6. Ainscough, Michael J. (2004). "Next Generation Bioweapons: Genetic Engineering and BW" (PDF). Retrieved 9 September 2020.
  7. Kelly, David (2002). "The Trilateral Agreement: lessons for biological weapons verification". In Findlay, Trevor; Meier, Oliver (eds.). Verification Yearbook 2002 (PDF). London: Verification Research, Training and Information Centre (VERTIC). pp. 93–109. ISBN 978-1-899548-35-4. External link in |chapter= (help)
  8. 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. PMC 111474. PMID 10627550.
  9. Imai, Masaki; Watanabe, Tokiko; Hatta, Masato; Das, Subash C.; Ozawa, Makoto; Shinya, Kyoko; Zhong, Gongxun; Hanson, Anthony; Katsura, Hiroaki; Watanabe, Shinji; Li, Chengjun; Kawakami, Eiryo; Yamada, Shinya; Kiso, Maki; Suzuki, Yasuo; Maher, Eileen A.; Neumann, Gabriele; Kawaoka, Yoshihiro (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. Bibcode:2012Natur.486..420I. doi:10.1038/nature10831. PMC 3388103. PMID 22722205.
  10. Tucker, Patrick (n.d.). "To Protect Ourselves From Bioweapons, We May Have to Reinvent Science Itself". Defense One.
  11. Zhang, Y.; Zhang, Q.; Kong, H.; Jiang, Y.; Gao, Y.; Deng, G.; Shi, J.; Tian, G.; Liu, L.; Liu, J.; Guan, Y.; Bu, Z.; Chen, H. (2013). "H5N1 Hybrid Viruses Bearing 2009/H1N1 Virus Genes Transmit in Guinea Pigs by Respiratory Droplet". Science. 340 (6139): 1459–1463. Bibcode:2013Sci...340.1459Z. doi:10.1126/science.1229455. PMID 23641061. S2CID 206544849.
  12. Connor, Steve (2 May 2013). "'Appalling irresponsibility': Senior scientists attack Chinese researchers for creating new strains of influenza virus in veterinary laboratory". The Independent.
  13. Akst, Jef (21 October 2014). "Moratorium on Gain-of-Function Research". The Scientist.
  14. "U.S. Government Gain-of-Function Deliberative Process and Research Funding Pause on Selected Gain-of-Function Research Involving Influenza, MERS, and SARS Viruses" (PDF). U.S. Department of Health & Human Services. Office of the Assistant Secretary for Preparedness and Response. 17 October 2014.
  15. McNeil, Donald G. Jr. (17 October 2014). "White House to Cut Funding for Risky Biological Study". The New York Times Company.
  16. Kaiser, Jocelyn; Malakoff, David (17 October 2014). "U.S. halts funding for new risky virus studies, calls for voluntary moratorium". Science. Retrieved 28 July 2016.
  17. Imperiale, Michael J.; Casadevall, Arturo (2016). "Zika Virus Focuses the Gain-of-Function Debate". mSphere. 1 (2). doi:10.1128/mSphere.00069-16. PMC 4894681. PMID 27303723.
  18. https://www.nationalacademies.org/our-work/gain-of-function-research-a-symposium
  19. 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; Thevenon, Audrey (eds.). Gain-of-Function Research: Summary of the Second Symposium (PDF). doi:10.17226/23484. ISBN 9780309440776. PMID 27403489. Retrieved January 29, 2021.
  20. "Recommended Policy Guidance for Departmental Development of Review Mechanisms for Potential Pandemic Pathogen Care and Oversight (P3CO)" (PDF). Department of Health and Human Services. Office of the Assistant Secretary for Preparedness and Response. 9 January 2017.
  21. "RECOMMENDATIONS FOR THE EVALUATION AND OVERSIGHT OF PROPOSED GAIN-OF-FUNCTION RESEARCH" (PDF). United States Department of Health and Human Services. National Science Advisory Board for Biosecurity. May 2016. Archived from the original (PDF) on 7 January 2017.
  22. Collins, Francis S. (19 December 2017). "NIH Lifts Funding Pause on Gain-of-Function Research". Director, National Institutes of Health.
  23. "Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens" (PDF). Department of Health and Human Services. Office of the Assistant Secretary for Preparedness and Response. 19 December 2017.
  24. Coelho, Ana Cláudia; García Díez, Juan (2015). "Biological Risks and Laboratory-Acquired Infections: A Reality That Cannot be Ignored in Health Biotechnology". Frontiers in Bioengineering and Biotechnology. 3: 56. doi:10.3389/fbioe.2015.00056. PMC 4412124. PMID 25973418.
  25. Rasmussen A (2021). "On the origins of SARS-CoV-2". Nature Medicine. 27 (9): 9. doi:10.1038/s41591-020-01205-5. PMID 33442004. S2CID 231606580.
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