Gain-of-function (GOF)
Gain-of-function (GOF) research became a topic of widespread interest due to the origin theory of SARS-CoV-2, the virus that causes Covid-19, which says it may have been accidentally released from the Wuhan Institute of Virology in China. Gain-of-function research is risky, with the possibility of a pandemic breaking out if a scientist doing the research became infected by accident.
In a 2012 article published in MBio, the journal of the American Society of Microbiology, director of the National Institute of Allergy and Infectious Diseases (NIAID) at the National Institute of Health Dr. Anthony Fauci said scientists alone should not decide on the fate of such research, which he described as risky but worth it. While gain of function research is very important, Fauci argued, the researchers “can no longer be the only player in the discussion of whether certain experiments should be done.” The voluntary moratorium against such research – in effect at the time – is good and should continue, he argued, “until policy decisions could be articulated” with the help of global and national public opinion, experts and public officials.
Research involving potential pandemic pathogens (PPPs) is essential to protecting global health and security. However, there are biosafety and biosecurity risks associated with undertaking such research that should be adequately considered and appropriately mitigated in order to safely realize the potential benefits. Seasonal influenza annually results in more than half a million deaths worldwide, and the possibility of an even more dangerous pandemic is a real and ongoing threat.
Experiments aimed at understanding how the flu evolves from an infection in birds, pigs, or other mammals to a pathogen capable of causing a pandemic in humans are crucial to staying ahead of the naturally evolving virus. Controlled experiments that may enhance pathogens, including the flu virus and others, are critical in helping identify, understand, and develop strategies or medical countermeasures to preserve public health in the face of evolving threats. But obviously those experiments need to be conducted with extreme care.
A potential pandemic pathogen (PPP) is a pathogen that satisfies both of the following: It is likely highly transmissible and likely capable of wide and uncontrollable spread in human populations; and It is likely highly virulent and likely to cause significant morbidity and/or mortality in humans. An enhanced PPP is defined as a PPP resulting from the enhancement of the transmissibility and/or virulence of a pathogen. Enhanced PPPs do not include naturally occurring pathogens that are circulating in or have been recovered from nature, regardless of their pandemic potential.
Gain-of-function (GOF) studies, or research that improves the ability of a pathogen to cause disease, help define the fundamental nature of human-pathogen interactions, thereby enabling assessment of the pandemic potential of emerging infectious agents, informing public health and preparedness efforts, and furthering medical countermeasure development. Gain-of-function studies may entail biosafety and biosecurity risks; therefore, the risks and benefits of gain-of function research must be evaluated, both in the context of recent U.S. biosafety incidents and to keep pace with new technological developments, in order to determine which types of studies should go forward and under what conditions.
The term “gain-of-function” [GoF] dates to a 2012 meeting for the NIH where is was used to replace more descriptive terms that indicated concerns about research that generates strains of respiratory viruses that are highly transmissible and highly pathogenic. GoF research done in the laboratory is a “proactive” approach to understand what will eventually happen in nature. GoF experiments for CoV research encompass a very diverse set of experiments that are critical to the development of broad-based vaccines and therapeutics. GoF studies, which enhance viral yield and immunogenicity, are required for vaccine development. The broad term “gain-of-function” needs some refinement to differentiate the type of experiments typically performed for basic virological research from experiments that clearly raise concerns. What is called “gain of function research of concern” includes the generation of viruses with properties that do not exist in nature. The now famous example is the production of H5N1 influenza A viruses that are airborne-transmissible among ferrets, compared to the non-airborne transmissible wild type.
A 2004 report from the National Research Council, Biotechnology Research in an Age of Terrorism, argued that biotechnology posed a “dual use dilemma” because “the same technologies can be used legitimately for human betterment and misused for bioterrorism” (NRC, 2004:1). Most policy discussions have focused on efforts to address a subset of “dual use research of concern” (DURC), which was defined by the National Science Advisory Board for Biosecurity in 2007 as research that, “based on current understanding, can be reasonably anticipated to provide knowledge, products, or technologies that could be directly misapplied by others to pose a threat to public health and safety, agricultural crops and other plants, animals, the environment, or materiel” (NSABB, 2007:17).
Examples of US policy initiatives stimulated by the controversy over GoF research that began in late 2011 include the USG Policy for Oversight of Life Sciences Dual Use Research of Concern (March 29, 2012), the HHS Framework for Highly Pathogenic Avian Influenza Research (2012), the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid Molecules (November 2013), and the USG Policy for Institutional Oversight of Life Sciences Dual Use Research of Concern (September, 2014). In addition, in response to the laboratory incidents revealed in July 2014, White House Science Advisor John Holdren and Homeland Security Advisor Lisa Monaco issued a memorandum in August 2014 on Enhancing Biosafety and Biosecurity in the United States that “urged departments and agencies to take specific steps to strengthen safety and security” in federal laboratories.
On October 17, 2014, spurred by incidents at U.S. government laboratories that raised serious biosafety concerns, the United States government launched a one-year deliberative process to address the continuing controversy surrounding so-called “gain-of-function” (GOF) research on respiratory pathogens with pandemic potential. The gain of function controversy began in late 2011 with the question of whether to publish the results of two experiments involving H5N1 avian influenza and continued to focus on certain research with highly pathogenic avian influenza over the next three years.
In December 2017, the Department of Health and Human Services (HHS) announced its Framework for Guiding Funding Decisions about Proposed Research Involving Enhanced Potential Pandemic Pathogens(link is external) to provide an additional level of review and oversight to help ensure such research is conducted with the utmost regard to safety and security. The HHS Framework formalizes robust oversight for federally funded research with enhanced pathogens of pandemic potential. With a rigorous oversight process in place, NIH announced in a statement and notice to the research community that it was lifting the funding pause on such research.
