Gain of function research: what is it and why should we care?

If mishandled, there is a very real danger that progressive scientific technology could have disastrous societal impacts. Of particular concern is gain-of-function research. A well-established methodology in microbiology and genetics, its application to infectious disease agents with pandemic potential has been called into serious question. My blog will briefly explore the importance of this technical issue, the associated biosafety and biosecurity risks and conclude with key policy considerations for making the most of the technology.

Gain-of-function (GoF) research, in a biosecurity context, refers to the genetic manipulation of pathogens, which results in the introduction of changes (which confer a new function) to that biological agent. Biologically, this primarily translates to the enhancement of an organism’s pathogenicity, transmissibility, or host range, which, resultantly, increases its capacity to cause disease. Particularly concerning are GoF experiments involving pathogens with pandemic potential, notably, influenza virus, MERS-CoV and Ebola. Whilst scientifically and socially informative, this type of research is fundamentally sensitive, primarily due to the potential of developing bioweapons, and safety concerns of laboratory-modified pathogens inadvertently causing pandemics.

A particularly pertinent example to highlight the concerns of GoF research is the genetic modification of influenza A(H5N1) viruses for transmission in ferrets[1]. A series of experiments published in 2012 revealed that researchers had created A(H5N1) viruses that were capable of transmission through the air between ferrets, a common animal model in viral research. Whilst broadly contributing to the assessment of the virus’s ability to adapt to humans and its pandemic potential, this research is rightly considered concerning: should the virus escape from the lab, either accidentally or deliberately, then it could trigger a human pandemic. Most notably, this research specifically conferred a previously non-existent function upon the virus: mammalian transmissibility. It is this distinction that makes such research particularly discerning. The work catalysed a heightened response from the U.S. Government, leading to a temporary pause on research, and instilled further energy into the continuing GoF debate.

A concerning biosecurity dynamic of GoF research is the potential for bioterrorism and biowarfare: the use of products or information gained from GoF research for nefarious action. Whilst such a risk is difficult to quantify, there has been proven historic intent of terrorists or terrorist groups wanting to get hold of, or using, bioweapons. One of the most revealing considerations from the H5N1 research highlighted above was the academic right to publish. In today’s world, when information is so readily available on the internet, publishing the results of GoF research must be called into question. If one publishes the mutations needed to confer increased pathogenicity for a certain organism, then both state and non-state actors have quick and easy access to this information. With developments such as 4D printing, and the ease of communication in today’s increasingly interconnected world, such deliberate misuse is especially concerning. Further, the rise of DIY-biology and a growing trend of bio-engineering are widening the community of individuals with the technical capabilities to conduct the manipulation of biological materials.

The risk of misuse of GoF research is not just due to security (biosecurity), but also safety (biosafety).  In fact, the biosafety concerns are arguably more acute, with recent reports of serious biosafety lapses at US federal institutions involving anthrax, smallpox and H5N1 facilitating the year-long pause on some GoF research with pathogens with pandemic potential. The risk of such biosafety lapses includes not only the infection of laboratory workers, but also the general public and the environment at large. Biosafety risks stem from human error, noncompliance with biosafety protocols and equipment failures. The most extreme risk is, of course, the accidental release of a modified (through gain of function) pathogen, which leads to a pandemic in the human population. Such a risk is innately concerning to many stakeholders in the regulation of GoF research, including the general public and government: to mitigate this risk, a strong safety culture must be established.

Despite the risks of biosafety and biosecurity, the potential benefits of GoF research are significant: It enables the assessment of the pandemic potential of a particular pathogen, aids in the development of vaccines and drugs, and facilitates public preparedness strategies. GoF research is particularly useful for influenza research, and helping us to predict which strain will cause the next pandemic. Research of this nature provides information about virus transmissibility, host range, immunogenicity, resistance and virulence: such information is crucial to managing future pandemics, which will undoubtedly have disastrous consequences for the global society.

The effects of GoF research are far-reaching, impacting, non-extensively, public health practitioners, the general public, government, life scientists and clinicians. With such a diverse community, there are obviously large discrepancies in opinions on the risks and benefits of GoF applied to infectious disease agents with pandemic potential. Engaged discussion is the best way to produce policies that ensure best practice in GoF research. To ensure that society benefits from this research, but the risks are managed appropriately, coherent, preventative yet inclusive policy strategies are required. Firstly, strategies must be implemented to ensure that scientists are aware of the dual-use nature of their work. Secondly, the public must also be engaged in and informed about the benefits and risks to GoF research. Thirdly, stringent biosafety standards must be implemented, which are consistent at a regional, national and global level: pandemics are not constrained by geography and as such, neither should our safety standards.

GoF research applied to biological agents with pandemic potential is inherently compelling, as it questions the balance between the benefits of scientific research and the risks of such research to public health. The international community must act in an engaged, coordinated and collaborative manner in order to ensure that GoF research benefits but does not endanger society.

[1] https://www.sciencemag.org/content/336/6088/1534.full

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