Gain of Function Research and Model Organisms in Virology

Pence, Charles H. [UCL] Evans, Nicholas G.

Gain-of-function research is research in which a virus or other pathogen is created, in the course of scientific research, that has increased virulence, transmissibility, or host range. Gain-of-function research has generated considerable policy discussion because while these novel viruses may heighten the risk of a disease pandemic, advocates of the experiments highlight how this research might “prevent the next pandemic,” for instance, by giving virologists enhanced knowledge about the potential future evolutions of pathogenicity in viruses, or by giving vaccine manufacturers a “head start” in creating new vaccines against highly pathogenic viruses. Our response to the COVID-19 pandemic, however, does not seem to have involved, in any significant way, the results of gain-of-function research. Vaccines using mRNA technology were largely the fruit of basic-science research which dates back several decades (and, furthermore, had never been particularly well-financed throughout its history). Much of our knowledge about how coronaviruses replicate arose not from gain-of-function contexts, but rather from laboratory work on much less pathogenic strains. This provides yet a further example for scholars who question the ethical calculus surrounding gain-of-function research (e.g., Lipsitch and Galvani 2014, Herington and Tanona 2020, Evans 2013; Evans, Lipsitch, and Levinson 2015). The ethical costs and benefits of this research should thus likely be reevaluated in light of this practical experience. In addition to this ethical dimension, however, there are epistemic dimensions here, important for the philosophy of science and for our understanding (or even our financing) of biomedical research. Do there exist characteristics of this gain-of-function research might have led us to realize that, in fact, it would not have been suitable for preparing us for the COVID-19 pandemic? And do these features inform our preparedness for other potential pandemic pathogens? Here, we focus on one particular set of answers to these questions, drawn from philosophy of biology research on the nature of reasoning on the basis of model organisms. What about research in a mouse, for instance, lets us infer facts about the ways in which humans develop cancer? What might be the limitations of these kinds of inferences, and how do they relate to other sorts of scientific modeling? We identify three levels of “model organism” at work in gain-of-function research, using as our case study gain-of-function research in pandemic influenza (which has received the most attention). First and most obvious are ferret models, selected because ferrets share the same biochemical mechanisms for the aerosol transmission of respiratory diseases that are found in humans. Second, viruses are chosen as the base for gain-of-function research (e.g., the H5N1 avian influenza virus at the heart of the first major public controversy over gain-of-function research in 2011). Very often, gain-of-function research begins with highly pathogenic strains of viruses that are weakly or non-transmissible in humans, attempting to understand the way in which this transmissibility might evolve naturally. Third, we have the gene sequences which researchers believe will increase transmission in the virus being manipulated (e.g. from historic viruses such as 1918 influenza), which are taken as models for potential mutations that might arise in naturally occurring pandemic influenza. We tentatively hypothesize – perhaps with the exception of ferret models – the models used in gain-of-function research do not map cleanly onto the ways in which philosophers of science have explored model organisms. To take just one important disconnect as an example, we are not modeling the increase in transmission because we believe this is somehow analogous to or because it represents what is currently taking place in nature. (These would be natural ways to understand models, say, of cancer in mice – the processes of tumor formation are either analogous to or represent those same processes as they currently occur in humans.) Rather, we are attempting to predict the future of evolutionary change – to build an analogy with a potential virus that in fact does not yet exist. We need new epistemic approaches, we argue, to understand and evaluate these kinds of (significantly more tenuous) inferences about the use of model organisms in virology.