An Epistemological Perspective on the Value of Gain-of-Function Experiments Involving Pathogens with Pandemic Potential

In recent years, scientists have engaged in a vigorous debate regarding the value of so-called gain-of-function (GOF) experiments involving highly pathogenic avian influenza virus (HPAIV) and other pathogens with pandemic potential (PPP). Of particular concern have been experiments whereby something is done to PPP, such as HPAIV, and the pathogen acquires a new property, or GOF, that makes the microbe more dangerous, such as mammalian transmissibility, increased virulence, and/or the ability to defeat immunity and antimicrobial drugs. The debate has included arguments focused on biosecurity, biosafety, and ethics (1–5). Proponents of GOF experiments emphasized the utilitarian aspects of the work such as potential uses in vaccine development and strain surveillance, while opponents focused on risk (1). However, the debate has largely ignored the question of the epistemological value of such experiments, which is central to any scientific discussion of the merits of such work. Here we consider GOF experiments in the context of how information is acquired and valued in the fields of microbial pathogenesis and infectious diseases. Epistemology is the branch of philosophy that examines the nature of knowledge, its presuppositions and foundations, and its extent and validity (6). Most scientists, and microbiologists in particular, practice their art within specialized areas that include a set of normative standards that influence the pursuit and acceptance of knowledge, and such normative standards are a major focus of epistemological research within the philosophy of science (7, 8). Normative standards in science include the methodology that is accepted for making and accepting scientific discoveries. In this regard, different fields rely on partially different methods for the questions that they pursue. Before exploring the value of GOF experiments, we need to consider the current normative standards in the field of microbial pathogenesis that guide the approach to research. To understand the origin of such standards in the field, we must go back to the early days of the germ theory of disease. Although microbes and lack of hygiene were associated with infectious diseases by several individuals, in the mid-19th century, it was Robert Koch’s demonstration that anthrax was caused by Bacillus anthracis that introduced the powerful concept of associating specific microbes with specific diseases. These experiments in turn established a high standard for causation, as exemplified by Koch’s postulates, which themselves created a high bar for the acceptance of subsequent research (9, 10). For diseases where Koch’s postulates could not be directly applied, new tools were developed such as immunological proof of causation in which immune responses in the form of serology became surrogates for making causative associations. Today new molecular tools have led to the identification of many pathogens associated with certain diseases, and the high bar established at the end of the 19th century continues to demand extraordinary rigor for association of microbes and disease (11). The emphasis on causation led to the identification of numerous microbes as etiological agents for specific disease, and these causative associations allowed humanity to control many infectious diseases through improved sanitation, vaccination, and eventual antimicrobial drug discovery. For example, such experimental rigor led to the rapid association of HIV with AIDS within 3 years after the report of a new deadly clinical syndrome. In turn, this facilitated the development of numerous antiretroviral drugs that converted AIDS from a rapidly lethal disease to a treatable chronic condition. In fact, the germ theory of disease and the fields that originated from it, including vaccinology, are arguably the most important single scientific contribution to the increase in human life span and betterment of human health during those added years. The standards developed for disease causation were subsequently applied to other areas of microbiological research. For example, in the late 20th century, molecular biology tools that allowed disruption of specific genes became available. In the field of microbial pathogenesis, the ability to disrupt genes led to questions of how to associate gene function with specific effects on virulence. Consequently, Stanley Falkow proposed his “molecular Koch’s postulates,” suggesting that associations be made only when mutating the gene in question affected virulence, and the effect could be reversed by complementation (12, 13). Such approaches in both the identification of disease causation and gene function created a set of normative standards that have dominated how investigators approach problems in the field. Consequently, research in microbial pathogenesis and infectious diseases operates with a set of normative standards that have been repeatedly tested and established to provide actionable information that can directly impact health. However, we note that microbiology is not a homogenous discipline with regard to how it pursues knowledge, and whereas microbial pathogenesis can be highly reductionist in its attempts to identify specific genes and alleles associated with virulence, environmental microbiology places high value in trying to understand how complex systems interact (14). The types of experiments defined by Falkow, in which loss of function is used to identify determinants of virulence, are gener-