Gain of function Notes
The field of virology, and to some extent the broader field of microbiology, widely relies on studies that involve gain or loss of function.
Routine virological methods involve experiments that aim to produce a gain of a desired function, such as higher yields for vaccine strains, but often also lead to loss of function, such as loss of the ability for a virus to replicate well, as a consequence.
Such experiments in virology are fundamental to understanding the biology, ecology, and pathogenesis of viruses and added that much basic knowledge is still lacking for SARS-CoV and MERS-CoV.
Virologists ask at all stages of research on the emergence or re-emergence of a virus and specifically adapted these general questions to the three viruses of interest in the symposium (see Box 3-1). To answer these questions, virologists use gain- and loss-of-function experiments to understand the genetic makeup of viruses and the specifics of virus-host interaction.
The first category, which he called “gain of function research of concern,” includes the generation of viruses with properties that do not exist in nature. The now famous example he gave is the production of H5N1 influenza A viruses that are airborne-transmissible among ferrets, compared to the non-airborne transmissible wild type.
The second category deals with the generation of viruses that may be more pathogenic and/or transmissible than the wild type viruses but are still comparable to or less problematic than those existing in nature.
Finally, the third category, which is somewhere in between the two first categories, includes the generation of highly pathogenic and/or transmissible viruses in animal models that nevertheless do not appear to be a major public health concern.
*All these studies are experimental. There has never being a theoretical model for solving these. Thus, there is a knowledeg gap of scale. *
One of the important applications of GoF research is the development of animal models, especially in the case of pathogens with pandemic potential, because to get approval to study a countermeasure compound in humans, the Food and Drug Administration's animal rule requires the presence of disease that mimics the human disease in an animal model.
Whenever researchers are working with RNA viruses, GoF mutations are naturally arising all the time and escape mutants isolated in the laboratory appear “every time someone is infected with influenza.
- alternative scientific approaches are not only less risky, but also more likely to generate results that can be readily translated into public health benefits
Lipsitch M, Galvani AP. Ethical Alternatives to Experiments with Novel Potential Pandemic Pathogens. May 20, 2014. http://www.plosmedicine.org/article/info%3Adoi%2F10.1371%2Fjournal.pmed.1001646#s3
IRAT
https://www.cdc.gov/flu/pandemic-resources/national-strategy/risk-assessment.htm
The Influenza Risk Assessment Tool (IRAT) is an evaluation tool developed by CDC and external influenza experts that assesses the potential pandemic risk posed by influenza A viruses that currently circulate in animals but not in humans.
The IRAT uses 10 risk elements to measure the potential pandemic risk associated with each of these scenarios. These 10 risk elements can be grouped into three overarching categories: “properties of the virus,” “attributes of the population,” and “ecology & epidemiology of the virus.” Influenza subject matter experts evaluate novel influenza viruses based on each of these 10 risk elements. Each of the 10 risk elements is then weighted statistically based on its significance to each of the two scenarios. A composite score for each virus is then calculated based on the given scenario. These composite scores provide a means to rank and compare influenza viruses to each other in terms of their potential pandemic risk for each of the two scenarios.
As we learn more about influenza A viruses, these 10 risk elements may change, other risk elements may be added or some current risk elements may be dropped. The IRAT is designed to be flexible and responsive to current scientific advances.
Can the IRAT predict a future pandemic?
No. The IRAT is an evaluative tool, not a predictive tool. Flu is unpredictable, as are future pandemics.