the scientific advances that would be necessary to permit serious consideration of developing and implementing an oversight system for Select Agents that is based on predicted features and properties encoded by nucleic acids rather than a relatively static list of specific agents and taxonomic definitions. (Appendix A)
It is implicit in the charge that a “predictive oversight” system is not now feasible. It is also implicit that “gene sequence-based classification,” is synonymous with “predict[ing] features and properties encoded by nucleic acids.” However, it soon became clear that the committee was confronted by two quite different tasks, one of which is feasible and one is not. It is possible to classify a new sequence as belonging within a group of known sequences; it is not feasible to predict the function(s) that sequence encodes. Thus, it is essential to distinguish sequence-based classification from sequence-based prediction of biological function.
A sequence-based prediction system for oversight of Select Agents is not possible now and will not be possible in the usefully near future.
Select Agent is not a biological term; rather it is a regulatory designation. Some properties historically considered in assigning an organism to the Select Agent list are not biological properties, and therefore, can never be determined from the organism’s genome sequence.
High-level biological phenotypes—such as pathogenicity, transmissibility, and environmental stability—cannot plausibly be predicted with the degree of certainty required for regulatory purposes, either now or in the foreseeable future.
Reliable prediction of the hazardous properties of pathogens from their genome sequence alone will require an extraordinarily detailed understanding of host, pathogen, and environment interactions integrated at the systems, organism, population, and ecosystem levels. It is a prediction problem of the greatest complexity.
Biology is not binary. Microorganisms are not either “potential weapons of mass destruction” or “of no concern.” No single characteristic makes a microorganism a pathogen, and no clear-cut boundaries that separate a pathogen from a non-pathogen. Pathogenic microorganisms are not defined by taxonomy; it is common for a given microbial species to have both pathogenic and non-pathogenic representatives. An agent has multiple biological attributes, and the degree to which these are expressed fall along a spectrum for each biological characteristic;1 consequently, agents present varying degrees of risk.