Bioaerosol Dispersal Models and the In Silico Design of a Synthetic Strain of Bacillus subtilis with Stringent Growth Regulation.

摘要

A critical component of biodefense research is the modeling and simulation of the spread of Bacillus anthracis spores. Of the three primary approaches used to study the dispersal of such bioaerosols - mathematical modeling, physical simulation, and biological simulation - the direct dispersal of biological simulants offers the most accurate results. However, the dispersal of viable simulants risks colonization of undesired environments, such as immunocompromised persons within exposed populations. During its Cold War biological weapons research program, the US government dispersed biologically viable simulants, exposing human subjects (often unbeknownst to them) to these ostensibly safe but potentially pathogenic organisms. An analysis of these open-air tests illustrates three improvements to ensure that future biodefense research is conducted ethically: reduced pathogenicity of the biological simulant, obtaining informed consent (either standard or de facto) from potentially exposed populations, and ensuring that the unique concerns regarding military bioethics are addressed for any military service members who may be exposed.;One way to mitigate the potential pathogenicity of viable simulants is to use synthetic biology to design a novel strain of Bacillus subtilis with both essential and lethal genes regulated by multiple inducible and repressible promoters. Because of the stringent growth regulation of this strain, only bacteria germinating in the presence of the proper combination of six inducing chemicals would be able to survive, providing the system with multiply-redundant safeguards against colonization of undesired environments.;Due to its extremely stringent growth restrictions, the designed B. subtilis system behaves as a biologically viable organism only within a specifically-defined, artificially-supplied chemical environment where growth is desired and as an unviable physical simulant in environments where growth is undesired. By combining the robust research possibilities afforded by the former with the safety of the latter, the B. subtilis strain described here can be used as a safe simulant for direct analysis of bioaerosol dispersal. This novel synthetically-designed B. subtilis strain could be an ideal bioaerosol dispersal model, particularly for simulating dispersal of B. anthracis spores, and a valuable tool for the biodefense research community.