EAGER: Probing the Interactions of Mirror DNA with Cellular Machinery using Cell-Free Systems

There is rising concern regarding the possibility that synthetic organisms might be constructed using biomolecules of opposite chirality (molecular twist) to those found in natural biological systems. Experts in synthetic cell research and immunology have posited that the creation of such "mirror bacteria” might be possible in the relatively near future and that these organisms could evade many of the body’s defense mechanisms, potentially leading to crises in public health and environmental contamination. However, despite increased discussion of the possible risks associated with developing mirror life, scientific understanding of how basic cellular processes behave in systems of mixed chirality remains limited. This project will address that knowledge gap by studying how “heterochiral” DNA (that combines both DNA chiralities) behaves in non-living, non-replicating, yet cell-like experimental systems. This will allow the interactions between native biological enzymes and opposite chirality nucleic acids to be probed in a safe context. By deepening scientific understanding of how biological processes interact with opposite-chirality substrates, this project will provide critically needed insights into potential risks and opportunities associated with mirror-life biotechnology. The results may suggest possible strategies to detect and defend against such threats, which could constitute a substantial threat to national security and economic prosperity. The project will thereby benefit human health and natural security and inform future risk assessment surrounding possible dangers from mirror life. This project will use cell-free transcription/translation (TX/TL) systems to study the possible dangers of chirally inverted "mirror life." Cell-free systems are non-living and lack the capability to replicate and propagate genetic information yet are transcriptionally and translationally active, making them a safe testbed to probe key assumptions regarding the behavior of mirror-image nucleic acids in the presence of biological systems. In particular, the project will study how heterochiral nucleic acids interact with a range of basic biological processes, including DNA degradation, transcription, and transcriptional regulation. This will not only expand the toolkit for engineering and tuning cell-free expression systems but will also enhance scientific understanding of the potential threat posed by mirror life. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria. NSF Award ID: 2614686 | Program: 01002627DB NSF RESEARCH & RELATED ACTIVIT | Principal Investigator: Matthew Lakin | Institution: University of New Mexico, ALBUQUERQUE, NM | Award Amount: $400,000 View on NSF Award Search: https://www.nsf.gov/awardsearch/show-award/?AWD_ID=2614686 View on Research.gov: https://www.research.gov/awardapi-service/v1/awards/2614686.html