From mRNA stabilisation to mirror life: Biological orthogonality, incremental risk, and anticipatory governance

Abstract

Molecular stabilisation of mRNA is central to the development of therapeutics. Stabilisation is gained through modifications that cause mRNA to resist degradation, evade immune recognition, and prolong expression. These modifications introduce degrees of biological orthogonality, which, in this context, is the extent to which a molecule becomes invisible to the natural systems that would otherwise process or eliminate it. We propose that orthogonality provides a framework for understanding biosecurity risks across the spectrum of synthetic nucleic acid modification, from current mRNA therapeutics to mirror life. We develop this framework through a five-stage continuum from engineered mRNA to fully orthogonal mirror-life systems, using the 2024 scientific moratorium that was recommended for mirror life as a biosecurity governance endpoint. Across this spectrum, there is an increasing degree to which engineered genetic material can resist degradation and evade immune recognition, and a threshold at which this genetic material could be replicated. mRNA has minimal biosecurity issues because it is detectable, immunologically decomposable and unable to replicate, whereas mirror life would be highly undetectable, minimally decomposable, and replicable. Orthogonality, however, does not appear only at these extremes, and we suggest that biosecurity-relevant risks can accumulate progressively as we engineer greater orthogonality. Orthogonality should be a significant factor in designing biosecurity governance, alongside sequence screening and product-level assessments. We suggest a trajectory-focused oversight that monitors, across research programmes, the properties that turn orthogonality into risk and triggers staged reviews as they advance. The properties in question are persistence, reflected in half-life extension, nuclease resistance, and environmental persistence, along with invisibility to recognition and surveillance and the capacity for autonomous replication.