{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T07:15:58Z","timestamp":1788419758958,"version":"build-2803163510"},"reference-count":81,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["320225"],"award-info":[{"award-number":["320225"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["226801"],"award-info":[{"award-number":["226801"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Bioeng. Biotechnol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fbioe.2026.1833212","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:41:33Z","timestamp":1788417693000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["From mRNA stabilisation to mirror life: Biological orthogonality, incremental risk, and anticipatory governance"],"prefix":"10.3389","volume":"14","author":[{"given":"Christopher H.","family":"Lean","sequence":"first","affiliation":[{"name":"Philosophy, Macquarie University","place":["Sydney, NSW, Australia"]},{"name":"Australian Research Council Centre of Excellence in Synthetic Biology, Macquarie University","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russel M.","family":"Vincent","sequence":"additional","affiliation":[{"name":"Macquarie Medical School, Macquarie University, Sydney, NSW, Australia","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kate E.","family":"Lynch","sequence":"additional","affiliation":[{"name":"School of History and Philosophy of Science, The University of Sydney","place":["Sydney, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Euzebiusz","family":"Jamrozik","sequence":"additional","affiliation":[{"name":"Ethox and Pandemic Sciences Institute, University of Oxford","place":["Oxford, United Kingdom"]},{"name":"Department of Infectious Diseases at The Peter Doherty Institute & Royal Melbourne Hospital Department of Medicine, University of Melbourne","place":["Melbourne, VIC, Australia"]},{"name":"Monash Bioethics Centre, Monash University","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul R.","family":"Jaschke","sequence":"additional","affiliation":[{"name":"Australian Research Council Centre of Excellence in Synthetic Biology, Macquarie University","place":["Sydney, NSW, Australia"]},{"name":"Macquarie University School of Natural Sciences","place":["North Ryde, NSW, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1126\/science.ads9158","article-title":"Confronting risks of mirror life","volume":"386","author":"Adamala","year":"2024","journal-title":"Science"},{"key":"B2","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1016\/j.appet.2017.08.021","article-title":"An experiment assessing effects of personalized feedback about genetic susceptibility to obesity on attitudes towards diet and exercise","volume":"120","author":"Ahn","year":"2018","journal-title":"Appetite"},{"key":"B3","doi-asserted-by":"publisher","first-page":"6265","DOI":"10.1038\/s41467-020-20096-1","article-title":"Patient and public perspectives on cell and gene therapies: a systematic review","volume":"11","author":"Aiyegbusi","year":"2020","journal-title":"Nat. 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