Reprogramming the genetic code

Published in Nature Reviews Genetics in 2021, this review article synthesises the principles, tools, and applications of genetic code expansion and reprogramming, providing the conceptual framework that connects Constructive Bio's individual technical advances into a coherent platform.

The review traces the field from its foundations in orthogonal translation systems through to whole-genome recoding and its emerging applications in biology and biotechnology. It covers the logic of how orthogonal aminoacyl-tRNA synthetase/tRNA pairs are engineered to recognise non-canonical amino acids, how these pairs are directed to read specific codons, and how genome-scale codon reassignment creates the dedicated coding capacity needed for reliable multi-ncAA incorporation.

For readers seeking to understand Constructive Bio's technology in its scientific context, this review is the most comprehensive single source. It explains why amber suppression (the earlier approach using the TAG stop codon) is limited to incorporating one ncAA type per molecule and why sense codon reassignment in a fully recoded genome overcomes this limitation. It discusses the engineering of orthogonal translation machinery, the challenges of maintaining organism fitness during genome-scale changes, and the applications that become accessible when the genetic code is expanded beyond the canonical 20 amino acids.

The review also covers the broader implications of genetic code reprogramming for biosafety (organisms with refactored codes are genetically isolated from natural microorganisms), for virus resistance (phages that depend on standard codon usage are locked out), and for the production of polymers and materials with properties not found in natural biology.

As a review rather than a primary research paper, this publication does not report new experimental results. It serves as the scientific reference document for the field of genetic code expansion, written by two of its leading practitioners, and provides the intellectual foundation for the therapeutic manufacturing applications that Constructive Bio's BioForge platform delivers.