Genetic Code Expansion: A Brief History and Perspective

Mia Ann Shandell, Virginia Cornish, Zhongping Tan

Research output: Contribution to journalSpecial issuepeer-review


Since the establishment of site-specific mutagenesis of single amino acids to interrogate protein function in the 1970s, biochemists have sought to tailor protein structure in the native cell environment. Fine-tuning the chemical properties of proteins is an indispensable way to address fundamental mechanistic questions. Unnatural amino acids (UAAs) offer the possibility to expand beyond the 20 naturally occurring amino acids in most species and install new and useful chemical functions. Here, we review the literature about advances in UAA incorporation technology from chemoenzymatic aminoacylation of modified tRNAs to in vitro translation systems to genetic encoding of UAAs in the native cell environment and whole organisms. We discuss innovative applications of the UAA technology to challenges in bioengineering and medicine.
Original languageEnglish
Publication statusPublished - 1 Jul 2021

Bibliographical note

© 2021 The Authors. Published by American Chemical Society


  • Peptides and proteins
  • Bacteria
  • Genetics
  • Monomers
  • Fluorescence

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