At the time of its elucidation the genetic code was suggested to be universal in all
organisms, and the result of a ‘frozen accident’ unable to evolve further. Today we know
22 natural amino acids: selenocysteine, the 21st, and pyrrolysine, the 22nd, are directly
inserted into growing polypeptides during translation. The incorporation of selenocysteine
directed by UGA requires the action of specific RNA and protein elements, a fact that has
restricted engineering of selenoproteins. Based on the realization that protein plasticity is a
feature of living cells, man‐made expansion of the genetic code based on orthogonal
translation systems (OTSs) is an active research field. Although the design of in vivo
specific and highly active OTS systems is still not ideal, the increasing number of
successful recoding strategies promises a bright future for genetic code expansion.
