Creation, Optimization, and Use of Semi-Synthetic Organisms that Store and Retrieve Increased Genetic Information

[Display omitted] •Medicinal chemistry approach used to develop unnatural base pairs (UBPs).•UBPs selectively pair in oligonucleotides and during enzymatic replication.•UBPs deployed in living cells to create semisynthetic organisms (SSOs).•SSOs use UBPs and can store and retrieve more information than natural organisms.SSOs are being used to produce optimized protein therapeutics. With few exceptions, natural proteins are built from only 20 canonical (proteogenic) amino acids which limits the functionality and accordingly the properties they can possess. Genetic code expansion, i.e. the creation of codons and the machinery needed to assign them to non-canonical amino acids (ncAAs), promises to enable the discovery of proteins with novel properties that are otherwise difficult or impossible to obtain. One approach to expanding the genetic code is to expand the genetic alphabet via the development of unnatural nucleotides that pair to form an unnatural base pair (UBP). Semi-synthetic organisms (SSOs), i.e. organisms that stably maintain the UBP, transcribe its component nucleotides into RNA, and use it to translate proteins, would have available to them new codons and the anticodons needed to assign them to ncAAs. This review summarizes the development of a family of UBPs, their use to create SSOs, and the optimization and application of the SSOs to produce candidate therapeutic proteins with improved properties that are now undergoing evaluation in clinical trials.