Life on Earth relies on two natural base pairs (A-T and C-G) to store and retrieve genetic information. Artificial genetic systems will open the doors to many endeavors and provide powerful tools for various biological applications. However, most of the components of the systems proposed to date are not recognized by the cellular machinery and are therefore not compatible with classical molecular biology techniques such as the polymerase chain reaction (PCR). We developed a functional unnatural base pair (UBP) between the two unnatural nucleotides, d5SICS and dNaM, or analogs thereof that, unlike the natural base pairs, pair via hydrophobic and packing forces (Fig. 1). We next demonstrated PCR with the UBP, applied it to site-specific nucleic acid labeling, and elucidated its surprising mechanism of replication together with our structural collaborators. Finally, we integrated the synthetic UBP into the replication system of E. coli and demonstrated its faithful replication on a plasmid. This result established the first semi-synthetic organism with increased potential for information storage and retrieval, and provides a platform for the orthogonal re-engineering of life.

Award Address (Nobel Laureate Signature Award for Graduate Education in Chemistry Sponsored by Avantor Performance Materials). Expansion of the genetic alphabet in vitro and in vivo

249th National Meeting (2015)

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