The diversity of life as we know it is, and always has been, encoded by a four letter, two base pair genetic alphabet. We have developed an unnatural base pair, d5SICS–dNaM, that forms based on packing and hydrophobic interactions rather than complementary H-bonding. d5SICS–dNaM is replicated and transcribed with excellent efficiency and fidelity and has now been used as the foundation of a semi-synthetic organism. Using the nucleotide triphosphate transporter (NTT) from Phaeodactylum tricornutum (PtNTT2), E. coli is able to efficiently import the unnatural triphosphates of both d5SICS and dNaM (d5SICSTP and dNaMTP) from the growth media, and then utilize them to maintain a plasmid containing the d5SICS-dNaM base pair. This plasmid is replicated in vivo with a fidelity (retention per doubling) of &gt;99.4%, which corresponds to an error rate that is comparable to the intrinsic error-rate of some polymerases with natural DNA. The resulting semi-synthetic organism provides the first example of the integration of a fully synthetic component into the most conserved and fundamental system of life, demonstrates that natural DNA is not the only solution to the challenge of information storage, and is the first example of a living organism that stores information using a six letter, three base pair genetic alphabet.

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

249th National Meeting (2015)

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