A, C, G, and T – For some people, four letters are not enough.

Ever since the time of Phoebus Levene, we’ve known that DNA has contained 4 bases – G, C, A, and T. Erwin Chargraff showed that the number of Gs in DNA were equal to the Cs, and the As were equal to the Ts. Then some guys you have definitely heard of solved the structure of DNA and it all made sense: our genes were written in a four-letter alphabet, with Gs bonded to Cs and As to Ts in a scheme now called “Watson-Crick base pairing”.

Today, we’ve gotten good at reading and writing in this alphabet. We can solve crimes, produce drugs, retrace the steps of human evolution, and even solve complex computational problems by reading and writing As, Gs, Cs, and Ts.

But for some people, four letters are not enough. For many years, several research groups have been working on adding new letters to the language of DNA. For example, Eric Kool and his co-workers have made size-expanded DNA. By this they mean, what happens if you drop in another benzene ring to adenine?

One example of a new letter in the DNA alphabet.

One example of a new letter in the DNA alphabet.

Floyd Romesberg and his co-workers have been coming up with additional DNA letters for as long as just about anyone else. One exemplary finding: Watson-Crick base pairing is not even necessary for the creation of new DNA letters. Instead, purely hydrophobic forces can bind oligonucleotides together, as in the artificial base pair d5SICS and dMMO2.

Two new letters for DNA

Two more new letters for the DNA alphabet, d5SICS and dMMO2

Floyd Romesberg, Eric Kool, and many other workers are getting close to engineering new letters for DNA that can be read and written using existing DNA processing tools. That is, some recently reported synthetic nucleotide base pairs can be replicated by DNA polymerases with high fidelity and good catalytic specificity. The As, Gs, Cs, and Ts of DNA will have to make room for new letters.

Soothly we live in mighty years!

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