New research shows that it's possible to insert artificial letters into the genetic DNA alphabet without altering its natural structure. It also demonstrates for the first time that it's possible for DNA sequences that use those letters to evolve, just as natural DNA does.
Those breakthroughs are another step toward potentially retooling cells to make new types of proteins that can treat diseases, according to the Journal of the American Chemical Society. Tinkering with the genetic alphabet also will help us better understand how life actually works at the most basic level.
"The science is perhaps more important than the technology, as the artificial genetic systems are teaching us volumes about how natural genetic systems operate," says chemist and co-author Steven Benner via email.
When most of us think of DNA, the molecule that functions as a genetic blueprint for our bodies, we think of its familiar double-helix shape. But to a chemist such as Benner, of the Florida-based Foundation for Applied Molecular Evolution, the map of life actually is an alphabet with four letters, each representing a chemical base: adenine (represented by the letter A), guanine (G), cytosine (C), and thymine (T). The bases match up with each other – A with T and C with G – to form units called base pairs.
Various sequences of those bases form genes, the instructions that tell our cells how to combine amino acids to make millions of different proteins, and determine everything from our appearance to our vulnerability to various diseases. Each human DNA molecule contains about 3 million bases and 20,000 genes. (Here's a basic primer on DNA from the National Human Genome Research Institute.)
For years, scientists have been intrigued by the idea of inserting additional synthetic letters to the genetic alphabet. But actually doing that is tricky because it requires getting proteins to carry the artificial letters into cells, and then getting artificial pairs of letters to plug into the structure of DNA and replicate just as naturally occurring pairs do. Additionally, the artificial pairs have to accomplish that without being detected and removed by the natural mechanism that a cell uses to repair damaged DNA.
In 2014, scientists at the Scripps Research Institute managed to insert two artificial nucleotides called X and Y into the DNA of the bacterium E. coli. The resulting "semi-synthetic" organism was able to reproduce, though more slowly than a natural E. coli. It was the first time that a living cell had operated using an altered genetic alphabet.
The work by Benner and his colleagues advances things further. They not only added new synthetic letters P and Z to the alphabet, but the DNA with the enhanced six-letter alphabet actually evolved and created new molecules that bound themselves to cancer cells — more effectively than natural DNA could.
Andrew Ellington, a University of Texas at Austin chemist who wasn't involved in the study, told Quanta magazine that the artificial six-letter alphabet "seems to have won out" over the natural four-letter version.