Creating a new gene in a single day could soon be possible, thanks to a new technique that mimics the way the body copies its own DNA. Though the technology needs to clear a few more hurdles, it could one day let researchers speedily rewrite microbe genes, enabling them to synthesize new medicines and fuels on the fly.
"It's the future," says George Church, a geneticist at Harvard University who has pioneered numerous technologies to read and write DNA for synthetic biology. "This is going to be enormous."
Researchers have been able to make DNA since the 1970s. The traditional approach takes DNA nucleotides—the chemical letters A, G, C, and T—and adds them, one by one, to a growing chain called an oligonucleotide, or oligo. But the process, which uses a series of toxic organic reagents, is typically slow and error-prone, limiting oligos to about 200 letters—a tiny fraction of the thousands of letters that make up most genes.
Our cells make DNA differently. A variety of enzymes called polymerases read a single strand of DNA and then synthesize a complementary strand that binds to it. That has prompted dreams of re-engineering polymerases to write new DNA.
Over the decades, most researchers have settled on one particular polymerase, called terminal deoxynucleotidyl transferase (TdT), because, unlike other polymerases, it can attach new nucleotides to an oligo strand without following a DNA template strand. Natural TdT does this to write millions of new variations of genes for antibodies, which the immune system can then select from to target invaders. But the natural enzyme adds new DNA letters randomly, rather than controlling the precise sequence of letters as researchers want to do.
Scientists have tried for years to make TdT add one nucleotide at a time and stop, before repeating the process with a different nucleotide, says Sebastian Palluk, a Ph.D. student who worked on the project in chemist Jay Keasling's lab at the Lawrence Berkeley National Laboratory in California. They started by adding chemical groups to DNA's four bases that act as "stop" signals. So, when TdT adds a modified A to an oligo of any length, it would be prevented from adding the next base. The oligo is then fished out, washed, and treated with another compound to cut off the blocking group, readying it for the next extension.