Yale, Harvard researchers making strides on methods to recode the human genome

You’ve heard of decoding the genome — the monumental scientific project to learn the blueprint of a human being by reading the DNA book of life, letter by letter. Over the past few years, scientists have been making quiet progress on a less-publicized effort to recode the genome, by developing powerful tools that will allow them to edit or completely rewrite it on a massive scale.

When trying to understand why that’s important, the powerful “book of life” metaphor unravels a little bit — after all, what would be valuable about taking a finished work of Shakespeare and swapping in synonyms or completely new words at various spots in the text? It’s hardly likely to enrich the experience of reading a classic play.

To understand why it matters, one has to think about DNA more like an engineer trying to build new things. The letters of DNA are strung together in three-letter words, each of which makes an amino acid — compounds that cells combine to make proteins. Swapping out letters or words therefore means that scientists can create whole new organisms that manufacture novel kinds of proteins that might have industrial or biomedical uses.

“It’s expanding the chemical repertoire,” said Farren Isaacs, assistant professor of molecular, cellular, and developmental biology at Yale University. “By making these fundamental changes to the code, you can create organisms that are safer, . . . more useful for the biotechnology industry, and organisms with alternate genetic codes are actually resistant to viruses.”

On Thursday in the journal Science, Isaacs and George Church, a biologist at Harvard Medical School, reported in a pair of papers on new efforts to advance a technique developed a few years ago that enables massive editing of the genome.

In one paper, the researchers were able to replace several hundred instances of a particular sequence of three letters in E. coli with a different sequence that essentially instructed cells to create the same proteins. That meant the bacteria could still function. Then, they inserted a novel sequence, creating a bacteria that could create a protein not found in nature. They were able to show that these changes also made the bacteria resistant to viral infections.

In a second paper, the researchers were able to show the scope of genetic words they could tweak, not limiting themselves to a single sequence of three letters.

There have been a number of methods pioneered over the past few years to edit the genomes of organisms, giving biologists a large tool kit. Isaacs and Church used a technique that makes targeted changes to DNA and also takes advantage of the process of evolution to select the strains of altered bacteria that are most viable.

“There are different ways to skin the cat,” Isaacs said. “It’s pretty exciting right now — we’re suddenly in the past few years seeing this influx of new types of technologies that are allowing us to perform unprecedented changes to genomes, and that’s really exciting and powerful.”