MIT scientists invent technology to replace broken genes or upload new ones

“This is a major innovation,” said Maura McGrail, a biologist who uses gene editing to study brain development and diseases in animal models at Iowa State University. “It really opens up our ability to modify the genome in ways that can be useful for biomedical research as well as gene therapy.”

Such treatments are at least a few years away from being tested in people. So far, the technology has only been tested in human cells grown in a petri dish and in lab mice.

But biotech investors have already lined up to get a stake in the technology and related approaches. Cambridge-based Prime Medicine, Somerville-based Tessera Therapeutics, and Watertown-based Tome Biosciences — founded by Abudayyeh and Gootenberg last year — are all working on technologies that aim to add new genes or replace faulty ones to treat disease.

These firms, and others in earlier stages, are developing a third generation of technologies based on CRISPR gene editing — the revolutionary tool invented just over a decade ago that empowered biologists to manipulate DNA with ease and precision. Multiple Boston companies are testing experimental therapies based on earlier generations of CRISPR in clinical trials.

The first generation of CRISPR tools relied on a bacterial enzyme called Cas9 to cut DNA at specific sites in the genome, a method that can be used to shut down disease-causing genes. Scientists can also use Cas9 to create an opening to slot in a new gene, but that approach is inefficient and prone to introduce unwanted, and potentially dangerous, mutations.

A second generation of tools, known as base editors, can swap a single letter in the genetic code for another, which can correct typos responsible for inherited diseases. But many diseases are caused by several different genetic mutations, and creating base editing therapies for all of them is unrealistic.

The third generation of gene editing promises to overcome these limitations with tools and techniques that can tackle a wide variety of diseases more safely and efficiently. The methods go by many names. Prime calls it prime editing, Tessera calls it gene writing, and Tome calls it gene insertion. All of them use complex molecular machines, made from natural enzymes that are tweaked and stitched together, to add or replace DNA at precise locations in the human genome.

“We now have several technologies to solve a problem that not that long ago had zero solutions,” said Marc Güell, a synthetic biologist at Pompeu Fabra University in Spain who cofounded Integra Therapeutics in Barcelona to develop his own gene writing technology. Harvard University geneticist George Church is on the startup’s scientific advisory board.

The field is quickly becoming one of the most competitive and secretive sectors of the biotech industry. Experts say that many of these gene writing technologies have similarities, but because many of the companies are shy on the details of their approaches, it is hard to draw direct comparisons.

Tome, the company founded by Abudayyeh and Gootenberg, is developing “programmable gene insertion,” according to its website, language that mirrors the description of the PASTE. But Abudayyeh and Gootenberg declined to confirm that Tome is using the technology, and the company did not respond to a request for comment.

The newly published study reveals that a core part of the PASTE technology is an enzyme called an integrase, used by some viruses to sneak their own genes into bacteria. In nature, these enzymes only insert viral genes at specific segments of DNA that function like molecular landing pads. That restriction has made it difficult for scientists to repurpose integrases as a tool for inserting genes into human genomes.

Abudayyeh and Gootenberg sought to overcome that problem by combining the integrase with two other enzymes that collaborate to lay out a landing pad for the integrase at the exact spot in the genome where researchers want to insert the therapeutic piece of DNA.

“It’s impressive work, there’s no question about it,” said Erik Sontheimer, a gene editing researcher and vice chair of the RNA Therapeutics Institute at UMass Chan Medical School. New methods for precisely inserting DNA into the genome is “something everybody wants” in the field, he added. Sontheimer is on Tessera’s scientific advisory board.

Two of the three enzymes used in the PASTE technique are the same ones used in the prime editing technique developed by David Liu, a researcher at the Broad Institute of MIT and Harvard, which can be used to add dozens to hundreds of letters of DNA code into a genome.

Some researchers told the Globe that PASTE was essentially a new iteration of prime editing rather than a wholly new technology. Abudayyeh and Gootenberg acknowledged that PASTE builds on prime editing, but emphasized that it required a lot of engineering to get all three enzymes to work together. They also said that their approach can be used to add much larger pieces of DNA — up to 36,000 letters long — than prime editing.

Yet the PASTE technique was only 2.5 percent effective at integrating a new gene into liver cells in mice. Sontheimer said that means there’s a lot of room for improvement, but noted that other gene editing technologies also debuted with low success rates that have since improved.

“This is just the first attempt,” he said. “Once you establish your baseline, then you tweak, you optimize, you turn as many knobs as you can possibly access, and those numbers go up.”


Ryan Cross can be reached at ryan.cross@globe.com. Follow him on Twitter @RLCscienceboss.