MIT scientists invent technology to replace broken genes or download new ones - The Boston Globe

MIT scientists invent technology to replace broken genes or download new ones – The Boston Globe

“This is a major innovation,” said Maura McGrail, a biologist who uses gene editing to study brain development and disease in animal models at Iowa State University. “It really opens up our ability to edit 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 humans. So far, the technology has only been tested on human cells grown in a petri dish and on 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 to add new genes or replace faulty ones. to treat the disease.

These companies, and others at earlier stages, are developing a third generation of technologies based on CRISPR gene editing – the breakthrough tool invented just over a decade ago that allowed biologists to manipulate the DNA with ease and precision. Several Boston companies are testing experimental therapies based on previous 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 pathogenic genes. Scientists can also use Cas9 to create an opening to insert a new gene, but this approach is inefficient and susceptible to introducing unwanted and potentially dangerous mutations.

A second generation of tools, known as base editors, allow one letter of the genetic code to be swapped out for another, making it possible to correct typos that cause hereditary diseases. But many diseases are caused by several different genetic mutations, and it’s unrealistic to create base-editing therapies for all of them.

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. Methods have several names. Prime calls it Master Editing, Tessera calls it Gene Writing, and Tome calls it Gene Inserting. All use complex molecular machines, made from natural enzymes that are modified and stitched together, to add or replace DNA at specific locations in the human genome.

“We now have several technologies to solve a problem that not so long ago had no solution,” said Marc Güell, a synthetic biologist at Pompeu Fabra University in Spain, who co-founded Integra Therapeutics at Barcelona to develop its own genetic 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 secret sectors in the biotech industry. Experts say many of these gene-writing technologies have similarities, but since many companies are coy about the specifics of their approaches, it’s hard to draw direct comparisons.

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

The recently published study reveals that a key part of the PASTE technology is an enzyme called integrase, used by some viruses to introduce their own genes into bacteria. In nature, these enzymes only insert viral genes into specific segments of DNA that function as molecular landing platforms. This restriction has made it difficult for scientists to reuse integrases as a tool for inserting genes into human genomes.

Abudayyeh and Gootenberg sought to overcome this problem by combining integrase with two other enzymes that work together to establish a landing pad for integrase at the exact location in the genome where the researchers want to insert the piece of DNA. therapeutic.

“It’s impressive work, there’s no doubt about it,” said Erik Sontheimer, gene editing researcher and vice president of the RNA Therapeutics Institute at UMass Chan Medical School. New methods for precisely inserting DNA into the genome are “something everyone wants” in the field, he added. Sontheimer is a member of Tessera’s Scientific Advisory Board.

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

Some researchers told the Globe that PASTE is essentially a new iteration of the core edition rather than an entirely new technology. Abudayyeh and Gootenberg acknowledged that PASTE relies on core editing, but pointed out that it takes a lot of engineering to get the three enzymes to work together. They also said their approach could be used to add much larger pieces of DNA – up to 36,000 letters long – than the main edit.

Yet the PASTE technique was only 2.5% efficient at integrating a new gene into mouse liver cells. Sontheimer said that means there is plenty of room for improvement, but noted that other gene-editing technologies also debuted with low success rates that have since improved.

“It’s just the first attempt,” he said. “Once you establish your baseline, you tweak, you optimize, you turn as many knobs as you can possibly reach, and those numbers go up.”

Ryan Cross can be contacted at Follow him on Twitter @RLCscienceboss.

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