The gene-editing system CRISPR is the hottest subject in biology because of the technique’s ability to change DNA letters and potentially cure genetic disease.
So what could be better? What about a way to edit genes with no CRISPR at all.
A startup called Homology Medicines says it has a way to do that. The Bedford, Massachusetts, company has raised an impressive $127 million to treat genetic diseases using viruses it claims are capable of efficiently repairing human genes, all on their own.
If its claim is true, Homology may have hit on the safest, simplest way yet to change genes in the human body—one that doesn’t require slashing open a person’s DNA strands, as CRISPR does.
Having something better than CRISPR would be high-impact. But Homology’s scientific results aren’t yet widely accepted. In fact, several scientists told MIT Technology Review that they believe the claims are probably wrong.
“What’s surprising is this company raised so much money on something thought to be untrue in the scientific community,” says David Russell, a researcher at the University of Washington, in Seattle. “I think there is just a gene-editing frenzy.”
Right now, finding better ways to alter a person’s genes to eliminate disease may be medicine’s most important quest—and one of its most lucrative. On Wednesday, the U.S. Food and Drug Administration approved what it termed the “first gene therapy” in the U.S., a treatment from Novartis that uses gene-modified immune cells to treat leukemia. Drugs like it could eventually generate billions in sales.
Traditional gene-therapy methods can only add genes, often at random, using a virus to get them inside cells. Gene editing, by contrast, refers to powerful new technologies that also precisely delete or revise DNA letters. It’s sometimes called “gene therapy 2.0.”
So far, CRISPR is the most versatile gene-editing system known. To edit a genome, it relies on a nuclease—a protein enzyme that slices through the DNA double helix. That damage sets off emergency repairs inside a cell that scientists can harness to change letters in the DNA code.
Homology’s striking claim is that it has a way of making editing happen without adding a nuclease, and therefore without breaking the DNA strand. Think of surgery without a scalpel or a tailor without scissors.
It sounds impossible, but in fact Russell was first to demonstrate the phenomenon in 1998. If a DNA strand delivered by a virus closely matches a given gene (this similarity is termed “homology”) it can sometimes swap in for it when a cell divides. Thus, a DNA mutation can be replaced with a correct sequence, or edited.
The hitch is that such virus-driven repairs happen only very seldom and through a chance process that remains poorly understood. In some cell types only one in 1,000 cells are ever edited. That’s not enough to think about treating most diseases—so virus editing was never widely adopted by drug developers.
Now Homology says it has hit on a way to do it much better. In May, at the annual meeting of gene and cell therapy experts, researchers from the lab of the company’s scientific founder, Saswati Chatterjee of City of Hope National Medical Center, in Duarte, California, said they’d found viruses able to edit as many as 50 percent of cells in a test tube with a gene that makes them glow.
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“The Holy Grail was always to do gene editing with a simple viral vector and no nuclease,” says Russell. “There is no cutting of the DNA, minimal toxicity, and no problems with delivery. If you hit 50 percent it would be the greatest gene-editing technique ever.”
But Russell says he feels certain the result is too good to be true. Several other scientists said they are skeptical, too. “Many of us in the audience were not convinced that what they were claiming were supported by the data they presented,” says Matthew Porteus, a gene-editing specialist at Stanford University who attended the talk and who works on CRISPR.
The company got its start after Chatterjee decided to start mining bone marrow samples for traces of viruses, called AAVs, that are used in conventional gene therapy.
New virus types are valuable in their own right because each kind can help scientists infect specific organs, like the brain or liver. A growing array of new viruses is one reason gene therapy has become increasingly effective, allowing genes to be added to certain cells, but not others. Chatterjee found 17 new virus types and filed patents on them.
“It’s one of those experiments you kick yourself and say ‘Why didn’t I think of that?’” says Fyodor Urnov, associate director at the Altius Institute for Biomedical Sciences, in Seattle.
But Chatterjee made a further claim that had investors drooling. She says her viruses turned out to be major-league gene editors, too. “That ignited the beginning of the company,” says Homology’s CEO, the biotech executive Arthur Tzianabos.
If editing can be efficiently carried off with only a virus, it would combine the power of CRISPR with the simplicity of well-understood gene-therapy methods. “This would be single injections to do gene correction in the body; that would be a huge leap,” says Tzianabos. “We think it’s easier to develop, less complicated, and more precise.”
Investors who missed out on CRISPR were especially keen to get in on the action. The investors behind Homology Medicines include 5AM Ventures and ARCH Venture Partners, both well-known venture capital groups. Efforts by MIT Technology Review to reach partners at the two funds were not successful.
Stephen Elledge, a Harvard University specialist on DNA repair, was hired by Homology to be a scientific advisor and agrees there are open questions. “It’s not clear what they have found that makes it better; they could be getting more DNA in, or it could be something about the virus. That is not all worked out,” he says. “But I have seen some data and I thought it was impressive."
Homology is still carrying out laboratory research to confirm and extend its results, Tzianabos says. “There is always skepticism when there is something new, and this is very new. I recognize this is pretty early technology coming out of an academic lab. It’s our job to industrialize this process,” he says.
For her part, Chatterjee says her lab's detailed data, which she has submitted for publication, should soon quell the doubters. "There is no basis for saying our findings are impossible," she says.
Other startup companies are also pursuing virus editing, although they don’t claim they can do it nearly so efficiently. Russell runs a company called Universal Cells that is trying to make customized supplies of cells for transplants. And LogicBio, which has raised about $50 million, wants to use virus editing to treat children with inherited liver disease.
Tzianabos says Homology Medicines eventually wants to use its viral-editing trick to treat sickle cell anemia, a blood condition caused by a small genetic error and which is also a target of CRISPR scientists like Porteus.
Porteus says for now he’s sticking to CRISPR. “There is hard enough work doing that without worrying about a better mousetrap,” he says. “It’s going to take something very special to improve on CRISPR.”