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Breakthrough method means CRISPR just got a lot more relevant to human health

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'The most clever CRISPR gadget to date'

Mehmet Pinarci

The gene-editing tool CRISPR may one day change the way humans approach medicine — or at least that’s how it’s been portrayed so far. But for all the talk of using CRISPR to eliminate disease, the method was never very good at doing one important thing: altering single letters of DNA. (DNA is made of four chemical units, represented by the letters A, T, G, and C.) Now, scientists at Harvard University say they've modified the CRISPR method so it can be used to effectively reverse mutations involving changes in one letter of the genetic code. That’s important because two-thirds of genetic illness in humans involve mutations where there’s a change in a single letter.

The new method, described today in Nature, is called the "base-editing technique." It relies on the same basic mechanism as the standard CRISPR method, but unlike its predecessor, it doesn’t need to cut both strands of the DNA double-helix to alter the genetic code. Instead, the technique can directly convert a single letter of DNA to another, without deleting and inserting a bunch of random letters in the process. Because of this, the researchers were able to genetically alter human cells and mouse cells to reverse single-letter mutations that are associated with late-onset Alzheimer’s and breast cancer.

CRISPR just went from handling DNA like a meat cleaver — to handling it like a scalpel

The researchers think the new technique might eventually be able to edit human DNA to minimize the impact of the 25,000 single-letter mutations that are associated with human diseases. But that’s a long way off. Here’s the important thing to remember: the new technique basically means that CRISPR just went from handling DNA like a meat cleaver — to handling it like a scalpel. And for human health purposes, that might be a heck of a lot more powerful.

The standard CRISPR method is basically a genetic cut and paste tool that’s composed of two elements: an enzyme called Cas9 that snips both strands of the DNA double-helix, and a guide molecule that navigates Cas9 to a specific location in the genome, where a genetic variant associated with a certain disease is located, for example. To use CRISPR, scientists tweak the guide molecule to ensure that Cas9 cuts DNA at a specific spot, allowing them to slip in a corrected DNA sequence if they wish. But that approach can be messy because the act of cutting the double-helix often causes cells to add or remove elements of DNA in an effort to reattach the strands as quickly as possible. Because of this, researchers haven’t been able to efficiently alter single letters in the genetic code. Typically, when using the standard CRISPR method, researchers are able to make single-letter changes in about 1 percent of cells, says David Liu, a geneticist at Harvard University who co-authored the study.

As a gene-editing technique, CRISPR is extremely young. A decade ago, scientists mostly stuck to using it to protect yogurt bacteria from infections. Now, it’s being used to edit the genes of complex organisms, producing dogs with big muscles and mosquitoes that can resist the malaria parasite. Those are giant leaps in a short period of time — but there’s a good reason for that. Overall, CRISPR is a lot more versatile, cheap, and precise than other gene-editing methods. But that doesn’t mean it’s perfect. Even though scientists have been able to use it to mess up specific DNA sequences, or even insert new strands, CRISPR doesn’t do well when it’s used to accomplish more delicate tasks, like substituting a single letter of the genetic code. That’s why today’s study is a big deal for CRISPR researchers; it opens up a whole new world of possible gene edits — and it does it without changing the basic properties that made CRISPR so attractive in the first place.

The standard CRISPR method doesn't do well with more delicate tasks

To avoid the messiness of the standard CRISPR method, the Harvard researchers decided to glue two proteins to a type of Cas9 enzyme that doesn’t cause double-stranded breaks in DNA. Collectively, the two proteins gave Cas9 the ability to directly convert one specific letter in the four-letter genetic code to another, while bypassing any attempts that a cell might make to undo the conversion.

The researchers tested the new method on mouse and human cells. During one attempt, they found that the base-editing technique was able to convert a mutation associated with Alzheimer’s disease in 58 percent of the cells, without causing too many unintended changes. In another, it worked in 75 percent of cells. That’s a high rate of success. But more importantly, altering 75 percent of cells might be enough to minimize the symptoms of certain diseases, Liu says. Of course, that will have to be determined in future trials.

For many CRISPR researchers, the base-editing technique is a source of excitement. "This is arguably the most clever CRISPR gadget to date," says George Church, one of the pioneers of CRISPR and a geneticist at Harvard who didn't work on the study. The new method is like receiving "shiny, new ‘scalpels’" that are "specialized and sharp enough to precisely cut out specific sequences in hard-to-reach cells," Kris Saha, a biomedical engineer at the University of Wisconsin-Madison, told the Genetic Expert News Service.

But the technique isn’t all powerful — at least not yet. Chen Liang, an HIV researcher at McGill University who has worked with CRISPR, points out that because the technique can only be used to directly convert one letter, it’s somewhat limited. Still, the finding means that "high precision of CRISPR/Cas9 genome editing is becoming possible," he says, and that’s an important step forward.

The new method can only directly convert one letter

Liu knows that there’s only so much geneticists can do with base editing, but he thinks some of the technique’s limitations are temporary. Already, his group has begun working on versions of Cas9 that can perform conversions on other letters. The researchers also plan to do more work on cells to reverse mutations associated with different human diseases. Eventually, they’ll try the technique on live animals as well. "You can use animal models to answer the key questions of ‘if I correct the mutation, what will happen to the symptoms of the disease? Will they go away, will they not go away?’ et cetera," Liu says.

Even if the technique works well in animals, it’ll be a number of years before it’s used on humans. Scientists around the world have already raised concerns over the idea that CRISPR could be used to permanently alter the human race. As a result, an expert panel declared late last year that gene-editing tools shouldn’t be used to alter human embryos that might result in a person. They also said that scientists shouldn’t make changes that could be passed on to future generations.

Still, Liu thinks that it might be possible to treat human disease without permanently altering the human gene pool. For example, scientists may be able to minimize symptoms by making localized DNA alterations in the organs of adults. But even then, "it takes years to translate technologies that modify the genome into even animal models," he says. So it’ll be a while before scientists reach the human stage.