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Scientists successfully used CRISPR to fix a mutation that causes disease. This is huge.

These embryos were made in the lab with sperm carrying a genetic mutation known to cause hypertrophic cardiomyopathy. CRISPR/Cas9 was used to correct the mutation.

CRISPR/Cas9 is a gene editing technology that’s revolutionizing science at a breathtaking pace.

One of its most exciting, taboo, and controversial applications is tweaking the genes of eggs, sperm, or early embryos to alter a human life. This could one day mean the ability to create smarter or more athletic humans (yes, “designer babies”), but also the chance to knock out disease-causing genetic mutations that parents pass on to their children. We’re talking about eliminating mutations linked to diseases like breast and ovarian cancers or cystic fibrosis.

On Wednesday, a team of scientists reported that they have made major progress toward proving the latter is possible.

In a paper published in the prestigious journal Nature, a team led by Shoukhrat Mitalipov of Oregon Health and Science University described how it used CRISPR/Cas9 to correct a genetic mutation that’s linked to a heart disorder called hypertrophic cardiomyopathy in human embryos. And they did it without the errors that have plagued previous attempts to edit human embryos with CRISPR.

To be clear, the new work from OHSU was an experiment — the point was to test a concept, and the embryos used were never implanted into a woman’s uterus.

But the researchers were ultimately able to show that CRISPR/Cas9 can do what they hoped it would do. It cut the mutant gene sequence, prompted the embryos to repair the DNA with healthy copies of the gene, and eliminated the disease-causing mutation altogether from many of the embryos.

CRISPR chops up DNA so that cells can then repair it

Let’s pause for a minute and make sure we’re clear on what CRISPR/Cas9 is. You can read our full explainer here, but in a nutshell, it’s essentially a clever system built into bacterial DNA that allows them to recognize and fend off attackers, usually viruses. The way it works, as Brad Plumer described it, is that special enzymes in the CRISPR sequences — known as Cas9 — carry around stored bits of viral genetic code like a mug shot. When they find a match to the code, they will chop up the DNA and neutralize the threat.

(Javier Zarracina)

The real breakthrough, which appeared in a series of landmark papers published in 2012 and 2013, was figuring out that it was possible to program CRISPR/Cas9 to find any kind of DNA code, not just viruses, and get the enzymes to snip it.

Mitalipov and colleagues created embryos in the lab with sperm from a carrier of the disease-causing mutation in the MYBPC3 gene, and eggs from 12 healthy donors. And they sent CRISPR/Cas9 into the fertilized egg.

As the embryos developed, they found that after CRISPR/Cas9 cut the sequence in the embryo DNA with the problematic gene. In most cases the embryos repaired the breaks with a healthy copy of the gene from the maternal donor.

In all, 36 out of 54 embryos ended up with mutation-free copies of MYBPC3. (Another, slight different round of the experiment yielded 42 out of 58 embryos with mutation-free copies of the gene.) Which means that had those embryos become children, the children would have had practically no chance of developing hypertrophic cardiomyopathy. That’s pretty significant since this a disease that affects one in 500 people and can cause sudden cardiac death and heart failure. If one parent has a mutant copy of MYBPC3, their child has a 50 percent chance of inheriting the condition.

These results are also promising for people (mainly older women and couples) who have a limited number of viable embryos to use to get pregnant with in vitro fertilization. Currently, reproductive medicine doctors use something called preimplantation genetic diagnosis, or PGD, to identify embryos with harmful mutations. And when they find embryos with mutations linked to disease, they often discard them, which can leave patients with few healthy embryos to try to transfer into the womb. (Transfer success rates are overall pretty low.)

The researchers say that in the future, their technique could be used with PGD to help fix the mutations in embryos that otherwise would be discarded, giving women and couples more embryos to transfer and a better chance of getting pregnant.

These researchers got over some of the technical hurdles that stymied other studies

We’re not ready for gene editing in embryos that would be implanted for pregnancy anytime soon. But this is a big advance because the researchers got stronger results than anyone who has ever tried to target disease-causing genes with CRISPR-Cas9 before.

And while the experiment focused only on this particular gene and disease, the researchers say they feel confident the technique would work for many of the thousands of other inherited disorders out there linked to one mutation — because their approach has so far proved to be efficient, accurate, and safe.

But in a press conference on Tuesday, one of the co-authors, Paula Amato, an OB-GYN doctor at OHSU, stressed that many more safety tests would be needed before proceeding with a clinical trial. “We want to replicate the study with other mutations and other [sperm and egg] donors,” she said. In particular, she said she’s interested in seeing if it works on BRCA1 and 2, mutations that increase the risk of breast and ovarian cancers.

Other researchers, including Nerges Winblad and Fredrik Lanner at Karolinska Institutet in Sweden, who wrote an accompanying article in Nature, are encouraged by the results but still cautious about the safety of the technology. They zeroed in on issues that have shown up in previous studies: “off-target effects,” or undesirable mutations in genome regions close to the targeted sequence, and mosaicism, where not all embryo cells make the desired changes. According to Winblad and Lanner, researchers will have to keep showing that they can reliably avoid these and other abnormalities in edited embryos “before [the technology] can be used as a therapy for inherited diseases.”

Amato and her co-authors said there’s also plenty of room for other improvement. Some of their embryos’ DNA ended up with unintended additions or deletions. So their goal would be to get 80 to 90 percent of a large group of embryos mutation-free to ensure that the technique is reliable before attempting a clinical trial.

Again, this wasn’t the first time scientists had tried to use CRISPR to edit human embryos. Chinese researchers have done it twice: once in 2015 to modify a gene linked to the blood disorder called beta thalassaemia, and then in 2016 to make genes resistant to HIV. But both of these experiments were smaller, and one used abnormal embryos while the other used immature eggs. And the results from both were messy, suggesting that embryo editing had a long, hard road ahead.

It was precisely those messy results, along with a host of other concerns, that prompted the Organizing Committee for the International Summit on Human Gene Editing at the National Academies of Sciences, Engineering, and Medicine to advise researchers in December 2015 to be extremely cautious about editing sperm, eggs, and embryos (known collectively as the human germline). Then in a report in February, it said clinical trials on human genome editing might one day be allowed, but in the meantime, researchers could attempt to correct mutations that cause “a serious disease or condition” and only when no “reasonable alternatives” exist. And definitely no research on enhancement of human traits like intelligence or strength for now.

Clinical trials for this kind of embryo editing are probably still a long ways off for the US

At present, the US government does not fund any genomic editing of human embryos. (Mitalipov and his colleagues got funding from their university this new study.) And the Food and Drug Administration is prohibited by Congress from considering any clinical trials related to genetic editing of eggs, sperm, or embryos.

The impressive new findings in Nature raise huge questions about how the US should proceed with this field of research. How soon to allow clinical trials, for instance?

“I believe [the National Academies] can reconsider what mutations and what cases the gene corrections can be used and must be used” to allow clinical trials in the future to go forward, said Mitalipov. “We may not be in agreement with the committees. The work is back and forth, and the committees hopefully will consider new options.”

He added that he’d be willing to move this research to the UK, if necessary. He also is sensitive about how his results are portrayed, given the American public’s reticence, and in some cases fear, about genetic modification.

“I don’t like the word ‘editing,’” he said. “We didn’t edit or modify anything. ... We used CRISPR to correct, using existing maternal genes.”

Other CRISPR researchers have weighed in about where the field should go from here.

“In my opinion, we still need to respect the recommendations in the [National Academy of Sciences] report published in February that recommended refraining from clinical use of human germline editing until and unless there’s broad societal consensus about the value,” Jennifer Doudna, a UC Berkeley molecular biologist and a leading CRISPR researcher, told the Los Angeles Times.

It may be quite a while before a clinical trial is approved. In the meantime, any prospective parents who want to avoid passing on disease-causing genes to their kids will have to continue to use PGD during in vitro fertilization.

Further reading:

As we’ve reported, scientists from myriad fields are using CRISPR to try to grow better food, destroy viruses, and clean up the environment.

Hank Greely explains for Vox why in 20 to 40 years, most Americans won’t have sex to reproduce.