U.S. scientists are fixing genetic defects in human embryos. Should you be nervous?

So long space race. Hello CRISPR race.

As rumored last week and published formally Wednesday, geneticists in Oregon have become the first to genetically edit human embryos in the U.S. with the ever-popular CRISPR/Cas9 technique. Their work corrected a lethal heritable mutation in an embryo, a promising advance for parents who want conceive without passing a disease to their child. Similar research was conducted in China two years ago.

The Oregon research stands out, because unlike the Chinese projects, the team bypassed a downplayed flaw with CRISPR. This glitch can introduce unwanted changes to DNA, known as off-target mutations. Left unchecked, these off-target mutations could harm a resulting babe in unknown ways.

But the team did not solve the problem of off-target mutations for good, and their methods must overcome serious hurdles before CRISPR is ready for use in humans.

Pizza is good

Say you want to fix a mutation in your sperm or eggs’ DNA, so it doesn’t get passed on to your children. And for the sake of our example, let’s say your genetic code is made of regular words, rather than As, Ts, Gs and Cs. Your mutation reads as “pizza isn’t good” — a travesty if ever there was one.

To edit a mutation using CRISPR, you’ll need three things: an enzyme called Cas9, a set of compounds called guide RNAs and a DNA template.

The Cas9 enzyme does the heavy lifting. It cuts out the mutation — “isn’t — from your DNA. Cas9 is escorted to the mutation by the guide RNAs. They recognize the sections adjacent to the mutation — “pizza” and “good” — and orient the Cas9, so it can clip out the mutation.

But you can’t just leave a gaping hole in your genome. Your cells have machinery to repair such breaks in your DNA, but they need a template to copy from. Scientists can engineer small pieces of synthetic DNA that feed into these repair systems, like feeding paper into a printer. And if those artificial DNA strands say “pizza is good” then that’s what gets copied into your genome.

Correcting Humans

That’s what the Oregon team aimed to do with a mutation in the gene called MYBPC3.

“This gene mutation is one of the most common causes of hereditary cardiomyopathy, which is a heart condition that can lead to sudden cardiac death in young people,” Paula Amato, a reproductive endocrinologist at Oregon Health & Science University who co-led the landmark study published Wednesday in Nature, said at a press briefing. “It’s prevalent in certain ethnic populations.”

Your MYBPC3 gene builds thick and thin “wires” that allow your heart muscles to contract. Normally, humans inherit two healthy copies of this gene from their parents. One copy comes from mom (“pizza is good”), the other from dad (“pizza is good”). But MYBPC3 heart conditions, which affect 1 in 500 people, are autosomal dominant — meaning just one abnormal copy from a parent (dad’s “pizza isn’t good” + mom’s “pizza is good”) is sufficient to cause the disease.

Amato and her colleagues recruited a man who had this disease, due to having one abnormal copy, and used his sperm to fertilize eggs from 12 healthy women donors. Right after combining sperm and egg in petri dishes, the CRISPR components — Cas9, guide RNAs and synthetic DNA template — were injected into the mix.

CRISPR ultimately corrected the mutation in 72 percent of the resulting embryos. “All the cells in the [corrected] embryos contain two normal copies of the gene,” Amato said. (They all had two copies of “pizza is good”).

3D-printed model of CAS9, a DNA-cutting enzyme that features in the CRISPR gene editing system. Photo by NIH Image Gallery

This huge achievement was bolstered by their experiments yielding zero off-target mutations — accidental changes to the genomes outside of the MYBPC3 gene. Off-target mutations are inherent to CRISPR because the guide RNAs can sometimes lead the Cas9 enzyme to the wrong location.

“We found that typically Cas9 [enzymes] cleave the human genome at about 90 sites,” said Jin-Soo Kim, a genomicist at the Institute for Basic Science in South Korea, who co-led the Nature study. But there are multiple types of Cas9. Kim said their project got lucky by choosing a variety of Cas9 and a set of guide RNAs that were highly specific to the MYBPC3 mutant gene.

“Using whole genome sequencing [on the embryos], we did not observe any off-target effects,” Amato said.

Not ready for designer babies

Case closed? Can this technique be used to save the world from this debilitating disease and many others? Not so fast.

“I think we have room to improve,” said Shoukhrat Mitalipov, a stem cell biologist at Oregon Health & Science University who led the research. He wants to achieve 100 percent efficiency in correcting the mutation among embryos, rather than the 72 percent they saw.

Moreover, their synthetic DNA templates did not work, which surprised the team. As the embryos went about filling the gaps made by CRISPR, their repair machinery pulled in the healthy copy of the MYBPC3 gene provided by the mom’s eggs, rather than the synthetic strands.

The Oregon team’s technique can only be harnessed in situations where at least one parent can offer a healthy set of genes. Photo by MIKI Yoshihito/via Flickr

That’s both exciting and problematic. It suggests the Oregon team’s technique can only be harnessed in situations where at least one parent can offer a healthy set of genes, such as cystic fibrosis or the breast cancer mutation BRCA.

But there are many inherited diseases — like sickle-cell anemia — in which both parents pass on a mutant copy of a gene to an embryo. Doctors and scientists would absolutely need their synthetic DNA templates to work in these cases.

These kinks would need to hammered out before CRISPR can be approved for medical use, said Jessica Berg, a law and bioethics professor at the Case Western Reserve University Schools of Law and Medicine in Ohio. As a result, CRISPR techniques, including the one from the Oregon study, are years from being used as actual treatments in patients.

“So you’re not going to be able to say, “Listen I got the technique to work sometimes, and sometimes I got disaster,” Berg said. “That might work for a petri dish. That’s not going to work in babies.”

Some states prohibit all forms of embryonic research, but there is wiggle room on the national stage. Congress and the National Institutes of Health have banned the use of federal funds for gene editing research in human embryos. But the current study circumvented the latter restrictions by using self-raised funds and grants from private foundations.

That loophole raises questions of whether or not a private company, a foundation or rich individual in the U.S. could advance human tests without federal oversight. The answer is yes and no.

Berg said the Food and Drug Administration doesn’t currently regulate CRISPR, but the agency does have strict criteria ensuring that a medical technique does no harm before it is used in pregnant women, human fetuses and neonates. The National Academies of Science agreed on a set of guidelines that they finalized earlier this year. Any treatment — developed privately, publicly or otherwise — would need to adhere to the FDA’s criteria for it to be sold in the U.S., which is the largest drug market on the planet.

But if you’re a rich individual or privately funded, there is technically nothing to stop you from advancing research with CRISPR in humans. Mitalipov, for instance, said his lab would be open to moving the technology overseas where regulations on basic experiments on genetic editing in embryos are more relaxed.

“We would be supportive of moving this technology in different countries, [because] these mutations are pretty common in the human population,” Mitalipov said. He cited the UK as one possible destination, given the island nation has approved the use of genetic modification on embryos for mitochondrial diseases. Moreover, this mitochondrial replacement therapy is technically banned in the U.S., but that didn’t stop a pair of U.S. based parents from traveling overseas to receive the treatment.

Though there’s no international body in place to regulate such globetrotting. But Berg said most countries, from a regulatory standpoint, aren’t being cavalier about manipulating genetics when it comes to pregnancy. “Everyone is being cautions about making sure we have all the cards in place,” she said.

She is also less worried about the idea of designer babies or eugenics at this point. Complex traits — like intelligence, athletic performance, height, eye color and skin color — are dictated by dozens if not hundreds of genes. Right now, scientists can barely edit one gene at a time, even with a technology as sophisticated as CRISPR.

Berg’s main concerns, and those of the researchers in Oregon, lie with the safety of mothers and children.

But the payoff could be huge. Amato raised a case of an older woman with an MYBPC3 mutation who visited her clinic. The patient wanted a child, but was worried about passing on the disease, so Amato attempted preimplantation genetic diagnosis. That’s where doctors use in vitro fertilization (mix eggs and sperm in petri dishes), screen the embryos for mutations, then only implant ones without genetic defects inside the mother.

Older women tend to produce eggs with more genetic abnormalities, on top of whatever traits they’re born with. As a result, Amato’s patient had zero candidates for implantation after multiple expensive rounds of IVF. The embryos either carried MYBPC3 defect or other deleterious mutations. Relying on the luck of the draw, even with preimplantation genetic diagnosis, wasn’t enough.

“You’re talking about very small numbers, and multiple cycles to get normal embryos,” Amato said. By removing MYBPC3 mutations from the equation, the CRISPR technique developed by Amato and company would increase the odds of success.

“We could have rescued some of those embryos,” she said.