U.S. scientists edit genome of human embryo, but cast doubt on possibility of ‘designer babies’

Creating “designer babies” with a revolutionary new genome-editing technique would be extremely difficult, according to the first U.S. experiment that tried to replace a disease-causing gene in a viable human embryo.

Partial results of the study had leaked out last week, ahead of its publication in Nature on Wednesday, stirring critics’ fears that genes for desired traits — from HIV resistance to strong muscles — might soon be easily slipped into embryos. In fact, the researchers found the opposite: They were unable to insert a lab-made gene.

Biologist Shoukhrat Mitalipov of Oregon Health and Science University, who led the first-of-its-kind experiment, described the key result as “very surprising” and “dramatic.”

The “external DNA” provided to fertilized human eggs developing in a lab dish “was never used,” he told STAT. The scientists excised a mutated, heart-disease-causing gene from the embryos — a gene that came from sperm used to create them through in vitro fertilization — and supplied them with a healthy replacement. But every single one of the 112 embryos ignored it. Instead, they copied the healthy gene from their mother and incorporated that into their genome to replace the father’s.

“This is the main finding from our study,” Mitalipov said: Embryos’ natural preference for a parent’s gene “is very strong, and they won’t use anything else.”

The discovery suggests that opportunities for disease prevention are more limited than scientists assumed and that enhancement — giving a days-old embryo “better” genes — is unlikely to succeed, at least with current methods. Genetic tinkering can, however, eliminate a “bad” gene that an embryo got from one parent and replace it with a “good” gene from the other parent. And the experiment showed for the first time in a large number of embryos that this can be done efficiently and without harming other genes.

That offers the prospect of preventing inherited diseases such as cystic fibrosis, Huntington’s disease, and some cancers, as long as one parent carries a healthy gene to replace the disease-causing one. (The age-old desire of many couples to choose which parent’s traits their child inherits could also become a reality, though probably not for years.)

Polls show greater public support for using “germline editing” — changing the DNA of very early embryos — to prevent disease than for giving embryos souped-up genes for, say, extraordinary memories or unbreakable bones. Such traits would be passed on to all subsequent generations. Although some studies have identified genes associated with those enhanced traits, they are extraordinarily rare. To bestow the traits on an embryo would require creating the genes in a lab and injecting them — the exact thing that failed completely in the new study.

The surprise finding showed that “to introduce a novel gene is [an] issue,” said Fredrik Lanner, of Karolinska University Hospital in Sweden, who was not involved in the Oregon study. (Lanner received permission last year to conduct similar experiments editing the genome of human embryos). “More research would be needed to really know how efficiently a new gene version can be introduced.”

The discovery that human embryos might have natural barriers to accepting introduced DNA — something other kinds of human cells, and other animal embryos, have no problem doing — offers some assurance that designer babies are not in the offing anytime soon. But critics of editing the human germline were not mollified.

Marcy Darnovsky, executive director of the Center for Genetics and Society, argued that there are other ways for couples to have a biological child free of the known genetic defects carried by one parent or both: Screening the DNA of IVF embryos through a technique called preimplantation genetic diagnosis (PGD) lets parents choose only healthy embryos to implant.

“We have to weigh the medical benefit to a few” from correcting an embryo’s mutation “against the social risks for all of us,” she said, adding that “enhancement-type alterations” might in fact be possible. “I don’t see any reason to doubt that Mitalipov or others will pursue other new wrinkles in these procedures, to enable more extensive genetic alterations.”

The research hit other hot buttons. Mitalipov (a skilled reproductive biologist known for pushing boundaries) and his colleagues created human embryos. Doing that for research is legal in Oregon and some other states but illegal in others and ardently opposed by many religious groups. And the scientists destroyed them after a few days, which some critics regard as murder. (The researchers had no intention of implanting the altered embryos in a uterus.)

A 1995 law prohibits the use of U.S. funds to create human embryos for research or to destroy them, and the National Institutes of Health bans use of its grants to edit the genome of human embryos, but this study was funded by private foundations and university funds.

At first glance, the experiment ran according to script. The scientists created embryos by fertilizing (in lab dishes) eggs from a dozen healthy donors with sperm from a man with the mutation that causes the rare heart disorder called hypertrophic cardiomyopathy. At the same time, the scientists injected CRISPR-Cas9.

This revolutionary genome-editing technology typically has three components. A targeting molecule carries the CRISPR complex to the target gene within a cell. A molecular scissors snips out the target gene. A healthy gene is supposed to replace the excised one. In experiment after experiment in regular human cells (not embryos), this now-classic use of CRISPR-Cas9 shreds the targeted DNA and the double helix stitches in a replacement like a seamstress darning a sock.

That’s what happened when Mitalipov injected CRISPR into stem cells produced from the man with hypertrophic cardiomyopathy. The incurable disorder strikes about 1 in 500 people, said Dr. Carolyn Yung Ho of Brigham and Women’s Hospital in Boston, making the heart’s left ventricle abnormally thick; mutations in any of several genes, including one called MYBPC3, can cause it. As expected, CRISPR efficiently snipped out the mutated MYBPC3 gene, and the cells replaced it with the healthy version that was slipped in with the CRISPR complex. “We supplied a repair template and the cells used it,” Mitalipov said.

The research ethics committee at OHSU, which vets studies, questioned Mitalipov’s proposal to CRISPR embryos next. “They told me, ‘You have your answer [from the stem cell experiment]; why do you have to do embryos?’” Mitalipov recalled. “I told them I had a hunch that the results might be different. I said, ‘Let me do embryos.’”

His hunch was right. CRISPR seemed to work like a charm in the embryos. It excised the cardiomyopathy gene in 22 of the 112 embryos, an exceptionally high efficiency for CRISPR. It excised no unintended targets, contrary to what had happened in a CRISPR experiment in China, which got many such “off-target” effects. And CRISPR worked in all of the cells the embryo eventually divided into, probably because it was injected into the egg at the same time as the sperm.

But the embryos did not insert the healthy, lab-made heart gene in place of the CRISPR’d mutated one. The reason is a mystery, but bioengineer Neville Sanjana of the New York Genome Center said, “I don’t think it is a complete surprise. After all, this is likely how DNA repair evolved in the first place — to repair a damaged chromosome by using the other, intact one.”

Mitalipov suspects that an embryo responds to CRISPR’s snipping out one of its genes by “looking up and down and around the genome and somehow recognizing maternal DNA and inserting that” in place of the snipped-out paternal gene. If so, then any replacement gene that scientists offer stands little chance of getting accepted.

Chinese researchers reported earlier this year on an experiment in which they got about 10 percent of CRISPR’d human embryos to accept an introduced gene, but it used only a few embryos and had other limitations. The U.S. study suggests that the insert-a-gene recipe for designer babies will be tougher than expected: “To introduce a novel gene,” said Karolinska’s Lanner, “you would [have to] target both DNA copies” — mom’s and dad’s — with CRISPR. That might be possible, but “more research would be needed to really know how efficiently a new gene version can be introduced.”

Even if CRISPRing embryos can only cause a child to inherit a mother’s trait and not the father’s, or vice versa, that should be enough to eliminate a disease-causing mutation from an embryo and future generations. “The vast majority of patients” with a disease-causing mutation “have a partner with the [healthy] gene,” Mitalipov said. That healthy gene, with an assist from CRISPR, could replace the mutated one in an embryo, giving children only the healthy gene.

“Every generation on would carry this repair because we’ve removed the disease-causing gene variant from that family’s lineage,” he said.

That would obviate the need to screen IVF embryos to find a mutation-free one to implant. Unwanted embryos are usually destroyed. When the OHSU ethics committee pressed Mitalipov about destroying embryos in his experiment, he had an answer: If CRISPR can eliminate disease-causing mutations from embryos, as he hoped his research would help make possible, “I’m going to rescue the [IVF] embryos that are now thrown away.”

But not soon, and probably not in the United States. Federal law prohibits regulators from even considering a request to launch a clinical trial in which embryos would be genetically altered and implanted in a uterus.

Mitalipov has another hunch, this time about where that will lead: “Unfortunately, this technology will just be shifted to unregulated countries.”

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