The experiment raises major safety concerns for gene-edited babies
A team of scientists has used the gene-editing technique CRISPR to create genetically modified human embryos in a London lab, and the results of the experiment do not bode well for the prospect of gene-edited babies.
Biologist Kathy Niakan and her team at the Francis Crick Institute wanted to better understand the role of a particular gene in the earliest stages of human development. So, using CRISPR, they deleted that gene in human embryos that had been donated for research. When they analyzed the edited embryos and compared them to ones that hadn’t been edited, they found something troubling: Around half of the edited embryos contained major unintended edits.
“There’s no sugarcoating this,” says Fyodor Urnov, a gene-editing expert and professor of molecular and cell biology at the University of California, Berkeley. “This is a restraining order for all genome editors to stay the living daylights away from embryo editing.”
While the embryos were not grown past 14 days and were destroyed after the editing experiment, the results provide a warning for future attempts to establish pregnancies with genetically modified embryos and make gene-edited babies. (The findings were posted online to the preprint server bioRxiv on June 5 and have not yet been peer-reviewed.) Such genetic damage described in the paper could lead to birth defects or medical problems like cancer later in life.
This is a restraining order for all genome editors to stay the living daylights away from embryo editing.
Since CRISPR’s debut as a gene-editing tool in 2013, scientists have touted its possibilities for treating all kinds of diseases. CRISPR is not only easier to use but more precise than previous genetic engineering technologies — but it’s not foolproof.
Niakan’s team started with 25 human embryos and used CRISPR to snip out a gene known as POU5F1 in 18 of them. The other seven embryos acted as controls. The researchers then used sophisticated computational methods to analyze all of the embryos. What they found was that of the edited embryos, 10 looked normal but eight had abnormalities across a particular chromosome. Of those, four contained inadvertent deletions or additions of DNA directly adjacent to the edited gene.
A major safety concern with using CRISPR to fix faulty DNA in people has been the possibility for “off-target” effects, which can happen if the CRISPR machinery doesn’t edit the intended gene and mistakenly edits someplace else in the genome. But Niakan’s paper sounds the alarm for so-called “on-target” edits, which result from edits to the right place in the genome but have unintended consequences.
“What that means is that you’re not just changing the gene you want to change, but you’re affecting so much of the DNA around the gene you’re trying to edit that you could be inadvertently affecting other genes and causing problems,” says Kiran Musunuru, a cardiologist at the University of Pennsylvania who uses CRISPR in his lab to research potential heart disease therapies.
If you think of the human genome — a person’s entire genetic code — as a book, and a gene as a page within that book, CRISPR is like “ripping out a page and gluing a new one in,” Musunuru says. “It’s a very crude process.” He says CRISPR often creates small mutations that are probably not worrisome, but in other cases, CRISPR can delete or scramble large sections of DNA.
This isn’t the first time scientists have used CRISPR to tweak the DNA of human embryos in a lab. Chinese scientists carried out the first successful attempt in 2015. Then, in 2017, researchers at the Oregon Health and Science University in Portland and Niakan’s lab in London reported that they’d carried out similar experiments.
Ever since, there have been fears that a rogue scientist might use CRISPR to make babies with edited genomes. That fear became reality in November 2018, when it was revealed that Chinese researcher Jiankui He used CRISPR to modify human embryos, then established pregnancies with those embryos. Twin girls, dubbed Lulu and Nana, were born as a result, sending shockwaves throughout the scientific community. Editing eggs, sperm, or embryos is known as germline engineering, which results in genetic changes that can be passed on to future generations. Germline editing is different from the CRISPR treatments currently being tested in clinical trials, where the genetic modification only affects the person being treated.
While many scientists have opposed the use of germline editing to create gene-edited babies, some say it could be a way to allow couples at high risk of passing on certain serious genetic conditions to their children to have healthy babies. Beyond preventing disease, the ability to edit embryos has also raised the possibility of creating “designer babies” made to be healthier, taller, or more intelligent. Scientists almost universally condemned He’s experiment because it wasn’t meant to fix a genetic defect in the embryos or prevent disease. Instead, he tweaked a gene in order to make the resulting babies resistant to HIV.
In the United States, establishing a pregnancy with an embryo that has been genetically modified is prohibited by law. More than two dozen other countries directly or indirectly prohibit gene-edited babies. But many countries have no such laws. Since He’s fateful gene-editing experiment became public, a researcher in Russia, Denis Rebrikov, has expressed interest in editing embryos from deaf couples in an attempt to provide them with babies that can hear.
Niakan could not be reached for comment, but in a December 2019 editorial in the journal Nature, she argued that much more work on the basic biology of human development is needed before gene editing can be used to create babies. “One must ensure that the outcome will be the birth of healthy, disease-free children, without any potential long-term complications,” she wrote.
The embryos edited by Niakan and her team were never intended to be used to start a pregnancy. In February 2016, her lab became the first in the U.K. to receive permission to use CRISPR in human embryos for research purposes. The embryos used are left over from fertility treatments and donated by patients.
Niakan’s paper comes as the U.S. National Academies, U.K.’s Royal Society, and the World Health Organization are contemplating international standards around the use of germline genome editing in response to the global outcry over He’s experiment. The committees are expected to release recommendations this year or in 2021. But because these organizations have no enforcement power, it will be up to individual governments to adopt such standards and make them law.
Urnov says the new findings should influence those committee’s decisions in a substantial way.
Musunuru agrees. “Nobody has any business using genome editing to try to make modifications in the germline,” he says. “We’re nowhere close to having the scientific ability to do this in a safe way.”