Reengineering Life

New Evidence Shows Editing Human Embryos Wreaks Havoc on DNA

Three papers suggest it might not be safe to make gene-edited babies with CRISPR

Photo illustration. Photo: Westend61/Getty Images

Reengineering Life is a series from OneZero about the astonishing ways genetic technology is changing humanity and the world around us.

A few weeks ago, OneZero reported new findings from a group of U.K. scientists showing that the gene-editing tool CRISPR could cause unintended DNA damage when used in human embryos. The results raised serious concerns about the safety of creating gene-edited babies.

Now there’s even more evidence that CRISPR can cause unwanted genetic mutations in embryos. After our story was published on June 16, two U.S. groups uploaded papers with similar findings to the preprint server bioRxiv. The three papers have not yet been peer-reviewed, but together, they suggest that CRISPR isn’t yet safe enough to be used in human embryos in order to prevent genetic diseases.

“This isn’t even a stop sign at this point, this is a biohazard sign the size of a football field in front of embryo editing,” says Fyodor Urnov, a gene-editing expert and professor of molecular and cell biology at the University of California, Berkeley, who was not involved in any of the three papers.

In each of the studies, researchers aimed to edit a single gene in human embryos. But each team found that CRISPR didn’t just snip out the gene it was supposed to; it inadvertently made edits elsewhere in the genome, as well. Gene-editing experts who weren’t involved in the papers say that unintended DNA edits could potentially cause birth defects, cancer, or other health problems in babies born as a result of embryo editing.

In the first paper, posted to bioRxiv on June 5, developmental biologist Kathy Niakan and her team at the Francis Crick Institute in London successfully deleted a gene involved in embryo development called POU5F1. But the findings show that using CRISPR to remove the gene also caused major deletions and rearranged nearby DNA.

In a second paper posted June 18, researchers led by Columbia University stem cell biologist Dieter Egli used CRISPR in human sperm to try to correct a mutation in a gene called EYS2 that causes blindness. Then, they used that sperm to fertilize eggs in the lab in order to create embryos. When they analyzed the resulting embryos, they observed that about half of the 23 edited embryos contained large deletions of DNA on the chromosome containing EYS2.

A third team, led by reproductive biologist Shoukhrat Mitalipov of Oregon Health & Science University, used CRISPR in 86 embryos to correct a mutation in a gene called MYBPC3 that causes a hereditary heart condition that can be fatal. The researchers found that the editing altered large segments of the chromosome where the gene is situated. The authors shared their results on bioRxiv on June 20.

It’s unclear whether the three research groups coordinated the release of their papers. The authors of the papers have either not responded to interview requests from OneZero, or declined to comment on their findings since the papers have not yet been peer-reviewed.

Their results, if they hold up under peer review, could very well influence the debate around whether scientists should use germline editing — that is, editing sperm, eggs, or embryos — to prevent genetic disease. Germline editing is controversial because it results in a genetic change that can be passed down to children. So if scientists would make a mistake, that genetic mistake would continue to be passed on to future generations.

Establishing a pregnancy with an embryo that has been genetically modified is banned in the United States. More than two dozen other countries have laws on the books that directly or indirectly prohibit gene-edited babies, but many countries have no laws that address it. Currently, a World Health Organization committee is considering how to regulate germline genome editing around the globe. In July 2019, WHO issued a statement saying, “it would be irresponsible at this time for anyone to proceed with clinical applications of human germline genome editing.”

A second committee, convened by the U.S. National Academy of Medicine, U.S. National Academy of Sciences, and the U.K. Royal Society, is contemplating how to safely carry out germline gene editing and in what situations it might be ethically permissible.

The two committees formed after the shocking revelation in November 2018 that a Chinese researcher, Jiankui He, edited human embryos with CRISPR, then established pregnancies with those embryos, leading to the birth of the world’s first gene-edited babies. The groups are expected to release recommendations this year or in 2021.

On Twitter, Paula Amato, associate professor of obstetrics at Oregon Health & Science University and a co-author on the Mitalipov paper, said using CRISPR to prevent some diseases in human embryos would be “unsafe and inefficacious at this time.” However, she suggested that correcting genetic diseases safely in embryos might be possible with a newer iteration of CRISPR called base editing.

Traditional CRISPR works by using a guide molecule to search the genome for a particular DNA sequence. Once there, the editing machinery takes over and cuts out that sequence by breaking the DNA’s double helix. The DNA then tries to repair itself, but it doesn’t always do so perfectly. As a result, mutations like those described in the three recent papers can arise.

Base editing, invented in 2016, is more precise than the original CRISPR system first described in 2012. Instead of cutting DNA directly, base editing changes a single DNA letter into another. Doing so could potentially sidestep the damage caused by breaking DNA. In fact, a Chinese group reported in 2018 that base editing in human embryos produced few unwanted edits.

“Our results serve as a cautionary note for the use of induced double-strand breaks in editing the genome of human embryos for clinical use,” Egli and his co-authors write in their paper.

But base editing may not yet be foolproof. A 2019 study found that the technique produced a substantial number of unintended edits in mouse embryos. Even if researchers figure out how to edit human embryos safely, whether with base editing or another technique, society will ultimately have to decide whether and how we will use the technology to make babies free of genetic diseases.

Former staff writer at Medium, where I covered biotech, genetics, and Covid-19 for OneZero, Future Human, Elemental, and the Coronavirus Blog.

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