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Borges, the postdoc who conducted the analyses of all these tissues, remembered the relief he felt when additional testing showed that in male lambs, it was the support cells around the sperm-producing cells that glowed green. That meant their germlines were still untouched. But the same was not true when he looked in the ovaries of the female lambs. “There was clear overlap,” he said. It wasn’t much, but it was enough to be worried.
When he took the results to MacKenzie, she was floored. “It’s completely surprising,” she said. As part of the approval process, all gene therapies and gene-editing-based medicines have to be rigorously tested for the potential to contaminate the germline and be passed down to future generations of offspring. Study after study of these drugs in lab animals have failed to turn up evidence that AAV viruses used in these therapies deliver their genetic payloads into the DNA of sperm or eggs. But few studies have rigorously asked that question for in utero application of such therapies.
“We were the only ones not afraid to look,” MacKenzie said. The results didn’t raise as big of a concern for gene therapy because the AAV vector showed a very low probability of integrating in germ cells. But if you use AAV to deliver a gene editor, “regardless of integration, you’re going to have a heritable event,” MacKenzie said. “So it was really using AAV for gene editing that worried me so much.”
She was so concerned that a month after the London summit, she gathered together a group of gene editing experts, lawyers, and bioethicists at UCSF, and for two days they discussed the data and what it meant for moving forward with fetal genome surgery.
The data showed that the aspects of the uterine environment that are appealing for performing fetal genome surgery — stem cells that are more readily accessible to viral vectors, a tolerant immune system that won’t react to them — also increase the odds that the germline, in particular the fetal germline, could be inadvertently altered. What MacKenzie wanted to know was, if you know there’s a risk, even a teeny-tiny risk, can you really say it’s unintentional?
“Germline genome editing is no-go territory, and the worry here is that you would stray into that territory and unintentionally engage in something that’s taboo,” said Benjamin Hurlbut, a bioethicist at Arizona State University who attended the meeting. “That’s a legitimate and important worry.”
“She has the knowledge and the technical skills, but more than that, she’s open and listening and integrating feedback from the community in a great way.”
Matthew Porteus, Stanford School of Medicine pediatric hematologist
But he sees MacKenzie’s project, despite its futuristic sheen, as essentially a conventional practice of medicine. “There’s a patient that’s going to be severely sick and suffer profoundly but for an intervention,” he said. Embryo editing, in contrast, brings a patient into being for the sake of making the intervention. “Conceptually it’s a very important distinction,” he said.
Alta Charo, a bioethicist and legal scholar who was also in attendance, noted that although the risks are higher in a fetus, heritable germline modification is still probably a remote possibility, because of all the things that have to happen for those changes to be passed down. Women produce about a million eggs over their lifetimes, and if some of those get edited, what are the odds that those eggs get fertilized and implant and become a baby that becomes an adult that goes on to have their own children? “It’s a lot of probabilities multiplied against one another,” she said.
Others, like Porteus, argued that it’s not enough to assume the possibility is remote. Doctors and patients and ethicists need to be able to calculate the risk-benefit profile of editing the fetal genome, he said. “If it’s a one in a million chance but 100% of babies will die without it, maybe that’s a calculus that’s worth it. If it happens every time, maybe not. There is very little in the way of facts about any of this right now.”
MacKenzie came away from the meeting assured, and determined to start filling in those gaps.
Since then, her lab has launched a number of new projects — including a deeper investigation of why the female sheep cells were impacted but not the male ones, and a collaboration with a gene editing company to assess, in mice, whether lipid nanoparticles, a nonviral method for delivering gene therapies into cells, are any better at staying out of the cells that will become sperm and eggs.
p9