Neena Nizar’s earliest memory is of her father tying her to an ironing board. His beloved toddler, who seemed fine when she was born, had something very, very wrong with her: Neena’s bones bent and curved and she wasn’t growing normally, so his engineer’s mind desperately seized on the ironing-board solution.

But the problem — which some doctors diagnosed as polio and others as rickets or “we have no idea” — was even worse than bones that wouldn’t stay straight. They also broke down faster than they grew, with weak cartilage where strong bone should be. By the time other little girls were skipping and running and kicking balls, she was in pain and could barely get around. “I had to be carried into school, and I had rods in my hips and metal clamps to hold my bones in place,” said Nizar, who was born in Dubai. “Growing up, that was beyond hard. It was horrible.”

So when Nizar, now 41 and living in Nebraska, hears scientists’ emphatic calls to prohibit “embryo editing” of disease-causing genes, her reaction is shaped by decades of her own suffering — compounded by that of the two sons who inherited her devastating mutation.

advertisement

“It’s easy to get on your high horse when you’re not in our position,” she said. “If editing an IVF embryo is the best option to mitigate the pain that a child would otherwise suffer, then give us the choice.”

Dr. Nizar and her boys
Neena Nizar and her sons Arshaan Adam and Jahan Adam. Courtesy Neena Nizar

In 2012, scientists showed that CRISPR, an ancient bacterial immune system, can edit DNA much the way “find and replace” edits a document, setting off a race to refine the tool for human gene therapies. Barely three years after, leaders in the field convened a private meeting in California’s Napa Valley to discuss their concerns about the possible use of CRISPR in IVF embryos, concluding that it should not be done, at least not yet.

Changing a single DNA “letter” in the genome of a very early embryo has the potential to correct a genetic defect not only in any resulting baby but also in all of that baby’s descendants. That, warn opponents of such “germline editing,” would change the human gene pool, a step they worry could have unforeseen and irreversible consequences. They also argue that known carriers of genetic diseases could have embryos screened for harmful mutations before being used in IVF.

The opponents have largely dominated public discussion of this use of CRISPR, especially after a Chinese scientist announced last November that he had changed the genome of two IVF embryos and produced the world’s first “CRISPR babies.” Worldwide condemnation was instantaneous, and since then a group of prominent CRISPR experts called for a global moratorium on using CRISPR for reproduction — research stopping short of a pregnancy is OK, they say.

Dr. Francis Collins, director of the National Institutes of Health, endorsed that call. Asked whether he would always feel that way, Collins told STAT through a spokeswoman that “‘always’ is a really big word,” but that for now, he “can’t imagine a circumstance where he would feel differently.” NIH is prohibited from funding research that edits human embryos.

Watching all this have been people with a special interest in embryo editing: those who carry genetic mutations that can cause severe disease. They wonder whether experts who denounce embryo editing have any understanding of what millions of people with such inherited diseases — especially ones that have plagued their families for generations — suffer.

“Patients and their parents will be the ones pushing for research and eventually clinical trials” of embryo editing, said bioethicist Jeantine Lunshof of the Massachusetts Institute of Technology, who has been the in-lab ethicist for Harvard biologist George Church, who was one of the first scientists to edit human cells with CRISPR. Assuming the procedure is shown to be safe, “desperate parents who just lost a child [to a genetic disease] are going to say, ‘For our next pregnancy, we want this.’”

Despite dozens of surgeries and consultations with far-flung specialists, Nizar’s disease stumped every expert her father found. So when she and her husband decided to start a family, despite doctors telling her that her legs would crumble under the weight of a fetus, she had no idea she carried a devastating mutation — especially when her son Arshaan came into the world in 2008 at a robust 9 pounds, seemed perfectly normal, and walked at 1. Whatever crippling disease she had, Nizar felt, it stopped with her.

But when she was 32 and pregnant with her second son, a scan revealed skeletal and other abnormalities in the fetus. At about the same time, Arshaan, then 2, began to regress. It was as if time were taking him backwards to the hell his mother suffered as a child: His bones curved, and his walk became a waddle.

Finally, a geneticist diagnosed Nizar, Arshaan, and the soon-to-be little brother. All three have Jansen type metaphyseal chondrodysplasia. Caused by a mutation in a gene called PTH1R (parathyroid hormone-related peptide receptor), which controls the differentiation of bone and cartilage, its chief symptoms are the arms and legs having cartilage where they should have bone, making them abnormally short, weak, and painful.

To correct their curved bones, Arshaan and his brother, Jahan, 8, have had surgeries every year since they were diagnosed, “getting pins and rods to keep their bones straight,” said Nizar, founder of the Nebraska-based nonprofit Jansen’s Foundation. “But it’s like working with putty because the ‘bone’ is mostly cartilage.” As the limb grows it bends again, necessitating additional surgeries.

For unknown reasons, the second generation to carry the Jansen’s mutation usually develops more severe disease than the first. The boys often have to crawl on hands and knees to get around and miss out on simple things like playing at the park, not to mention anything as physical as contact sports. Their pain never stops, and they don’t understand what the “smiley face” on the pain scale means.

“The third generation might be even worse,” Nizar said. “We don’t know.” If her boys grow up and want to be fathers, she said, embryo editing should be an option. “You’re not changing who they are, but fixing a defect that causes agony and pain,” she said. “Having options is a personal right. No one knows the path you walk except yourself.”

Let them say we’re playing god,” she added. “This is not about something frivolous like changing eye color to make a designer baby. It’s about a child’s suffering.”

Another argument against germline editing is that many inherited diseases can be corrected later, once a child is born, including sickle cell disease and Duchenne muscular dystrophy. It is not clear whether that approach will be as successful as germline editing might be, especially in a disease that leaves lasting damage, as sickle cell does, or seemingly irreversible damage, as some neurological conditions do. What is indisputable, however, is that such a correction would not be inherited, so the next generation would have to undergo the therapy, too.

“You’re not changing who they are, but fixing a defect that causes agony and pain. Having options is a personal right. No one knows the path you walk except yourself.”

Neena Nizar, who has Jansen type metaphyseal chondrodysplasia, along with her two sons

Opponents of embryo editing argue that parents can have a healthy IVF embryo without it, by having their IVF embryos (each cycle yields eight or so) tested for a particular mutation and implanting only healthy ones. The odds of having at least one unaffected embryo vary with the genetics of a disease, however, including whether the mutation is dominant or recessive, and carried by one parent or both. In general, the odds of getting an unaffected IVF embryo range from 25 percent to 75 percent, but “a substantial percentage (27%) of [such] cycles produce no viable, disease-free embryos for transfer,” three experts in genetic medicine wrote in the New England Journal of Medicine last month. If both parents have the same recessive genetic disease, then all their embryos would be affected as well.

Andrea Taylor understands losing odds. She and her husband both carry mutations in a gene called SLC2A10. The mutation makes arteries elongate, twist, and turn, leaving vital organs starved for oxygen and forming aneurysms. This arterial tortuosity syndrome kills 40 percent of the children who inherit it by age 5, but because it is recessive, neither Taylor nor her husband have it or had any reason to suspect they were carriers. The chance that they’d meet, marry, and have children was hundreds of million to one; the chance that their sons would have it was 25 percent.

Their first, Aaron, is healthy. But Aiden lost the genetic lottery. Born in 2008, he inherited one ATS-causing gene from each parent. His life has been a series of operations, including open heart surgery to reconstruct his pulmonary arteries and three heart catheterizations.

Taylor, president and founder of the Arkansas-based ATS advocacy and awareness nonprofit A Twist of Fate, knows the philosophical objections to germline editing. “It’s hard for me to believe that the people saying this went through anything like what our families have, with a child tethered to a bed and the light blinking” to signal yet another medical emergency, she said. “It’s hard to reconcile the philosophical arguments against changing the human gene pool with what a child suffers. If there were a safe way to do it, a million times over I would do it, and every mom I know would do it, too.”

The “playing God” objection leaves her cold, said Taylor, who describes herself as a person of faith. “God gave us the knowledge and the ability to do this,” she said. “We would not have been created the way we were, with intelligence and the ability to make scientific discoveries, if we weren’t meant to do it. If you could fix something like this in a child from the very beginning, why would you not try?”

Monica Weldon, too, struggles to square the “playing God” objections with her son’s suffering. He was born with SYNGAP syndrome, the result of a mutation in a gene called SYNGAP1. The DNA misspelling causes abnormalities in neuronal growth and synapse function, leading to developmental delays, intellectual disability, and other neurological symptoms.

It starts slowly, said Weldon, who founded the Texas-based research and advocacy group Bridge the Gap. As a newborn, her son Beckett seemed as normal as his twin sister, Pyper. But while Pyper hit developmental milestones such as rolling over and sitting up and babbling, Beckett was “more like a limp noodle,” Weldon said, and hardly babbled.

Weldon compares the notion of embryo editing to prenatal surgery. Correcting spina bifida and other abnormalities in fetuses, once considered cowboy medicine, is now mainstream. “If someone wants to try to fix a gene to save their baby, they should have that option,” she said. “Obviously you have to move cautiously, but saying absolutely not, no, never … I don’t think you can say that unless you understand the patient experience.”

The “altering the human gene pool” concern also puzzles families — as well as some experts. CRISPR doesn’t introduce, say, fish genes into tomatoes, as old-line recombinant DNA does. It changes a disease-causing version of a gene into a healthy, far more common form. “It’s hard to see how giving someone the form of a gene that 6 billion other people have is changing the human gene pool,” Lunshof said.

In 2009 Diana Daus’s mother died of Huntington’s. The fatal, incurable disease destroys brain neurons, cruelly tearing away at a person’s physical and mental capacity, usually starting between ages 30 and 50, until there is nothing left. Daus’s brother, too, has Huntington’s, which is caused by repeats of the CAG nucleotide triplet; the repeats produce an abnormally long protein that accumulates in and kills neurons. The mutation is dominant; a single copy causes Huntington’s even if the copy from the other parent is normal.

Daus, an adjunct professor at the City University of New York, has devoted her adult life to developing occupational therapies for people with Huntington’s. Her mother, she said, would have opposed embryo editing. “She was a devout Catholic who believed that whatever God gave us, it was the decision of a greater power,” and one that people shouldn’t question, let alone undo, Daus said.

She disagrees: “I personally would be in favor of using any available technology so families would not have to pass down” the Huntington’s mutation.

Sign up for our Daily Recap newsletter

A roundup of STAT’s top stories of the day in science and medicine

Privacy Policy