Could editing the DNA of embryos with CRISPR help save people who are already alive?

Amid last year’s backlash against the birth of the world’s first genetically edited babies, some experts preached prudence: Editing the genomes of embryos, they argued, could one day “cure” people of diseases before they’re even born.

But there is another, less-discussed potential application of editing an embryo: tweaking its DNA to help save someone who is already alive.

Take the case of Jessica and Keith, a couple in the Bay Area with a 2 1/2-year-old daughter with Fanconi anemia, a genetic disease that leads to the failure of bone marrow to produce red and white blood cells and carries an increased risk of a number of cancers. The best treatment is a stem cell transplant from a sibling, and Jessica and Keith, who asked that their last name not be used, are now in the process of trying to have another child through IVF who can serve as a donor — what’s known as a savior sibling.

But making an embryo that’s both healthy and a suitable donor “match” for the older sibling is an exercise in long odds. It’s theoretically possible that altering an embryo’s DNA with the genome-editor CRISPR could improve the process.

“If that technology has any applicable means to help solve these genetic disorders, I’m hopeful that they’ll eventually find a way to deploy it in a productive way,” Keith said.

He and Jessica understand it’s too soon to use CRISPR in such cases. The technology is not advanced or precise enough yet — and might never be. The idea of editing DNA to produce a savior sibling would carry enormous technical and moral questions.

But it’s another example of the ways in which genome-editing could help patients where other reproductive technologies cannot.

“Families are driven to go to great lengths to seek technology that will address the health needs of even a single child with an ultra-rare disease,” said Dr. George Daley, the dean of Harvard Medical School, who has raised the notion, for now theoretical, of using CRISPR to produce savior siblings.

Editing the DNA of sperm, eggs, or early embryos for the purpose of reproduction — so-called “germline” editing — is controversial because any changes would be passed down to future generations. That raises profound ethical questions, unlike gene therapies that aim to correct mutations in, say, eye or blood cells — “somatic” edits that are not passed down.

For years, some experts had been open to the idea that CRISPR could eventually be used in embryos for certain medical reasons, such as remedying Huntington’s disease or sickle cell mutations.

But the hypothetical debates collided with reality last year when Chinese scientist He Jiankui announced the birth of twins whose DNA he had edited before they were carried to term and born. He was widely condemned for attempting the procedure before the scientific community had fully addressed safety concerns about the editing of embryos or ethics of doing so. Critics accused him of failing to follow proper clinical trial protocols and choosing an unnecessary target (he tried to introduce immunity to HIV, not fix a disease-causing mutation).

Some of the world’s leading scientists called for halting work toward clinical uses of germline editing — that is, trying to make babies, not just doing research — until international rules were established.

For families dealing with genetic illnesses, the backlash may have been understandable. But they also wondered if it would push a tool that had the potential to help them further out of reach.

After their daughter was diagnosed with Fanconi anemia at 9 months old, Jessica and Keith met other families who had children with the condition and who had unsuccessfully sought out stem cell transplants from unrelated donors. The transplanted cells, called hematopoietic stem cells, had failed to take root in the patients’ bones and replace their diseased cells.

Over time, success rates in stem cell transplants from unrelated donors have improved. But experts say a transplant from a sibling — either with cells from their bone marrow or taken from umbilical cord blood at birth — remains the best option for patients with Fanconi and a handful of other inherited diseases.

It’s why some families try to have another child who could be a donor.

The first savior sibling was born in 2000, also to help save an older sister with Fanconi anemia, or FA. But these rare cases are still debated. There are questions about whether the donor child undergoes any physical harm or will suffer from feeling he or she was born for, crudely speaking, spare parts.

Jessica and Keith had always planned to have a second child, even before their daughter’s diagnosis. And to avoid having another child with FA, they knew they would have to make embryos through IVF and screen them through a process called preimplantation genetic diagnosis, or PGD. The idea is to make sure an embryo has the healthy number of chromosomes and no disease-causing mutations before a pregnancy is started.

With their daughter’s disease, Jessica and Keith wanted to identify an embryo that was not only free of FA, but that could be a “match.” That would be the embryo they would transfer to Jessica’s womb in hopes it would implant and produce a child.

When clinicians look for a suitable donor — whether for bone marrow or another tissue like a kidney — they’re looking for someone whose immune proteins most closely resemble those of the recipient. That way, they reduce the odds that the recipient’s immune system or the transplant will recognize the other as foreign and revolt.

Siblings have about a 25% chance of having the same group of immune proteins, called an HLA complex. In other words, statistically, 1 in 4 embryos made by Jessica and Keith would be a “match” for their daughter. Three out of four of their embryos would be free of Fanconi anemia. So together, only 3 of 16 embryos they created would make an ideal donor. Technically, the odds were even lower because some embryos would not have a healthy number of chromosomes.

“Some people get it on the first cycle, and it’s hallelujah,” said Dr. Ilan Tur-Kaspa, Jessica and Keith’s fertility doctor and the president and medical director of the Institute for Human Reproduction in Chicago, who has proposed guidelines for these cases. “Some people it takes two, three, four, five cycles.”

Jessica and Keith started traveling to Tur-Kaspa’s clinic about a year ago to go through IVF. But three rounds — each involving hormone shots, egg retrieval, fertilization, tens of thousands of dollars, and anxious waiting for test results — failed to produce this needle-in-a-haystack embryo. All the while, they were wondering if they would be able to help their daughter.

“It was really devastating for us,” Jessica said.

In a presentation at the first International Summit on Human Gene Editing, in 2015, Daley told the story of a family that had gone through multiple rounds of IVF to create a savior sibling. It was a case not unlike the one Jessica and Keith are confronting three years later.

“Coupling gene editing with PGD would be a way forward of making this a much more efficient and somewhat less toxic approach,” Daley said then. At the time, he was the director of the pediatric stem cell transplant program at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.

In an interview this month, he said he raised the savior sibling example not to suggest that it would be the best application of CRISPR in embryos, or that it would be the first accepted clinical form of germline editing. Instead, he said, it pointed to the limits of IVF and PGD.

Some experts have argued IVF and PGD obviate the need for germline editing because such tools allow would-be parents to implant only healthy embryos. But they are not always enough, Daley said.

In his presentation, he cited a study from Spain of eight families with a child with Fanconi anemia trying to have a savior sibling. They went through, in total, 42 IVF cycles, which ultimately only produced one healthy baby.

“A lot of arguments have been put forth that the number of legitimate medical indications for using gene editing at the embryo level are so vanishingly rare that we need not go forth as a society to endorse this technology,” Daley said in the interview. But, he said, “rarity alone” is used as a “very specious argument to say we shouldn’t be developing a technology.”

He noted that progress in some fields, like gene therapy, was sparked by parents of children with rare conditions pushing to find treatments.

The case Daley mentioned in his 2015 presentation involved the Treviño family.

Andy Treviño was born in 1999 with a rare immune disorder called NEMO and was in and out of the hospital for the first few years of his life fighting off infections.

When his parents, Andrés and Ana Paulina Treviño, were told they could have another child and that stem cells from the cord blood could be transplanted into Andy and possibly cure him, “it sounded like science fiction,” Andrés recalled in a recent interview. But they consulted with a priest, and considered their other options, and started IVF in 2002.

“You don’t have a manual for parenting, but when you spend 1,000 days in the hospital, and you hear them screaming, and you’re in the ICU three times, you have to do something,” said Andrés, who lives with his family in the Boston area.

It took five IVF cycles before they made an embryo that was healthy and could be a donor — two embryos, in fact. They transferred both, and one successfully implanted and was carried to term. Sofía Treviño was born in March 2004, and cells from the cord blood and her bone marrow were transplanted to her brother.

Andy is now 20 and his immune system is healthy. Sofía is 15. The Treviños also had a third child, Tania, 10, through IVF.

While it worked out for them, Andrés said if CRISPR could have been used to produce the desired embryo on the first try — and the transplant could have been done sooner, and Andy could have been spared from more life-threatening infections — they would have considered it.

“If you experience your child in pain, you learn that that pain hurts even more than your own pain,” he said.

Whether CRISPR would be as effective as families might hope remains an open question. Theoretically, if CRISPR could be used to either make an embryo free of a disease or change the genes that define the HLA group, it could increase the odds of finding an embryo that could be a donor. But switching the type of HLA complex to ensure a match would require editing a much larger section of DNA than swapping one misplaced DNA “letter” — a type of error that causes some genetic diseases. Experts aren’t sure if that is possible.

In their case, Jessica and Keith recently went through a fourth cycle of IVF. They made an embryo that’s a match for their daughter and free of Fanconi.

They’re planning on transferring the embryo to Jessica’s womb in the next few weeks.