Mitochondrial replacement therapy is a promising innovation in fertility treatment
When Noah Shulman was born a few days after Christmas 2016, his parents Kristelle and Evan had no reason to worry about him. The pregnancy went smoothly, and so did the birth.
But within a few days of taking his first breath, Noah began to struggle. He wasn’t feeding, so he started losing weight. He was also lethargic. Several pediatricians reassured the Shulmans that they were probably just overly sensitive to Noah’s symptoms because Kristelle is a nurse and Evan is a physician assistant–a case of first-time-parent-white-coat syndrome. “They kind of dismissed us as neurotic parents,” says Evan.
But when Noah strained to breathe, the alarmed Shulmans took him to the emergency room, and he spent the next few months in the hospital. After a harrowing month of medical emergencies that included seizures and a heart attack, the Shulmans learned that their son had a rare genetic disease that affected his mitochondria.
About 1 in 4,000 people worldwide–20,000 in the U.S.–have mitochondrial diseases. Mitochondria are present in nearly every cell in the human body, and they provide energy for everything cells do, acting as the body’s molecular batteries. They also have their own DNA, and mutations can cause hearing loss, diabetes, muscle weakness, seizures and heart problems. There are no treatments for mitochondrial disorders, as it’s not yet possible to repair or alter the affected mitochondrial genes using gene therapy. Three months after he was born, Noah passed away.
As they tried to accept their son’s death, the Shulmans were dealt another emotional blow. Their doctors bluntly told them that they should not expect to have a healthy biological child; because of the way mitochondrial mutations occur, each pregnancy would be like playing a game of reproductive roulette, the variable being how severely affected their baby would be. “They gave us a blank stare and very matter-of-factly told us there was really no way we would have another biological child,” says Evan. They were advised to consider adopting or using donor eggs.
While they explored these options, they weren’t ready to give up on having biological children. “We knew right away that we wanted another child,” says Kristelle. “After meeting Noah, having our own child and holding him–it’s a different feeling, an emotional bond and connection.”
That’s when they learned about mitochondrial replacement therapy (MRT), a promising innovation in fertility treatments that could allow couples like the Shulmans to have healthy children. It involves replacing just the mutated mitochondria with healthy mitochondrial DNA from a donor, while keeping the biological mother’s and father’s DNA intact. In vitro fertilization (IVF), which traditionally combines genetic material from two people, is taken a step further by introducing a small amount of DNA, from the mitochondria, from a third.
“We are breaking down a barrier that has certainly never been crossed before,” says Dr. Michio Hirano, medical director of the laboratory of molecular genetics at Columbia University, who plans to perform MRT for the Shulmans as part of a study. “Clearly biologically the embryo or person generated has three different sources of DNA, and that’s a unique or novel concept.”
Scientists like Hirano and families like the Shulmans are far more comfortable with that than are policymakers. Where scientists and families see a desperately needed strategy for having a baby, ethicists and lawmakers see sticky questions of how to define parental rights and whether permanently rewriting someone’s genetic code is morally acceptable. Genetic treatments are currently being tested to treat cancer and other diseases because those tweaks affect only the individual receiving the therapy. But scientists face much stricter rules when it comes to studies involving altering eggs, sperm or embryos, given that those modifications can be passed on to future generations, and ethicists and lawmakers are not ready to accept the social implications of such a scientific leap.
MRT is considered a form of genetic editing. In the same way IVF redefined reproduction when it moved fertilization from the womb to the lab in 1978, MRT–and, more broadly, the new era of gene-altered embryos it represents–is pushing the boundaries of human reproduction. Despite the concerns it raises, researchers say, the technology is worth pursuing because broader understanding of mitochondria themselves can lead to new solutions for infertility that may benefit even people not affected by mitochondrial diseases. There is evidence, for example, that reactivating mitochondria could improve the quality and function of aging eggs. That could increase pregnancy rates for the nearly 80% of older women who struggle to produce healthy enough eggs to conceive using IVF.
“We’re really changing the landscape of opportunity for people to have a baby,” says Jonathan Tilly, the chair of the biology department at Northeastern University, who is pioneering that work.
It wasn’t until Noah became sick that the Shulmans learned about mitochondrial diseases and how this suite of conditions is often passed from mothers to their children, because the embryo generally keeps the egg’s mitochondria and just a tiny bit of the sperm’s. Once Noah was diagnosed, Kristelle got genetically tested and learned that 70% to 80% of her mitochondria were mutated, although she does not experience any symptoms.
Each egg contains anywhere from hundreds of thousands to a million mitochondria–no one has really counted exactly how many–and each, researchers have only recently found, has a different function in the cell. While the cell’s long strand of DNA is wound tightly into its nucleus, a mitochondrion–which is a separate organelle that lives inside the cell–has its own DNA made up of 37 genes. The number and type of mutations affecting the mitochondria produce varying effects on cells, which can lead to a range of unpredictable symptoms.
“The biggest problem with women with mitochondrial disease is that there is no way of knowing what level of mutation their child will have,” says Mary Herbert, professor of reproductive biology at Newcastle University in the U.K., who is leading a program to test MRT among people who are affected. “A woman could produce eggs with a widely variable mutation load, so she could have a perfectly healthy child, or she could have a severely affected child; it’s impossible to tell.”
One way to control that unpredictability is to use IVF and screen embryos with pre-implantation genetic diagnosis (PGD), which is commonly used to detect a number of genetic diseases, including Down syndrome and muscular dystrophy. In those cases, technicians can remove a single cell from a days-old embryo and analyze its DNA for the amount of mutations it carries. The same strategy can be applied to mitochondrial DNA, and doctors would transplant only those embryos with less than 18% to 20% mitochondrial mutations, which they believe won’t contribute to debilitating symptoms. While mitochondrial PGD is available in the U.K. and other countries, it’s available only in research studies in the U.S., so the Shulmans have turned to PGD programs overseas for that screening.
PGD can only reduce the risk of mitochondrial disease in the next generation, while MRT, because it introduces healthy mitochondria from a donor, can eliminate it, so the Shulmans have also decided to try MRT–or least as much of the process as U.S. law currently allows. Not only does federal policy prevent scientists from using government money for research on human embryos that would result in their harm or destruction, but Congress also prohibits the Food and Drug Administration, which evaluates new therapies like MRT, from even accepting applications to consider approving the procedure. That’s why Hirano found private funding for his study, which the Shulmans and five other couples have joined. Even so, he can only perform MRT; he cannot transfer the embryos for pregnancy. They remain frozen until policies change. “Right now we are in suspension with these embryos,” he says. “We can’t move forward until we have permission to move forward.”
Dieter Egli, a developmental cell biologist at Columbia and an expert on manipulating the DNA inside eggs, is performing the genetic swaps. He removes the DNA from a donor egg that has healthy mitochondria and replaces it with DNA from the egg nucleus of the woman affected by mitochondrial disease. The resulting egg, containing the affected woman’s DNA and the donor’s nonmutated mitochondria, can be fertilized by the father’s sperm and produce a child who will be more than likely spared from mitochondrial disease.
The Shulmans, who are waiting for an egg donor to create their MRT embryos, understand why the idea of creating embryos that are genetically different from combining parents’ egg and sperm causes some people concern. Altering genes in eggs, sperm or embryos can theoretically make it possible for parents-to-be to pick and choose the traits they value and want to see in their children–from physical features like eye color or height, to more complex characteristics like intelligence or athletic ability. But the Shulmans hope that studies like the one in which they are participating will help people better understand how lifesaving such genetic intervention can be, and appreciate what MRT is–and what it isn’t.
“People have all kinds of crazy reasons for opposing this,” says Evan. “They are afraid that we are creating designer babies, but that’s a failure of people to understand that this is not about creating what we want, but purely about removing a fatal disease that is devastating to so many people.”
For families affected by mitochondrial diseases, that’s the only moral imperative–their right to use every option available to have their own healthy children. Shelley Beverley, a psychologist in Tasmania, Australia, who has mitochondrial disease, says she desperately wants her own biological child as a biological legacy in case the disease claims her life early, as it did with her brother and her mother. “I really want a child with my genes and my husband’s genes, because if anything were to happen to me, I’d like my husband to look at our child and think, You remind me of your mom, you’ve got her eyes,” she says. “We don’t want a designer baby, we don’t want to play God. We just want to get the healthiest child we can.”
The Beverleys tried PGD, but after five cycles of IVF they learned their embryos were too heavily affected by mitochondrial mutations and were not good candidates for transferring for pregnancy. “We’re running out of options,” she says. “MRT is the only option for us to reduce that risk.”
But as in the U.S., MRT is not approved in Australia–yet. Last summer, however, one of the country’s Senate committees held hearings to debate whether MRT should be allowed, and invited families affected by mitochondrial diseases to make their case. After the testimony, the committee issued a report supporting research on MRT under the strict condition that it be used to help people like Beverley conceive a healthy child. If legislation passes, Australia could be only the second country to approve MRT. In 2015 the U.K. became the first, and last year researchers began a study using MRT to help two people affected by the disease have healthy babies. The team conducting the study, including Herbert, is proceeding carefully to protect the privacy of the participants and to ensure the results are properly presented in a scientific publication so doctors can learn from the cases. They plan to expand the study to couples from other countries, but are currently accepting only those from the U.K. so they can follow the babies closely after they are born.
They have reason to be cautious. In 2016, Dr. John Zhang, an infertility specialist in New York City, reported the birth of the first-ever baby, a boy, born using MRT, in Mexico, and that was followed by others, including in Ukraine. But because those were individual case studies and not part of a rigorous trial, questions remain about how effective and safe the procedure is. One concern relates to how precisely the technician can remove just the affected mother’s nuclear DNA from the tiny egg, and how much of her mutated mitochondrial DNA might carry over unintentionally into the donor egg; in a study published in 2017, Zhang said it ranged from undetectable levels to 9% in the baby’s different tissues. Zhang says he plans to follow up periodically with the boy until he reaches age 18 to assess what effect, if any, the donated mitochondria has on his health.
The Shulmans, and the other couples in Hirano’s study, realize that for them to get pregnant, U.S. law would have to change. That’s a long shot given that any effort to study human embryos in this country tends to get caught up in the abortion debate’s questions about whether embryos are considered human beings who have a right to life as well as a say in whether they should be subjects of experimental studies. Traditionally, says Josephine Johnston, an ethicist and director of research at the Hastings Center, a bioethics research institute, “The starting position of the federal government has been that we’re not going to do research on human embryos–we won’t fund it and we won’t condone it.”
Many researchers argue that universal dismissal of any research involving genetic alteration of human embryos, like MRT, closes off valuable work that could lead to treatments for diseases. But they also acknowledge that some fast-moving scientists overseas, who are already introducing permanent genetic changes in embryos, may be going too far, as it’s not yet clear how safe and effective these interventions are. In November, a Chinese bioengineer alarmed both the scientific community and the public when he announced he had used a powerful but still untested gene-editing tool called CRISPR to introduce a genetic change in twin girls when they were embryos to make them resistant to HIV infection. CRISPR’s developers noted that the long-term implications of editing the human genome aren’t known, and stood by their previous call for a voluntary moratorium on work on genetically editing human embryos that will be transferred for pregnancy.
Even in the U.K., MRT is allowed only under strictly regulated conditions. And before making its decision, the government invited public debate about the benefits and risks of the therapy and, as in Australia, heard from families affected by the disease. It also didn’t greenlight any and all requests to perform the procedure but issued a license only to the group at Newcastle University, which will collect data from the study and report the results so the rest of the medical community can learn from their experience.
One person supporting that stepwise, methodical approach is Tilly of Northeastern University, who is hoping to turn better understanding of how mitochondria function into new infertility treatments that would benefit more than just women affected by mitochondrial diseases. In 2012 Tilly shattered a long-held truth about female fertility–that women do not make new eggs but are born with their lifetime’s supply. He found a population of egg stem cells, or precursors to mature eggs, which in the lab he showed can indeed produce new eggs, theoretically throughout a woman’s lifetime. What these egg stem cells need, however, is the right set of signals that are active early in life but tend to shut down with age.
But it’s not sufficient to have enough eggs; they also need to be of good quality. Tilly found mitochondria are critical for producing viable eggs. In early work in mice, and in human cells in the lab, Tilly is showing that by reactivating these mitochondria using hormones, among other things, the egg’s functions can be restored and, in the case of the animals, produce embryos that can develop into healthy pups.
The results weren’t exactly accepted by either the scientific community or the public at first, although several independent groups have since confirmed his findings. For some ethicists, Tilly’s work leads to a slippery slope toward reproduction on demand, because it would make it possible for women to delay menopause if their ovaries are able to continue producing new eggs that could then be fertilized and carried to term. But he maintains, “We’re not trying to make a 40-year-old egg look like a 20-year-old egg. There’s no reason to do that. But we want to make sure that the 40-year-old egg uses everything at its disposal so we can do all we can to help women who can’t have a baby, to have a baby.”
He’ll have to wait for more studies to see whether those effects also appear in people. But like the Shulmans, he believes that time will have been well spent if it leads to new ways for people to have families. Kristelle and Evan continue to hope for more children and take solace in the fact that Noah’s life, and their participation in the study, could benefit not just them but also others like them in coming years. “Even if it doesn’t work out for us now, we hope one day it will for everyone affected by mitochondrial diseases,” says Kristelle.