“Family Planning” with Gene Technology

The introduction of third-party DNA through mitochondria
When Noah Shulman was born a few days after Christmas in 2016, his parents Christele and Evan were not worried about his health at all. Because everything goes well during pregnancy, so does childbirth.
But within days of his birth, Noah began to suffer. He didn’t eat, his weight began to fall off and he was sleepy all day. Several pediatricians advised the Shulmans to relax, saying they might be too sensitive to Noah’s symptoms, because Christele is a nurse and Evan is a physician assistant-their performance is typical among first-time parents. “We are all classified as neurotic parents.” Evan said.
But when Noah showed signs of losing his breath, the panicked Shulmans decided to take him to the emergency room. Noah stayed in the hospital for the next few months. One month, he had several sudden emergencies, including epilepsy and heart attacks, and his body was devastated. After that, the Shulmans learned that their son suffered from a rare hereditary disease and mitochondria were affected.

Globally, one in 4,000 people (one in 20,000 in the United States) suffers from mitochondrial diseases. Mitochondria are found in almost every cell of the human body. As the “molecular battery” of the human body, they provide energy for all activities of cells. Mitochondria also have their own DNA. If DNA mutates, it may lead to hearing loss, diabetes, muscle weakness, epilepsy and heart disease. At present, the medical profession is helpless in dealing with mitochondrial diseases, and gene therapy cannot be used to repair or change the affected mitochondrial genes. Noah died three months after his birth.

Just as they tried to accept their son’s death, the Shulmans suffered another emotional shock. The doctor said bluntly that they should stop thinking about having a physically healthy child. Mitochondrial variation occurs in such a way that every pregnancy is like playing roulette. The variable is how seriously their children are affected. “They looked at us with a straight face and said calmly that we would not have another baby.” Evan said. Doctors advise them to consider adopting children or using donated eggs to conceive children.
Although they have also examined these options, they still do not intend to give up the idea of having their own children. “At that time, we realized that we were going to have another child,” Christele said. “I still remember when Noah was born, we held him-the feeling was different, it was an emotional connection and bond.”
It was also at that time that they learned about mitochondrial replacement therapy (MRT), an innovative fertility therapy that is very promising and can enable people like the Shulmans to have healthy babies. Including the use of healthy mitochondrial DNA from donors to replace mutated mitochondria while keeping the DNA of biological parents intact. Traditional in vitro artificial insemination (IVF) combines genetic materials from both parents. In this therapy, a small amount of DNA from a third party is introduced through mitochondria.
“We are crossing an obstacle that we have never crossed before.” Dr. Ping Ye Dawson, medical director of Columbia University’s Molecular Genetics Laboratory, said. As part of his research, he plans to apply mitochondrial replacement therapy to the Shulmans. “Obviously, there are three different sources of DNA in the physiology of the embryo or the baby. This idea is unique or novel.”

After Noah’s 3-month-old son died of mitochondrial diseases, the Shulmans hoped to have another child.
Scientists engaged in research in this field such as Ping Ye Dawson and families such as Shulman couple are more likely to receive mitochondrial replacement therapy. In their eyes, this is a birth measure that is urgently needed. However, in the eyes of ethicists and legislators, it is a thorny issue concerning how to define the right to be a parent and whether it is ethical to permanently rewrite one’s genetic code. At present, gene therapy is being used to treat cancer and other diseases to test its efficacy. Because in this treatment, rewriting the genetic code only affects the recipient himself. However, some studies involve modifying the genetic code of eggs, sperm or embryos. At this time, scientists are faced with much stricter rules because these changes will be passed on from generation to generation, while ethicists and legislators are not ready to accept the social impact of this technological leap.
New therapies broaden the boundaries of human reproduction
Mitochondrial replacement therapy is considered as a form of gene editing. In 1978, with the transfer of pregnancy from the womb to the laboratory-the world’s first test-tube baby was born in Britain-IVF redefined fertility. Similarly, mitochondrial replacement therapy-more broadly, it represents a new era of modifying embryonic genes, broadening the boundaries of human reproduction. Researchers said that despite some concerns, the technology is worth pursuing because a wider understanding of mitochondria can provide new solutions to infertility, and even people who are not affected by mitochondrial diseases may benefit from it. For example, there is evidence that reactivating mitochondria can improve the quality and function of aging eggs, which increases the chances of successful pregnancy by nearly 80% for older women who try every means to discharge enough healthy eggs to conceive children by in vitro artificial insemination.

“We have really changed the chances of people getting pregnant and giving birth successfully.” Jonathan Tilly, head of biology department at Northeastern University, said he was the initiator of the project.
Only after Noah became ill did the Shulmans understand mitochondrial disease and why it is often passed on from mother to child. Because embryos usually retain mitochondria of eggs, while retaining only a small part of mitochondria of sperm. As soon as Noah was diagnosed, Christele tested the gene and found that 70% to 80% of her mitochondria had changed, although she did not suffer from any disease.
Each egg contains hundreds of thousands to millions of mitochondria-no one has really counted how many-researchers have only recently discovered that each mitochondria functions differently in cells. Although the long-chain DNA of a cell is tightly wound in its nucleus, mitochondria, as an independent organelle existing in the cell, has its own DNA composed of 37 genes. The number and type of mutations acting on mitochondria will affect cells to varying degrees and may lead to a series of unpredictable symptoms.
“For women with mitochondrial diseases, the biggest problem is not knowing to what extent their children will mutate.” Mary Herbert, professor of reproductive biology at Newcastle University in England, said she was leading a project to test mitochondrial replacement therapy in people affected by diseases. “A woman will produce eggs with variable load fluctuations, so she may have a completely healthy child or an unhealthy child, which is hard to say.”
One way to control this unpredictability is in vitro artificial insemination and preimplantation genetic diagnosis (PGD), which is usually used for the detection of a variety of genetic diseases, including Down syndrome and muscular dystrophy. In the treatment of these diseases, medical experts can extract a cell from an embryo several days old and analyze the variation carried by its DNA. The same strategy can be applied to mitochondrial DNA. Doctors will only implant embryos with mitochondrial variation of less than 18% to 20% into their mothers. They believe that this variation will not lead to debilitating symptoms. PGD can be done in Britain and other countries, but in the United States, such diagnosis is only for research purposes, so the Shulmans have to resort to PGD programs abroad for genetic screening.

PGD can only reduce the risk of mitochondrial diseases in the next generation. Mitochondrial replacement therapy can eliminate the risk due to the introduction of healthy mitochondria from donors. Therefore, the Shulmans also decided to try mitochondrial replacement therapy-at least try as many steps as possible currently allowed by US law. Not only did the U.S. federal government issue policies to prevent scientists from using government funds for human embryo research (on the grounds that such research would cause embryos to be damaged or destroyed), but Congress even prohibited the U.S. Food and Drug Administration from accepting applications to consider approving this procedure, which is responsible for evaluating new therapies, including mitochondrial replacement therapy. This is the reason why Ping Ye Daoxiong has personally sponsored his research. The Shulmans and five other couples joined his research. But even so, he can only implement mitochondrial replacement therapy and cannot implant embryos into the mother for pregnancy. They can only be frozen before the policy changes. “At present, we have suspended the research,” he said. “We can’t move forward until it is approved.”
Columbia University biologist Dieter Eggli is an expert at manipulating DNA in eggs. He is currently conducting research on gene exchange to remove DNA from donated eggs containing healthy mitochondria and replace it with nuclear DNA from women with mitochondrial diseases. The resulting egg contains the DNA of the female patient and the donor’s non-mutated mitochondria, which can combine with the father’s sperm to form a fertilized egg and give birth to a child with little mitochondrial disease.

| “They’re worried we’re customizing babies” |
The Shulmans, who are waiting for donated eggs to use mitochondrial replacement therapy to create embryos, understand why some people are worried, because genetically, the embryos created in this way are different from those created by combining parents’ eggs and sperm. Changing genes in eggs, sperm or embryos makes it theoretically possible for prospective parents to pick out the characteristics they value and want their children to have-from physical characteristics such as eye color or height to more complex characteristics such as intelligence or motor ability. But the Shulmans hope that the kind of research they are involved in can help people better understand that this kind of genetic interference is actually a way to relieve sentient beings and really understand mitochondrial replacement therapy.
“People have many strange reasons to oppose it,” Evan said. “They worry that we are customizing babies, but what people don’t understand is that this is not creating what we want, but purely to eliminate diseases that endanger people’s lives.”

For families troubled by mitochondrial diseases, this is the only moral mission-the right to give birth to their healthy children using any feasible scheme. Shelley Beverly, a psychologist in Tasmania, Australia, who suffers from mitochondrial diseases, said that she can’t wait to have her own children, so that even if she dies prematurely due to the disease like her brother and mother, her life will continue. “I really want a child who inherits my genes and those of my husband, because even if something happens to me one day, I hope my husband can look at our child and think,’ you remind me of your mother, and your eyes are like hers. “She said,” We don’t want to customize babies or play God. We just want a healthy child. ”
This is purely to eliminate diseases that are deadly to many people, not to customize babies. “-Evan Shulman
The Beverly couple tried PGD, but after five cycles of in vitro artificial insemination, they learned that their embryos were seriously affected by mitochondrial mutation and were no longer suitable for transfer to their mother for pregnancy. “We don’t have many options,” she said. “Mitochondrial replacement therapy is our only option to reduce risks.”

Like the United States, mitochondrial replacement therapy has not been approved in Australia. However, last summer, a Senate committee in the country held a hearing to discuss whether mitochondrial replacement therapy should be released. The hearing also invited families affected by mitochondrial diseases to come as examples. After the hearing, the committee released a report expressing support for the research on mitochondrial replacement therapy, provided it is used to help people like Beverly conceive a healthy baby. If the legislation is passed, Australia will become the second country in the world to approve mitochondrial replacement therapy. In 2015, Britain became the first country to approve this therapy. Last year, researchers in the country began a study using mitochondrial replacement therapy to help two people affected by mitochondrial diseases conceive healthy babies. The research team, including Herbert, is carefully conducting the research to protect the privacy of participants and ensure that the research results are accurately presented in scientific publications for doctors’ reference. At present, their research object is limited to British couples, which is convenient to pay close attention to babies after they are born. According to the plan, couples from other countries will also be studied in the future.

| Modification of Embryo Genes Raises Public Concern |
They are cautious for a reason. In 2016, Dr. John Zhang, an expert on infertility in new york City, released a report that the first baby conceived by mitochondrial replacement therapy was born in Mexico and was a boy. Since then, such babies have been born one after another, including those born in Ukraine. However, as these are all case studies, the effectiveness and safety of the program are still in doubt. One of the questions is how accurately can technicians remove maternal nuclear DNA affected by mitochondrial diseases from tiny eggs, and how much of her mutated mitochondrial DNA may be inadvertently brought into donor eggs. Zhang said in a study released in 2017 that in different tissues of infants, this possibility is between “undetectable” and 9%. John Zhang said he planned to track the boy regularly until he was 18 years old to assess the impact of donated mitochondria on his health, if any.
The Shulmans and other couples involved in Ping Ye Dawson’s study realized that in order to have children, changes must be made to US laws. In this country, any attempt to study embryos will fall into the debate about abortion, arguing whether embryos should be regarded as people with the right to life, that is, whether they should be regarded as experimental subjects. Considering these, the hope of successfully amending the law is very slim.

Many researchers believe that banning any research involving modification of human embryo genes, such as mitochondrial replacement therapy, is a restriction and hindrance to the development of new therapies for diseases. But they also admit that outside the United States, some fast-moving scientists are already making permanent genetic modifications to embryos, which is too far away, because the safety and effectiveness of these interventions are still uncertain. In November 2018, a Chinese biological engineer announced that he used CRISPR, a powerful but untested gene editing tool, to genetically modify the embryos of twin girls to make them naturally resistant to AIDS. After the news was released, the scientific community and the public were shocked. The CRISPR developers pointed out that the long-term impact of editing the human genome is still unclear, and reiterated that the study of transferring modified human embryos into utero for gestation should be suspended.

Even in Britain, mitochondrial replacement therapy can only be used under strict supervision. Before deciding to use it, the government will invite the public to discuss the advantages and disadvantages of the therapy and, like Australia, listen to what families affected by mitochondrial diseases say. It will not approve any application for the implementation of the procedure, but will only issue a license to a team at Newcastle University, which will collect data and report the results in the study so that the medical profession can learn from it.
Jonathan Tilly, head of biology department at Northeastern University, supports this gradual and orderly approach. In 2012, Tilly shattered a long-standing truth about women’s fertility-the number of eggs laid out in a woman’s life is determined at birth, and they will not produce new eggs. Tilly discovered an egg-making stem cell, or “precursor” of a mature egg, which can indeed produce new eggs under laboratory conditions. In this way, theoretically, women can produce new eggs at all ages in their life.

It is not enough to have enough eggs. They must be of good quality. Tilly found that mitochondria are crucial to the production of viable eggs. Tilly’s early studies on mice and studies on human cells in the laboratory showed that activation of these mitochondria with hormones can restore egg function. Animals are used for experiments, and healthy puppies can be produced after embryos are bred.

For some ethicists, Tilly’s research will lead to a “landslide effect” in terms of reproductive needs, because if the ovaries can continue to produce new fertilizable and pregnant eggs, it will definitely lead to the postponement of female menopause. However, he insisted: “We don’t want a 40-year-old egg to look like 20 years old, but to ensure that after we do everything we can to help infertile women, the 40-year-old egg can fertilize itself and eventually become pregnant and give birth.”

He is still waiting for more research results to see if these effects will also appear on people. But he and Shulman both believe that if people can enjoy the happiness of family ties, it is worthwhile to spend time waiting. Christele and Evan hope to continue having children. Noah’s journey in the world and the experiments they participated in will benefit not only themselves but also others in the next few years. At the thought of these, they felt deeply gratified. “Even if we haven’t benefited yet, we still hope that one day it will benefit patients with mitochondrial diseases.” Christele said.