In 2016, in a Mexican hospital, Dr. John Zhang and his team delivered a baby boy who had three genetic parents. The boy was conceived via in vitro fertilization (IVF) and a novel method called spindle nuclear transfer. Spindle nuclear transfer involves transferring the mixed DNA from the mother and father to a new donor egg from a third person. In this case, the boy’s mother had a rare neurological disorder called Leigh syndrome caused by a defect in her mitochondrial DNA (mtDNA). As I mentioned last week, mtDNA is passed directly from the mother through the mitochondria in her egg. Leigh syndrome often leads to early mortality before the age of three years old, and this couple had already lost two children to the debilitating disease before going to Dr. Zhang at the New Hope Fertility Center in New York City.
The IVF procedure was done at a Mexican branch of the Fertility Center because of laws in the U.S. that effectively ban the genetic modification of human embryos. Since 2016, the spindle nuclear transfer method has been used in fertility clinics across Europe, like in Greece and Ukraine, for women suffering from mitochondrial defects or infertility. But it remains banned in the U.S., and there is plenty of controversy surrounding the method. Do the benefits of spindle nuclear transfer outweigh the potential ethical and practical risks? Legally and ethically, how do we draw the line between this kind of IVF treatment and embryonic genetic editing?
In 1978, the first baby born through in vitro fertilization, Louise Brown, was born in England. The IVF procedure was performed and published by Dr. Robert Edwards and Dr. Patrick Steptoe. Louise Brown’s mother had blocked fallopian tubes (the passages that bring the egg from the ovaries to the uterus), which caused infertility. Because of the blocked fallopian tubes, her eggs could not be collected directly from her uterus. Instead, Dr. Steptoe had to collect the eggs directly from the ovary using laparoscopic surgery. At the time, the practice of laparoscopy, a minimally invasive form of abdominal surgery involving small incisions and the use of a camera to direct the operation, was relatively new and had not been used in gynecology. Dr. Steptoe is considered the pioneer of gynecological laparoscopy at a time when the practice was considered “unacceptable” by other gynecological experts.
There was a great deal of controversy surrounding IVF in the beginning. Edwards and Steptoe spent most of the 1970s unsuccessfully attempting IVF procedures while the media swirled up hysteria over “test-tube babies.” When, in 1977, they were finally able to successfully implant an embryo in a woman via IVF, the media frenzy surrounding the pregnancy was intense. Journalists camped outside of Mrs. Brown’s house, infiltrated hospitals posing as staff, and leaked confidential medical reports. There was even a bomb scare in the hospital less than a month before the baby was born. Despite these obstacles, Louise Brown was born on July 25th, 1978. Since then, over 5 million children have been born via IVF and, in 2010, Edwards was awarded the Nobel Prize.
These days, the process of in vitro fertilization begins with hormone therapy that stimulates the release of multiple eggs at once into the uterus. The eggs can be retrieved directly from the uterus, without the need for a laparoscopy, in most cases. The eggs can be frozen for long-term storage if necessary (many women choose to do this if they plan to have children later in life). The eggs that are healthy and mature are fertilized with healthy sperm just by mixing them together and incubating them at body temperature. In some cases, where normal fertilization has been unsuccessful, the sperm can be injected directly into the egg.
Following fertilization, the embryo is allowed to develop in an incubator for a short amount of time until a sample can be removed for preimplantation genetic testing. This allows the doctor to screen all the viable embryos for heritable genetic disorders, chromosome abnormalities, or even mitochondrial DNA defects. Doctors and parents can select embryos for implantation that don’t possess undesirable or debilitating genetic defects. Controversially, some fertility clinics also allow parents to select for the biological sex of their child or even their eye color (blue is the most common request followed by green, which is the wrong order if you ask me—green is obviously best). Parents often want even more control—asking fertility clinics to select for traits like height or athleticism. But, for the most part, these traits cannot be selected for because we still don’t have enough of an understanding of the genes that control them.
Once the desired embryos are selected, they are moved backed to the mother’s uterus where at least one of them will hopefully become an implanted pregnancy. Because implantation is never guaranteed for any embryo, doctors often try multiple embryos at once. This leads to a higher than average chance of fraternal twins or even triplets. Otherwise, the health risks associated with IVF aren’t much more different than with traditional pregnancy. Even though the IVF process can be stressful, time-consuming, and costly, many women still choose IVF for a variety of reasons including infertility, age, or risk of passing on a genetic disorder.
For mothers with mitochondrial diseases, like Leigh syndrome, IVF screening may not be enough to prevent the disorder from being passed on. Because these disorders are passed directly from mother to child, pretty much all of the embryos will have the defective mitochondria. In these cases, three-parent baby methods are the only effective way to prevent babies from inheriting potentially fatal mitochondrial defects. The spindle nuclear transfer method builds off of the existing principles of IVF, starting with the retrieval of multiple eggs from the mother. The doctor picks out healthy, mature eggs to undergo the spindle nuclear transfer.
Technically speaking, there are multiple methods for producing an embryo free of mitochondrial defects, and many of these methods have been tested in multiple animal systems with variable success. The most successful methods have been pronuclear transfer and spindle nuclear transfer. The difference between the two is trivial on the surface level. In pronuclear transfer, the egg is fertilized first, in the same way as normal IVF. The donor egg is fertilized at the same time and, directly following fertilization, the egg becomes a zygote (the state of a fertilized egg before it begins to divide into a multicellular embryo). The sperm has fused with the nucleus of the egg and formed what is called pronuclei that contain the DNA from both parents. At this moment, the pronuclei of the donor egg are removed from the zygote and replaced with the pronuclei from the mother and father. After the transfer, IVF can be continued normally.
In spindle nuclear transfer, the DNA is removed directly from the egg in the middle of the second phase of meiosis (if you remember from a couple of weeks ago, the second round of meiosis is exactly like mitosis—and spindle nuclear transfer removes the DNA while it’s lined up at the equator). This DNA is injected back into a donor egg that’s had its DNA removed. The result is a mature egg that contains a selection of the mother’s (haploid) DNA, but healthy mitochondria. The sperm has to be directly injected into the egg for fertilization, but the rest of the IVF process is the same.
In terms of efficacy and risk, there doesn’t seem to be much difference between the two methods. In the case of Dr. Zhang’s patient, the paper clarified that the patient selected spindle nuclear transfer for religious reasons. Because pronuclear transfer involves discarding one fully fertilized zygote. Ultimately, the choice has to belong to the patient. Dr. Zhang’s patient also refused to subject her new baby to ongoing mitochondrial testing, meaning the success of the first human spindle nuclear transfer cannot be fully evaluated.
Both spindle nuclear transfer and pronuclear transfer occur at clinics outside of the U.S. and women in the U.S. can obtain these services at foreign clinics (add the cost of travel to the already costly venture of IVF—and good luck getting insurance to cover any of that). Even the U.K. approved the use of three-parent baby methods back in 2015. Many of the arguments and fears surrounding three-parent babies are the same ones that surrounded IVF in the 1970s. Fears of designer babies and rampant genetic manipulation have, for the most part, not come to pass (beyond the surface level choices of eye color and gender).
In reality, the biggest ethical issue surrounding three-parent babies is unequal access. Since 2016, Dr. Zhang has started a company, Darwin Life, offering spindle nuclear transfer IVF services for $80,000-$120,000. Since the technique remains illegal in the U.S., Darwin Life only operates overseas. This means additional long-term travel costs for women in the United States. These prohibitively high price tags mean a lot of women simply cannot access these therapies. Lifting the ban in the U.S. and enacting strategies to provide equal access to IVF and three-parent baby methods (cough universal health care cough) would help to close this access gap. And it would allow the U.S. to effectively regulate the use of this technology to prevent abuse.
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