Stem cell technology and reproductive medicine have always been tightly linked. After all, the early embryo is essentially a ball of stem cells. For this post, I will delve into a hot topic in reproductive medicine—three-person embryos. Similar to what we have seen with many cell therapies, this technology illustrates the potential of discoveries in this area to create new options for patients, while at the same time raising complex questions around ethics and safety.
In February 2016 Nature News reported on recommendations from the U.S. National Academies of Sciences, Engineering and Medicine (NAS) calling for the Food and Drug Administration (FDA) to approve clinical trials of so called three-person embryos. But new legislation blocks FDA approval, creating another hurdle in moving this technology into the clinic.
Three-person embryos are generated by a procedure known as mitochondrial replacement, with the aim of preventing genetic diseases caused by mutations in mitochondrial DNA. Most people will remember the mitochondrion from high school biology class as the “power house of the cell.” These organelles are responsible for the production of energy-containing ATP molecules that are required for cellular metabolism.
The mitochondrion contains its own small genome, made up of approximately 37 genes. Unlike genomic DNA, which is derived from both the mother and the father, mitochondrial DNA is inherited only from the mother. For reasons that are not entirely clear, mitochondrial DNA accumulates mutations at a rate 1,000 times faster than the DNA contained in the cell nucleus. It is estimated that one in 5,000 children will inherit conditions caused by these mutations. Mitochondrial disorders have the most prominent effects on muscle and brain cells because of their increased energy needs. Besides managing symptoms with medication or special diets, patients have no other treatment options for these debilitating and sometimes fatal conditions.
An individual inherits his or her mitochondria from the few thousand contained in the mother’s egg. In mitochondrial replacement, or three-person in vitro fertilization (IVF), faulty mitochondria in a mother’s egg are replaced by normal mitochondria from the egg of a second female donor. The result is an embryo created by two mothers and one father.
The excitement over this technology has been tempered by warnings about unforeseen side effects. While the mitochondrion does contain DNA, it does not have the full complement of genetic material required for normal function. Nuclear genes encode components the mitochondrion needs to carry out its essential energy producing functions. There are concerns that incompatibilities between the nuclear and mitochondrial genomes could cause unwanted side effects. This is supported by studies in mice, fruit flies and other organisms that demonstrate a link between mitochondrial replacement and abnormalities in metabolism, cognition, and fertility. Furthermore, the potential psychological impact for children, with three biological parents, has been raised as a concern.
The use of three-person IVF has been approached with great caution internationally. In many countries, including Canada, this practice is illegal. In 2015, Britain became the first country to change its laws and allow three-person IVF. The NAS is now calling on U.S. regulators to do the same. A recent report recommends that three-person IVF move to the clinical testing phase. The report makes several recommendations for safety measures that include the testing of this procedure in males only, who would not be able to transmit altered mitochondria to their offspring. In contrast, Britain did not put any restrictions on the sex of modified embryos.
The report from NAS puts the U.S. one step closer to the use of three-person IVF in humans. However, a legislative loophole prevents the FDA from approving clinical trials that use embryos created via three-person IVF. Any researcher can apply to the FDA to conduct a clinical trial using modified embryos. However, in 2016, the government enacted a spending bill that prevents the FDA from using federal funds to evaluate technology involving modified human embryos. This effectively puts the breaks on any federally funded clinical trials of three-person IVF.
From both a health and basic biology standpoint, we are only beginning to understand three-person embryos. Advancing our knowledge will require more basic research, but this cannot meaningfully progress without human clinical trials.
In assessing how to move forward, it is useful to remember that the restrictions placed on three-person IVF are a result of blanket legislation designed to protect against the misuse of any and all reproductive technology.
Here is where one would typically insert a discussion about how safeguards like these are good because they will prevent the creation of designer babies and a potential descent into our worst dystopian nightmares. But it is highly unlikely that three-person IVF will lead to the creation of the designer babies that science fiction has warned us about.
Manipulating the mitochondrial genome through broad replacement is very different from creating designer babies by targeting specific traits through the manipulation of genomic DNA. Three-person IVF was designed for therapeutic purposes and should be tested for potential risks and benefits like any other therapy. For now, this process will be stalled in North America until we have the political will to move forward with new legislation.
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