Two is Company, but Three’s a Crowd: The Development of “Three-Parent” In Vitro Fertilization

Everyone in the world has two parents that they originated from. It is common knowledge that one’s DNA comes from a combination of copies of their parent’s genomic sequence.  But is it possible to have more than two biological parents? According to recent studies, it is.

The method of creating a “three-parent” baby has gained popularity, especially in the UK, where the House of Commons just recently voted to legalize it. The in-vitro fertilization technique utilizes a combination of DNA from two female and one male donor. The purpose of the technique is to limit the amount of gene defects associated with mutated mtDNA, which could potentially act as a detriment to the human body.

Most individuals recognize mitochondria as the “powerhouse” of the cell. Their purpose is to produce adenosine triphosphate (ATP) that the cell uses as packable energy to synthesize other processes within the body. Mitochondria are also very important in the development of oocyte cells. Studies have also shown that based on the mitochondria’s common location near the MII spindle, it has a huge impact in the formation of meiotic spindles before fertilization.[1]  Mitochondrial DNA, also known as mtDNA, also plays a crucial role in the development of the cytoplasm in early cells. The mtDNA is only heritable from the mother’s egg cells. The mtDNA from sperm cells is destroyed as the sperm penetrates the egg cell wall.

Unfortunately, the mutation rate in mtDNA is around 10 to 20 times higher than in nuclear DNA. This high occurrence can lead to many negative effects on early oocyte cells, as well as long-term effects on a parent’s offspring. In the United States, 1 in 4,000 children are born with an inherited mitochondrial disease.[2] 60-90% of abnormal DNA cases are also due to mtDNA disease as well. This poses an issue for mothers who want to have children, but are at a high risk of transferring mutated mtDNA to their offspring. Dysfunctional mtDNA is also the cause of fertilized zygotes not being able to mature in older women.

In order to counteract these issues, scientists have discovered the process known as “cytoplasmic transfer.” The process was first proposed as an infertility treatment. In 1997, the first cytoplasmic transfer method that resulted in a pregnancy was reported.[3] The process is now considered a favorable optional therapy for getting rid of mitochondrial mutations. The in-vitro technique involves substituting an oocyte with defected mitochondrial genes with the cytoplasm from another female donor egg cell that contains healthy mitochondria. The nuclear genetic information in the cell comes from the separate female egg cell and male sperm cell, as per usual. The third “mother’s” DNA comes into play by inserting the fertilized cell with healthy mitochondria.

  

http://www.rbej.com/content/12/1/111/#B26 

There is still much process being down regarding “cytoplasmic transfer.” In the United States, the research is not supported by federal funding agencies, but clinical trials are being conducted.  “Three-parent” in-vitro fertilization holds much promise, however. Offspring would still retain nuclear genetic information from both parents, yet their genetic makeup would be enhanced by the donated healthy mtDNA. This healthy mtDNA can potentially be passed down to other offspring, thus eliminating mitochondrial disease in future generations.

On the other hand, there are many cons and risks to the in-vitro procedure. For example, the long-term safety effects of “cytoplasmic transfer” are still unknown. Although the animal studies have all produced positive results, there still needs to be further research in human subjects.  There is also the chance that the mutated mtDNA could still persist in the offspring due to errors in transfer methods of the donor cytoplasm.  The potential “incompatibility” between nuclear and mitochondrial genomes may pose as a risk as well.

There are also many ethical issues surrounding “cytoplasmic transfer” that raise concern.  For example, the replacement of mitochondrial genes leads to changes in the offspring’s genome, without the offspring’s consent. This becomes crucial when the implanted genes may pose a risk to the offspring’s health in the future. This leads to the question of whether the parents be making decisions regarding the genetic makeup of their future child. It also may lead to advances towards genetically modified humans.[4]  The concept of in-vitro fertilization is also controversial within itself. This technique of using the DNA of three different parents only adds to the debate.

Despite many setbacks, the UK is making much progress in regards to “cytoplasmic transfer.” For example, the Human Fertilization and Embryology Authority created a panel to review mitochondrial disease prevention techniques and “found broad public support for mitochondrial replacement.”[5]  The Nuffield Council on Bioethics also concluded that if researchers could prove that the techniques were safe, research could be approved. This contrasts greatly in the USA, where federal funding for embryo research is still banned. If “cytoplasmic transfer” really is the future of the prevention of mitochondrial diseases, then the USA may possibly fall behind in future advancements.

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[1] Heide Schatten, Qing-Yuan Sun, et. al. “The impact of mitochondrial function/dysfunction on IVF and new treatment possibilities for infertility,” Reproductive Biology and Endocrinology (2014). Accessed March 6, 2015. doi http://www.rbej.com/content/12/1/111/#B26

[2] Paula Amato, Masahito Tachibana, et al. “Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases,” Fertility and Sterility (2014). Accessed March 6, 2015. doi http://www.fertstert.org/article/S0015-0282(13)03290-1/fulltext

[3] Amato, Tachibana, et al. “Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases”

[4] Charlotte Pritchard, “The girl with three biological parents,” BBC News, August 31, 2014. Accessed March 6, 2015. doi http://www.bbc.com/news/magazine-28986843?OCID=fbasia&ocid=socialflow_facebook

[5] Amato, Tachibana, et al. “Three-parent in vitro fertilization: gene replacement for the prevention of inherited mitochondrial diseases”