The Making of Three-Parent Babies

By Cristina Riquelme Vano

Where does a baby from? The answer used to be quite simple; the fertilization of the paternal sperm and the maternal ovum gives rise to a new-born baby nine months later. However, recent medical advances have challenged this question. What if a baby could come from three parents instead of two? Mitochondrial transfer has recently made this possible, combining DNA from three individuals to create “three-parent babies”. This emerging technique seeks to offer mothers a way to have a child without passing on metabolic disorders. 

On 6^th  April 2016, Mexico, the world’s first “three parent” baby was born (Hamzelou, 2016). A couple had been trying to start a family for almost twenty years, which saw four miscarriages and two children loss around the age of six due to Leigh syndrome, a mitochondrial disorder which severely affects the brain, nerves and muscles of the developing infant. About 20–25% of Leigh syndrome cases are caused by a mutation in mitochondrial DNA (mtDNA). The mother was a carrier of a mutation for Leigh syndrome. Her normal and mutant mitochondrial genome co-existed and her mtDNA mutation load was not enough for her to develop symptoms. Desperate to have a child, the couple attempted for the first time to use mitochondrial transfer is assisted reproduction. The baby was born showing no symptoms of Leigh syndrome.

Mitochondria is one of the most important organelles in eukaryotic cells as it provides the energy needed to power the cell’s biochemical reaction. They are made up of proteins encoded both by nuclear and mitochondrial DNA. Mitochondrial disorders are fairly common. At least 1 in 5,000 people in the world’s population have a mutation in mitochondrial DNA, leading to mitochondrial dysfunctions which can be maternally inherited. Mitochondrial dysfunctions are maternally inherited because, at fertilisation, the sperm only delivers it’s nuclear DNA to the egg, mtDNA can only be inherited from the mother. The most common mutation is mtDNA 8993T > G, which impairs the function of ATPase. ATP synthesis is reduced by 50-70% leading to a failure in the respiratory chain which can lead to death.

Until recently, there were limited options to prevent transmission of mtDNA mutations to offspring. Options included adopting a child, using a donor oocyte or pre-implantation genetic diagnosis to abort an affected pregnancy. Selection of pre-implantation embryos with mtDNA mutations was often unreliable and adopting a child or using a donor oocyte was not an option considered by many couples who wanted to have both their maternal and paternal DNA in their future baby. In 2016, Dr. John Zhang, an infertility expert at the New Hope Fertility Centre in New York City, overcame these problems by attempting to create a three-parent baby using mitochondrial transfer, a technology that has been around since 1983 (Zhang et al., 2017). The world’s first baby was born with “three parents and showed no symptoms of Leigh syndrome”, seemingly preventing the inheritance disease.

Mitochondrial transfer, also referred as pronuclear transfer, works by replacing the damaged mitochondria in the mother’s egg with healthy mitochondria from a woman’s donor egg. This is done by removing the genetic material from the donor egg. The donor egg is enucleated but contains all other organelles, including healthy mitochondria. The mother’s genetic material is isolated from its egg and transferred into the enucleated donor egg. The newly engineered egg containing the maternal nuclear DNA is fertilized in vitro with the father’s sperm and implanted into the mother’s womb, giving rise to a healthy child nine months later. This way, the developing embryo has nuclear DNA from both parents and mitochondrial DNA from the donor egg.

The Human Fertilisation and Embryology Authority (HFEA) granted scientists at the University of Newcastle a licence to carry out the three-parent technique in 2017. In February 2018, the first two women were given approval to have a baby using the method (Sample, 2018). Since its first use in 2016, this technique has been highly controversial due to its biological, legal and ethical concerns. There have been raised concerns on the side effects of having DNA from three parents in one person and the rapid expansion of this technique before its safety has been fully determined. An ethical issue arising from the use of this technique is that the new-born baby carries mitochondrial DNA from a third unknown donor which if female, she will pass on this on to future generations, thus, making genetic heritage more difficult to predict in the future. Some religious believers also oppose to the move, pointing out that this technique involves the destruction of human embryos as part of the process.

Once safety concerns are fully understood the ethical implications of this emerging technology might be reconsidered worldwide. All we can say about this pioneering technique is that it could give women with mitochondrial disease the chance to have a healthy child, without the fear of passing on this condition which can lead to babies born with this condition having multiple disabilities and indeed life-limiting impairments, as Robert Meadowcroft said, head of Muscular Dystrophy UK (UK experts give green light to ‘three-parent babies’, 2016).

References:

Hamzelou, J., 2016. Exclusive: World’S First Baby Born With New “3 Parent” Technique Read More: Https://Www.Newscientist.Com/Article/2107219-Exclusive-Worlds-First-Baby-Born-With-New-3-Parent-Technique/#Ixzz6ktezsgrs. [online] Available at: <https://institutions.newscientist.com/article/2107219-exclusive-worlds-first-baby-born-with-new-3-parent-technique/&gt; [Accessed 24 January 2021].

Zhang, J., Liu, H., Luo, S., Lu, Z., Chávez-Badiola, A., Liu, Z., Yang, M., Merhi, Z., Silber, S., Munné, S., Konstantinidis, M., Wells, D., Tang, J. and Huang, T., 2017. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Reproductive BioMedicine Online, 34(4), pp.361-368.

Sample, I., 2018. UK Doctors Select First Women To Have ‘Three-Person Babies’. [online] the Guardian. Available at: <https://www.theguardian.com/science/2018/feb/01/permission-given-to-create-britains-first-three-person-babies&gt; [Accessed 24 January 2021].

Medicalxpress.com. 2016. UK Experts Give Green Light To ‘Three-Parent Babies’. [online] Available at: <https://medicalxpress.com/news/2016-11-uk-experts-green-three-parent-babies.html&gt; [Accessed 24 January 2021].