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Biomedical Research

Mitochondrial Replacement Therapy: An Ingenious Breakthrough or Recipe for Disaster?

Mitochondrial replacement therapy is an emerging reproductive technology that produces an embryo with three genetic contributors. In 2015, the United Kingdom legalized mitochondrial replacement therapy. The New Scientist reported the birth of the first healthy child conceived by mitochondrial replacement therapy in 2016. This was led by New York-based physician Dr. Zhang. This was followed by a media frenzy, scientific debates, and ethical concerns from around the world. This article explores the aim, procedures, types, policies, and debates on this novel assisted reproductive technology.

By Ruhana Mahmud

Published 12:25 EST, Tues December 7th , 2021

Mitochondrial replacement therapy: a brief introduction

Three-parent IVF or mitochondrial replacement therapy is a unique form of in-vitro fertilization that produces an embryo possessing the nuclear DNA of two parents and the mitochondrial DNA (mt-DNA) from a female donor. Different types of this procedure include maternal spindle transfer, pronuclear transfer, and polar body genome transfer. The primary aim behind the development of this technique is to allow women with defective mitochondrial DNA to have biologically related healthy offspring without fatal mitochondrial dysfunction. It also increases the chances of pregnancy in older women.

WHAT ARE MITOCHONDRIAL DYSFUNCTIONS?

To understand mitochondrial dysfunctions, let’s go back to mitochondria. Mitochondria are intracellular organelles that are responsible for ATP production in eukaryotic organisms. Mitochondria contain their own genome consisting of approximately 37 genes. Mitochondrial disorders originate from the mutations of this genome. Organs with high energy demands such as the heart, central nervous system, and endocrine system are particularly affected by this. About 100 babies are born with severe mt-disorders in the UK, the majority of which die in the infant stage These conditions are exclusively inherited from the mother.

TYPES OF MRT

Pronuclear transfer Technique

In this technique, both the mother and donor eggs are fertilized by the father’s sperm. The pronucleus of the donor zygote (containing healthy mitochondria) is replaced by that of the biological parents’. The biological mother then carries the embryo to term.

Maternal Spindle Transfer (MST)

This technique extracts the maternal spindle complex in the metaphase of the mother’s egg and transplants it into the donor’s egg with healthy mitochondria. It is a form of preimplantation genetic diagnosis. This lowers the chances of mt-DNA carryover and mutations.

Polar body genome transfer (PBT)

In this technique, the polar body is removed from a zygote in the pronucleus stage and transferred to a zygote with the maternal nucleus and the polar body previously removed or the polar body is withdrawn from the oocyte in meiosis II and transferred to an oocyte in MII with the spindle previously removed, followed by fertilization of the reconstructed oocyte.

MRT AROUND THE WORLD

The United Kingdom

In February 2015, the United Kingdom became the first country in the world to legalize maternal spindle transfer and pronuclear transfer. In 2017, the UK fertility clinic was granted the first license to start its first clinical trial by HFEA.

Mexico

On 6th April 2016, the world’s first baby was born in Mexico conceived via maternal spindle transfer to a 36-years old Jordanian woman who was a carrier of Leigh’s disorder. This was done with the consent of the Internal Review Board (IRB) of the Mexican clinic.

Ukraine

On 5th January 2017, the world’s second 3-parent baby was born in Ukraine conceived via pronuclear transfer. The procedure was approved by the Ukrainian Association of Reproductive Medicine.

United States of America

The mitochondrial replacement therapy remains illegal in the United States because of social and privilege stemming from social and economic peculiarities is the main cause. Mitochondrial disorders have an extremely low prevalence in the United States and according to 2017 data, only 12,423 American women were at the risk of passing on their defective mitochondrial DNA to their offspring. Hence, the country refrains from allocating large amounts of resources to MRT.

Greece

On 9 April 2019, using the maternal spindle transfer technique of MRT, a woman in her early 30s conceived a child in Athens. This is considered unique as it was termed as a “Global first” because the motive was not to avert a genetic disorder, it was to treat infertility.

MRT- A revolutionary technology?

Reproductive Autonomy

Reproductive autonomy is a basic human right. Mitochondrial replacement therapy allows women to have biologically related children without passing on possible life-threatening disorders. Inability to have children has been shown to have profound psychological impact on women. MRT can be a solution to both these problems. The risks of mixing the mother and donor mt-DNA is negligible and such a case has not yet been reported.

No suitable alternatives

Egg donation cannot establish a genetic link between the child and the mother as the child will possess both the nuclear DNA and mt-DNA of the donor. It may also cause ovarian hyperstimulation. Surrogacy cannot also be a possible solution as the child will get the mt-DNA from the mother. Preimplantation genetic diagnosis is only appropriate for women with low amounts of defective mt-DNA.

Creation not Cure

Mitochondrial replacement therapy is meant to create healthy offspring free of a genetic mitochondrial disorder and not as a cure. It can indirectly reduce the prevalence of mitochondrial disorders in society.

Lesbian Couples

Lesbian couples can particularly benefit from this novel technology as the nuclear and mitochondrial genomes can each come from one of the two partners. This will allow both women to establish a hereditary link to the child.

Treating infecundity in older women

Older women have fewer mitochondrial DNA in their oocytes compared to younger women.Defective mt-DNA can lower the stability of nuclear DNA of oocytes leading to embryo aneuploidy and subsequent infections. Using mitochondria from a younger woman can thus improve the quality and fertility of the older woman’s eggs.

Some Concerns

Economic concerns

The technique is extremely expensive. Mitochondrial diseases have a low occurrence. 1/40000 in the United States suffer from this. Critics question the feasibility of investing a massive sum of money and resources for a small segment of the population.

Scientific concerns

MRT does not cure mitochondrial disorders and does not guarantee prevention. A wide variety of heteroplasm may occur in the children. If the nuclear genome does not co-operate with mt-DNA may have terrible medical results. Due to ethical concerns of reproductive research on humans and lack of related data, there is a fear of unknown conditions developing in the future. This is also germline as a female offspring can pass on this genetic change to the next generations.

Germline modifications

Mitochondrial replacement therapy alters the germline as the offspring inherits the genetic change. If the child is female, the new mt-DNA will be passed on to her offspring.

Effects on specific interest groups

There are an increasing number of people to trace their genetic ancestry using the Y-chromosome and mitochondrial DNA. This information can provide individuals a sense of identity. If MRT is applied, they might receive misleading information which can affect their personal perspectives of themselves.

Ruhana Mahmud, Youth Medical Journal 2021

References

Three-parent babies: Mitochondrial replacement therapies, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169912/

Three persons, three genetic contributors, three parents: Mitochondrial donation, genetic parenting and the immutable grammar of the ‘three x x’, © The Author(s) 2017 , https://pubmed.ncbi.nlm.nih.gov/28127993/ Rishishwar, L., Jordan, I.K. Implications of human evolution and admixture for mitochondrial replacement therapy. BMC Genomics 18, 140 (2017). https://doi.org/10.1186/s12864-017-3539-3

Bartha Maria Knoppers, PhD;1 Arthur Leader, MD;2 Stacey Hume, PhD;3 Eric A. Shoubridge, PhD;4 Rosario Isasi, MPH;5 Forough Noohi, MSc;1 Ubaka Ogbogu, SJD;6 Vardit Ravitsky, PhD;7,8 Erika Kleiderman, LLB, https://mitocanada.org/wp-content/uploads/2018/10/Knoppers-et-al.-2017-Mitochondrial-Replacement-Therapy-The-Road-to-the-Clinic-in-Canada.pdf

 Hitika Sharma, Drishant Singh, Ankush Mahant, Satwinder Kaur Sohal, Anup Kumar Kesavan, Samishka, Development of mitochondrial replacement therapy: A review, https://www.sciencedirect.com/science/article/pii/S2405844020314870#bib76

Hana Carolina Mozeira Farnezi, Ana Carolina Xavier Goulart, Adriana dos Santis, Mariana Gontijo Ramos and Maria Leticia Firpe Penna, Three Parent babies: Mitochondrial replacement therapies, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169912/

By Ruhana

Hey there! I just completed my A-Levels this year and hope to study medicine. I am from Bangladesh. Although I love anything about medicine, the brain is my all-time favourite.

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