Mitochrondrial replacement therapy (MRT), often referred to as “3-person in-vitro fertilization (IVF),” is a technology that combines the mitochondrial DNA (mtDNA) of a donor with the nuclear DNA of a couple in an embryo that is carried to term. This technology has been proposed to prevent the transmission of maternally transmitted mitochondrial disease. Mitochondrial diseases are often caused by genetic mutations affecting both adults and children, that can lead to diseases across multiple organs and have no cure. While strategies exist to prevent the vertical transmission of mutated mtDNA, such as adoption, or egg and embryo donation, the lack of a genetic link does pose a problem for some couples looking to have children. In this article, we will discuss the history behind MRT, its successes and some ethical concerns and controversies that have arisen since its inception.
History of MRT:
The research that went into the modern processes of MRT began as early as the 1980s when Dr. Jacques Cohen and others used cytoplasmic transfer to assist in reproduction. Cytoplasmic transfer is a process in which a small amount of cytoplasm from a healthy donor’s oocyte is transferred to an oocyte from a person experiencing fertility issues. The first baby was born from this technique in 1997. Prior to 2002 and regulation of this technique by the USA’s Food and Drug Administration, Cohen’s clinic used this technique for the conception and birth of 13 children. Since then, the promising research has led to the birth of 30-50 children worldwide (as of 2016). In 2009, two research teams published studies on mitochondrial donation that progressed the technology further. In 2010, Craven et al. conducted human trials with oocytes that yielded a carryover rate of only 2% mutated mtDNA. In 2015, the UK passed the Human Fertilization and Embryology (Mitochondrial Donation) Regulations making mtDNA donation legal under rare cases where a couple is at a higher risk of transmitting mitochondrial disease to their children. Since then, this technique has seen to the births of several children, including fewer than five children in the UK as of April 2023. While this procedure has been used and/or approved in some countries (Greece, Ukraine, Australia, Mexico), it is still restricted in many countries including Canada and the USA.
Methods of MRT:
The historical method of cytoplasmic transfer is no longer used in modern procedures of MRT. Rather three main methods exist: maternal spindle transfer, pronuclear transfer, and more recently, polar body transfer. In all these techniques, “donor” refers to a person with healthy mitochondria, and “recipient” refers to a person with mutated mtDNA that is trying to conceive a child.
In spindle transfer, the spindle-chromosome complex that contains the genetic material from the recipient is removed from an egg during cell division. This spindle-chromosome complex is inserted into a donor oocyte with the nucleus removed. This egg is fertilized and investigated for genetic mutations, particularly in the mtDNA, prior to implantation in the recipient.
In pronuclear transfer, an oocyte is removed from the recipient and donor. Both oocytes are fertilized with sperm from the same person. All pronuclei (nucleus from sperm or egg cells) are removed from each fertilized egg prior to the fusing, and the pronuclei from the recipient is transferred into the fertilized egg from the donor. Like in the spindle transfer procedure, the egg is investigated for genetic mutations prior to implantation.
The final technique is the newest and is called polar body transfer. A polar body is a small cell with very little cytoplasm that is created when an egg cell divides. In polar body transfer, a polar body from the recipient is used in its entirety instead of nuclear material from the recipient’s egg as in the other methods. This is a promising technique as polar bodies have very few mitochondria, thereby reducing the risk of transmitting recipient mitochondria compared to maternal spindle transfer and pronuclear transfer which both have a small carryover of recipient mitochondria. Despite this, polar body transfer requires further research to increase reproducibility and replication.
Benefits of MRT:
Several benefits exist for the use of MRT for IVF. First and most importantly, it is a strategy to allow couples to birth a biologically related child that does not have mitochondrial disease. In addition to the reduction in mitochondrial disease transmission, MRT may provide benefits for age-related infertility, where traditional IVF is unsuccessful. Despite these benefits, there has not been sufficient research to suggest that mitochondrial disease transmission can be lowered or avoided altogether by MRT, although preliminary research in animals may provide some insight into this in the future.
Scientific and Ethical Concerns of MRT:
Although MRT can provide some families the benefit of having biological children without transmitting mitochondrial disease, there are some scientific and ethical concerns about the procedure. Reversal is cited as a main concern in MRT and involves carried-over mitochondria increasing over time, ultimately replacing donor mitochondria in cells. In a study by Costa-Borges et al., 1 out of 6 children born from MRT exhibited reversal, where 30-60% of mitochondria were inherited from the mother despite a carryover rate of only 1% from the maternal egg. While the child studied did not have any risk for a mitochondrial disease, this is not always the case. This carryover rate may mean that MRT might not be successful in limiting mitochondrial disease in the offspring of individuals with mitochondrial mutations. One possibility to explain this may be that genetic factors from the recipient increase the efficiency of replication for their own mitochondria, compared to that from the donor. It may be necessary to find similarities in mitochondrial DNA between recipient and donor to reduce the risk of reversal.
In addition to scientific concerns, ethical concerns have been raised regarding the use or MRT. These ethical concerns encompass various categories that can include harms to egg providers and harms to potential offspring.
Harms to egg providers with healthy mitochondria: Although egg donation is voluntary, it is not without its physical and psychological risks. Donors are required to undergo several interviews, screens, as well as hormonal stimulation and egg retrievals with no “benefit” of having a child. These hormonal treatments can cause acute physical pain (cramping, nausea, vomiting). Also, they can potentially cause long-term effects including but not limited to risk of cancer and decreased fertility. The ethics of egg donation comes into play when considering the financial aspect of egg donation, where economically disadvantaged women may become targets for this process.
Harms to offspring: MRT still remains experimental, and as a result, long-term safety and efficacy must be investigated further. At this moment, there is no information on the impact that mixing genetic material and mtDNA may have on future progeny. Although there is always risk in new technologies, thereby necessitating the need for clinical trials, it is necessary to assess the technique in preclinical trials rather than foregoing these processes by conducting the procedures in countries without regulations against the technique. This introduces further ethical concerns into medical tourism.
Overall, MRT provides a rewarding solution for couples who would like to have biologically related offspring without risking the transmission of mitochondrial disease. However, scientific and ethical concerns subject this technology to further scrutiny prior to its popularization. Ultimately, national health organizations must continue to objectively analyze the research into MRT and its future use.
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