What is mitochondrial replacement therapy?
MRT is a novel technique that can be used during IVF where a type of DNA, normally inherited from the oocyte, is replaced by DNA from a female donor. The type of DNA that is replaced is called mitochondrial DNA (mtDNA).i This is different from the DNA that codes most of the genetics of the embryo, which is found in the nucleus of the oocyte, not in the mitochondria. MRT may be recommended if there are abnormalities in the intended mother’s mtDNA that can lead to devastating mitochondrial diseases in the baby. These diseases are passed through the mtDNA from the egg to the fetus/baby and are associated with an array of health disorders that can lead to early death in children.ii
Babies conceived with the assistance of MRT contain nuclear DNA from the female providing the egg, nuclear DNA from the male providing the sperm, and mtDNA from the MRT donor. Though a baby created using MRT will contain DNA from three individuals, only a small portion of the baby’s total DNA comes from a mitochondrial donor.
What are mitochondria?
Mitochondria (singular = mitochondrion) are organelles (membrane-bound structures inside human cells) that make most of the energy required for a cell to function. Mitochondria make energy through a process called cell respiration. Cell respiration produces small molecules called adenosine triphosphate (ATP); ATP is the main energy “currency” of the cell. It is used for everything a body’s cells do – from allowing muscles to contract, to helping send nerve impulses. ATP is also essential for replicating one's DNA.
Mitochondria are special organelles for a variety of reasons. Perhaps most interestingly, they have their own DNA, which is genetic material separate from the primary DNA of the cell. The number of mitochondria in each human cell depends on how much energy is required for the function of that cell. For example, there are thousands of mitochondria in a human heart cell, making up 40 percent of the total cell mass, owing to the large quantity of energy required by heart cells.iii Oocytes are rich in mitochondria with primary oocytes containing approximately 6000 per cell.iv Mature oocytes can have up to 100,000 mitochondria per cell.v In comparison, mitochondria make up only 2-6 percent of the total volume of the cells that line our blood vessels (endothelial cells), as these cells do not require as much energy to function.
Mitochondrial DNA vs nDNA
To better understand MRT and how the therapy is performed, it is important to be familiar with the ways in which DNA and mtDNA are distributed when an embryo is formed after conception. This unique distribution also plays a role in the development of mitochondrial disease.
Mitochondria—and therefore the mtDNA—are typically passed down exclusively from the egg to the embryo. This contrasts with nuclear DNA (nDNA), which is passed down equally from both the egg and sperm (50 percent from the egg, 50 percent from the sperm).vi It is thought that when the sperm fertilizes the egg, the mitochondria inside the sperm head are destroyed. This almost always leaves only the egg mitochondria – with the DNA they contain – to become part of the embryo.vii
MtDNA makes up only a small fraction of the total genetic material in a human cell. Current estimates are that there are approximately 21 000 genes in the nuclear human genome; in comparison, mtDNA includes the sequences for only 37 genes. These 37 genes determine mitochondrial function.viii,ix
As each human cell has many mitochondria, there are many copies of mtDNA in each cell. In almost all cases, all these mtDNA copies are identical (homoplasmy) and the same as the mtDNA from the egg. In rare cases, mtDNA copies can be different (heteroplasmy) due to a spontaneous mutation or from a small amount of mtDNA inherited from the sperm.x Despite the small number of mtDNA genes, many of these genes encode proteins that are essential for egg and embryo survival.
Mutations in mtDNA cause a series of genetic disorders known as mitochondrial diseases. MtDNA mutations are detected in approximately 1 in 250 live births, and at least 1 in 10 000 adults are affected by a mitochondrial disease.xi,xii,xiii There are limited treatment options for mitochondrial disease, and many of these disorders are fatal.xiv
Because of the inheritance pattern of mitochondria, inherited mitochondrial diseases are generally transmitted through the maternal lineage. In some cases, a woman using her own eggs to conceive is a carrier of the disease and does not have any symptoms, but all offspring will inherit the disease. Preimplantation genetic testing (PGT, genetic testing prior to embryo transfer) is not useful for patients with heteroplasmic mtDNA mutations and not all genetic platforms offer testing for mitochondrial disease. This is because PGT checks primarily for abnormalities in nuclear DNA, not mitochondrial DNA.xv
There are dozens of mitochondrial diseases, many of which have severe symptoms or effects. These diseases are often disorders of the brain and/or muscles, with a range of symptoms such as epilepsy, blindness, muscle weakness, difficulty with balance, and respiratory failure. The exact clinical manifestations vary by the type of mutation in the mtDNA.xvi,xvii The most common mitochondrial disease is Leber Hereditary Optic Neuropathy (LHON), which causes permanent blindness before 40 years of age. While always inherited maternally, carriers do not always have symptoms of the disease.xviii
The idea that MRT could address these serious genetic disorders is partially why MRT has been an area of scientific study. If mitochondrial mutations are removed and replaced, the transmission of these devastating diseases may be prevented.
What is mitochondrial replacement therapy used for?
One indication for MRT is to prevent the transmission of mitochondrial disease from an egg to the embryo. In these cases, mitochondria from the donor egg replaces the mutated (abnormal) mtDNA from the egg of the intended parent.xix
MRT may also be used as part of IVF for couples with infertility where advanced maternal age is a factor. It is theorized that aging of the egg leads to acquired mtDNA mutations and may contribute to infertility and increased risk of miscarriage in women over the age of 35 years. In theory, by replacing the “aged” mitochondria with “younger” mitochondria from a donor, the embryos created may have better odds of success. Thus, MRT has been proposed to mitigate age-related mitochondrial deterioration and improve IVF success rates in women of advanced maternal age.xx It is important to note, however, that the rising rates of infertility and miscarriage in women of advancing age is primarily due to abnormal genetics of nuclear DNA (aneuploidy).xxi
How does mitochondrial replacement therapy work?
In MRT, nDNA from the donor oocyte is removed. This leaves only the donor mtDNA, along with the rest of the donor oocyte contents. The intended mother’s nDNA is removed from her oocyte and transferred into the donor oocyte. Thus, the resulting oocyte will have 100 percent of its nDNA from the intended mother and all 100 percent mtDNA from the donor.xxii This new oocyte can then be fertilized by sperm to form an embryo.
The egg and embryo structure
To better understand mitochondrial replacement therapy, one must first look at the egg and embryo structure, as well as how chromosomes are distributed. In primary human oocytes, the nDNA is arranged inside the nucleus in pairs of 23 chromosomes, each with a set of chromatids (46 chromosomes - diploid). As an oocyte matures, a process called meiosis divides up the nDNA so that only half of the chromosome set is remaining (23 chromosomes - haploid). There are two division steps in meiosis, and both are important in making sure that the final oocyte is genetically ready for fertilization by sperm. The combination of a haploid oocyte and haploid sperm leads to a diploid embryo.
During the first meiotic cell division, the envelope that keeps the nucleus separate from the rest of the cell dissolves. This frees the nDNA to enter the cell cytoplasm. The nDNA is lined up on a spindle apparatus made up of microtubules. This spindle apparatus is like strings or a web which orients each of the chromosomes in a line, so the chromosomes are evenly divided between newly formed cells as the oocyte divides.
The two cells that result from the first meiotic division are the secondary oocyte and the first polar body. Each of these resulting cells has 23 chromosomes each with 2 chromatids. The first polar body contains less cytoplasm (and therefore much less mitochondria) than the secondary oocyte.
The secondary oocyte then undergoes a second meiotic division. As with the first meiotic division, the chromosomes are lined up by the spindle apparatus so that equal division of the chromosomes can occur. The secondary oocyte expels a second polar body with one set of chromatids, and now contains 23 chromosomes, each with one chromatid.
There are three types of mitochondrial replacement therapy, including Maternal Spindle Transfer (MST), Pronuclear Transfer (PNT), and the less-common Polar Body Genome Transfer (PBT). Below is a further explanation of each type of MRT.
Maternal Spindle Transfer (MST)
MST involves transferring specific genetic material from the intended mother’s oocyte to the oocyte of the donor. This process takes place before the eggs are fertilized and become embryos.
In the MST technique, the intended mother’s chromosomes, which contain nDNA arranged on spindles, are removed from one of the oocytes. This oocyte is then discarded. The nuclear chromosomes and spindle apparatus are removed from a donor oocyte, and these are discarded.xxiii The intended mother’s nuclear chromosomes (suspended in the spindle apparatus) are then placed into the donor oocyte, which still contains all the donor mitochondria and their presumably healthy mtDNA. In effect, the donor oocyte still contains all its original components, except the nDNA has been replaced.xxiv
The transfer of material will be repeated using more donor oocytes and nDNA spindles from the mother. Once all the nDNA spindles available from the intended mother have been transferred to all the donor eggs, the eggs will be fertilized in the lab. The embryos created will be grown in the lab until day 3 or 5, after which an embryo transfer will be performed. Alternatively, embryos may be cryopreserved (frozen) for future use.
Pronuclear Transfer (PNT)
In PNT, both the intended mother’s oocyte and the donor oocyte are fertilized by sperm. Upon successful fertilization, there are two pronuclei (2PN) within the embryo – one representing genetic material from the egg and one from the sperm. The 2PN, containing nDNA from the donor and sperm, are removed from the embryo made from a donor egg and discarded. The 2PN from the embryo made by the intended parents’ egg and sperm are removed from the maternal embryo and placed into the donor-derived embryo (from which the 2PN had previously been removed). The empty embryo created from the intended mother's oocyte is then discarded as it presumably contains mtDNA mutations.
The reconstituted embryo will have nDNA from the intended parents and presumably normal mtDNA from the donor.xxv Embryo culture is performed as above with embryo transfer or cryopreservation.
Polar body genome transfer (PBT)
When oocytes divide, the division is typically asymmetric. Division creates a secondary oocyte (which will continue to mature) and another cell, which is called a polar body. The polar body is smaller, contains less cytoplasm, and will eventually degenerate 17-24 hours after being expelled from the oocyte.xxvi
Because polar bodies contain less cytoplasm, they contain very few mitochondria and therefore very little mtDNA. However, the polar body contains the same-sized nucleus and the same amount of nDNA as a secondary oocyte.xxvii
In PBT, either 1) the entire polar body 1 of the intended mother is transferred into a donor oocyte (PB1T), which is then fertilized by sperm, or 2) both the donor oocyte and the intended mother’s polar body are fertilized by sperm to create two embryos. The pronucleus is removed from the donor zygote so there is no nuclear genetic material in this embryo, and the fertilized polar body from the intended mother is inserted inside the donor embryo which contains only mtDNA from the oocyte donor (PB2T).xxviii
What are the pros and cons of mitochondrial replacement therapy?
The primary advantage of MRT is the potential that the treatment could offer significant health benefits to families that face the risk of transmitting mitochondrial disease. Essentially, a parent with mitochondrial disease could have offspring that are genetically related to them without the risks of mitochondrial disease transmission.xxix,xxx Nevertheless, MRT also comes with certain disadvantages as well.
First, though there have been successful live births resulting from mitochondrial replacement, MRT is an experimental therapy. Because of the limited number of live births, data on success rates and risks of mitochondrial replacement is lacking.
Secondly, generally when using an egg donor, the recipient is not genetically related to the conceived child, since the nuclear genome of the donor is passed on to the offspring, not the recipient’s nuclear genome. MRT does allow the recipient to be genetically related to their child, because genetic material is manipulated. It is unclear what, if any, possible genetic damage occurs when genetic material is extracted from an oocyte or early embryo and inserted into another oocyte/embryo. Manipulating the zygotes in this manner could lead to abnormal embryo development.
One additional theoretical risk is that since the mtDNA will be from a different individual than the nDNA, the mitochondria in the fetal cells will not interact normally with the nucleus of the cells. The possible effect of this is unclear.xxxi
Finally, as the first live birth resulting from mitochondrial replacement therapy occurred in 2016, there is so far no long-term follow-up documenting any possible future risks to the resultant offspring.xxxii
What is the history of mitochondrial replacement therapy?
MRT is not a well-established treatment option when it comes to fertility, and so there is not a well-established history of the procedure or the outcomes of the procedure. This is largely because access to MRT remains limited to a few specific labs.
Successful MRT has been performed and is legal in Mexico, Ukraine, Greece, and Spain, and is legal in the United Kingdom as well. The first live birth of a boy was to a Jordanian couple in the United States in 2016, after treatment by a US-based team in Mexico. The first live birth of a girl was in Ukraine in 2017. There are reports of several additional live births in Ukraine, though the fertility group responsible has not published their results. Spanish and Greek scientists were the first to successfully treat infertility (unrelated to mitochondrial disease) with MRT, resulting in a live birth in 2019 in Greece.xxxiii
What countries have access to mitochondrial replacement therapy?
MRT is extremely controversial due in part to the ethical questions surrounding the treatment. In the United States, the FDA released a statement in 2018 affirming that MRT is currently not able to be legally performed, even in a clinical trial or research setting.xxxiv MRT is also not legally allowed in Canada or Israel and is restricted to research use in Australia.xxxv In Germany, laws are more vague. There is no mention of MRT specifically in the German Embryo Protection Act, so MRT is technically legal, though no one is currently using this technology in Germany.xxxvi
The United Kingdom was the first country to legalize MRT, under the Human Fertilization and Embryology (Mitochondrial Donation) Regulations of 2015, though with some restrictions on the type of MRT and the indication. Presently, MRT is only legally permitted to prevent a mother from passing a specific mitochondrial disease to her offspring; it cannot be used to treat infertility alone. At the time of publication of this article, there have been no successful births after MRT in the UK.xxxvii
What ethics questions surround mitochondrial replacement therapy?
While MRT may be a valuable tool in the prevention of genetic disease, objections to mitochondrial replacement techniques tend to stem from moral, social, or medically ethical objections.
From a medical perspective, as MRT involves manipulating the genetic material of the resultant offspring, all future progeny of a female child born after MRT would have this same mtDNA. Thus, these genes would be passed on to future generations, as would any problem with the donated mtDNA.xxxviii
There are concerns from a social standpoint as well. The resultant child could struggle with their familial identity as they have genetic material from three individuals, which could raise confusing questions as to parentage.xxxix This could potentially raise legal problems. However, the UK addressed this concern through draft regulations explicitly stating that a mitochondrial donor would not be a legal parent to the child, but more akin to an organ donor. Once again it should be noted that, presently, MRT is only legally permitted in the UK to prevent a mother from passing a specific mitochondrial disease to her offspring. MRT cannot be used to treat infertility alone.xl
Moral objections have made MRT controversial in some countries. Many countries have restrictions on embryo research, which stems in part from religious concerns related to when life begins. This argument is often applied to MRT research.xli
Conclusion
Mitochondrial replacement therapy may eventually hold promise as an option in reproductive medicine, especially when it comes to avoiding genetic diseases. However, the procedure is highly controversial with objections coming from ethical, moral, and social standpoints. Even though MRT is starting to gain acceptance as a therapeutic option in a few countries, it may be several years before the procedure is accepted on a broader scale.
Continued study of MRT will yield more insight into the efficacy of the procedure to help avoid serious mitochondrial disease, the option of its use in treating ovarian aging, and the long-term safety of the technology. However, for now, the option of mitochondrial donation and genetic engineering remains theoretical for most of the world.
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