Mixing mitochondrial DNA from mother and donor may have harmful effects in the medium and long term warns a study published in Circulation.

The study was conducted by a team from the Carlos III National Center for Cardiovascular Research in Madrid (CNIC) in collaboration with other Spanish research centers, including the Center for Cooperative Research in Biomaterials (CIC biomaGUNE), the Networked Biomedical Research Center for Respiratory Diseases (CIBERES) and the Networked Biomedical Research Center for Cardiovascular Diseases (CIBERCV). This research confirms the suspected risks of so-called mitochondrial transfer or replacement techniques, which use mitochondria from a female donor to prevent women with a mitochondrial disease from transmitting it to their children. (See more HERE).

What are mitochondrial replacement techniques?

Mitochondria are small organelles that are found in large numbers within our cells and are essential to generate the energy we need to function. These organelles have a unique feature: they have their own DNA, mitochondrial DNA (mtDNA). Mitochondria function partly because of this DNA, but they also need a multitude of genes found in the DNA of the cell nucleus (nuclear DNA, nDNA). For this reason, different mutations in the two genomes can end up producing a mitochondrial disease, which can be very serious and even fatal. Mitochondria are inherited exclusively from our mothers. Generally, all mtDNA copies in a cell are identical, which is called homoplasmy; in contrast, when there is a mutation in the mtDNA, we find a mixture of healthy mtDNA and mutated mtDNA, which is called heteroplasmy. It is the ratio between the two mitochondrial DNAs, the healthy and the mutated, that will determine whether or not the disease manifests.

Because mitochondrial diseases have no cure, a number of techniques combined with in vitro fertilization (IVF) have been developed to replace the mitochondria of sick mothers with healthy donor mitochondria, thus preventing their children from inheriting the disease (see more HERE). These techniques can also be used in some cases of infertility, as a way to rejuvenate the oocytes (eggs) of infertile women by providing mitochondria and other cellular components of oocytes from young, healthy donors. The risks of these techniques to the resulting children mean that only a few countries permit their use, including the United Kingdom.

Mitochondrial replacement techniques can be performed using two different procedures: maternal spindle transfer (MST) and pronuclear transfer (PNT). In MST, the nuclear genetic material is extracted from the oocytes of women with mitochondrial disease (or infertility) and transferred to donor oocytes that have their nuclear genetic material removed. The resulting oocytes are then fertilized with sperm to create embryos. In PNT, oocytes with abnormal mitochondria are fertilized in vitro to create zygotes, single-cell embryos; their nuclear genetic material will be extracted from these embryos to be transferred to other embryos free of mitochondrial abnormalities, generated with donor oocytes and sperm. As we will discuss later, on an ethical level, this second technique is much more problematic than the first, since it requires the creation and subsequent destruction of an embryo for each embryo to be produced. In MST, however, the gametes are manipulated before fertilization, although it is true that subsequent IVF is performed. Several children have already been born through these procedures.

Another technique, called cytoplasmic transfer, emerged earlier in the 1990s to treat infertility. It involves transferring part of the cytoplasm of young donor oocytes to the oocytes of infertile women, with the aim of “rejuvenating” them. At least 30 children have been born as a result of this technique, but serious safety concerns led the US Food and Drug Administration (FDA) to ban it in 2001. Nevertheless, it is offered in other countries, such as India, the Turkish Republic of Northern Cyprus, Ukraine, Armenia, Georgia, Israel, Turkey, Thailand, Singapore, Germany and Austria.

Meanwhile, approaches involving the transplantation of isolated mitochondria to individuals with a related pathology are currently being developed. This would not be limited to prevention of transmission, but is a truly therapeutic approach.

What are the findings of the new study?

“The question as to why mtDNA is transmitted to descendents from only one parent has yet to be answered, but until now the issue had no health implications,” says Dr. Ana Victoria Lechuga-Vieco, first author of the abovementioned article. She warns, however, that “The new medical therapies that breach this biological barrier can generate, intentionally or non-intentionally, mixtures of mtDNA from more than one individual in the same cell” (Source: CNIC).

Indeed, mitochondrial replacement techniques do not completely eliminate the maternal mtDNA, so a mixture of two mtDNAs is obtained, maternal and donor. This situation is called divergent nonpathologic mtDNA heteroplasmy (DNPH). The research discussed herein starts from the hypothesis that DNPH is maladaptive and is usually prevented by the cell.

To test this hypothesis, the scientists engineered DNPH mice, i.e., mice in which a mixture of maternal and donor mtDNA was obtained. The study of these mice over their lifetime showed that most cells rejected having the two mitochondrial variants and eliminated one of the two mtDNAs. However, some important organs such as the heart, lung, skeletal muscle, and eye were unable to do so. Thus, in their paper, the researchers say that “DNPH impairs mitochondrial function, with profound consequences in critical tissues that cannot resolve heteroplasmy, particularly cardiac and skeletal muscle. Progressive metabolic stress in these tissues leads to severe pathology in adulthood, including pulmonary hypertension and heart failure, skeletal muscle wasting, frailty, and premature death”.

An additional highly relevant finding is that symptom severity is strongly modulated by the nuclear context, i.e., that the nucleus-mitochondrial interaction will be decisive in the effectiveness of the techniques. Earlier publications had already drawn attention to this risk, which is now confirmed.

For Dr. José Antonio Enriquez, research leader and director of the Functional Genetics Laboratory of the Oxidative Phosphorylation System (GENOXPHOS) at CNIC, the information is especially relevant to the field of donor mitochondrial transfer therapies, because, in the study, “animals generated through these procedures appear healthy early in life but go on to suffer in later life from heart failure, pulmonary hypertension, loss of muscle mass, frailty, and premature death. […] Organs that could eliminate one of the mtDNA variants, like the liver, recovered their mitochondrial metabolism and cellular health, but those that could not progressively deteriorated as the animals aged”.

The study also shows that recipient cells have a great capacity to select and amplify the pre-existing mtDNA, which may be initially undetectable. “The same problem arises with oocyte rejuvenation by microinjection of donor cytoplasm,” says Dr. Enriquez. Likewise, adds the CNIC researcher, “A similar risk can arise when purified donor mitochondria are used to treat damaged cells implicated in cardiopulmonary or neurological diseases” (Source: CNIC).

What is the conclusion of these findings?

The conclusions of the article are given in the form of a recommendation: “Medical interventions that may generate DNPH should address potential incompatibilities between donor and recipient mtDNA”.

Just as in blood transfusions or organ transplants, donor-recipient compatibility must be monitored. Dr. Enriquez recommends that any therapeutic strategy that may involve the mixing of healthy mitochondrial DNA from two individuals should “ensure compatibility between the donor and recipient mitochondrial genomes”.

100% compatibility could be achieved if the donor was related by maternal line to the recipient, but in this case it is most likely that the donor would also have the mitochondrial mutation. Even if this were not the case, it should not be forgotten that part of the maternal mtDNA would remain and that, in many tissues, it would proliferate over the donor mtDNA.

Bioethical assessment

From a bioethics perspective, the safety risks are not the only problem posed by mitochondrial replacement techniques. One important issue is the destruction of human embryos. PNT in particular involves generating — for its subsequent destruction — one embryo for each healthy embryo sought. MST does not directly involve the destruction of embryos, but the fact is that it currently requires the use of IVF techniques, with the associated selection and discarding of embryos. Other bioethical difficulties arise from the genetic link with the donor and its possible implications, and the issue of the slippery slope with respect to germline genetic modification.

But when not even the safety problems are yet resolved, we must stress that the application of these techniques in humans is completely premature and irresponsible. Against this, it could be argued that there is no need to reduce the risks to zero, but that a favorable risk-benefit balance would suffice. In our opinion, however, the risk-benefit balance argument would not apply to such techniques, as they are not a therapy in themselves, but a reproductive option. In other words, it is not a question of curing a patient, but of infertile women or women whose mtDNA has a mutation being able to have genetically-related healthy children. The benefit would be for the mother and the risk for the future child, and both are of such a diverse nature (satisfying the desire to be a mother and be the mother of a healthy child versus health problems in the child such as those described in the paper discussed herein) that they cannot be compared.

Article discussed: Lechuga-Vieco, A. V., Latorre-Pellicer, A., Calvo, E., Torroja, C., Pellico, J., Acín-Pérez, R., García-Gil, M. L., Santos, A., Bagwan, N., Bonzon-Kulichenko, E., Magni, R., Benito, M., Justo-Méndez, R., Simon, A. K., Sánchez-Cabo, F., Vázquez, J., Ruíz-Cabello, J., & Enríquez, J. A. (s. f.). Heteroplasmy of Wild Type Mitochondrial DNA Variants in Mice Causes Metabolic Heart Disease With Pulmonary Hypertension and Frailty. Circulation, 0(0) [Ahead of Print]. https://doi.org/10.1161/CIRCULATIONAHA.121.056286

 

Lucía Gómez Tatay and Julio Tudela

Bioethics Observatory – Institute of Life Sciences

Catholic University of Valencia

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