The United Kingdom became the first country to approve the use of mitochondrial transfer as an assisted reproductive technique earlier this year as other countries continue to grapple with the scientific and ethical issues regarding mitochondrial transfer.
David Keefe, MD
“Mitochondrial transfer is neither likely to be effective as a treatment for women with reproductive aging nor safe,” said David Keefe, MD, Stanley H. Kaplan Professor and chair of obstetrics and gynecology at New York University Langone Medical Center.
“Mitochondrial treatments can be administered in a safe and responsible way and effective way,” responded Kutluk Oktay, MD, FACOG, professor of obstetrics and gynecology, medicine, cell biology and anatomy, and pathology and director of reproductive medicine and infertility at New York Medical College and founder of the Innovation Institute for Fertility Preservation and IVF.
The two took opposing sides during the Irvin M. Cushner Memorial Lecture on Monday morning, “Mitochondrial Transfer for Curbing Oocyte Aging and Treating Genetic Disorders: There is a Responsible Way — A Debate.” Audience polls before and after the debate showed that few attendees were swayed by the arguments.
Dr. Keefe said that basic biology suggests that mitochondrial transfer is unlikely to improve pregnancy outcomes or be safe. It is widely recognized that fertility decreases with age and aneuploidy increases with age. Natural fertility begins to decrease in the early 30s and falls to around ten percent by the mid-40s.
Kutluk Oktay, MD, FACOG
At the same time, aneuploidy rates increase from the early 20s and climb steeply in the late 30s. Chromatid and chromosome non-disjunction produces aneuploidy. The most common culprit is premature separation of sister chromatids during meiosis.
“The sister chromatids seem to just fall apart,” Dr. Keefe said. “Multiple groups have confirmed that the aging phenotype follows the nucleus in the oocyte, not the cytoplasm, which contains the mitochondria. Adding new mitochondrial DNA has no effect on the nucleus, which is the seat of oocyte aging.”
Animal models suggest that adding mitochondrial DNA is also likely to have deleterious effects. Mixing and matching mitochondrial DNA is genetically unstable. It also generates changes to behavior and cognition that mimic autism and various neurologic disorders.
“Mitochondrial transfer is costly, invasive, and ineffective,” Dr. Keefe said. “The reported pregnancy rates from doing nothing are on the same order of magnitude as those claimed for mitochondrial transfer. Aneuploidy is the major cause of reproductive aging in women. It is driven by chromosomal changes, not by mitochondrial changes.”
Don’t dismiss the human science in favor of animal data so quickly, Dr. Oktay said. Mitochondria support multiple cell functions. Mitochondrial DNA defects and mutations are associated with a variety of problems, including Parkinsonism, premature menopause, premature ovarian failure, Alzheimer’s, cancer, diabetes, obesity, immune diseases, and other problems, including infertility.
“There are no medical options for treating mitochondrial diseases,” he said. “That leaves us with ART options, cytoplasmic transfer, pronulei transfer, spindle transfer and autologous mitochondrial injections.”
All four methods have been used successfully in human oocytes, he continued. Cytoplasmic transfer has produced at least 29 babies, although one found to have Turner’s — a member of the twin pregnancy where the other twin was healthy. On follow up, one child developed pervasive disorder. In addition, one pregnancy miscarried and found to have Turner’s karyotype. Human pronuclear transfer has been demonstrated in the UK, and human spindle transfer has moved successfully at least to the blastocyst stage. Autologous mitochondrial injection showed a 25 percent clinical pregnancy rate in an initial human trial and 12.5 percent ongoing pregnancies.
Mitochondrial treatment is clearly possible and effective, Dr. Oktay said. Approval in the UK shows that ethical considerations can be satisfied.
“It can be done responsibly with the proper IRB oversight and registries to follow the results,” he said. “We can use mitochondrial transfer to help our patients conceive children when other techniques have not.”
