Dubbed the “three-parent baby” by the media, a paper published in Reproductive Biomedicine Online in April 2017 details the live birth of a child through experimental spindle transfer, a procedure which involves the use of mitochondrial DNA from a donor.1 Aside from garnering much publicity, the study has raised important questions in the scientific community about ethics and the limits of science.
Doctors at the New Hope Fertility Center (with locations in Mexico, China, and New York) received a patient seeking help to conceive a child (1). The 36-year old woman had a history of miscarriages and had lost two children due to Leigh syndrome. Leigh syndrome is a neurological disease affecting young children characterized by a loss of motor abilities, which usually results in death within two to three years (2). Leigh syndrome, in the case of this mother, was transmitted to her offspring by a mutation in her mitochondrial DNA (1).
The doctors proposed mitochondrial replacement therapy, which aims at preventing the transmission of mitochondrial diseases from a mother to her biological child by using a mitochondrial donor (3). For this therapy, there are different procedures, two of which are spindle transfer and pronuclear transfer. The key difference between them is that spindle transfer involves the transfer of nuclear DNA before fertilization, while pronuclear transfer is the transfer of pronuclei from zygotes (and, as such, involves discarding the donor zygote) (4). In this case, they indicate that the patient decided on spindle transfer over pronuclear transfer for religious reasons (1).
As such, spindle transfer was performed: spindles from the patient’s metaphase II oocyte (immature egg cell) were inserted into the cytoplasm of the donor oocyte (1). After this, the new oocyte was fertilized with one sperm from the patient’s partner (1). Once blastocysts (early stage embryo) formed, they underwent testing for aneuploidy (abnormalities in the number of chromosomes in the cell) and the embryo found to be euploid (having the normal 46 chromosomes) was transferred into the patient at New Hope Fertility Center’s clinic in Mexico (1).
The patient delivered the baby at 37 weeks gestation after an “uneventful pregnancy” (1). The child’s mitochondrial DNA (mtDNA) mutation load varied between undetectable to 9.23% (depending on the tissue surveyed), which is low compared to the mother’s mtDNA mutation load of up to 34% (1). (For reference, carriers are typically asymptomatic if their mutation load is less than 30%) (1).
As such, the patient was able to give birth to a healthy male child in the first instance of mitochondrial spindle transfer to reduce mtDNA mutation transmission. The authors wrote that “at the time of writing, the baby is healthy at 7 months of age” but “we are still following the baby closely” (1).
Interestingly, the authors conclude at the end of their paper that “there is certain to be much controversy over this treatment, and further study is mandatory” (1).
A few months after the article came out in Reproductive Biomedicine Online, in August 2017, Mary Malarkey, of the U.S. Food and Drug Administration’s Center for Biologics Evaluation and Research, sent John Zhang (principal author of the article, founder and CEO of New Hope Fertility Center) a warning letter. This letter explains that after the publication of the article, John Zhang submitted a request for a pre-investigational new drug (IND) meeting to begin a clinical investigation of spindle transfer therapy for assisted pregnancy (5). However, the letter states, the FDA, per regulations set forth by Congress, is prohibited from accepting IND submissions that involve the use of human embryos with “intentionally created . . . heritable genetic modifications”, and as such, the FDA declined his request (5). The letter further details violations by New Hope Fertility Clinic, including marketing mitochondrial replacement therapy in the United States (5).
This was not the first time that New Hope Fertility Clinic received a warning letter from the FDA, as they had previously received warning letters on violations of the regulations regarding the handling of human cells and tissues (6). Nonetheless, a spokesperson for New Hope Fertility Clinic said that they were taking the matter seriously and would work with the FDA to resolve it (6).
Backlash and Controversy
Shortly after the results of the study came out, several news outlets published articles with headlines drawing attention to a “three parent baby” (7). Meanwhile, John D. Loike and Nancy Reame, part of the Bioethics faculty at Columbia University, wrote an article for The Scientist in which they discuss the ethical dangers of mitochondrial replacement therapy (8).
They bring up issues of parental rights, or more specifically the question of whether the mtDNA donor has parental rights (they state that the genetic contribution, although small, still exists from this donor and should be considered as such) (8). Loike and Reame also worry about the extreme cost of this therapy, which can range from $25,000 and $50,000, which would not only leave this therapy almost exclusively available to the wealthy, but could also possibly exploit impoverished women, as they would be paid extremely well for mtDNA donation (8). They conclude, however, that mitochondrial replacement therapy “should not be banned because of presumed social or ethical complexities” but that “governments and the scientific community should invest time and money into making [it] widely available to patients” (8).
On the other hand, the United Mitochondrial Disease Foundation (UMDF) states on its website that they believe that mitochondrial replacement therapy is “NOT genetic manipulation, but rather a technological innovation and an expansion of in vitro fertilization, a clinically-approved technique used for four decades” (9). This patient advocacy group, however, says that the technique should be made available and accessible to patients with mtDNA mutations only “if demonstrated to be safe and efficacious” (9).
Contrasting opinions and views make this issue a complicated one to tackle. Moving forward, it will be of particular interest to consider the role of the U.S. government in the use of mitochondrial replacement therapies. The United Kingdom in 2015 already approved the use of mitochondrial donation techniques as part of in vitro fertilization (3). The National Academy of Sciences, Engineering, and Medicine stated that mitochondrial replacement therapy is considered ethical when done in male embryos for mothers with mitochondrial diseases (presumably limited to males so that the genetic modification of mtDNA will not be passed down to future generations) (8). With different organizations rallying around to support mitochondrial replacement therapy, the government will likely be forced to reevaluate its laws soon, and lawmakers will have to decide whether they believe it is ethical or not. Issues of parental rights, patient rights, accessibility, and exploitation will all have to be considered. Should we deny this therapy to patients because of a resulting 0.1% difference in the child’s DNA? Should we continue to not be allowed to genetically edit embryos at all? Is all of this a step towards modification and selection of the human population’s genome pool? Moving forward, there are many factors to be considered and debated on the issue of mitochondrial replacement therapies and spindle transfer.
Ana is a first year in Thayer
 Zhang, J. et al. RBM Online 2017, 34, 361-368.
 Genetics Home Reference. https://ghr.nlm.nih.gov/condition/leigh-syndrome (accessed October 2018).
 Castro, R. Journal of Law and the Biosciences 2016, 726-735.
 Reznichenko A. S., et al. Applied & Translational Genomics 2016, 11, 40-47.
FDA.https://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/UntitledLetters/UCM570225.pdf (accessed Oct 2018).
 FDA Warning Letters. https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm424065.htm (accessed Oct 2018).
 Neimark, J. WBUR [Online]. 2017. http://www.wbur.org/npr/523020895/a-baby-with-3-genetic-parents-seems-healthy-but-questions-remain (accessed Oct 2018).
 Loike, J. et al. The Scientist [Online]. 2016. https://www.the-scientist.com/critic-at-large/opinion-ethical-considerations-of-three-parent-babies-32320 (accessed Oct 2018).
 UMDF’s Postion. United Mitochondrial Disease Foundation [Online]. 2017. https://www.umdf.org/mitochondrial-replacement-therapy/ (accessed Oct 2018).
Image credit: NICHD NIH