Three Parent In Vitro Fertilization

January 27, 2015 marks the date that a formal request was submitted to the FDA to assemble a committee to seek approval for clinical trials; testing egg and zygote modification within in vitro fertilization. The goal of this specific technique is to eradicate the transmission of specific mitochondrial diseases between the mother and child. 

Mitochondria are a specific type of organelle found within human cells responsible for creating the vast majority of the energy with separate genome from the genetic material present within the nucleus. Mutations within mitochondrial DNA can cause a variety of mitochondrial diseases, many of which remain unknown and uncharacterized due to the fact that they cause a variety of symptoms, which differ on a case-to-case basis. These defects arise when inherited from past generations or from spontaneous mutations in both mitochondrial and nuclear DNA. Mitochondrial diseases most often affect the organs with a high metabolic demand such as the heart, brain, and liver. For this reason, those that have a mitochondrial genome defect often undergo multi organ failure and eventually die. There is currently no living cure for these genetic defects and the resulting conditions that ensue from them.

Three-parent in vitro fertilization is a technique that was developed as a solution to mitochondrial disease by performing a “mitochondrial replacement.” Two major techniques have been developed in order to solve this problem, each of which would lessen the amount of mitochondrial diseases that occur from parent-offspring transfer and mutations within the mitochondrial DNA. Mitochondrial disease resulting from nuclear DNA defects and those from spontaneous mutations within a person’s lifetime will remain cureless.

The first technique was given the name pronuclear transfer. Within this method the intended, mutated mother’s egg and donor’s egg are fertilized with sperm in vitro. Before the sperm and ovum fuse they both contain pronuclei. After one day, when the fertilized eggs are still single-celled organisms, the pronuclei are removed from zygotes. The pronuclei from the donor egg and sperm are discarded and replaced with the pronuclei from the intended, mutated mothers egg and sperm. The resulting embryo will grow and develop, eventually being placed back into the mother to undergo typical in vitro fertilization processes. The mutated mitochondrial DNA from the intended mother is discarded and majority of her genome is transfer to her offspring through the nuclear transfer. The resulting zygote contains nuclear DNA from the intended mother and healthy mitochondria and cytoplasm from the donor egg. Though the transfer has been successfully carried out in mice, when attempted on human zygotes, many attempts have resulted in abnormal fertilizations. 

From Center for Genetics and Society

http://www.geneticsandsociety.org/article.php?id=6527

 The second technique being investigated; called spindle transfer, is similar to the pronuclear transfer, though a zygote is not formed until later in the process. The nucleus is removed from the oocyte with a mutated form of mitochondrial DNA. The nucleus is then placed into an enucleated donor oocyte, in which the healthy mitochondria remain in the cytoplasm. Sperm will then fertilize the reconstructed oocyte and the zygote will be implanted within the intended mother to undergo a typical in vitro fertilization process. The transfer has successfully been complete on primates resulting in less then 1% of mitochondrial DNA transfer to the healthy oocyte.

From Center for Genetics and Society

http://www.geneticsandsociety.org/article.php?id=6527

The United Kingdom has recently approved the procedure to be available within fertility clinics starting at October 29, 2015, while the United States has begun assembling a committee to review the techniques and determine whether human clinical trials will proceed. Mitochondrial replacement techniques are currently surrounded by countless ethical and medical debates throughout the nation.  

This technique has not been studied long-term in humans. The method of mitochondrial replacement is one of the first implemented that will modify the human germline and the affect on subsequent generations is a still a complete mystery to scientists. Human embryonic modification also walks the “slippery slope” of where science can and should be involved in people’s lives. The nature vs. nurture debate arises when some people choice to believe that science should not be involved in processes that in the fast have been left up to ‘fate.’ The altering of embryos ultimately affects the future of the resulting child. Embryonic modification completely takes away any informed consent due to the fact that the child has no say and the parents are not fully informed with the limited knowledge of the techniques.

Three-parent in vitro fertilization is an entirely new technique that is becoming available for people who have been diagnosed with specific mitochondrial mutations in order to not transmit them to their future offspring. Though this technique is not applicable to a large portion of the population, with progress on embryonic modification and gene transfer techniques scientists may be able to eradicate the transfer of multiple diseases.


References:

"Inheritable Genetic Modification: 3-Person IVF." Center for Genetics and Society. N.P. 5 March 2015. Web. 13 March 2015. <http://www.geneticsandsociety.org/article.php?id=6527>

Amato P, Tachibana M, Sparman M, Mitalipov S. Three-Parent IVF: Gene Replacement for the Prevention of Inherited Mitochondrial Diseases. Fertil Steril. 2014 101(1) : 31–35.

Brenenoord AL, Braude P. "Ethics of Mitochondrial Gene Replacement from Bench to Bedside." BMJ 341, c6021 (2010).