Stem Cells, Mitochondrial Disease, and the United Kingdom’s Ethical Dilemma

As the Vatican prepares to host the Second International Conference on Regenerative Medicine, stem cells have been pushed once again into the international spotlight. In the medical community, tangible progress in the last six months has sparked much conversation of the next steps in bringing therapies to the public.

Of particular note is a study published in the December 2012 edition of Nature out of Columbia University and the New York Stem Cell Foundation exploring the transfer of the nuclear genome in human oocytes to eliminate mitochondrial DNA variants.

This study is now extremely important, after the UK’s Human Fertilisation & Embryology Authority (HFEA) revealed in March the broad public support for pronuclear transfer — an IVF-based technique to enable couples with mitochondrial disease risk to “re-home” IVF-created embryos in a healthy donor egg.

Variants of the ‘HFEA method’ involve fertilization of two eggs — a parent egg and donor egg — with the same sperm, and the removal of nucleus from the parent embryo into the donor embryo, replacing the donor nucleus. To the contrary, the study completed by Columbia and the NYSCF has taken the opposite approach — performing a pronuclear transfer of a donor egg’s mitochondrial DNA with that of the embryo carrying mother in hopes to remove mitochondrial disease carrying nuclei and any related variants.

This is now colloquially referred to as “The Three Parent Method” — and the practices, implementation, and ethics of which the HFEA will now be advising law-makers on. Certainly, there are questions to be addressed concerning the ethical implications of producing a child from three different people’s zygotes surround the concept of ‘manipulating’ DNA and the slippery slope that could follow.

Further, the Columbia/NYSCF study raises significant questions concerning logistics, success and potential consequences of such processes. Despite promising results that suggest a scientific breakthrough soon upon us, questions well beyond the scope of ethical dilemma still remain.

The following is a summary of the problem faced, the promising conclusions of the Columbia/NYSCF study, and the challenges faced.


Stem cell research has greatly affected the research industry since its debut in the early 1900’s, and we are now on the cusp of reaching major milestones — and for this technology to reach patients.

These sophisticated biological cells contain the ability to differentiate into diverse specialized cells and self-renew in order to produce more stem cells. With the proper utilization, stem cells have the potential to revolutionize the healthcare industry.

These possibilities first crystalized in 1968, when physicians successfully transplanted human bone marrow cells in a pair of twins, one of whom had leukemia. Since the 1960’s, stem cell research has innovatively transitioned from successful disease treatment in bone marrow to the idea of disease prevention in the mitochondria.

The mitochondria are cellular organelle that play a vital role in several biochemical pathways released for energy production. Mitochondrial diseases are the result of either inherited or spontaneous mutations in mutant DNA or nuclear DNA which lead to altered functions of the proteins or RNA molecules that normally reside in mitochondria, according to the United Mitochondrial Disease Foundation. Since mitochondrial activity spans across various tissues in the cell, there exist hundreds of different mitochondrial diseases.

What has served as a challenge for physicians in the past is the ability to detect this disease early in its progression.  In addition, each disorder creates different abnormalities because of the complex and unpredictable interactions between the hundreds of genes and cells to keep the metabolic machinery running smoothly. The hallmark and thus the challenge in preventing mitochondrial diseases is that patients may display similar mutational genotypes, but the clinical presentations greatly vary. Common symptoms of a patient affected by a mitochondrial disease include poor growth, loss of muscle contraction, neurological problems, developmental delays and much more.

To date, no “cures” have been discovered for mitochondrial diseases. However, based on the various symptoms and different sicknesses associated with this disease, numerous treatments have been developed. Common treatments include: dietary therapy; supportive therapies; avoidance of toxins (alcohol and cigarette smoking); supplementary vitamin and cofactors; prescribed medications, and the avoidance of physiological stress.

While these alternatives may be respected as proven therapies, they only aid in alleviating symptoms and slowing the progression of the disease, not in its elimination. Furthermore, the effect of the therapy varies on a patient-to-patient basis. Mild cases tend to benefit to the therapy moreso than to the severe diagnoses. Overall, many challenges are presented to patients who have to live with these diseases.

But what if inheriting this disease was avoidable all together? Has stem cell research become so advanced that scientists can prevent a mitochondrial disease in a child if the mother is a carrier? The answer is yes.

A team of physicians from Columbia University in collaboration with the New York Stem Cell Foundation has successfully transferred the nuclear genome in human oocytes to eliminate mitochondrial DNA variants.

In this study, researchers removed the nucleus of an unfertilized egg cell and replaced it with the nucleus of another donor’s egg cell. The resultant egg cell contained the genome of the donor, but not her mitochondrial DNA. Therefore, the genetic make up of the offspring would be of his mother’s, but the mitochondrial DNA from the donor would eliminate the mutational DNA traits, and thus prevent the potential development of a mitochondrial disease.

The team’s development of a unique and novel technique for cell transfer required overcoming several challenges. During the exchange, low levels of heteroplasmy were detected. If levels of heteroplasmy reach a minimal threshold than mitochondrial mutations may appear. However, after clonal expansion and cellular differentiation heteroplasmy levels remained low, eliminating any chance of a clinical presentation.

Manipulation of the intact spindle chromosome presented the biggest challenge: this manipulation frequently resulted in premature activation of the oocyte and in turn karyotypes abnormalities. The prevention of the premature activation and karyotype abnormalities was a key component in the success of this study in a clinical setting. The research team overcame this obstacle by exposing the karyoplast (but not the cytoplast) to low temperatures to delay the induced activation. When the spindle chromosome complexes are placed in a below room temperature setting, they show a decrease in the rate of their alignment. Afterward, when complexes were placed in room temperature, the microtubule alignment would finish, allowing polar body extension, normal pre-implantation development, and ultimately karyotypically normal cells.

To account for their results, the research team carried out their developed technique in a controlled setting of solely room temperature. The results in the control experiment resulted in the loss of half of the oocytes, a failure in polar body extension, and the formation of karyotypically abnormal embryos. Still, the procedure yielded a number of successful results, suggesting this method may justify refinement going forward.

The final challenge that has risen during this study is whether transferring portions of the maternal genome between oocytes will introduce epigenetic changes. Based on trials conducted in this study, there were no significant differences in gene expressions between the genomes exchanged and unmanipulated cells. The maternal nuclear genome transferred did not relay any adverse effects or consequences to the embryo. Whether the chromosomes segregating in meiosis II are safe and accurate will need to be determined next by an increase in the number of trials.

In the initial levels of this breakthrough study, it is clear that the research team is on the brink of revolutionizing our approach to mitochondrial disease, and potentially accellerating medicine on the whole. A child is born with a mitochondrial disease every 30 seconds, and 1 in 200 individuals carry mutant mitochondrial DNA. With the progression of CUMC and NYSCF’s study, the healthcare industry can guide those numbers closer to zero.

Still, Nature concludes that before the study is officially approved to conduct human clinical trials on the transfer of the maternal genome, some issues are left unresolved. Nature says patient needs, ethical considerations, and appropriate guidelines for the use of oocyte nuclear genome transfer in assisted reproduction need to be established.

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