Jonathan Bushman graduated from the University of Southern California in December 2015 with a Bachelor of Science in Biochemistry. During his time at USC, he performed research at Children’s Hospital Los Angeles’ Saban Research Institute and USC’s School of Pharmacy. He plans to continue his research in a PhD program. Outside of academics, Jonathan enjoys snowboarding, photography, and making pottery.
In the past few decades, the fast pace of scientific research has not always allowed time for sufficient discussion of the ethics involved. This is especially true of new and unregulated medical techniques which may be put into practice with high hope and good intentions, but with inadequate regard for safety and ethical implications. Matters become more complicated when new procedures intersect with highly charged debates such as those surrounding reproductive rights and genetic modification. One such technique is mitochondrial replacement, an emerging therapy aimed at preventing the transmission of inherited mitochondrial diseases from mother to child. The U.K. is a hotspot of research and interest in this technique, leading the government to commission the Human Fertilisation and Embryology Authority (HFEA) to assess related safety and ethical considerations (Reinhardt et al., 2013, p. 1345). Although this is a step in the proper direction, the HFEA must be careful to ignore public pressure to approve this new technology prematurely since they are likely setting a precedent for the rest of the world to follow. Due to current gaps in the existing research, fertility and in vitro fertilization (IVF) clinics should refrain from the adoption of mitochondrial replacement therapy until the health risks for future children can be thoroughly evaluated.
Mitochondria are essential structures within cells responsible for the production of the cell’s energy. They contain their own genome of mitochondrial DNA (mtDNA) distinct from the nuclear DNA (nDNA). Importantly, this mtDNA originates solely from mitochondria in the mother’s egg and is inherited exclusively through the maternal line. Thus, harmful mutations in mtDNA are always passed from mother to child to some degree with higher amounts of defective mitochondria corresponding to more serious manifestations of mitochondrial diseases. A 2008 study estimated that “one in 200 children is born each year with a disease-causing mitochondrial DNA mutation,” and “around one in 6,500 children is thought to develop a more serious mitochondrial disorder” (Nuffield Council on Bioethics, 2012, pp. 24-25). The current options for women carrying defective mtDNA focus on genetic screening of embryos to reduce the chance of passing on a mitochondrial disease. This science is imprecise and restricted by limited knowledge of the genetics behind mitochondrial disease thus providing a “reliable diagnosis for only a minority of mtDNA mutations with specific characteristics” (Nuffield Council on Bioethics, 2012, p. 28). Mitochondrial replacement (MR) therapy sidesteps the uncertainty of passing on defective mtDNA by substituting the nDNA of an intending mother into an enucleated donor egg with healthy mitochondria. This results in a mutation-free egg for IVF procedures, and ideally, in the eventual birth of a child free of any defective mitochondria. As the current policy of the HFE Act 2008 in the U.K. mandated that “eggs, sperm or embryos which have had alterations made to their nuclear or mitochondrial DNA may not be placed into a woman’s body,” this technique is unlawful until new legislation is passed (Nuffield Council on Bioethics, 2012, p. 44). Before this occurs, however, thorough evaluation of the ethical implications and safety of MR is needed.
One concern is over the significance of producing children with a genetic connection to three people. Offspring of MR, termed “three-parent babies” by the media, appear to present a novel situation open to interpretation by legal systems (Nuffield Council on Bioethics, 2012, p.78). If two parents became unable to care for their child conceived by MR, could the third “parent” be held responsible for the child as well? This type of question could prove especially relevant if children produced by MR manifest medical conditions related to their unique conception. Egg donors may fear being held liable for expensive medical bills if their mitochondria and DNA end up in a child suffering from mitochondrial disease. Careful legal wording would be needed to prevent this type of scenario. The Human Fertilisation and Embryology (HFE) Act of 2008 in the U.K. specifies through a section explicitly titled “Woman not to be other parent merely because of egg donation” that status as a mother is granted by the condition of pregnancy, not by genetic relatedness to the child (Nuffield Council on Bioethics, 2012, p. 46). This concern for gestational motherhood rather than genetic motherhood sets a reasonable precedent that could be applied to future developments in IVF techniques as well. Countries seeking to approve MR for use in fertility clinics would be wise to adopt similar legislation ruling out parenthood of the mitochondrial donor.
Though identifying the rightful parents of a child of MR is primarily a legal concern, there exists an ethical concern over altering the personal identity of these children. Especially in an age when forensic DNA analysis is used to identify individuals in court, the notion that a close relationship exists between personal identity and genetic identity has been cemented in public perception. A closer look at the genetics of MR is required to clarify its impact on identity. In comparison to the 20,000-30,000 genes contained in the nuclear genome, MR would account for the substitution of only 13 protein-encoding genes in the mitochondrial genome (Nuffield Council on Bioethics, 2012, pp. 18-19). Unlike the nuclear genes influencing skin color, height, facial features, personality, and other traits associated with personal identity, mitochondrial genes encode proteins associated with the electron transport chain that generates chemical energy for our cells. The media has likened MR to “replacing the batteries of a camera,” a slight modification to the basic function of a camera that does not change the model of camera itself (Reinhardt et al., 2013, p. 1354). This analogy recognizes the minimal influence of mtDNA on traits we typically associate with personal identity by highlighting its basic role in providing energy.
Bone marrow transplantation is another situation illustrating the negligent impact of certain genetic changes on identity. It would be strange to claim that this life-saving cancer treatment alters personal identity in an unethical way. Like MR, however, bone marrow transplantation can permanently replace genetic material in the blood with DNA from the donor. Both bone marrow recipients and offspring of MR would be considered chimeras, possessing genetically distinct components that otherwise have little effect on their overall identity. However, some detractors of MR note that substituted DNA is only passed on to offspring in the case of MR (Pritchard, 2014, p. 4). This distinction of MR as a germ-line therapy is another strong source of contention.
Germ-line therapies can be recognized by the introduction of genetic changes that may be passed from one generation to the next. The U.N. already takes a strong stance on germ-line therapies. The Universal Declaration on Human Genome and Human Rights refers to the human genome as “the heritage of humanity” and disallows “practices that could be contrary to human dignity, such as germ-line interventions” (Nuffield Council on Bioethics, 2012, p. 49). Unfortunately, this strong stance fails to distinguish between the uses of germ-line therapy to introduce desirable traits versus the prevention of diseases. It is easy to recognize the ethical differences between pre-selecting a baby’s appearance and taking measures against relaying devastating mitochondrial disorders. However, there is still significant concern that opening a legal loophole for a germ-line therapy like MR could lead to the adoption of therapies catering to eugenics. Contrary to this concern, the Nuffield Council on Bioethics argued, “the clear material difference between mitochondrial and nuclear genes means, in practice, that the adoption of [MR]… would not necessitate the adoption of nuclear transfer or nuclear modification technologies if they were to emerge in future” (Nuffield Council on Bioethics, 2012, p. 88). Again, reliance on unambiguous legal wording is necessary to avert problems. Interestingly, MR’s status as a germ-line therapy only truly applies to female offspring after the first generation. Male offspring conceived by MR will not pass on the substituted mtDNA received from the egg donor, as mitochondria are only inherited through a maternal line. This presents a unique “solution” to the ethical problem of germ-line MR therapy: only selecting male children to be conceived by MR.
Objections to this skewed suggestion reach the heart of the argument against MR—there is simply not enough research indicating the long-term safety of MR to advocate for its immediate adoption. Dr. Ken Taylor and Professor Erica Haimes argued to the Nuffield Council on Bioethics:
[It] would be unacceptable and render the children born [from MR] “experimental offspring” [;]… the boys born would need to be monitored throughout their lives and deemed healthy before females could be conceived in this way: they would in effect be experiments. In suggesting that only males be conceived initially, there is an underlying assumption that the unknown long-term adverse consequences would relate only to the mitochondria. (Nuffield Council on Bioethics, 2012, p.80)
This argument recognizes that the desire to protect future generations from potential negative effects of MR is also an admission that we do not know enough about MR to conclude that it is wholly safe for the offspring. Studying the effects of MR therapy on children who reach sexual maturity and adulthood should be a precedent for establishing sound MR policy, not a result of the lenient MR policy that the HFEA is pushing. To suggest that boys would serve as a cautionary group to test the safety of MR is particularly troublesome, considering that multiple studies have confirmed the sensitivity of males to MR-induced effects.
The fact that mtDNA is inherited through a maternal line has further implications than the heritability of germ-line modifications. Since males do not transmit mtDNA, natural selection cannot select against harmful mtDNA mutations in males. Dr. Steven A. Frank aptly coined phrase for this effect: a “sex-biased ‘selective sieve’ [that] inevitably causes deleterious mitochondrial mutational effects to accumulate more strongly in males than in females” (Frank, 2012, p. 797). This places males at a distinct disadvantage in inheriting harmful mtDNA. Frank’s research also indicated that natural selection compensates for this effect, strongly favoring nuclear genes that mask the effects of harmful mtDNA, leading to “rapid divergence between populations in nuclear-mitochondrial interactions” (Frank, 2012, p. 799). This means that men from different populations rely on a correct match between their mtDNA and nDNA to prevent deleterious conditions. Disruption of this match is likely responsible for the accelerated aging and infertility seen in several model organisms used to evaluate MR (Reinhardt et al., 2013, p. S1). This revelation highlights the primary flaw of MR, the assumption that mitochondria can be substituted without impacting the relationship between mtDNA and nuclear DNA. The interaction of mitochondria and the nucleus is especially important in males, so disruption of this interaction by MR poses a higher risk to health in males than in females. Although female offspring from MR pose the ethical dilemma of allowing heritable germ-line genetic modifications, male offspring pose the practical dilemma of legalizing a medical practice that favors the safety of only one sex. Studies in mice showed lower levels of male exercise ability, growth, learning, and explorative behavior (Reinhardt et al., 2013, p. S1). Fruit fly studies demonstrated that only males have altered nuclear gene expression, accelerated aging, impaired mitochondrial function, and infertility as a result of genetic MR (Reinhardt et al., 2013, p. 1345). It is not ideal that a germ-line therapy intended to solve a female reproductive issue could produce similar unfortunate effects on male reproductive health. It is also imprudent that the HFEA has chosen to ignore the findings in the studies, dismissing them as “not relevant to humans because they were done on inbred animals” (Pritchard, 2014, p. 5). This explanation is highly unusual, since inbred animals are frequently used to improve the quality of a study with more stable and reproducible results from a more homogenous genetic background. As an organization tasked with gathering and evaluating scientific data, the HFEA should not dismiss relevant data based merely on the model organism studied. Mice and fruit flies are both well-established research models, so it is reasonable to worry that similar harmful effects in these organisms may be seen in human adults.
The dismissal of research in distantly related model organisms highlights the importance of the need for relevant data in humans. The furthest that human studies have progressed is only to the examination of embryo development to the blastocyst stage. Deemed successful, only 43% of embryos produced by MR developed normally to blastocyst stage (Tachibana et al., 2013, p. 628). Although this study proves the technical possibility of MR, the success rate is less than half, and no attempt is made to assess safety for the offspring. Studies in a monkey model evaluate overall health up to an age of three years. Although this study found no detrimental effects, the sample size was small (n=4), and the monkeys were not examined for reproductive health issues at sexual maturity (Tachibana et al., 2013, p. 630). The limited evidence from the general health parameters of these four monkeys is not sufficient to give meaningful information about nuclear and mtDNA interactions. Despite this lack of concrete evidence, the authors of the above study still problematically “speculate that nuclear-mtDNA interactions are conserved within species” (Tachibana et al., 2013, p. 631). Though more distantly related to humans, fruit flies provide a model much more amenable to studying the population genetics that cause concern in MR. As noted earlier, fruit fly studies have shown data in direct contradiction to the authors of the monkey study.
To truly evaluate the safety of MR therapy, studies must be undertaken to examine the health of MR offspring at reproductive age. For the monkey model, this would require examining offspring to an age of 4-7 years. In the case of humans, there exists a small population that could be of use in evaluating the safety of MR. In the late 1990s, a technique called cytoplasmic transfer was used to boost the success of IVF procedures. Unlike MR, there was no large-scale effort by the scientific community to assess the safety of this technique before adoption. Before this technique was banned due to safety concerns stemming from health problems with a few children, 30-50 couples conceived in this manner. As with MR, they produced offspring that possess mtDNA from a third donor (Pritchard, 2014, p. 2). Follow-up studies of these children, now reaching sexual maturity, could provide valuable insight into the safety of introducing foreign mtDNA into an egg. As several of the children conceived by cytoplasmic transfer have already been shown to possess developmental defects, this episode in reproductive technology also serves as a cautionary example against premature adoption of poorly studied fertility therapies.
Although the HFEA has failed to substantively confront data regarding the risks of MR, they do support continuing research to perform MR in a safe manner. Gaps in our knowledge of the effects of MR on offspring, particularly males, are unlikely to be fully closed before this therapy is made available. Evaluating relative acceptable levels of risk has often been a significant component of determining medical care. As such, there are likely to be families severely impacted by mitochondrial disease for which the risks of MR outweigh the risk of not choosing the treatment. Though the scientific community will be responsible for clarification of the risks involved, fertility clinics will ultimately be responsible for accurately conveying these risks to their patients. Current research should play a large role in the development of a working risk assessment framework. Until all risk factors of MR for the children and the potential risks for subsequent generations are fully explored, fertility clinics must refrain from the adoption of this technique.
Frank, S. (2012). Evolution: Mitochondrial burden on male health. Current Biology, 22(18), R797-R799.
HFEA, Mitochondria public consultation 2012; Retrieved from www.hfea. gov.uk/6896.html.
Nuffield Council on Bioethics, Novel Techniques for the Prevention of Mitochondrial DNA Disorders (Nuffield Council on Bioethics, London, 2012), Retrieved from http://nuffieldbioethics.org/project/mitochondrial-dna-disorders/.
Pritchard, C. (2014, August 31). The girl with three biological parents. BBC News Magazine.
Reinhardt, K., Dowling, D., & Morrow, E. (2013). Mitochondrial replacement, evolution, and the clinic. Science, 341, 1345-1346.
Tachibana, M., Amato, P., Sparman, M., Woodward, J., Sanchis, D. M., Hong, M., Gutierrez, N. M., Tippner-Hedges, R., Kang, E., Hyo-Sang, L., Ramsey, C., Masterson, K., Battaglia, D., Lee, D., Wu, D., Jensen, J., Patton, P., Gokhale, S., Stouffer, R., Mitalipov, S. (2013). Towards germline gene therapy of inherited mitochondrial diseases. Nature, 493, 627-631.