This post is a part of our Bioethics in the News series. For more information, click here.
By Monica List, DVM, MA
A June 3rd headline from The Guardian reads: “Genetic treatment using three-parent embryos may be ready in two years.” This provocative headline surely raised many hackles. The thought of genetically modifying humans commonly produces a visceral reaction, even in those who in principle are not opposed to genetic modification. Perhaps this visceral reaction is well founded; after all, it is one thing to tinker with the genome of a corn plant to make it more resistant to pests or drought, but to modify the genetic code of human beings may change what it means to be human.
This deeply ingrained fear of genetic modification in humans may be responsible in part for negative reactions to proposals to conduct Phase 1 clinical research trials for mitochondrial replacement, the novel procedure that this Guardian article refers to. Mitochondrial replacement involves the replacement of defective maternal mitochondria with mitochondria from a healthy female donor.
Mitochondria, the cellular organelles that act as tiny powerhouses, are always inherited from the mother. An interesting feature of mitochondria is that they have their own form of DNA, mtDNA, which consists of 37 genes, an insignificant amount relative to the estimated 25,000 genes that make up the human genome. However in some women mitochondria carry mutations that may result in severe and often fatal disease in their children. (Callaway, 2014)
While maternal carriers can appear to be perfectly healthy, mtDNA is much more susceptible to mutation – it mutates about 1000 times faster than chromosomal DNA – so when defective mtDNA is passed on to the offspring the effects of those mutations can manifest as mitochondrial disease. Among other conditions, mitochondrial disease, for which currently there is no treatment, can result in kidney disease, blindness, deafness, neurological problems, and dementia. (Nuffield Council on Bioethics, 2012)
Two mitochondrial replacement techniques, maternal spindle transfer and pronuclear transfer, have been developed but the idea behind mitochondrial replacement is far from new. Researchers started performing pronuclear transfers in mice back in the 1980s. More recently, research has been conducted on maternal spindle transfer in rhesus macaques, producing five healthy monkeys. Currently, a research team at Newcastle University has been performing pronuclear transfers on healthy, fertilized human eggs. To date they have performed around 100 successful transfers. (Callaway, 2014)
While experimental treatment could offer those mothers who are carriers of abnormal mitochondria the possibility of having a healthy child, ethical and legal controversy could prevent this procedure from moving forward to the clinical trial phase. In the UK, the law prohibits any procedure involving the modification of a person’s DNA. This means that although the described procedure could be ready to go to clinical trial in 18-24 months, the law first would have to be modified for this to occur. According to an article published in The Washington Post, in February of this year a US FDA expert advisory panel held a two-day meeting to discuss the issue. Although the FDA has not yet released official comments, the advisory panel recommended that a public hearing be held.
Most of the arguments against the use of this procedure in humans involve some sort of slippery slope scenario: allowing mitochondrial replacement will inevitably lead to cloning, designer babies, and other horrors worthy of a dystopian fiction novel. These arguments easily can be countered by referring to the scientific facts underlying mitochondrial replacement. First, as previously pointed out, mtDNA is distinct from chromosomal DNA, and as such mtDNA is not responsible for a person’s genotypic or phenotypic characteristics. Second, mitochondrial replacement does not involve genetic modification. No individual genes are being altered or replaced. What are being transferred from donor to recipient are cellular organelles. So in a way, it is a form of micro-organ donation, and not genetic modification.
A more interesting set of arguments against mitochondrial replacement raises questions pertinent to research ethics, for example, those related to risk/benefit ratio, and boundaries between research and clinical practice. On the surface the risk/benefit analysis does not seem too problematic. To begin with, extensive preliminary research has been conducted successfully on animal models; moreover, no other treatment options are currently available for mitochondrial disease patients. The next logical step would be to conduct Phase 1 clinical trials. A report from the Nuffield Council on Bioethics seems to agree with this approach, stating: “subject to appropriate oversight, it is ethical to gather further information about these techniques, in order that they can be considered for treatment use.” (Nuffield Council on Bioethics, 2012) However, the risk/benefit analysis may not be so simple, considering that the procedure being tested not only will affect the involved subject, but also potentially the subject’s future offspring. We may be facing a whole new set of ethical questions related to intergenerational risk/benefit analysis.
Even more ethically problematic than the risk/benefit issue is the matter of establishing effective boundaries between research and clinical practice. In this case there is little distinction to be made; consenting subjects would be enrolling in a trial that offers them the only option to bear a healthy child. While it may be clear to those subjects that they are in fact participating in research, due to the nature of the procedure as well as to the desired outcome (a healthy baby) it is plausible to think that researchers and clinicians will work together very closely to monitor the process, thereby blurring, more than usual, accepted boundaries between research and practice.
These and other important ethical questions should be seriously considered, but in and of themselves they should not prevent mitochondrial replacement research from moving forward, especially when serious suffering and untimely death can be prevented. What is unnecessarily distracting is the moral panic related to the possibility of this research leading to genetic modification of chromosomal DNA. Hopefully, for now that panic will remain confined to the pages of science fiction novels.
References:
Callaway, E. Reproductive medicine: the power of three. Nature 509 (7501). May 21, 2014. http://www.nature.com/news/reproductive-medicine-the-power-of-three-1.15253#/video
Clark, Stuart. Genetic treatment using three-parent embryo may be ready in two years. The Guardian. Published online June 3, 2014.
http://www.theguardian.com/science/2014/jun/03/genetic-treatment-mitochondrial-replacement-three-parent-embryo-dna-law
Eunjung Cha, Ariana and Sandhya Somashekhar. FDA panel debates technique that would create embryos with three genetic parents. The Washington Post. Online, February 25, 2014. http://www.washingtonpost.com/national/health-science/fda-panel-debates-technique-that-would-create-embryos-with-three-genetic-parents/2014/02/25/60371c58-9e4d-11e3-b8d8-94577ff66b28_story.html
Mitalipov, S. et al. Limitations of Preimplantation Genetic Diagnosis for Mitochondrial DNA Diseases. Cell Reports, 7 (4): 935 – 937. May 22, 2014.
Nuffield Council on Bioethics. Summary of report. Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review. June 12, 2012. Available online: http://nuffieldbioethics.org/sites/default/files/Mitochondrial_DNA_disorders_summary_web.pdf
Monica List, DVM, MA, is a doctoral student in the Department of Philosophy at Michigan State University. She earned a veterinary medicine degree from the National University of Costa Rica in 2002, and an MA degree in bioethics, also from the National University, in 2011.
Join the discussion! Your comments and responses to this commentary are welcomed. The author will respond to all comments made by Thursday, July 10, 2014. With your participation, we hope to create discussions rich with insights from diverse perspectives. You must provide your name and email address to leave a comment. Your email address will not be made public.
MSU Bioethics 
Hi Monica,
I think you make a few good points but I’d like to point out a few things about the biology/genetics of mitochondria that you do not cover and which make a significant difference to how we view the ethics of this therapy.
First, although there is a lot of discussion (especially in the media) about slippery slope there are other objections to the procedure based primarily on its safety. One safety issue is that when transferring the mother’s genetic material (this applies to both methods) to the donor’s enucleated ovum it will be placed with an entirely new mitochondrial genetic background and incompatibilities can occur. My colleagues and I write about this problem of mismatching here:
http://bit.ly/1lkdmOE
Second, you say that “mtDNA is not responsible for a person’s genotypic or phenotypic characteristics”. As we point out there is in fact a great deal of evidence that the mtDNA influences the phenotype of an individual because the two genomes interact with one another. Experimental manipulations of this “cross talk” between the genomes in model organisms influences very important fitness related traits like metabolism and reduce cognitive, male sterility, reduced survival, accelerated ageing and changes the expression of many hundreds of genes.
This interaction between genes can be classified as epistasis. So while the gene content is not modified (all the same genes are replaced), the actual sequences of DNA will be changed/modified, and more importantly the outcome of the epistatic interactions between the nuclear and mitochondrial genomes will be modified too. This then raises the ethical question, is the therapy acceptable given that it may influence traits that one might consider as part of an individual’s identity.
It’s interesting to note also that while in the UK the Nuffield Council concluded MR was ethical if it was safe, a similar exercise carried out in Sweden came to a different conclusion: it was not ethical because of outstanding questions about it’s safety:
bit.ly/1iEJpOJ
Best wishes
/Ted
Ted,
Thank you for your interesting and very informative comment, as well as for sharing your article on mismatching, which I had not previously read. While doing research for this post, I also came across a recent article published in PNAS by Edwards et al (http://www.pnas.org/content/111/21/7719.abstract?sid=f0ea750c-97f5-437f-a0a4-f29a82636725) that points to interactions between mtDNA and chromosomal DNA as being responsible for non-chromosomal heritability. I completely agree with you that these, and other safety concerns should be adequately addressed before moving on to the clinical trial phase, and this may require further research on animal models, or, as you propose, longer term observation of current results.
However, I stand by my point that safety concerns should not prevent this research from moving forward, however slowly that needs to happen, considering the lack of alternatives for these families. This lack of alternatives in fact brings up another ethical concern that I failed to mention in my post, which is the vulnerability of these families. As you very well point out in your article on mismatching, given the lack of alternatives, these families, and especially ones that have already lost one or more children to mitochondrial disease may be more willing to take risks, and should this research go forward, they need to be carefully counseled and supported perhaps above and beyond what we already do for clinical trial participants.
Best,
Monica.
Hi Monica,
The concerning thing is that in the UK at least, the safety issues over mismatching are not going to be addressed before moving on to clinical trial – the HFEA made no recommendations that they should, they do not consider it to be an important problem. The view that mismatching is not a risk would therefore directly influence how the therapy is portrayed to the families concerned, and being fully informed is imperative to be able to balance the risks and benefits fully.
Best,
Ted
Ted, I agree, the potential consequences of mismatching (and other serious risks) require proceeding with caution, and perhaps not enough caution is being exercised in this case. A more liberal perspective would be to say that the role of Phase 1 clinical trials is precisely to assess safety, and that it is clear that participants are assuming significant risks. However, we know well that the portrayal of those risks may be misguided, or misunderstood, as may be the case here.