When I first mentioned to some colleagues that I was thinking of writing this post in the journal blog, a few quizzical expressions surfaced on the faces of Nature Protocols’ editors. After all, the ethical and philosophical implications of the protocols we publish aren’t the usual remit of Nature Protocols. Yet, when I found out that a method for mitochondrial DNA ‘transplantation’ introduced by Oregon Health & Science University’s Shoukhrat Mitalipov and co-authors is now technically almost ready for the fertility clinic1, my mind started to wander into all kinds of questions and considerations that I thought I’d like to share with my colleagues and the readers of this blog.
In 2010, Nature Protocols published “Chromosome transfer in mature oocytes”2, by Tachibana, Sparman and Mitalipov, an article that details the transfer of chromosomes from the mature oocyte of a rhesus monkey to the enucleated egg from a different rhesus monkey, so that the resulting oocyte has the nuclear DNA of a female primate and the mitochondrial DNA of another. This protocol was based on the ground-breaking 2009 Nature paper “Mitochondrial gene replacement in primate offspring and embryonic stem cells”3, which also reported that healthy monkeys had been born as a result of the procedure. These were monkeys that displayed no detectable presence of mitochondrial DNA of their biological mothers, but only that of the oocyte cytoplasm donor.
Mitochondria are often — and possibly too simplistically — called the cell’s power plants, because it’s in these cytoplasmic organelles that most of the ATP, the organism’s energy currency, is produced. Mitochondria have their own DNA (two to ten copies per organelle), which, as opposed to nuclear DNA, is passed en bloc from mother to offspring, without any paternal contribution.
Because of their role in ATP synthesis, mitochondria are exposed to a high concentration of free oxygen radicals, which, in conjunction with a lack of histones and limited mitochondrial DNA repair mechanisms, possibly explains why mitochondrial DNA mutations occur at a tenfold-plus rate compared with nuclear DNA mutations3. In humans, serious and often fatal disorders caused by mitochondrial DNA mutations affect 1 in ~4,000 children. Although current treatments alleviate symptoms and slow disease progression, no cures are available for these mitochondrial diseases.
At least in principle, a method that enables the complete replacement of mitochondria in the egg or embryo from a woman with known mitochondrial DNA defects with mitochondria from a donor with no such defects could act as an effective, ‘pre-emptive’ treatment of diseases linked to mitochondrial dysfunction. Just recently, Nature published another paper by Mitalipov et al.1, which reports how the approach described in the Nature Protocols 2010 paper2 has been successfully implemented to produce normally fertilized human zygotes that contained mitochondrial DNA only from the donors of oocyte cytoplasm (and not from the nuclei donors). These zygotes were found capable of developing blastocysts and of producing embryonic stem cells, which suggests that, if implanted in the womb, they could develop into healthy babies.
Of course, a breakthrough of this magnitude gives hope that a clinical application may not be too far down the road. This optimism is further encouraged by the significant success in achieving similar results in terms of mitochondria replacement in human embryos4 — albeit via a different approach — by a research group based in Newcastle, UK, and led by Professor Doug Turnbull. Incidentally, Dr Turnbull and co-authors published a method for the transfer of nuclear genome as a promising approach for the prevention of transmission of human mitochondrial DNA disease5 in 2010 in the Protocol Exchange.
The optimism, however, is tempered by substantial legal obstacles to the clinical application of these approaches. For instance, UK law currently forbids the genetic modification of human embryos or human eggs for treatment purposes, which prevents clinical use of both the approach developed by the UK-based group and the approach developed by the US-based one. In the US, the NIH restricts funding for research that destroys human embryos, so Mitalipov’s research group had to conduct its research using money from private donors6.
These legal and procedural hurdles are not mere technicalities, and a number of fundamental ethical and philosophical questions have to be univocally answered before the medical community embarks on the clinical use of pre-natal mitochondrial DNA replacement. Mitochondrial DNA only encodes 37 genes, or about 0.2% of our entire genetic make up. But the question still stands: what will be the exact relationship between a child and the woman to whom that child’s mitochondrial DNA originally ‘belonged’? Surely children who have not received their mitochondrial DNA from their biological mothers will look like their parents, but arguably efficient mitochondrial activity is vastly more important for the biology of a human being than the color of his or her eyes or whether his or her hair is straight or curly.
Furthermore, replacing a mother’s mitochondrial DNA does not make a difference just to her children, but given that it is passed down, more or less intact, from generation to generation along a matrilineal route, mitochondrial replacement may have permanent effects on many generations to come, including any possible unforeseen adverse consequences of the procedure. In order to observe, probe and record any such potential long-term adverse effects, subsequent generations of people who owe their mitochondrial genetic makeup to mitochondrial replacement will most likely have to be enrolled, basically at birth, in long-term, follow-up medical studies for decades to come; but presumably, once the age of consent has been reached, these individuals will have the right to refuse participation in such studies, won’t they? And what about their personal lives? Given the medical implications and the health concerns for their offspring, are the people involved going to be expected to disclose their genetic origin to partners they may want to have children with? A case could easily be made that the latter question applies only to female descendents of the woman who underwent the initial mitochondrial replacement. And shouldn’t the inherently discriminatory nature of this uneven burden be an additional cause for profound and unsettling moral questioning? After all, men are essentially genetic dead-ends when it comes to their mitochondrial DNA.
These are questions that no sensible person would ever volunteer to answer unless they had to, but we find ourselves exactly at that point in time. An answer must be sought and given, as the suffering of many men and women, children and babies may be avoided and their early death averted by the implementation of procedures to replace mitochondrial DNA. The UK government has launched a national, public consultation on mitochondrial replacement, which is to run until Friday December 7th 2012, and which will advise whether change in legislation is appropriate. At the very least, this consultation must serve to stress the fact that in democratic societies, a decision on whether to go ahead, and in which terms, with the clinical application of these techniques, ultimately rests with the will of its members.
I argue that the scientific community at large should feel a particular responsibility to contribute to the moral, ethical, and philosophical discussion that is taking place. Scientists, researchers and science experts in general are among the people who are best equipped to know, understand, and anticipate the wide range of implications and ramifications of applying a technique such as mitochondrial replacement to the treatment of mitochondrial diseases. Ultimately, the Nature Protocols blog is as good an informal venue as any to discuss these matters and to air one’s views on the trove of thorny questions forced open by the publication, among other articles, of protocols in Nature Protocols2 and the Protocol Exchange5…
1. Tachibana, M. et al. Towards germline gene therapy of inherited mitochondrial diseases. Nature http://dx.doi.org/10.1038/nature11647 (2012).
2. Tachibana, M., Sparman, M. & Mitalipov, S. Chromosome transfer in mature oocytes. Nature Protocols 5, 1138–1147 (2010).
3. Tachibana, M. et al. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Nature 461, 367–372 (2009).
4. Craven, L. et al. Pronuclear transfer in human embryos to prevent transmission of mitochondrial DNA disease. Nature 465, 82–85 (2010).
5. Craven, L., Tuppen, H., Taylor, R., Herbert, M. & Turnbull, D. Pronuclear transfer in abnormal human embryos. Protocol Exchange http://dx.doi.org/10.1038/nprot.2010.54 (2010).
6. Cyranoski, D. DNA-swap technology almost ready for fertility clinic. Nature http://dx.doi.org/10.1038/nature.2012.11651 (2012).