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Our Editors share their views on topical issues in the fields of stem cell research and regenerative medicine.
It has been quite a momentous time in Britain and particularly in Newcastle, a city with a growing track record in stem cell research. It is not every day that something so controversial and yet potentially beneficial as the pronuclear transfer technique makes it into the headlines. This has been referred to as a “three-parent IVF” in the British media, and for the last few months you couldn’t have escaped hearing about the debate even if you had taken a long holiday on Mars! On 3 February, 2015, the UK parliament voted to permit the generation of IVF babies using pronuclear transfer.
Pronuclear transfers aim to treat mitochondrial diseases. As we all know, mitochondria, the ATP generating organelles of nearly every cell in our bodies, are built from proteins encoded by the nuclear genome except for a small number encoded by a separate genome present in the mitochondrion itself. The mitochondrial genome is a simple beast; it has few genes but, importantly, the cell seems to invest a lot less effort in keeping mitochondrial DNA ship-shape and mutation free. This contrasts with the care lavished on the nuclear genome and, as a consequence, mitochondrial genomes have a much higher mutation rate. This is where the root of the problem of mitochondrial disease lies. Deleterious mutations arise quite frequently and if they escape the cell’s monitoring systems (i.e. they don’t kill it!) there is a good chance the mutation will propagate in daughter cells, if it is a mitotic cell type, or even in post-mitotic cells if the mechanisms that control mitochondrial replication are not affected. If the mutation is present in a female and manages to slip through unchecked into her oocytes, (the only route of mitochondrial transfer to the next generation), it will be passed on to her offspring, carrying a significant probability that some will develop mitochondrial diseases. These are nasty conditions; because the genes encoded by the mitochondrial genome are central to the oxidative phosphorylation process, cells that have a high ATP demand don’t work so well in patients with a high mitochondrial mutation load. Muscles, neurons, cardiomyocytes – if it needs a lot of ATP, it will have problems. Patients typically show heart diseases, deafness, blindness, muscle weakness, and wasting, and may even have enhanced dementia. Add to this the possibility that they may age more rapidly and it is clear that mitochondrial diseases are in need of a cure and quickly!
Enter Prof. Doug Turnbull and his pronuclear transfer idea. The concept has been around for some time since McGrath and Solter removed the pronuclei from fertilized mouse embryos and fused them with other enucleated zygotes to give “reconstructed” embryos capable of developing to term in pseudopregnant foster mothers. The idea can potentially eliminate a mitochondrial disease as it transfers the cohort of genetic information needed to build the new embryo out of the oocyte containing faulty mitochondria into a new one in which only healthy copies of the mitochondrial genome are present. If ontogeny goes to plan after implantation in the mother’s uterus, she should produce a child with a healthy component of mitochondria thereby preventing the possibility of mitochondrial disease in that individual. For prospective parents known to carry a potentially pathogenic mutation, this technique offers peace of mind by removing the possibility of condemning their children to a lifetime of disability. It would be foolish if our society did not grasp this possibility with both hands but, since there is a requirement to “re-engineer” an IVF embryo, it is easy to understand the need for careful scientific review of the validity of this method. What if the individual acquires other problems as a result of pronuclear transfer? What if the embryonic genome cannot interact correctly with the new mitochondria it encounters?
I remember these questions and arguments only too well from my own experience of consultations associated with changes to the Human Fertility & Embryology Act and predictably the doomcriers and naysayers come out of the woodwork with their horror stories of slippery slopes, designer babies, cloning, etc. The fact is that this technique is unlikely to change the characteristics of the individual. We are not swapping the human genome – only a few small segments of DNA involved in power generation that some argue don’t even belong to our genetic makeup anyway (if you believe that mitochondria arose from a symbiotic association between early eukaryotes and bacteria) so could there really be a problem here? What we are doing is only tantamount to changing the cell’s batteries! No doubt one could argue that permitting pronuclear transfer brings designer babies one step closer, but in my opinion those risks are there already. The laws preventing any attempts at human reproductive cloning have been in place for many years and they seem to be holding up quite well – the world is not awash with cloned humans but no laws can prevent rogue individuals from trying something. The same applies to pronuclear transfer; you can ban it, and although that won’t remove the risk of designer babies, it will almost certainly remove the possibility of eliminating mitochondrial diseases for the foreseeable future.
Fortunately the British Government thought this idea was worth pursuing. After detailed reviews by the Human Fertility & Embryology Authority and the Nuffield Council on Bioethics, Parliament voted for a change in our legislation to permit the technique by a margin of 3:1. So then, it seems we now have a robust way of eliminating mitochondrial diseases. As a member of one of the groups to derive the first ESC in the UK, I remember comments from many circles that stem cell related cures were “just around the corner.” Such opinions often fail to acknowledge that no matter how important initial groundbreaking studies may be, there is still a long lag time from discovery to therapy. All told, this option for treating mitochondrial disease has been thirty years in the making but with the publication of Prof. Turnbull’s method in STEM CELLS, a cure is no longer around the corner. Some might say the corner has been turned.