In-Vitro Fertilisation: Threesome By Law

5. May 2015
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The UK in October became the first country to permit fertility clinics to use IVF using three donors. A blessing for women with mitochondrial diseases and infertility. Critics fear that the decision could pave the way to making designer babies.

After the British Parliament’s Lower House approved the amendment on February 3, the House of Lords followed on 24 February 2015. Previously, implantation of genetically modified embryos had been banned in the UK. The first in-vitro fertilisation (IVF) might be able to be carried out as early as autumn. The vote was preceded by many years of debate and numerous studies on the safety of the technology.

“This vote will change the lives of many women who live with mitochondrial disease by giving them the valuable opportunity to bring healthy children into the world, to eradicate the disease from the family tree and to reduce the number of those who are faced with the devastating effects of the disease”, declares Robert Meadowcroft, managing director of Muscular Dystrophy UK, a British charity.

Ahead of the vote critics had warned that the technology would constitute a form of eugenics and could have uncontrollable consequences. The emotionally-charged word “designer baby” inevitably made the rounds. “We are opening a Pandora’s box” warns Fiona Bruce, conservative MP in the Lower House and chairman of “Pro-Life” group. Dr. Robert Winston, fertility expert in the Labour Party and member of the House of Lords, commented in response to the accusation that doctors would be interfering with nature: “We are sometimes accused of playing God […] We’re not trying to replace God, but we are trying to improve his work”.

Finally a child of one’s own – despite genetic defect

Mitochondrial DNA (mtDNA) is passed down through the mother’s line – the few mitochondria which are present in the sperm are broken down after fertilisation. Previously there were only few options available to affected parents to prevent a child being born with a mutation in its mtDNA:

  • adoption
  • IVF using donor eggs
  • IVF using one’s own egg cells and subsequent preimplantation genetic diagnosis (only useful for heteroplasmy, that is when only part of the mitochondria carries mutated DNA)
  • Chorionic villus sampling and/or amniocentesis followed by abortion in the instance of a positive finding (subject to the same restrictions as preimplantation genetic diagnosis)

A panel of experts appointed by the UK Human Fertilisation and Embryology Authority (HFEA) in 2014 studied the safety of mitochondria exchange methods and came to the conclusion that maternal spindle transfer (MST) and pronuclear transfer (PNT) are potentially helpful for those patients who wish to have a genetically related child, but where there is a risk due to mutations in the maternal mtDNA of descendants developing serious or fatal diseases. The expert panel was also not able to find any evidence that the methods are unsafe. As a precaution, however, she recommends that the IVF mitochondrial donors come from the same haplogroup as the oocyte donor, that is that the mtDNAs be as similar as possible.

Many paths, one goal: mitochondrial exchange

The two methods differ in the timing in which the defective mtDNA is replaced: with MST, the spindle is removed from the mother’s egg along with the associated chromosomes and fused with an enucleated donor egg with intact mitochondria, following which the IVF occurs via intracytoplasmic sperm injection (ICSI). With PNT in contrast the parental pro-nuclei are removed from the fertilised egg cell and transferred into an enucleated fertilised donor egg after IVF. The experts are of the opinion that presently neither of the two techniques can be considered superior to the other. For this reason, both techniques should be pursued at first.

Polar body transfer (polar body transfer, PBT) – only described last year – is another technique used to replace genetically defective mitochondria. Polar bodies arise from meiosis and in addition to a complete haploid set of chromosomes carry significantly less cytoplasm than the ovum. As with MST this set of chromosomes is able to be extracted from the mother’s egg cell nucleus and implanted into an enucleated donor egg. The British expert committee, however, is of the opinion that this method has not been studied extensively enough to make statements about its effectiveness or safety. The method should definitely be explored in more detail, as it brings some potential advantages compared to MST and PNT. For example, the number of transferred mitochondria could be reduced via PBT.

Mystery mtDNA

The mitochondrial DNA encodes only 37 genes – with chromosomal DNA, however, this figure is about 25,000. In addition, mtDNA is organised entirely differently – according to endosymbiont theory as a direct result of its bacterial origin. All the 13 protein-coding genes are responsible for manufacturing elements of the mitochondrial respiratory chain. Although the genes in mtDNA make up only a small fraction (0.2%) of all genes, there are many diseases to which defects in mitochondrial genes are attributable. According to estimates, pathogenic mutations in the mtDNA appear in one in 200 newborns; on the basis of epidemiological studies the prevalence of mtDNA-induced mitochondriopathies is “only” calculated to be between 1: 5,000 and1: 10,000.

Since mtDNA encoded proteins are essential components of the respiratory chain, in which oxidative phosphorylation provides energy in the form of ATP, several tissues and organs are usually affected. In particular the nervous system, muscles and the eyes are often damaged. Examples of mtDNA-conditioned mitochondriopathies include Leigh syndrome, NARP syndrome, MERRF syndrome, MELAS syndrome, MIDD syndrome and Leber Hereditary Optic Neuropathy (LHON).

The extent and severity of the disease depends on both the penetrance of the mutation as well as how large the proportion of mutated mtDNA is compared to unmutated mtDNA (extent of heteroplasmy) – a mature egg can contain up to 100,000 copies mtDNA, spread over 1-2 copies per organelle. Chance decides the proportion of defective mitochondria which is inherited. For this reason, a familial mitochondrial disease often only shows up when a child that has a high proportion of mutated mtDNA shows clinical symptoms, while the mother due to having a small proportion of the mtDNA is asymptomatic.

The ravages of time

Another characteristic of mtDNA is that it mutates faster than chromosomal DNA. The mitochondria is thus lacking a repair system to eradicate replication errors – with time mutations accumulate. It is therefore likely that spontaneous and inherited mutations, and epigenetic modifications of the mtDNA, influence the pathogenesis of age-related diseases such as Alzheimer’s disease, Parkinson’s disease, diabetes mellitus and atherosclerosis.

The question of whether children produced via mitochondria exchange techniques such as MST, PNT and PBT have, for example, a higher risk of chromosome aberrations can only be assessed when sufficient data becomes available. Interestingly however, there are already children with three parents: between 1997 and 2002 in the US a technique called cytoplasm transfer was being practised. Using this technique, older women in particular, who were still childless despite IVF, had the opportunity to have a child. The idea that aged oocytes could be “rejuvenated” by injecting fresh cytoplasm (also containing mitochondria) from a donor egg proved to be correct. Approximately 30 children were conceived in this way before the technology was laid on ice by the FDA because of safety concerns. In view of the new laws in Britain, interest in the fate of these children is now being reawakened: their health and development status is to be investigated as part of a follow-up study.

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