EXPERT REACTION: Senate report on allowing 'three person IVF' to prevent mitochondrial disease

The number of available assisted reproductive technologies is expanding and their applications have the potential to help an increasing number of couples. Women who are carriers of mutations in their mitochondrial DNA are at risk of having children who could be affected by mitochondrial disease.

For a long time now, the mitochondrial disease community has been seeking alternative ways to help couples have children that would not be affected by the disease. Mitochondrial donation has been proposed as a technology that could be used to help in this situation.

Whilst I am in favour of the potential introduction of mitochondrial donation into clinical practice in Australia, there is still some work that needs to be undertaken to determine if the technology is safe. Furthermore, there is room for improvement in the technology that would reduce some of the potential risks.

One of the risks is associated with the ‘carryover’ of some mutated mitochondrial DNA as the technology is performed. Another risk relates to identifying suitable ‘matched’ donor eggs, as we need to understand how eggs from a different genetic background affect the outcome.

I urge some caution and hope that further scientific investigation can proceed so that we can help affected couples to give them greater reassurance with respect to the available technology.

The Senate Committee report on mitochondrial donation is a major step forward in allowing families affected by devastating mitochondrial DNA disorders to be able to have a healthy child in subsequent pregnancies.

I have run the main Australian lab involved in diagnosis of children with mitochondrial energy generation disorders for over 25 years and helped to diagnose more than 600 affected children. Most of these children have died before 5 years of age as we continue to lack effective treatments.

Mitochondrial DNA disorders can also cause severe adult-onset disease. The unique genetics of mitochondrial DNA means that regular reproductive options for having a healthy child, such as prenatal diagnosis and preimplantation genetic diagnosis, are not suitable for most women at risk of having a child with mitochondrial DNA disease.

The Senate report sets out a path for mitochondrial donation to be legalised in Australia. They recommend public consultation on specific options for legislative change, a very limited review around three aspects of the science around mitochondrial donation, engagement with the States via COAG, and an interim measure of engaging with UK authorities to see if Australian families can access the UK facility for mitochondrial donation.

The report is seen as highly positive by the Australian Mitochondrial Disease Foundation, offering enormous hope for affected families. Like them, I am keen to see that the committee’s recommendations are acted on as swiftly as possible.

The Senate Committee’s report provides qualified support for changing Australian law to allow mitochondrial donation. I welcome its findings. The report gives a balanced and well-informed view on the potential use of mitochondrial donation in Australia.

The significant promise of mitochondrial donation for families living with mitochondrial disease is recognised, without over-hyping it as a cure. It acknowledges this technology may not be the same as other forms of so-called germline intervention. It will not give children three parents.

Safety aspects are carefully weighed up. It grasps that this is a specialist technology, likely to be used by a small number of couples at risk of passing on mitochondrial disease to their children.

The journey ahead is likely to be slow – the government is not rushing into this and there will be further scientific and public consultation.

Interestingly, the report recommends the Government talks with United Kingdom authorities to see whether Australians could access mitochondrial donation there, where it is legal under licence. While it is unusual for a government to suggest this kind of cross-border reproductive care, this will help ensure that Australians don’t seek mitochondrial donation in unregulated countries.

On September 27, 2016, New Scientist announced the birth of a baby boy. His birth made it into the news because the boy is the first human to be born after mitochondrial replacement therapy (MRT), creating, as the media so nicely put it, a three-parent baby.

His mother suffers from a severe mitochondrial disease. By replacing her faulty mitochondria with those of a healthy female donor prior to IVF, the resulting baby boy carries the genetic material of three parents.

The aim of MRT is to prevent the transmission of mitochondrial diseases to offspring. Yet, multiple studies have shown that MRT results in heteroplasmy, the presence of more than one mitochondrial lineage. While heteroplasmy itself can be detrimental to an organism, the specific danger here is that the original mitochondrial lineage (e.g. originating from the mother) appears to increase in frequency at the expense of the mitochondria from the donor. Not only does this suggest that the original mtDNA has a within-cell replicative advantage despite its detrimental effect on the host, it also defeats the purpose of MRT.

In mice and monkeys born after MRT, changes in mitochondrial composition are particularly noticeable in the female germline and in offspring. Mitochondria are clearly not selectively neutral, and we cannot equate MRT with ‘replacing the batteries of a camera’.

While society appears to be ready to create humans via MRT, we simply lack the understanding to predict the success and foresee the potential consequences of this new technique. We urgently need to understand how selection acts on mitochondria.

An important issue is genetic variation in the selection of the donors.

The primary function of mitochondria is energy production by a process called oxidative phosphorylation. This energy production is driven by enzymes, which have components encoded by genes in both the mitochondria and the nucleus of the cell. 

All the components need to work together properly. If genes in the mitochondria of a donor are not completely compatible with the genes in the nucleus of the recipient, this may not happen. Donor-recipient incompatibilities are possible because the DNA sequences of genes in the mitochondria vary greatly. 

This risk could easily be addressed by selecting donors with the same or very similar mitochondrial genomes to recipients.

Matching mitochondrial genomes of donors and recipients should be part of these procedures, in much the same way as major histocompatibility complex (MHC) matching is part of donor-recipient matching for tissue transplantation.