Mitochondria are the ‘powerhouse of the cell’.

Sound familiar? This fact was likely drilled into you during high school biology classes (or by looking at memes). Beyond this, you may not have given mitochondria a second thought - but you should! This organelle has been at the centre of some heated parliamentary debates relating to mitochondrial donation. This new IVF technology, which aims to prevent women from passing on mitochondrial disease, will reshape Australia’s approach to genetic and reproductive technologies. Mitochondrial donation was legalised in Australia last year when ‘Maeve’s Law’ was passed in the Senate. This law reform has generated a minefield of social and ethical questions that are yet to be fully answered.   

​

What is mitochondrial disease?

​

Mitochondria are the small but mighty structures found in all our cells (except red blood cells) that produce more than 90% of the energy used by our bodies (Cleveland Clinic, 2023). This organelle is vital for the functioning of important organs such as the heart, brain and liver (Cleveland Clinic, 2023). Mitochondria also have their own DNA, with a relatively small genome size of 37 genes (Garcia et al., 2017), compared to the 20,000 genes in our nuclear DNA (Nurk et al., 2022). Mitochondrial disease refers to a group of disorders in which ‘faulty’ mitochondria results in a range of symptoms such as poor motor control, developmental delay, seizures and cardiac disease (Mito Foundation, 2023). Half of the cases of mitochondrial disease are caused by mutations in mitochondrial DNA. These mutations are transmitted through maternal inheritance, which means that all the mitochondria in your cells are passed on from your biological mother (Mito Foundation, 2023). It is believed that about 1 in 200 people have a mutation in their mitochondrial DNA, with 1 in 5000 people having some form of mitochondrial disease (Mito Foundation, 2023). There is currently no cure for this group of conditions.

​

How does mitochondrial donation work?

​

Mitochondrial donation, also known as Mitochondrial Replacement Therapy (MRT), is an IVF technology which aims to prevent women from passing on mitochondrial disease to their children. For individuals with mitochondrial disease, this technology is currently the only way to have biological children without the risk of passing on their disease. MRT is used to create an embryo containing the nuclear DNA from two parents, in addition to mitochondrial DNA from an egg donor. This process involves taking the nuclear DNA from an embryo (created using the mother’s egg and father’s sperm) and inserting it into a donor egg which contains healthy mitochondria (NHMRC, 2023). The child will still inherit all of their unique characteristics, such as hair colour, through the nuclear DNA of their prospective parents. Therefore, it would be impossible to tell that an individual had been conceived through MRT simply by looking at them.

Challenges in defining parenthood.

​

Children conceived through MRT have been popularly referred to in the media as ‘three-parent babies’ since the technique creates an embryo containing DNA from three different individuals. However, this label is inaccurate and misleading. It suggests that all three parents make an equal contribution to the identity of the child, when in fact mitochondrial donors contribute only 0.1% of the child’s total genetic material. So, technically the term ‘2.002-parent babies’ would be more accurate! Under Australian law, mitochondrial donors will not have legal status as parents since their genetic contribution is not thought to influence the unique characteristics of the child. However, there are some concerns about the potential psychological impacts on children conceived through MRT, as the definition of parenthood is becoming increasingly blurry. It is possible that children conceived through mitochondrial donation will regard their mitochondrial donor as significant to their identity, considering how different their life may have looked without them. As researchers learn more about the function of mitochondria, we may indeed find that mitochondrial DNA has a greater influence on a person’s characteristics than we once thought. More recent studies have linked mitochondrial DNA to athletic performance (Maruszak et al., 2014), psychiatric disorders (Sequeira et al., 2012),  and ageing (Wallace, 2010).

​

Should mitochondrial donors remain anonymous?

​

If mitochondrial donors contribute such a tiny amount of DNA to a child, and do not influence any of their personal characteristics, should they be obligated to disclose their identity to the recipient? Australia no longer allows egg or sperm donors to remain anonymous in order to protect the rights of individuals to know their biological origins. Yet, in the case of mitochondrial donation, there is a much smaller proportion of DNA involved. Some experts have compared mitochondrial donation to organ donation, in the sense that the donation also provides someone with the organ (or organelle) that enables them to live a healthy life, without altering their unique characteristics. It has therefore been argued that mitochondrial donation should be treated in a similar way to organ donation, allowing donors to remain anonymous. Considering that donated eggs are often in low supply, permitting anonymous donors may provide a way of improving the availability of donor eggs. It is likely that Australia will follow the lead of the UK by permitting anonymous donation.

​

Are we ‘playing God’ by altering the genome?

​

By making heritable changes to an individual’s genome, we are heading into new and potentially dangerous territory. Opponents of mitochondrial donation have voiced fears about the ‘slippery slope’ between trying to eradicate mitochondrial disease and taking this technology too far into the realm of ‘designer babies’. Considering that mitochondrial donation does not involve making any changes to nuclear DNA, and can only be used for medical reasons, these statements seem a bit sensationalist. However, there are some genuine reasons to be concerned about the safety of this technology and its implications for the future of humankind.

​

While MRT is generally considered to be safe based on clinical research, there are still some uncertainties about its efficacy in clinical practice. For example, clinical research has found that there is a chance of ‘carry-over’ of unhealthy mitochondria during the MRT process (Klopstock, Klopstock & Prokisch, 2016). If this carry-over occurs, there is a potential for the numbers of unhealthy mitochondria to gradually increase as the embryo develops, essentially undoing all the hard work of creating an embryo free from mitochondrial disease. However, the percentage of carry-over is usually less than 2% and is likely to become lower as the technology advances (Klopstock, Klopstock & Prokisch, 2016). 

​

Unfortunately, we won’t know about any negative long-term impacts of MRT until we are able to observe the development of children conceived through this technology. However, adults over the age of 18 cannot be forced to participate in a study, which makes it more challenging to track long-term outcomes. An important consideration is the privacy and autonomy of these individuals - that they are not over-medicalised or viewed as some sort of ‘spectacle’ to the public.

​

The future of mitochondrial donation in Australia.

​

‘Maeve’s Law’ was named in honour of Maeve Hood, a cheerful 7-year-old who was diagnosed with a rare mitochondrial disease at 18 months old. The law was passed with the aim of preventing the transmission of mitochondrial disease in Australia, which affects around fifty families each year. This revolutionary law permits the creation of a human embryo containing genetic material from three people and allows heritable changes to be made to the genome (although under strict guidelines). Such practices were previously illegal in Australia due to understandable concern that these technologies could be destructive in the wrong hands. Maeve’s Law introduces an exception to these prohibitions solely for the purpose of preventing serious mitochondrial disease.

While MRT is no longer illegal in Australia, Maeve’s Law does not authorise the immediate use of MRT in clinical practice. The law outlines a two-stage approach in which the technology will be implemented, provided that clinical trials are successful. This initiative will be conducted by Monash University through the mitoHOPE (Healthy Outcomes Pilot and Evaluation) program, for which they received $15 million in funding (Monash University, 2023). Stage 1, which is expected to last around ten years, will involve clinical research aimed at improving MRT techniques and validating its safety. After an initial review, mitochondrial donation may become available in a clinical practice setting in Stage 2.

Mitochondrial donation is an exciting technology which provides hope to the many Australians touched by the devastating effects of mitochondrial disease. However, it is important that more research is conducted into its safety and efficacy, as well as the long-term implications of its use. As is often the case with groundbreaking technologies such as this, the laws and policies lag behind the science. The passing of Maeve’s Law is only the start of what will be a long journey to the successful implementation of mitochondrial donation in Australia. The next ten years will be crucial in setting a precedent for how our society approaches the use of other novel genetic technologies in healthcare. The question is no longer ‘should we use mitochondrial donation?’ but ‘how can we implement this technology in a safe and ethical way?’

References

​

Cleveland Clinic. (2023). Mitochondrial Diseases. 

https://my.clevelandclinic.org/health/diseases/15612-mitochondrial-diseases

Garcia, I., Jones, E., Ramos, M., Innis-Whitehouse, W., & Gilkerson, R. (2017). The little big

genome: The organization of mitochondrial DNA. Frontiers in Bioscience (Landmark Edition), 22, 710.

Klopstock, T., Klopstock, B., & Prokisch, H. (2016). Mitochondrial replacement approaches:

Challenges for clinical implementation. Genome Medicine, 8(1), 1-3.

Maruszak, A., Adamczyk, J. G., Siewierski, M., Sozański, H., Gajewski, A., & Żekanowski,

C. (2014). Mitochondrial DNA variation is associated with elite athletic status in the Polish population. Scandinavian Journal of Medicine & Science in Sports, 24(2), 311-318.

Mito Foundation. (2023). Maybe Mito Patient Factsheet.

https://www.mito.org.au/wp-content/uploads/2019/01/Maybe-Mito-Patient-Factsheet1.pdf

Mito Foundation. (2023). Mitochondrial Disease: The Need For Mitochondrial Donation.

https://www.mito.org.au/wp-content/uploads/2019/01/Brief-mitochondrial-donation-2.pdf

Monash University. (2023). Introducing Mitochondrial Donation into Australia. The mitoHOPE

Program. https://www.monash.edu/medicine/mitohope

National Health and Medical Research Council. (2023). Mitochondrial Donation.

https://www.nhmrc.gov.au/mitochondrial-donation

Nurk, S., Koren, S., Rhie, A., Rautiainen, M., Bzikadze, A. V., Mikheenko, A., & Phillippy, A.

M. (2022). The complete sequence of a human genome. Science, 376(6588), 44-53.

Sequeira, A., Martin, M. V., Rollins, B., Moon, E. A., Bunney, W. E., Macciardi, F., & Vawter,

M. P. (2012). Mitochondrial mutations and polymorphisms in psychiatric disorders. Frontiers in Genetics, 3, 103.

Wallace, D. C. (2010). Mitochondrial DNA mutations in disease and aging. Environmental

and Molecular Mutagenesis, 51(5), 440-450.