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Everything You Need To Know About Mitochondrial Replacement Therapy

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In May, news broke of the first UK baby to be born through a new type of IVF procedure, called mitochondrial replacement therapy (MRT) or mitochondrial donation therapy (MDT). This novel technique – which utilizes genetic material from three people – has been pioneered to help couples conceive a healthy child in instances where the woman carries harmful mutations in her mitochondrial DNA. It was legalized in the UK in 2015.

What are mitochondria?

Mitochondria are a type of membrane-bound organelle found in a cell’s cytoplasm, often nicknamed the “powerhouse” or “battery” of a cell due to their critical role in energy production. While much of our DNA is stored in the cell nucleus, mitochondria are unique organelles in that their DNA is stored in a circular chromosome, which is inherited through the maternal line. This genetic material is essential for mitochondria to function properly.

The Newcastle Fertility Centre at Life has the only license in the UK to conduct research and treat patients using MRT, the Human Fertilisation and Embryology Authority (HFEA) states. An estimated 32 patients have received approvals for the treatment by the HFEA Statutory Approvals Committee as of May 2023.

Elsewhere in the world, MRT’s regulatory landscape varies; it is still considered controversial in some countries. It is effectively banned in the US, where Congressional laws prevent the Food and Drug Administration from accepting applications for MRT research. In 2015, a US team headed up by Dr. John Zhang, medical director at the New Hope Fertility Centre in New York City, traveled to Mexico – where no laws prohibit MRT – to conduct the procedure for a Jordanian couple; they welcomed a baby boy in 2016, and Zhang published the research in Reproductive BioMedicine Online.

The recent news of the UK MRT birth roused excitement and debate in the medical community, with conversations centering around the ethics of the procedure and whether it is successful over the long-term. Many scientists have called for more data from the team at Newcastle, which is yet to be released, though the HFEA says, “we understand that the team at Newcastle hopes to publish information of their mitochondrial treatment programme in peer reviewed journals shortly.”

Taken from Technology Networks. 

To learn more about MRT, why it has been pioneered to help patients with mitochondrial disorders and why its ethics are debated, Technology Networks spoke with Dr. Tora Smulders-Srinivasan, a senior lecturer in Biomedical Science at Teesside University. Previously, Smulders-Srinivasan was an NIH fellow at Newcastle University with Professor Bob Lightowlers and Professor Sir Doug Turnbull, investigating the roles of mitochondrial defects in neurons. During this time, she worked in the same research group as scientists developing the MRT technique pioneered at the university.

Molly Campbell (MC): Can you explain what MRT is and why it has been developed?

Tora Smulders-Srinivasan (TSS): Mitochondria are the parts of our cells that convert the food that we eat into the essential energy that our cells need to work. Fascinatingly, mitochondria also have DNA – a much smaller amount than our DNA in the nucleus which tells our cells what to do. But the mitochondrial DNA is essential for mitochondria to function properly. If there are changes in our mitochondrial DNA, they can cause severe disease as the cells can’t get the energy they need to work.

Severe mitochondrial DNA changes can cause numerous miscarriages, stillbirths or infant deaths. It is not difficult to imagine how devastating this must be to the mother and father of these affected children.

One solution for this devastating problem is MRT. In this therapy, healthy mitochondria from a donated egg are combined with the nuclear DNA from the mother and father to establish an embryo that should only have healthy mitochondrial DNA. Thus, the child should not have any of the defects from the changes in the mitochondrial DNA and should live a healthy life. This is a huge advance and could really change the lives of parents who have had devastating miscarriages, stillbirths or deaths of their young babies. Having a healthy child with mostly the DNA of the parents can make a huge difference.

MC: What are some examples of mitochondrial diseases, and why are they a significant health burden?

TSS: The most common types of mitochondrial disease are (1) mitochondrial encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, and (2) myoclonic epilepsy with ragged red fibers (MERRF). Overall, approximately 1 in 5000 people have a mitochondrial disease, but this is when all the different kinds are considered together.

Mitochondrial disease can be caused by many different changes in over 250 genes in mitochondrial or nuclear DNA and affect children or adults, depending on the exact change in DNA. Different organs can be affected in different patients and with different severities. Our brains and muscles use the most energy and so those are some of the organs most often affected in mitochondrial disease.

Sadly, mitochondrial disease is a progressive condition which means that it will get worse over time. As the disease is so variable in each patient, the rate the disorder gets worse also varies hugely between patients, depending on the specific DNA changes and the organs affected in that person. The symptoms are chronic but can remain stable for some years in some people. Others can have a slow progression, while still others might have a rapid downhill progression. Currently there is no effective treatment or cure for mitochondrial diseases, though the symptoms are treated to improve the quality of life for the patient. Thus, mitochondrial diseases are a large burden on the patient, their families, and society.

MC: The HFEA, the UK fertility regulator, confirmed that fewer than five UK children had been born using the procedure as of April 2023. The HFEA provided no further information about the procedure or the children. What do you think it is important we know about the procedure and its outcomes?

TSS: The procedure is similar to IVF, in that the egg is fertilized by the sperm in a dish. In MRT, a donor egg is also involved and the mitochondria come from the donor egg. The nucleus is the combination of the nucleus from the egg and the sperm of the parents. The important thing to realize is that the mitochondrial DNA only has genes for mitochondrial proteins. So, the donor egg only donates genes that are mitochondrial – the genes that help make the whole body are in the nucleus and come from the parents.

Someone with an organ transplant gets more different kinds of genes from the donor of the organ – since they’d have all the genes from the nucleus and the mitochondria in the cells of the organ. Someone who has MRT only gets the mitochondrial DNA from the donor – just the genes that make some of the mitochondria.

It is different, of course, as in MRT, the whole baby receives the genes, and in a transplant it is only the organ that is transplanted. However, a stem cell transplant will also have genes from the nucleus and the mitochondria spread all over the body of the recipient – and again, these will be all the genes, not just the ones that make some of the mitochondria.

As far as the outcomes, the expectation is that these children born through MRT will be healthy and not show any signs of mitochondrial disease. The children will be carefully checked by doctors, but there should not be anything else to worry about.

MC: Why do you think the procedure is restricted in countries such as the US?

TSS: As there are changes made to the genes of the embryo, this is a serious ethical question compared to any other kind of therapy currently available in the world. Each country needs to debate those ethical questions. Ukraine and Greece, as well as the UK, have carried out MRT.

MC: There are ethical considerations surrounding the treatment. What are your opinions here, and how do you think we can discuss this without limiting the progress of cutting-edge treatments such as MRT?

TSS: I believe that mitochondrial replacement therapy is a special case, but the ethical implications need to be discussed by society and the appropriate authorities. In the UK, after initial research, scientific review, public consultations, and debate the government recommended that MRT should be legalized. The HFEA regulated the process of research and debate and then also now regulates the process for any parents that wish to use mitochondrial replacement therapy. I believe that any further kinds of changes to genes are and should be put through the same rigorous process.

MC: What is your opinion of MRT?

TSS: I believe MRT is an amazing breakthrough, and a really great technique to help parents with mitochondrial disease to have healthy babies. I feel very lucky to have seen colleagues developing this technique as well as discussing the ethical implications when I was in the same research group.

Dr. Tora Smulders-Srinivasan was speaking to Molly Campbell, Senior Science Writer for Technology Networks.