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A good concept: The science of mitochondrial DNA

20 Jan, 2012
Three mitochondria surrounded by cytoplasm

Three mitochondria surrounded by cytoplasm

When new scientific understanding makes novel medical treatments a possibility, it is right that society should have the opportunity to debate whether the new treatments should be adopted. This is especially important if the technology involved could present ethical concerns.

Such democratic debate, as much as the final decisions made by policy-makers, should be based on a proper understanding of the science behind the treatment. That is not always helped by the way potential medical advances are reported in the media.

Two announcements were made yesterday concerning a potential new technique using in vitro fertilisation (IVF) to prevent children inheriting mitochondrial diseases. We announced a £4.4 million award to establish the new Wellcome Trust Centre for Mitochondrial Research at Newcastle University. A large part of the centre’s remit is to undertake research necessary for the new treatment to be introduced, building on years of previous work by the centre’s scientists funded by the Trust, the Muscular Dystrophy Campaign and others.

At the same time, the Government has asked the Human Fertilisation and Embryology Authority (HFEA) to run a public dialogue exercise to gauge views as to whether this kind of treatment would be acceptable.

The technique has been reported before – notably last year when it was the subject of a report by an HFEA expert scientific panel. Their study concluded that while there was no evidence to suggest the technique was in any way unsafe, more research was needed before it could be licensed because it was a new technique for use on human embryos and, while any new medical technique has associated risks, these risks should be managed to be as small as possible in this case.

Many media reports of the panel’s 2011 conclusions described the proposed procedure as ‘three-parent IVF’ (here are some examples: BBC, New Scientist, Independent). Several reports of yesterday’s announcements repeated this phrase (see the Financial Times, Daily Telegraph, Channel 4 and the BBC, who have since changed their wording to “Three-person IVF”), which is in danger of becoming a common, but flawed, concept of the technique.  

1 + 1 + 0.00001 ≠ 3

While it is correct that genetic material from three people contributes to the resulting child’s DNA, the mitochondrial DNA that comes from a donated egg is such a tiny component of their total DNA that, if you really want to count parents according to their genetic contribution, you might say a child born using this technique would have 1 father and about 1.00001 mothers. Added to that is the fact that the mitochondrial DNA produces only proteins used in the mitochondria – it has no influence over physical or psychological attributes of the child such as hair colour or taste for brussels sprouts.

Mitochondria are often described as being cells’ batteries – they provide the energy our cells need to work properly. It is a good analogy and in this new technique, we have a way of changing faulty batteries before they do irreversible damage to the body they are in. And just as changing the batteries in a torch doesn’t change the colour of light it shines, switching mitochondrial DNA won’t change a person’s appearance or personality.

This is not to say that there is no ethical dimension to the technique and the researchers leading this work welcome public discussion of it. The Nuffield Council on Bioethics has also launched a call for evidence on the ethical issues raised by the technique for consideration by its Working Group of experts. Clearly, human DNA is transferred from one egg to another in order to eliminate the mutated DNA that would otherwise cause a mitochondrial disease in the resulting child. If the child is a girl, she will pass on the donated mitochondrial DNA to any children she, in turn, may have.

To some, the benefits of eliminating the risk of these debilitating and often deadly mitochondrial diseases will far outweigh any possible ethical concern; for others, manipulation of human genetic material is just beyond the pale, no matter what potential good it might do. The important thing is that these positions (and any others in between) be reached with a proper understanding of the science involved and not in response to casually constructed headlines about ‘three-parent’ babies.

The Wellcome Trust’s position was clearly set out this morning by our Director, Sir Mark Walport, in an article in The Times: “Medical procedures that introduce a donor’s biological material into the body are … long accepted. If a child with donated mitochondria can be said to have three parents, then the recipient of a heart transplant could be said to have four.”

So here’s the science…

The cells in our bodies need energy to work. They get their energy from mitochondria – like tiny batteries, mitochondria store and release energy when it is needed. Every cell (except red blood cells) has lots of mitochondria, each with its own DNA kept separately to the rest of our genes, which are held in the cell nucleus. However, just like nuclear DNA, mitochondrial DNA is prone to damage and mutations, which can lead to a number of diseases, although the nature of the diseases can be very different, even if people have the same mutations.

Mitochondrial DNA is thought to have evolved separately from nuclear DNA. It has just 13 genes that produce proteins, compared to around 23,000 in our nuclear DNA, and is passed only from the mother to her offspring.

Like most other human cells, a woman’s egg cells contain nuclear DNA and lots of mitochondria which, of course, contain her mitochondrial DNA. If a woman’s mitochondrial DNA is faulty, then her children would be at a high risk of having mitochondrial disease.

It is not feasible to replace all of the egg’s faulty mitochondria with fully functional ones from a donor. Instead, the Newcastle researchers have pursued the possibility of exchanging the nuclear DNA instead. They can do this in two ways, one of which is done with fertilised eggs, the other at a stage before the mother’s egg is fertilised by the father’s sperm.

Pronuclear Transfer

Pronuclear TransferAny fertilised egg reaches a point where the nuclear DNA from both the sperm and the egg has formed two pronuclei (see diagram A above) that are visible under a normal light microscope. The pronuclei containing nuclear DNA from both parents (the red circles in the cells in the second row) can be taken from the fertilised egg and placed in a donated egg (upper row) which has had its pronuclei (blue) removed.

The donated egg with its healthy mitochondria (green) and replaced nuclear DNA (red) is then implanted in the mother as per standard IVF procedures.

Spindle Transfer

Spindle TransferA similar process can be used to transfer nuclear DNA before fertilisation. The spindle (see diagram B above) is a structure that contains the mother’s nuclear DNA in unfertilised eggs. It is visible under polarised light and can be extracted and put into a donated egg (upper row) that has had its spindle removed. This egg can then be fertilised and implanted in the mother’s womb.

In each case, the donor egg can be altruistically donated or come from unused eggs from other IVF procedures.

Both of these techniques have been shown to be technically feasible. The Wellcome Trust funding, along with a further £1.4m from Newcastle University, will support a great deal of the additional research required by the HFEA expert panel’s 2011 report, while the HFEA’s public consultation will find out what people think of the technology and its proposed use to prevent the passing on of mitochondrial diseases.

The aim of doing both research and consultation in parallel is that there should be no delay in introducing the new therapy, assuming it is proved to be safe and effective as well as acceptable to the UK public. It is vital that both processes be done with as accurate an understanding of the science and the ethics underpinning this groundbreaking therapy.

For a more detailed account of the science of mitochondrial DNA and disease, have a look at this open-access review in the Journal of Pathology by authors including Professor Doug Turnbull, Director of the new Wellcome Trust Centre for Mitochondrial Research at Newcastle University:

Greaves, L., Reeve, A., Taylor, R., & Turnbull, D. (2012). Mitochondrial DNA and disease The Journal of Pathology, 226 (2), 274-286 DOI: 10.1002/path.3028

Image credits: Top image – Dr David Furness / Wellcome Images; Diagrams – Prof Mary Herbert, Newcastle University

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