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Viewpoints: the promise and perils of three-parent IVF

Three-parent IVF is about allowing women who carry genetic diseases in their mitochondria to avoid passing them on to their children. Glenn/Flickr

Far from creating designer babies, three-parent IVF is about allowing women who carry genetic diseases in their mitochondria to avoid passing them on to their children. The process involves replacing the mitochondria from the ovum of a woman who has a mitochondrial disease with one from a healthy donor.

It’s controversial because it requires a third “parent”, a woman who can donate a healthy mitochondria. The technology is currently prohibited throughout the world although the UK government has announced its intention to draft proposals allowing it.

The technology could work in two ways – transferring the chromosomes from the mother into an egg from a healthy donor that has only the mitochondria (with other chromosomes removed) before fertilisation. Or we could take all the chromosomes out of a fertilised egg and put them into a donor egg that, again, has been “emptied” apart from the mitochondria.

An article published in the journal Science today raises some potential concerns about the technique. Here, one of the authors of the paper, Damian Dowling explains some limitations of the process. And professor of mitochondrial genetics Justin St John responds.

Damian Dowling: Our article outlines key research findings, as well as the outcome of a public consultation by the UK Human Fertilisation and Embryology Authority (HFEA) into the safety and ethics of mitochondrial replacement, which is also known as mitochondrial replacement-assisted IVF, or popularly as three-parent IVF. We believe the technique holds exciting promise for prospective mothers suffering from mitochondrial disease.

We talk about a body of scientific literature that is highly pertinent to the technology, but has been by-and-large overlooked in the scientific and public forums of this debate.

People have different nuclear genomes (genetic make-up) and different mitochondrial DNA sequences (mtDNA or haplotypes). How we make energy is determined by how these genomes work in tandem with our mitochondrial haplotypes. Indeed, experimental research on model organisms, ranging from mice to insects, indicates that how the mitochondrial DNA interacts with the genome is tightly preserved by natural selection – nature’s quality control process.

This interaction (mito-nuclear) is salient to life as we know it because it regulates much of our energy production.

When researchers have used mitochondrial replacement-type techniques to mix-and-match different combinations of putatively healthy mitochondrial haplotypes and nuclear genomes, they have typically found that new mito-nuclear combinations change how organisms function – from altering development rates to cognitive ability, reproductive success to life expectancies. Sometimes, this is for the worse.

Mitochondrial replacement-assisted IVF can make novel combinations of mito-nuclear interaction in ways that normal sexual reproduction cannot.

Under normal conception, a copy of the mother’s nuclear genome is transmitted to her children in 100% of cases, along with her mitochondrial genotype. This gives natural selection the fuel to preserve optimally functioning mito-nuclear gene combinations, perpetually across generations.

In public discussions of this technology, mitochondria have been likened to batteries in a camera; it doesn’t matter what brand of battery you use, the camera will function well. The body of research we bring to the table suggests this analogy needs rethinking – the brand can affect the expression of many health-related traits.

We don’t want to block the transition of this technique to the clinic. But, we feel it’s our obligation to bring to the discussion the research that has been overlooked. This research should be considered by the authorities involved in bringing mitochondrial replacement-assisted IVF to the clinic, who should decide how relevant the results and principles highlighted in this literature are to humans.

Ultimately, it will be difficult to predict how relevant this all is to the human case.

Women who suffer mitochondrial disease and might benefit from this technique should at least have access to the full array of evidence. They should understand its potential implications, so they can make an informed choice that is right for them and their situation.

While we don’t claim that this is the whole solution, perhaps matching mitochondrial haplotypes of the donor and mother would make sense and should be explored further. This option has been discussed by the HFEA.

Justin St John: The authors of the Science piece mention that the research they are highlighting hasn’t been included in the public debate. It’s important to note that it has not been overlooked by the scientists working on the technology or the agencies involved.

For quite a while now, scientists have been trying to develop approaches to prevent future generations from inheriting diseases associated with the mitochondrial genome.

Proposed assisted reproductive technologies offer the opportunity to prevent these diseases from being passed from one generation to the next. This is a highly worthwhile pursuit, but there are a number of safety issues that still require further explanation.

The most important issue that Damian Dowling raises above is that research he is drawing attention to has been considered by the Human Fertilisation and Embryology Authority (HFEA). I have also previously argued this case in the scientific literature.

I would even go a step further and suggest the technology needs an all-round safety assessment, which is also the view of the UK’s Nuffield Council on Bioethics and the HFEA. It’s important to note that the HFEA is the only body in the world considering proceeding with the technology.

I want to be sure that there’s no accompanying mutated mitochondrial DNA introduced into the egg when the chromosomes from the mother are transferred into the donor egg. Modifications to this technology could prevent that.

I would also want to ensure that there are no other abnormal processes resulting from the transfer. It has previously been argued that the transfer of chromosomes from one egg to another could affect chromosomal gene expression patterns through epigenetic factors.

To overcome these concerns, we are currently developing technologies to prevent the transfer of accompanying mitochondrial DNA. Once we have perfected this, we will test the outcomes in model systems.

That data would be available to the scientific community and the regulatory authorities, and it would enable informed decisions to be made about safety.

Sometimes, the public debate about complex science is simplified but that doesn’t mean that the science has been simplified, careless or rushing ahead heedless of negative consequences. It’s good that as we move closer to using this technology that the public debate becomes deeper, but that doesn’t mean that this depth is new in scientific circles.

We all seek to ensure that this area of research doesn’t generate another problem while solving one.

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