The Demise of Three-Parent Babies

Yes, yes, I know, I’m a couple of days late; but I have a good excuse. Yesterday was my final deadline for this semester and I had 5,000 words to write so these words had to wait a little. On the upside I am now free of uni work till about October so I’ll hopefully do about three posts per week here. Starting now.

Three-parent babies. I hate this term. The title of this post, therefore, refers not to the demise of the concept itself but of the phrase. But first, a little background.

Mitochondrial diseases are a very broad range of disorders that can affect any organ or system of the body, at any time of life in absolutely anyone. Phenotypes can run the gamut from a lifetime of almost unnoticeable weakness to rapid onset heart failure, deafness, diabetes, blindness, neurological problems and a hundred other things.

Most people will remember mitochondria from high school as the ‘powerhouses’ or ‘energy factories’ of the cell. They are responsible for producing about 90% of the energy in your body in the form of a molecule called adenosine triphosphate, or ATP for short. We get through so much of this stuff, constantly recycling the molecule again and again, that the average person will get through more than 50 kilograms of ATP each day.

Anyhoo, what you may not know is that the mitochondria we all have inside us have a genome of their own separate from the one inside the nuclei of our cells. It’s only very small, about 16,000 base pairs of DNA compared to the 3-4 billion in the nuclei. It is a remnant of the humble origins of this most important of organelles.

It is believed that, billions of years ago before there were any eukaryotes or multi-cell organisms, a bacteria of some kind was merrily munching its way through a delicious dinner of other bacteria but instead of digesting its meal away like it normally would the two formed a symbiotic relationship. The meal in question was some kind of primordial mitochondrion-like cell that happened to be rather good at making chemical energy. The diner obviously didn’t ‘choose’ not to digest it but it must have very quickly gained an advantage from having all this energy floating about all of a sudden and so the eukaryotic kingdom was born.

Over time, most of the genome inside the mitochondria migrated its way into the nucleus along with the rest of the genome but 16,000 base pairs have remained. It is errors in the code of these 16,000 base pairs that are largely responsible for the array of mostly devastating diseases that encompass mitochondrial disorders.

At the moment of conception a sperm impregnates an egg cell. Each of the pair have one half of a complete nuclear genome within them. But that’s not enough; we need those mitochondria and their 16,000 base pairs too. These are provided solely by the mother, they are floating around in the egg cell waiting to power a new human being. The father does not contribute any mitochondrial material and so mitochondrial diseases are only inherited through the maternal line.

This, though, provides a therapeutic avenue for us to exploit. Using modern IVF techniques it should be possible to take the genome-containing nucleus from a mother with mitochondrial disease and transplant it into the enucleated egg cell of a donor, healthy woman. Sperm can then be allowed to fertilise the new egg cell and voila! The miracle of life. It is the children created by this procedure that the press, fed a line by those who have ideological objections to the treatment, call three parent babies. Let’s be very clear about this, there is no reasonable definition of what it is to be a parent that would include the donation of some mitochondria. The mitochondrial donor would be contributing about five ten thousandths of one percent of the total DNA. It is nonsense to begin to stigmatise these children before they’re even born, and it is a nasty trick indeed to whip up the kind of fear in the public mind that the anti-GMO/pro-organic lobby have so successfully fostered these past twenty years.

There is certainly a legitimate debate to be had here about how to proceed. Though it is yet to actually happen, this technique has been approved in the UK for a couple of years now. We are in a period of basic research where we are trying to figure out if real life will play out as we expect. A new, open access paper published in Cell Stem Cell deals with just this question. Unfortunately, their early findings point to a potential problem.

What they did was to take mitochondria from two women, both of them healthy but which they could distinguish one from the other. In tissue culture they then put a small amount of one type of mitochondria into the cell of another kind, about 1-2.2% of the total. They then let the cells grow as they pleased for 60 generations. At various stages they took samples from the culture, both single cells and a group of them together to get an average, and measured the relative quantities of each kind of mitochondria within them. The results varied wildly.

Image taken from Yamada et al, 2016

As you can see from the graph on the right, the amount of ‘foreign’ DNA started off low at just over 1%. By the time 30 generations has passed, however, it made up more than half of the mitochondria in the culture with some individual cells having as much as 90%. By the 60th generation it had died back down to negligible levels.

It should be noted here that nothing sinister is going on. Mitochondria don’t go around fighting and attacking each other; this is just an example of what we call ‘genetic drift’. It is a random process but highlights how something rare can randomly become very common.

This is a problem because we can’t yet guarantee that there won’t be any defective mitochondria hitching a ride when the nucleus is transported from one cell to the next. Put another way, our current techniques can’t guarantee that we would actually prevent a child being born that has a mitochondrial disorder. This is obviously a problem and one of the reasons why no one has undertook this technique even though it is legal.

No doubt the procedure will be refined in time, but this new information has told us that we are going to have to set the bar extremely high if we ever want this to work in a clinical setting. In the meantime, let’s talk about this, let’s inform the public of want we want to do, why this is needed, what measures we’re taking to make sure that it works; let’s keep having the debate. But, please, for my sake, let’s never again use the phrase ‘three parent baby’.

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