July 10, 2020

The Niche

Knoepfler lab stem cell blog

A 250,000-fold oversight on 3-person IVF mitochondrial transfer?

Remember the debate over so-called 3-person IVF?

The goal of this technology, also referred to as mitochondrial transfer and 3-parent IVF, is to prevent mitochondrial disease through nuclear transfer in oocytes or one-cell embryos.

The resulting genetically modified (GM) human embryos and ultimately children if it works could have dodged mitochondrial disease, but also could have serious or even fatal problems due to the technology itself.

The fact that 3-person IVF would create GM people and the concerns over the limited amount of data on the safety and efficacy of this technology, have sparked a rousing debate.

One of the subplots in this debate has been the assertion by many that modification of nuclear genes (e.g. CRISPR-mediated modification of as little as a few base pairs of a single nuclear gene) is far more of a concern than 3-person IVF. Nuclear genes and the nuclear genome are in their way of thinking dramatically more important than the mitochondrial genome.

It seems to me that in this discussion we’ve missed a hugely important factor that may tip the balance in the other direction.

All nuclear genes are present in only two copies per somatic cell and only one copy per gamete such as an egg. For a fertilized egg there are two copies.

mitochondrial DNAIn contrast, there can be thousands of separate mitochondria in every single somatic cell and every single mitochondrion has an entire genome.

If we start looking at the relevant cells for 3-person IVF things get even more super-charged for mitochondria.

In fact, human eggs have the most mitochondria of any known type of cell with the number estimated at 100,000-600,000 per cell. I’ve seen other estimates around 500,000.

That means in one human egg there are let’s say 500,000 mitochondrial genomes and that same number of copies of all the mitochondrial genes and other genomic elements such as non-coding RNAs.

This means that in any one given fertilized egg there are 2 copies of any nuclear gene, but that same cell might have 500,000 copies of any given mitochondrial gene.

What this means is that the potential impact of any one given mitochondrial gene is amplified in a fertilized egg by having 500,000 copies relative to the only 2 copies of nuclear genes. Further, this also means that the potential impact of 3-person IVF technology (where the entire cytoplasm and all mitochondria are changed via nuclear, spindle, or polar body transfer) must be multiplied perhaps by 250,000 relative to a change in a single nuclear gene in a fertilized egg.

So for example to those who say that the mitochondrial genome “only” has 37 protein coding genes versus the perhaps 25,000 human genes in the nucleus, you should at least take into account that all those nuclear genes are only present at 2 measly copies per zygote whereas there might be 500,000 copies of any given mitochondrial gene in that same single cell. That’s a 250,000-fold difference.

That’s a very big number and confers a potentially equally huge impact on how 3-person IVF could work out in terms of risks.

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