Post by Charlotte Koster

Recently, there was some exciting science news from the UK: Eight healthy babies were born through a 'three-person IVF'. Their mothers all carried mutations in the mitochondrial DNA, which could lead to severe diseases in their children. By combining the mother's DNA (from the nucleus) with the healthy mitochondria of a donor, a healthy egg cell was made. This cell could then be fertilized by IVF. Out of 22 embryo's fertilized in this way - 8 resulted in pregnancies and completely healthy babies! Why am I so excited about this? I spent my PhD trying to develop genetic engineering methods for mitochondria, based on CRISPR-Cas. CRISPR-Cas is an incredibly powerful technique for gene therapy, to cure diseases caused by DNA mutations. Successful studies already cured people from sickle-cell anaemia and angioedema. However, we just can't get the technique working efficiently for lethal and disruptive mitochondrial diseases. Why? Parts of the CRISPR-Cas system, just won't go inside the mitochondria. They just won't. Or it seems like they do, but then they don't. Or do they? Either way - we can't cure sick mitochondria yet without fully replacing them. We just published one of the chapters from my PhD thesis on BioRxiv. We aimed for a breakthrough, but we ended up with a long list of confounding results. We illustrate the struggle that comes with mitochondrial engineering, show that mitochondria do not always follow the rules of molecular biology and highlight a lot of gaps in our knowledge on mitochondrial biology. We show the current methodological limitations we have to properly study what is going on in the mitochondria, and came up with an innovative laboratory evolution technique to improve this. Mitochondrial biology is elusive, confusing and exciting, and I hope this story inspires others to publish their confounding results as well, because together, they may lead to the breakthrough! Until then, I'm happy that three-person IVF can help in combating severe mitochondrial diseases, it buys us genetic engineers a lot of time 🔥 This study was conducted together with Pascale Daran-Lapujade at TU Delft | Applied Sciences. A big chunk of this work was done by Kavish Kohabir, and experiments were also performed by Marijke Luttik, Erik de Hulster, Maxime den Ridder and Martin Pabst. Read it here: https://lnkd.in/erg83BAx