Bio Eats World

Journal Club: Turning a Toxin into a Genome Editing Tool

Episode Summary

with @JorgeCondeBio, @andy23tran, and @lr_bio In this episode of Journal Club we discuss the development of the first genome editing enzyme capable of performing precision edits to the mitochondrial genome. Mutations in the mitochondrial genome cause over 150 different human diseases, but none of our existing gene editing tools have been able to edit this DNA. This newly developed tool can be used to create better models of these diseases and and perhaps one day be used to treat them with gene therapy.

Episode Notes

Over the past 15 years we have made huge advances in our ability to engineer the genome, meaning that we now have the ability to edit DNA in a programmable and precise manner. In the lab, these editing tools allow us to create models of disease and to investigate how changes in the genome lead to changes in cell and organismal biology. And excitingly, these genome editing technologies are now entering clinical trials to treat, and possibly cure, diseases like sickle cell anemia. But there is a component of the human genome which even the much lauded and powerful CRISPR system has not been able to touch: the mitochondrial DNA. 

The mitochondria are the powerhouses of the cell and contain their own, much smaller, genomes which encode several essential proteins and RNAs. Mutations in the mitochondrial genome are the cause of over 150 diseases, but to date, fixing these mutations with gene editing and gene therapy has been off the table due to the inaccessibility of this genome. 

In this episode of Journal Club, a16z general partner Jorge Conde and bio deal team partner, Andy Tran – experts in genomics and genome engineering – join Lauren Richardson to discuss groundbreaking research creating the first genome editor able to target the mitochondrial DNA: "A bacterial cytidine deaminase toxin enables CRISPR-free mitochondrial base editing" by Beverly Y. Mok Marcos H. de Moraes, Jun Zeng, Dustin E. Bosch, Anna V. Kotrys, Aditya Raguram, FoSheng Hsu, Matthew C. Radey, S. Brook Peterson, Vamsi K. Mootha, Joseph D. Mougous & David R. Liu, published in Nature. 

We discuss what makes the mitochondrial genome distinct, how this new tool – which was derived from a bacterial toxin – was engineered for both safety and specificity, and the important applications for this new editor.