Question: How do you remove the genes from parasite genomes, and how does that help you find cures for malaria?

Sophie Adjalley answered on 9 Jul 2020: last edited 9 Jul 2020 12:35 pm

Hi Sasha, that is a great question!
Removing genes from parasite genomes is quite a laborious process. It involves sending pieces of DNA to the parasite’s nucleus, and this process alone is quite inefficient in the malaria parasite. These pieces of DNA are designed so that they are sufficiently similar to the parasite’s genome to be recognized by its DNA repair machinery and contain fragments that are adjacent to the region of the genome one wants to remove, but they do not contain that region itself.
It used to be that we would wait for DNA breakages to happen at the precise region we wanted to modify and although they happen fairly often, including when the cell makes more copies of its DNA, it could take some time before obtaining the modified genome! The parasite’s DNA repair machinery would use the piece of DNA we provide to make the repair and if the design worked, the damaged genomic region would be repaired, but would miss the part that was not provided on the piece of DNA. We now use CRISPR to trigger these DNA breaks, which allows to specifically target the regions of the genome we are interested in, instead of hoping for the DNA breaks to happen near or at the gene we want to remove. Thus, the entire process happens much faster! Note that the same strategy is used to introduce or remove mutations. Instead of providing a piece of DNA that misses a bit, we provide a piece of DNA that contains the modification(s) we want to make to the genome. Finally, the whole approach allows us to study how mutating or removing a gene affects the parasite’s growth. If that gene has a very important function, which is impacted when the gene is removed or modified, the parasite may not survive. We are especially interested in these essential genes, as if we find drugs that prevent these genes from functioning, we might have found a way to inactivate/kill the parasites!