RESEARCH

Plasmo GEM – The Plasmodium Genetic Modification platform.

The genomes of malaria parasites are difficult to study because the DNA of the major species has an unusual base composition and is therefore hard to modify experimentally. The Plasmo GEM project was started to overcome these problems (). We made a resource of gene targeting vectors designed to disrupt most P. berghei genes very effectively (). Each vector has a molecular barcode that allows us to analyse mixtures of mutants simultaneously. We will continue to grow the P. berghei resource at the Sanger Institute, but we have also pointed the platform at Plasmodium species infecting humans. The barcoded Plasmo GEM vectors are at the heart of our ability to carry out genetic screens in P. berghei.

The evolution of sexual reproduction.

Malaria parasites must reproduce sexually to infect mosquitoes. Studying the underlying molecular processes is important to find ways of blocking disease transmission. Due to its position in the tree of life, we have also been able to use P. berghei to reveal some of most conserved molecular mechanism involved in fertilisation (). Genetic screens will now reveal components of the axoneme in the male gamete, help us understand better how gametes fuse and identify the conserved core machinery involved in meiosis.

Mechanisms of lineage differentiation in a parasite.

Surprisingly little is known about the molecular mechanisms that control the complex Plasmodium life cycle. Transcriptional regulation is important, and we are therefore interested in a small family of plant-like transcription factors in P. berghei (). In close collaborators with the Waters lab https://www.gla.ac.uk/researchinstitutes/iii/staff/andywaters/ , we recently identified one of them as master regulator of commitment to sexual reproduction (). A genetic screen is now leading us to other nucleic acid binding proteins that interact to bring about the male and female transmission forms. Through genetics screens we can, for the first time, hope to gain a nearly comprehensive understanding of the genes that contribute to parasite development and transmission.

Single cell biology of malaria

With the advent of single cell transcriptomics, it has become possible to identify cell states and cell types that were previously unrecognised because they could not be isolated or were of very low abundance. We find that single cell transcriptomics opens up new avenues to study parasite differentiation, immune responses () and mosquito tissues. We are also planning to develop single cell approaches that will provide a scalable method to phenotype parasite mutants in a very deep and meaningful manner.