Malaria is a mosquito-borne disease caused by the parasitic organism called Plasmodium, of which there are several types that cause the different kinds of malarial fever. This age-old infection still kills over 400,000 people every year, all over the world.
A new study published in the journal Cell on November 14, 2019, shows how a simple tweaking of the genes of this organism could quite conceivably lead to the elimination of this disease altogether.
Plasmodium has about 5,000 genes, compared to the 25,000 or so that are present in human DNA. However, it has a haploid genome. In other words, its genetic material is composed of only one copy of each gene. In humans, the DNA contains two copies of all genes, as well as promoter and enhancer regions that are essential to switching them on and regulating their activity. Thus in humans, all chromosomal matter is present in duplicate, one from each of the parents. Thus humans have a diploid genome.
The researchers specifically removed over 1,300 individual genes in the malaria parasite Plasmodium (in red, host cells in green) and were thus able to identify many new targets in the pathogen. Image Credit: Institut für Zellbiologie, Universität Bern
The current study exploits the haploid nature of the Plasmodium genome. By changing one gene, the external expression of the organism changes because there is no compensating ‘extra’ gene to recreate the missing genetic component. Any change in the genotype of the organism is therefore mirrored by a change in the phenotype. They carried out a whole-genome gene deletion study on the parasite, removing 1300 genes in a stupendous one-by-one effort.
With the deletion of each gene, they observed how the organism changed in each of its multiple forms over its complex life cycle. This helped them to find a number of new targets to prevent malaria. Researcher Rebecca Stanway says, “The deletion screen carried out jointly with the Sanger Institute enabled us to identify hundreds of targets, particularly in the parasite's metabolism.”
The malarial parasite was allowed to infect mice for this experiment, carried out at the Institute of Cell Biology at the University of Bern, where Volke Heussler and his team have been studying the liver stage of the parasite for years in the hope of contributing towards vaccine development. Each gene was deleted in turn, to be replaced by a bit of genetic code. This helped the researchers understand how the loss of that gene affected the parasite. By using a standard genetic code for insertion in place of the deleted genes, the researchers were able to study a number of parasites at the same time, cutting down on the total duration of the study.
The Bern team later collaborated with two other research laboratories, that of Vassily Hatzimanikatis of the EPFL in Lausanne and of Dominique Soldati-Favreof the University of Geneva, to complete a systematic analysis of the whole set of genes that they had identified as being crucial to parasite metabolism. This “MalaX” consortium, as it has been dubbed, used the genomic screening information to produce models that depict the vital metabolic processes occurring within the parasite. Modeling expert Anush Chiappino-Pepe reports that these models now make it possible to predict the best targets to attack to control the parasite, in terms of which are most essential for the parasite.
The Bern team has already experimentally verified some of these predictions, working with the Chris Janse group at the Dutch University of Leiden. The researchers say, “The genome-wide screen with the corresponding metabolic models represents a breakthrough in malaria research. Our results will support many malaria researchers worldwide. They can now concentrate on essential parasite genes and thus develop efficient drugs and vaccines against various stages of the parasite’s life.
The whole experiment involved 22 researchers, and took three years, but has now yielded a complete picture of how each gene works through all the stages of the lifecycle of Plasmodium. Heussler says, “This illustrates the effort in conducting the study, analyzing the data and model the experimental findings to bring them in a meaningful context.”
He attributes the successful outcome to the close collaboration and sharing of resources that happened, between the genetic sequencing and cloning technology at the Sanger Institute, the advanced facilities at Bern, where the whole of the Plasmodium life cycle is established. Microscopy is a very important part of this work, and is responsible for the many published works on early Plasmodium infection.
Genome-Scale Identification of Essential Metabolic Processes for Targeting the Plasmodium Liver Stage Stanway, Rebecca R. et al. Cell, Volume 179, Issue 5, 1112 - 1128.e26, https://www.cell.com/cell/fulltext/S0092-8674(19)31180-8