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Malaria Parasite Genome Study Reveals Potential Drug Targets

NEW YORK (GenomeWeb) Researchers at the Wellcome Trust Sanger Institute and collaborators have used a molecular barcoding and sequencing method to conduct a functional screen of more than half of the malaria parasite's genome and uncover a slew of new genetic markers for antimalarial drug development.

Examining more than 2,500 genes of one malaria-causing parasite, scientists found that its success is due to stripping its genome down to crucial genes. This important discovery is expected to help in the production of antimalarial drug treatments.

"The parasite is fine-tuned and retains the absolute essential genes needed for growth," Julian Rayner, joint lead author at the Sanger Institute, said in a statement.

In the first ever large-scale study of malaria gene function, published this week in Cell, scientists examined the expression of genes in Plasmodium berghei in a single blood stage of the parasite's complex, multi-stage life cycle in mice. To do this, they developed a new method in which they switched off, or knocked out, 2,578 genes — more than half the parasite's genome — and assigned each knocked out gene a unique DNA barcode. Researchers used the Plasmodium genetic modification community resource PlasmoGEM, which contains knockout vectors that integrate efficiently and carry gene-specific molecular barcodes —work that the Sanger Institute researchers and others described in a previous paper in Cell Host & Microbe. The method allows scientists to track individual mutant genes and measure the parasite's growth by counting the number of barcodes via a benchtop sequencer.

The researchers used the method to measure the growth of each genetically modified malaria parasite. If the switched-off gene was not crucial, the numbers of parasites skyrocketed, but if the knockout gene was crucial to growth, the parasite disappeared.

The team methodically demonstrated that malaria can quickly discard genes that produce proteins that mark its presence to the host's immune system. This adaptive ability poses problems for scientists attempting to develop a consistent malaria vaccine, since Plasmodium rapidly alters its genetic appearance to the human immune system, leading to a resistance to the current vaccine.

The genetics of Plasmodium also presents a challenge to decode because half of its genes lack homologs to any other modern day organism.

"[The parasite] can easily get rid of the genes behind the targets we are trying to design vaccines for, but the flip side is there are many more essential gene targets for new drugs than we previously thought," said Rayner.   

"This work was made possible by a new method that enabled us to investigate more than 2,500 genes in a single study — more than the entire research community has studied over the past two decades" Oliver Billker, joint lead author at the Sanger Institute, said in a statement. "We believe that this method can be used to build a deep understanding of many unknown aspects of malaria biology, and radically speed up our understanding of gene function and prioritization of drug targets."

Nearly half of the world's population is at risk of malaria. In 2015, there were an estimated 210 million malaria cases and almost half a million malaria deaths. Young children, pregnant women, and non-immune travellers from malaria-free areas are particularly vulnerable to the disease.

Francisco Gamo, director of the Malaria Unit at GlaxoSmithkline, said in a statement that "The Holy Grail would be to discover genes that are essential across all of the parasite life cycle stages, and if we could target those with drugs, it would leave malaria with nowhere to hide."

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