Combating malaria: The genomic wayApril 9, 2019
New methods of treatment and prevention have emerged to treat malaria from the growing field of genetics. The first of these methods involves targeting the Plasmodium genome. By conducting genome-wide analyses, researchers have been able to identify core genes of the malarial parasite that offer targets for new drugs. One of the most important of these studies – and possibly indicative of the future course of the disease treatment – was conducted at the University of Melbourne. The researchers used genetic analysis and basic biology to discover what could be an instrumental chink in malaria’s armour of mutability.
Atovaquone is an anti-malarial drug that was not under use for fear of the development and spread of resistance. However, the study showed that although malaria parasites can develop resistance to atovaquone, but they cannot spread it. The mutation that makes it possible to resist atovaquone also render it impossible for the parasite to survive the subsequent step of its life cycle – entering a mosquito. And since malaria cannot be transferred from one person to another, the atovaquone-resistant parasite cannot spread. This illuminates a new strategy for managing drug resistance. The mutation pathway that results in this genetic quandary can be targeted by drug developers while creating new drugs.
Researchers at the Wellcome Sanger Institute and the University of South Florida used a new, specialized technique – piggyBac-transposon insertional mutagenesis – to inactivate random Plasmodium falciparum genes and incorporated a newly developed sequencing tool to identify the relative importance of each gene in terms of survival. They found that around fifty percent (over 2,600 out of 5,400) of the genes were essential for its growth and propagation in erythrocytes – a list of 2,600 targets for drug developers. In addition, approximately 1,000 of those 2,600 targets are common to all Plasmodium species, and although their exact functions are currently unknown, their status as integral genes make them potential targets for anti-malarial drugs. Many of these genes were also found to be involved in a proteasome pathway that is responsible for degrading proteins in the cell, which is thought to be linked to artemisinin resistance. Thus, drugs targeting these genes would be extremely effective as ‘partner’ drugs, working in tandem with artemisinin.
Extinction by gene drive?
The second of these new methods involves targeting the Anopheles genome. In a recent study, genetic engineers used CRISPR/Cas9 to render a population of Anopheles gambiae mosquitos – Africa’s primary malaria-spreading mosquito species – incapable of producing offspring within twelve generations. Based on the results of further trials using this tool, it could be the first to be able to eliminate an entire species of disease-carrying mosquitos. The tool used to create such a groundbreaking effect was a gene drive. These use the CRISPR/Cas9 ‘scissor’ enzyme to insert themselves into an organism’s genome at specific loci. This gene drive in particular exploits a recessive Anopheles gene called doublesex. If a female mosquito inherits two copies of the broken doublesex gene, it develops like a male, which are incapable of biting – and therefore infecting – humans. Any mosquito that inherits only one copy of the exploited gene will develop normally. The gene drive was designed to circumvent the natural laws of inheritance. Normally, if a parent carries two different alleles of a gene, the offspring will have a 50% chance of inheriting either one. However, with the doublesex gene drive, more than 95% of the offspring inherited the exploited gene, allowing it to spread through the population much faster. Once all the members of a generation carried two copies of the gene drive – which took between 8 and 12 generations in the study – none of the mosquitos were capable of laying eggs or biting, forcing the population to die out without biting other organisms. The gene drive creates the prospect of causing the extinction of malaria-carrying species, which could eventually result in the extinction of malaria itself.