A new weapon to fight Malaria

08 May 2018

Interview with

Julian Rayner, Wellcome Sanger Institute

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Anopheles mosquito

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A new weapon in the fight against Malaria. The disease, which kills over half a million people every year, is caused by a parasite transmitted by mosquitoes. The parasite is becoming resistant to our current treatments so scientists are in a race against time to come up with new ones. New research from the Wellcome Sanger institute may help, as they’ve identified which genes inside its DNA are vital to its growth, meaning we can design drugs more effectively. Katie Haylor heard more from author Julian Rayner.

Julian - There is currently a treatment for malaria, but one of the central problems with malaria is that the parasites rapidly develop drug resistance. The current frontline treatment, which is a drug called artemisinin, is currently failing in some areas of southeast Asia because the parasites have developed resistance to that drug. So there’s always a need to develop new drugs to replace the drugs that we lose.

Katie - This brings us on to your recent work. What did you set out to do?

Julian - Well, we set out to try and understand gene function in the most deadly human malaria parasite, plasmodium falciparum. What we tried to do is, essentially, mutate every gene in the parasite genome and see which ones were essential for the parasite to live and grow inside red blood cells, and which ones the parasites could do without, were redundant.

Katie - How did you separate these genes?

Julian - We used an approach called Transposon Mutagenesis. What that means is that we inserted a small fragment of DNA, called a Transposon, at random throughout the genome of the parasite and then developed and used a system to try and identify where those insertions had occured. Over a long time; this took many months, we generated more than 30,000 different insertions randomly throughout the genome and then we identified where those insertions were.  And what we saw is that some genes had several insertions; the transposon had gone in multiple times in different parasites, whereas some genes had no insertions whatsoever.

What that tells us is that the genes that had the transposon insertions, those insertions essentially disrupt that gene and made it non-functional and the parasite could still grow, so those must be genes that are redundant, whereas the other genes we never saw any insertions. Even though we counted more than 30,000 insertions, we never saw an insertion in a significant number of genes. Those are genes that the parasite must need to grow and multiply inside the red blood cell.

Katie - Oh, I see. And it’s those essential genes that would make sense to target then?

Julian - Absolutely. If you wanted to develop a drug against the malaria parasite, you need to target a gene that the parasite needs to grow. And this was the first time, in the human parasite - plasmodium falciparum - that we were able to essentially generate a full list of all of the genes that are essential for the malaria parasite to live. What we’ve done is, essentially, created a shorter list of genes that drug development can be targeted against, hopefully saving time, hopefully saving money, and also hopefully saving lives.

Katie - Would you be able to clarify where these potential targets would come into the life cycle of this condition, as it were?

Julian - The malaria parasite life cycle is quite complex. It gets passed between mosquitoes and humans and back again. Within us, it first affects our liver, and then comes out of our liver into our red blood cells. All the symptoms and all the pathology of the disease happen when the malaria parasite’s inside our red blood cells; that’s what makes us sick. And that’s also where almost all drugs work, they kill the parasite’s when they’re in the red blood cells and that’s why they cure you.

The stage of the parasite that we were working on was the red blood cells stage. We were growing the parasites in our lab, feeding them red blood cells, and mutating them with this approach to try and find essential genes. So this gene list that we’ve developed says which genes are important for the red blood cell stage. There are very interesting next steps to then take the same approach and apply it to other stages, because there are various reasons why you might want to target the malaria parasite either in the liver or even, in some cases, in the mosquito to try and block transmission from one person to another. There aren’t good drugs that do that at the moment, and we’re excited by the opportunity to take our approach and apply it to these other stages of the life cycle.

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