David Baker, LSHTM
Kat - Malaria kills hundreds of thousands of people every year worldwide, and the parasites that cause the disease are rapidly evolving resistance to all the treatments that we can throw at them. By studying the molecules that cause certain forms of malaria - known as gametocytes - to change shape, David Baker, from the London School of Hygiene and Tropical Medicine, may have found an unusual new approach for anti-malarial drugs - and it comes in the form of a well-known little blue pill.
David - In humans, the problems caused by malaria, all the symptoms and pathology are caused by quickly replicating farms and they invade red blood cells. As they grow over 48 hours, they rupture and burst out up to 20 or 30 new malaria parasites which invade red cells. So, you can imagine as those parasites expand, you become anaemic and thatís often associated with severe malaria. So, those are one type of malarial parasite.
For reasons we donít understand very well, some of those malaria parasites when they invade red blood cells, turn into sexual forms Ė male and female gametocytes, we call them. We call them that because they're the precursors of gametes. Because when they get into the mosquito, the male and female fertilise to continue the cycle. So, those gametocytes, they donít divide in the human and they simply mature over about 2 weeks.
These sexual forms, these male and female malaria parasites, they get quite large and crescent-shaped and normally, if a red blood cell, it comes misshapen like that, it would be filtered out by our spleen in our body, aiming to hide in the body, stop being cleared by the immune system in the spleen. They do that when they're very young. They go into the bone marrow and hide.
Itís only when their mature that they become flexible and they enter the circulation. Once they're flexible, they're safe from the spleen because they can squeeze through the capillaries in the spleen and circulate throughout the body. So, when the mosquito takes a blood meal, it will take up some of these gametocytes so that the gametes can fertilise inside the mosquito and continue the cycle.
And so, what we want to understand was exactly how it becomes flexible. So, we focused on a particular signalling molecule called cyclic AMP. We wanted to ask the question, does cyclic AMP make these sexual cells, these males and females become flexible to allow them to circulate in the bloodstream.
Kat - So, how did you go about investigating that? How does a molecule - cyclic AMP Ė how does that change the shape of these parasite cells?
David - Thatís a very good question and really, itís a next step for us to understand the mechanism how it happened. The first step was just to ask whether it happened or not. So, we used two ways, in the lab, to find out whether increased levels of cyclic AMP made these sexual cells become flexible. So, one approach we took in my lab, we knocked out a gene encoding an enzyme called a phosphodiesterase in the malaria parasite. Normally, phosphodiesterase enzymes degrade this cyclic AMP signal. So, when we deleted the gene, the levels of cyclic AMP went up as we wouldíve predicted. So lo and behold, when we knocked out this gene, the gametocytes became less flexible.
Kat - So normally, low levels of cyclic AMP is keeping them bendy and when it rises up, they become stiff and rigid.
David - Thatís right. I mean, that was the problem. When we raised the cyclic AMP levels due to knocking out that gene, instead of becoming bendy, they became stiff essentially. And the other way we raised the cyclic AMP levels was to use small molecule inhibitors of phosphodiesterases. So, we used several and one of the ones we used was Viagra. Now, thatís quite a well-known inhibitor phosphodiesterase thatís used to treat male erectile dysfunction. And so here, we had a situation where increasing cyclic AMP levels with Viagra, we could make these sexual cells. Malaria parasites become stiff as well. In a human, if that happened, if those mature gametocytes became stiff, it will be filtered by the spleen and inactivated, and you wouldnít get any transmission.
Kat - I was there a little bit sniggering in the lab when you realised that that what was going on.
David - Yeah, absolutely. Iíll always want to mention weíre working with Viagra in the lab for people sort of have the odd snigger, so absolutely. Katherine came up with a good headline that it made gametocytes stiff, so yes.
Kat - That was David Baker, from the London School of Hygiene and Tropical Medicine.