Science Primer – Winning the War on Malaria.

Malaria is a disease that is caused by protozoans of the genus Plasmodium. The most common species seen causing this disease are Plasmodium falciparum and Plasmodium vivax.. If you look at the WHO Executive Summary on the subject of Malaria, which you may duly find here you will see that there were around 225 million cases worldwide reported in 2009 with 900,000 odd deaths from it in 2009.

Now these numbers are staggering and indicate a severe healthcare problem. Current approaches involve the use of insecticide treated mosquito nets and drugs like quinine and combinations of artemisinin with other drugs, but drug resistance is a problem with malaria. It would make great sense to look for ways that subvert the ability of Plasmodium spp to evade drugs and also to find low-intervention, high-impact ways of dealing with the transmission, which occurs through mosquitoes.

In this primer, I would like to introduce you to two landmark studies which offer strategies that may prove immensely useful and effective in the war on malaria.

Malaria Life Cycle - An explanation for laymen. Courtesy Metrohealth.org.

[1] Inhibiting PAK-MEK Signalling in Erythrocytes Kills the Parasite.

Now Plasmodium spp (species) are intracellular (inside cells) parasites, and this often implies that there will be molecular interactions between the cells of the host and the cells of the parasite, and in some cases this opens up targets for therapy on the host side of things.

I wish to introduce a paper here, which should make for illuminating reading, titled “Activation of a PAK-MEK signalling pathway in malaria parasite-infected erythrocytes, Sicard et al, Cellular Microbiology, doi:10.1111/j.1462-5822.2011.01582.x” which you may duly access here

The authors of the work report certain things that are of importance in the fight against malaria. They report that there is a group of three enzymes that comprises the core of the signalling pathway they investigated, MAPK (aka ERK) , MAPKK (aka MEK) and MAPKKK (aka MEKK), all upstream of MAPK/ERK.

That is, if you took the core module, it would work like this

MEKK activates MEK activates MAPK.

MEK can also be activated in the absence of MEKK, by an enzyme called PAK, which gives us two potential links in the chain to knock out. The particularly interesting thing to come out of the study is that they managed to identify that these pathways are stimulated by P.falciparum infection of erythrocytes (or RBCs) and that there are no clear orthologues (malarial genes that do the same thing as the human genes mentioned above) in the P.falciparum genome. They also tested if this attribute was evolutionarily conserved in other members of the genus by analysing the genome of a species of Plasmodium that infects mice. This was done to see if P.falciparum inherited orthologues from its ancestors and then lost it or if the genus never had it in the first place. They found that the latter was true.

So we now have a target in the cell that malarial parasites need to use but don’t have a usable version of those targets themselves, it is like a person who cannot breathe needing a ventilator, take away the ventilator and the person is a goner.
In this study, the authors investigated if they could take away the signalling pathway safely to kill the parasite.

They treated cell cultures that were infected with P.falciparum with drugs that block the signalling pathway, and found that this halts the growth and development of the parasite in RBCs, and since this is a critical step in the life cycle of the parasite it cannot develop further, thus stopping the infection in its tracks. Inhibitors that work to block these pathways allosterically (that is, by modifying kinases upstream in the signalling pathway) were found to kill these parasites while being in concentrations that didn’t harm cells.

There are several drugs in development and use for cancer that work by inhibiting the same signalling pathways, the study suggests that a repurposing of those drugs to treat malaria could be a very effective strategy. They also found that it can disrupt other stages of development of the malarial parasite, both in the case of P.falciparum and in the case of the rodent-infecting-species (P.berghei)

I hope you read the paper to know more about the hows, whys and whats of the study. I will now move on to the next part of the article.

[2] Transgenic mosquitoes that are resistant to malaria can be engineered to take over populations.

Current approaches that involve a focus on killing mosquitoes (especially Anopheles spp) aim to work by preventing transmission of the parasite from human to mosquito and vice versa, thus stopping it from spreading in the population and infecting people.

I now wish to introduce you to advances that take this approach further with great effect.

Now originally the problem was that if you inserted a copy of a gene that imparted resistance to malaria in male mosquitoes, it would be difficult to expect it to take over the population unless there was a strong selective pressure acting on those mosquitoes. To get round this, scientists have developed something called a homing endonuclease that carries a modified mosquito gene. The endonuclease cuts the DNA of the mosquito at a certain location and the mosquito, when it repairs the break, will use the modified version of the gene that has been put in to patch it up, and this modified gene then gets into all sperm of modified mosquitoes instead of about 50% with the traditional approach.

They carried out a caged study on an experimental population and found that genetic modification was easily able to spread through it, which opens the door to any approach that may seek to modify mosquito populations such that they are not amenable to spreading malaria using small amounts of transgenic mosquitoes to introduce desired traits into the population.

For a popular science account of this, please see the BBC News article here. For a detailed scientific treatment of the homing endonuclease research in question, please see this paper from Nature (which unfortunately is stuck behind a paywall)

I have however been able to locate a copy on the web that is available for access from the University of Washington, you may duly find that paper here
which looks like a cracking read (don’t take my word for it, read it yourself :P)

So we now have potential methods that can kill the parasite in case of infection and can prevent infection in the first place by using genetic engineering in combination with knowledge of inheritance. We could be very much on the verge of a breakthrough, science could soon be saving millions of lives. I also wish to make a mention of the very cool technology that enables malaria to be diagnosed with the help of a cellphone at this juncture, which you may read about here

Cellscope - The device that may change the way diseases are diagnosed in rural areas.

That is all from me on this science primer, see you soon with one more.

– Ankur “Exploreable” Chakravarthy