At the start of this month, a statistical analysis published in _The Lancet _claimed that deaths due to malaria worldwide are almost twice as high as was thought – 1.24 million in 2010 rather than 655,000, as estimated by the World Health Organisation (WHO). While there is controversy over the study’s methodology, its implications for the international malaria eradication drive are troubling – the WHO also estimated that 216 million people became ill with malaria in 2010. Fortunately, these are not the only large numbers associated with the disease: annually, US$2 billion is contributed for malaria control measures, and over US$600m for research and development to fight it. Progress is being made, and funnily enough, it tends to involve much smaller things. Two recent advances have illustrated how the tiniest things can make the greatest difference.

Around 50 antimalarial drugs are in development right now. The pace is high because researchers are trying to find replacements for artemisinin, the principle malaria treatment worldwide, before it is rendered useless by spreading resistance. In January, an American group at Washington University in Missouri solved the structure of an enzyme, a protein which catalyses a reaction, that is needed by every parasitic cell to grow. It provides an example of how exploiting the subtle differences between our cells and malaria parasites may allow us to cure the disease.

Plasmodium, the microbe that causes malaria, is a protozoan and therefore part of a separate kingdom of life to animals and plants. However, its biochemistry shares some peculiar features with plants due to an ancient evolutionary event in which it took on an alga as an “endosymbiont”, a permanent resident of its cells, similarly to the way in which plant cells acquired their photosynthetic chloroplasts. The relic of this alga, known as the apicoplast, performs certain chemical reactions for the parasite very unlike those done by our cells.

Cell membranes are made of molecules called phospholipids such as phosphatidylcholine, which the parasite must synthesise to grow and divide. It does this in the apicoplast via a plant-like chemical pathway subtly different from our own, which includes a step that never happens in our cells. The Washington group’s protein is responsible for this reaction. The team has worked out its exact structure and is trying to explain its activity at the atomic level. If someone can use this information to develop a drug that blocks it, malaria parasites could be killed with no harm to patients – the most difficult challenge to overcome in development of new treatments.

Drugs are essential to cure people infected with malaria, but eradication is a fantasy unless a vaccine to prevent infection is developed. A vaccine called RTS,S has shown promise, as reported in Felix on November 4 last year. However, RTS,S is not very effective compared to other vaccines and its protection may not last long. It will save the lives of many children under five, who suffer over 80% of deaths from malaria, but better vaccines will be needed to stop the disease spreading entirely.

In December, a team based at Oxford University demonstrated a new vaccine target in rabbits. They exploited a weakness in the parasite’s infective strategy revealed only in November by a group at the Sanger Institute in Cambridge. Malaria parasites multiply by invading and parasitising red blood cells (RBCs), and until recently it was thought that they used such numerous ways of gaining entry that no one method was used by every strain. The Sanger group tested several strains and discovered that every one needed a particular RBC protein to get its foot in the door, a protein called basigin.

Basigin’s exact function remains unknown, and scientists originally recognised it only as the determinant of a rare blood group, Ok-, found in a handful of Japanese families. Nonetheless, a parasite protein called PfRh5 binds to basigin and is somehow crucial for invasion. The Oxford group produced a vaccine by incorporating PfRh5 into a virus and used it on rabbits, who developed immunity. The antibodies in their blood prevented all parasite strains from infecting blood cells.

This leap forward was unexpected. Malaria is a successful disease precisely because it works so hard to avoid being recognised by our adaptive immune system. PfEMP1 protein, the main protein to which we do become immune, comes in 60 different versions so that the parasite can repeatedly change between them before the body can eliminate it. People who live where malaria is common become infected many times during their lives, never developing full immunity, because Plasmodium is so adept at evading our defences.

However, in rabbits, a vaccine granted immunity to PfRh5, of which there is only one copy. Why? PfRh5 seems to have escaped natural selection for variation because the immune system does not normally ‘see’ it. The reason why remains unknown, though it may be because it is only released by the parasite at the moment of invasion, straight into the unlucky RBC. This is important because it may mean that all Plasmodium strains rely wholly on PfRh5 to infect our blood. By ‘showing’ it to the immune system with a vaccination, protection far greater than that from RTS,S could be achieved – perhaps enough to thwart malaria for good.