Science cannot be accused of neglecting malaria as a subject for research. The disease is not only a huge public health problem but also a formidable intellectual challenge because of its biological complexity – and scientists love such a challenge.
After decades of intensive research, we are still far from understanding the extraordinary life cycle of the plasmodium parasites that cause malaria – the many different stages through which the microscopic protozoa pass, as they alternate between human and mosquito hosts.
However, genomics has given a boost to scientists studying the basic biology of malaria. In 2002 researchers published the entire DNA sequences both of plasmodium falciparum, the parasite that causes the most severe disease, and of anopheles gambiae, the main mosquito carrier of malaria.
With the human genome also published, scientists have “a triad of critical genetic information relevant to all stages of the malaria transmission cycle,” as an editorial in the journal Science put it.
The genomic data has inspired a wave of malaria drug discovery, with researchers focusing on biochemical pathways that are vital for plasmodium but are absent in human beings – raising the prospect of medicines that might kill the parasite without causing side-effects in patients.
Intensive screening programmes are under way at academic and industry laboratories, to look for drugs that block key steps in plasmodium biochemistry.
The latest recruits are Adam and Eve, “robot scientists” at Aberystwyth University in Wales; they combine laboratory robotics with artificial intelligence, which gives them the ability to plan and carry out experiments. Adam gained publicity this month when his creators published a paper in Science, claiming Adam as the first machine in history to have discovered new scientific knowledge on its own. The robot formed a hypothesis on the genetics of bakers’ yeast and carried out experiments to test its predictions.
Ross King, the (human) project leader at Aberystwyth, says a new robot called Eve is now ready to start working with Adam. Their first task will be to find new anti-malarial drugs, he says: “The idea is to put plasmodium genes into yeast and use that as a screening target.”
Scientists are also working on better ways to produce existing drugs, particularly artemisinin, the most effective medicine. Artemisinin is in short supply because the only source is the Chinese medicinal plant Artemisia annua (sweet wormwood).
At York University in the UK, the Centre for Novel Agricultural Products is applying rapid breeding technology (but not genetic modification) to produce varieties of Artemisia that contain higher concentrations of artemisinin.
A more ambitious project has been under way for five years at the University of California, Berkeley, with $42m funding from the Gates Foundation.
Jay Keasling, the research leader, is using “synthetic biology” – re-engineering a micro-organism by changing several genes and biological pathways at the same time – to make artemisinin from yeast in a microbial fermenter.
Prof Keasling hopes to be ready to mass-produce artemisinin in partnership with Sanofi-Aventis, the French pharmaceutical company, next year. The aim is to have plentiful and inexpensive supplies of artemisinin that can be used in combination with other drugs – plasmodium can develop resistance to artemisinin used on its own. The project is being led and managed by OneWorld Health, a US-based non-profit pharmaceutical company.
Another group of projects targets the mosquitoes that spread malaria. The latest results come from Andrew Read and colleagues at Penn State University, who have designed an “evolution-proof” insecticide that kills only mosquitoes more than about 12 days old.
The problem with controlling mosquitoes by spraying ordinary insecticides is that the insects quickly evolve resistance to them. Restricting the effects to older mosquitoes would still prevent the transmission of malaria, because the parasites need a couple of weeks to grow inside the insects and migrate to the salivary glands where they can infect people who are bitten. Older mosquitoes will already have bred, so there will be little selection pressure to evolve resistance – unlike with a general-acting insecticide such as DDT.
The Penn State team is developing a late-acting biopesticide, based on a fungus that takes 10 to 12 days to kill the insects. “We could spray it on to walls or on to treated materials such as bed nets, from where the mosquito would get infected by fungal spores.” Prof Read says. Field trials are planned in Africa.
Another recent finding comes from Johns Hopkins University, where researchers are trying to boost the mosquito’s immune system so that it can kill plasmodium parasites before they develop inside the insect and pass malaria to people. “In the lab we activated this immune response [through genetic modification] in advance of infection, giving the mosquito a head start in defeating the invading parasite,” says George Dimopolous, the project leader.
The genetically modified mosquitoes seem to match their wild counterparts in survival and egg-laying fitness.
But public resistance to the prospect of releasing GM mosquitoes into the wild may pose more of a problem. Such opposition has already emerged to another proposal to control a mosquito-borne tropical disease through GM insects. Oxitec, an insect biotechnology company spun out of Oxford University, plans to fight dengue fever by releasing sterile male GM mosquitoes. These would mate with all females – which would fail to produce offspring.
But some residents are objecting to the first open field trial of sterile mosquitoes planned for Malaysia.
Scientific merit may not be the only factor controlling the approaches that will make an impact on malaria.
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