Sock! Pow! Blam!

Further adventures in the fight against malaria, as the Gates Foundations seeks to stomp it out permanently. Two dozen new grants limn an ominous foe pitted against vivid human imagination.
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Mosquito, the malaria-carrying menace

Further adventures in the fight against malaria, as the Gates Foundations seeks to stomp it out permanently. Two dozen new grants limn an ominous foe pitted against vivid human imagination.

Today'ꀙs arsenal for combating malaria is almost retro: bed nets, DDT, and drugs largely based on a fourth century Chinese anti-malarial. We lack a vaccine. Malaria parasites and mosquitoes have learned to sidestep the bombardment of insecticides and drugs, developing resistance through deft genetic twists.

With its Grand Challenges Explorations research program, the Gates Foundation seeks adventurous, even absurd-seeming ideas for subduing some of the world'ꀙs most severe health problems. The first Exploration grants announced last October emphasized HIV/AIDS. In the second round, which backed 81 projects, malaria came to the fore with a portfolio of 23 grants. The pages of these unusually imaginative proposals present a real-life comic book of plots to kill, maim, reengineer, immunize, or simply distract the much-maligned mosquito. The malaria parasite, a.k.a Plasmodium, likewise meets a multiplicity of dooms.

In our impromptu graphic novel, the assault begins by targeting mosquito senses. First, Guirong Wang of Vanderbilt University blasts the heat sensors of a swarm of attacking mosquitoes with an infrared jammer. In the next frame, concerned and sweating bugs are greeted by Anandasankar Ray of University of California-Riverside. He whips the cover off a vat labeled 'ꀜLong-Range Olfactory Repellents,'ꀝ blocking mosquito carbon dioxide detection — allowing humans to sigh in relief. The proboscis-disabling coup de grace is delivered by Thomas Baker and colleagues at Penn State University whose inveiglings with a fungus gives mosquitoes a hopeless head cold.

There follows a gauntlet of decoys, traps, and even insecticide-laced paint. Still, a beleaguered mosquito somehow gets through to take a bite. 'ꀜYuck!'ꀝ reads its balloon text: Paul Breslin of the Monell Chemical Sense Center has made humans taste bad! Beckoning from the next frame, Jefferson Vaughan of the University of North Dakota gestures towards a nice juicy cow. But it'ꀙs a zooprophylactic trick. Only as little black Xs are drawn over their eyes do the mosquitoes realize: this cow has been rigged with mosquitocidal immunity! Last, under a small red cross at a Johns Hopkins mosquito aid station, Marcelo Jacobs-Lorena endeavors to immunize mosquitoes against malaria using genetically engineered bacteria.

So much for the mosquito. Maybe.

In the next picture, a malaria drug factory, puffing smoke, wears an expression of concern and worry on its face. Even though the factory chuffs away with all its heart, it knows it'ꀙs not making new drugs fast enough. The malaria parasite has learned genetic dodges to evade two different drugs that used to have smart missile lethality. And resistance to the latest drug is on the rise. As a result, researchers in Thailand are rewiring the guidance system of one of the drugs that lost its effectiveness so that it also hits the mechanism of resistance, bringing a crucial antimalarial defense back online.

With the antimalaria drug Primaquine, we face the opposite problem: it'ꀙs too deadly. Primaquine'ꀙs blast zone consumes the malaria parasite but also does substantial damage to humans. Molecular monkey wrench in hand, researchers are disassembling the overachieving compound. Uncoupled, Primaquine'ꀙs two parts will hopefully still go off on malaria parasites but leave humans unscathed.

The body'ꀙs own defenses muster an array of lethal antimicrobial proteins. Doron Greenbaum at the University of Pennsylvania hopes to enhance the best of these, replicating and delivering them in vast numbers as an antimalarial drug — a clone army in a pill.

However, outright preemption of malaria by vaccination would be ideal. One scheme affixes a sort of homing beacon to partially disabled malaria parasites. Inside the body, the immune system swarms to these beacons, taking out the practice targets and learning to defend against the real foe. Another vaccine effort takes a high-resolution look at how a malaria parasite actual forces its way into human red blood cells, obviously with the idea finding ways to stop it.

But if infection can'ꀙt be forestalled, it might be possible to smother the resulting harm. Malaria produces a many-lettered and toxic substance called glycosylphosphatidylinositol. Inducing antibodies to this toxin might make malaria less severe, much as 'ꀜvaccines'ꀝ for tetanus and diphtheria do.

In an intuition-defying leap, a Swiss team has proposed inducing antibodies to malaria drugs. Antibodies are jugglers, catching suspicious molecules but releasing them perhaps a few minutes later to be caught by other antibodies. Why not use this act to keep an antimalarial drug suspended in the bloodsteam for longer? The size of a dose or its frequency could be reduced, saving money and making it easier to comply with a full treatment regimen.

Many malaria treatments are given presumptively. For example, if a child living in sub-Saharan Africa has a fever, health care providers automatically break out the anti-malarials. It'ꀙs a very good guess, unfortunately, but one forced by the absence of inexpensive and accurate diagnostic technology. This also contributes to uncertainty in estimates of malaria cases which range from 189 million to 327 million cases worldwide.

Nothing a tricorder couldn'ꀙt fix — and such a Star Trek-like device might be on the way, one that uses magneto-optics to detect crystal byproducts of malaria. Just hold it by a person'ꀙs body and it (hopefully) tells you if the patient has malaria. No needles, no blood sample. Whizzier still, however, and possibly more practical, might be a urine dipstick, now also under investigation.

Traditional government agencies (insert your favorite caricature), would be unlikely to fund such outlandishness. Thus, with the fate of humanity on the line, the burden of saving the day falls to the Gates Foundation. On the last page of our graphic novel, a new global hall of justice (the foundation'ꀙs headquarters) is under construction, rising with silhouetted Space Needle in the background.

Will the powerful imaginings of the Explorations leap from the page into the real world? Can the Gates Foundation lead an international campaign to vanquish an ancient malarial foe? The stakes — life or death, disease or health for hundreds of millions — burst the confines of rational comprehension. It'ꀙs the absurdo-realist stuff of comic books.

Stay tuned for the next episode.


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