Domino theory is back in Southeast Asia. If newly drug-tolerant malaria triumphs in that region, it will spread inexorably, subverting all of Asia before wheeling south to engulf Africa. A world-wide eradication program began in 2007 — an epic undertaking that might require half a century to achieve. Now, malaria threatens to knock out today'ês first line of defense, artemisinin, leaving only already-defeated drugs or ones easily overrun by resistance. The loss of artemisinin, according to malaria researcher Arjen Dondorp, 'êwould cause millions of deaths, without exaggeration.'ê
A bite from an infected mosquito transmits just a few dozen malaria parasites but, unchecked, these pollute the bloodstream with trillions of progeny. Such overwhelming infections kill about a million people each year, mostly children. Perhaps another 300 million people — the population of the United States — suffer malaria'ês debilitating fevers and other agonies. Artemisinin, especially paired with a second drug, cures malaria with marvelous efficiency.
A proxy war is set to unfold which will likely determine whether artemisinin stands or falls — and possibly global malaria eradication efforts along with it. It'ês a movie we'êve seen before, twice. Earlier mutations reduced the once potent drugs chloroquine and then sulphadoxine'êpyrimethamine to mere molecular bystanders of malaria'ês ill frolic. Both times, the drug-resistant strains originated in western Cambodia before diffusing worldwide.
Today resistance radiates from Pailin in western Cambodia, near the Thai border. An effort orchestrated by the World Health Organization will descend on resistance hot spots in the region, cut them off, and attempt to systematically eliminate the resistant parasites they harbor. The containment strategy will encompass an area the size of Indiana, the largest such intervention of the current eradication campaign. An international eradication effort last century faltered and failed, in large part because of an enormous resistance push-back.
Do we get to win this time? The battleground appears to favor the parasite. Bed nets and spraying DDT inside homes are highly effective control measures against malaria-bearing mosquitoes, but not in this theater. Unlike in much of Africa, mosquitoes here hunt and bite before sundown. The happy coincidence of the circadian rhythms of humans and a protection measure (bed nets) is broken.
In any event, much of the vulnerable population sleeps outside. Many are young men in the timber and gem trade, primordial capitalists not always eager for contact with governing authority. They are spread thinly all over and move often as if to directly thwart public health efforts. There are broad patterns of movement, but these too are ominous: perhaps 200,000 migrants circulate from Cambodia to Thailand, an annual pulse almost certain to carry any resistant parasites to the rest of the world.
While not given to superstition, scientists have accorded almost mystical powers to a malaria strain native to Southeast Asia. The organism seems possessed of a general mechanism for performing the complicated genetic evasions necessary to shrug off pure poison — a suspicion that now appears justified. Recent lab experiments show that it takes a thousand times fewer parasites to develop resistance than would be required by blind, random mutation. 'êSpooky,'ê says University of Washington scientist Pradip Rathod, who has been probing the underpinnings of malaria drug resistance for more than a decade. When resistance arises, he says, 'êit'ês not because the parasite is hacking itself to death.'ê Rather they seem to know what they'êre doing, conceivably because they'êve done it before and can do it again.
An effective strike against resistance must somehow penetrate from the multilateral heights of the World Health Organization (WHO), through numerous yet critical intermediate institutions, down to the ground and a local administration still tinged by the Khmer Rouge. That will be hard. Victory, if won, will come less on the wings of science and more from elbow grease and execution, organized people grinding out a slew of different measures.
There is currently no vaccine for malaria. Instead, we'êre castling the king of antimalarial drugs, artemisinin, deploying a therapy known as Malarone. Malarone is effective but brittle: just a single mutation of the malaria parasite can break it, short work for the world'ês 250 quadrillion malaria parasites. At least three African countries already have strains resistant to Malarone, just out of sheer genetic diversity. Malarone hasn'êt even been used in those nations yet.
New first line drugs are not on the horizon. The drug 'êpipeline'ê is more like a brutal, class 6 whitewater: about 93 percent of candidate compounds don'êt come out the other end. The successful transit of a single malaria drug costs about $420 million. As well, the best antimalarial drugs originated from natural sources: chloroquine from the bark of the cinchona tree and artemisinin from wormwood. Compounds engineered de novo are expected 'êby the dozen,'ê according to Rathod, but these will likely come with lesser durability in the face of resistance, like Malarone.
Compounds fabricated by human hands are comparatively crude and robotic, usually having a single target. Natural molecules perform a more complicated pharmacokinetic dance, which an admiring Rathod calls 'êbeautiful.'ê And rare: Humans have unearthed just these two sources, both centuries ago. Perhaps we have missed something since, but so far systematic searches for other natural products have been unavailing. Neither has evolution, toiling for millennia, discovered a solution that fully protects humans against malaria.
With funding from the Gates Foundation, this generation'ês best and brightest are working to save artemisinin. They must succeed if there'ês to be any possibility of rolling back malaria. Artemisinin must be saved, or there will be millions of deaths, without exaggeration.
Also riding on the outcome is the hope of making health a new ordering principle of international politics. Global credibility is once again at stake in Southeast Asia. If malaria eradication fails, governments won'êt believe in — or fund — global health crusades. It would be the worst of the 1960s, repeated.
