That was the year malaria returned to the flatlands of South Africa after an absence of 50 years. The disease came roaring back after the government stopped spraying with the pesticide DDT in favor of more environmentally friendly–and less effective–chemicals. By 2000, the number of malaria cases had swelled to 64,000 in South Africa alone. “In 2000, we handled more than 30,000 cases,” says Hervey Vaughan-Williams, a doctor at Mosvold Hospital. “I used to see 100 patients a day.” The situation got so bad that in February 2000 South Africa’s KwaZulu-Natal province switched back to DDT, despite its detrimental effects on wildlife. Other parts of southern Africa followed later. At the time, provincial health-department spokesman Dave McGlew explained: “Given the deteriorating malaria situation and the growing threat to human life, we had very little choice but to opt for the most effective way of combating the disease.”
Such is the fragile standoff between humans and the malaria parasite. For more than a century, medical science has looked for a way to break the cycle of infection, and it has yet to find one that’s workable–at least in places like Africa and Latin America. Inexpensive drugs like Fansidar and chloroquine grow less effective with overuse. Some drug cocktails have recently shown better results, but they’re too expensive for many. Efforts to come up with a vaccine have failed, and no killer pesticide more salubrious than DDT is on the horizon.
Part of the problem is that scientists have known too little about the biology of both the parasite and the mosquito that carries it to attack them effectively. Last week scientists from dozens of medical centers in the United States, Europe and elsewhere announced in the journals Nature and Science that they had taken a big step toward filling that knowledge gap. They succeeded in cracking not only the genetic code of the most common and deadliest malaria parasite, Plasmodium falciparum, but also that of Anopheles gambiae, the mosquito that carries it.
The feat itself adds nothing to the arsenal of weapons against malaria, but it holds promise for developing new ones down the road. “The genome paper really lays out a road map of the parasite’s metabolism,” says Dyann Wirth, a biologist at Harvard who wasn’t part of the consortium. “To say we now know how the parasite works and everything it needs to do to stay alive would be overdoing it. But we can now begin to make predictions that will help in developing new drugs and vaccines. It opens up enormous possibilities.” The key question is: how long will these cures remain mere possibilities? Malaria has proven over the years to be a formidable opponent. Chances are, the bug may yet confound its pursuers.
Malaria is not just another human disease. It is, in many ways, the human disease. Plasmodium falciparum is not adapted to horses or cows or birds or any other creature. Except, of course, for Anopheles gambiae, whose blood-sucking habits make it an ideal conduit to the human circulatory system. Once in the bloodstream, the parasite makes its way in a matter of minutes to the liver, where it hides from the body’s immune system and replicates. Only when it has multiplied prodigiously do the parasites launch themselves like storm troopers out of the liver and back into the bloodstream. They commandeer red blood cells too quickly for the immune system to stop them. And once inside the cells, the parasites change form constantly, tricking the immune system into passing them by.
The first draft of the parasite’s genome has only deepened scientists’ awe of this creature that evolution designed so perfectly for piercing the human body’s defenses. Of its 5,300 genes, 60 percent look like nothing scientists have seen before. “That the organism devotes more than half of its genes to things we don’t understand is both terrifying and exciting,” says Wirth. “There are things going on in this organism that we haven’t even thought about.” Says Malcolm Gardner, a researcher at the Institute for Genomic Research and leader of the team that sequenced the parasite genome: “It turns out we didn’t know as much as we thought we did.”
The new genomic data, and an analysis of the proteins these genes produce, are already giving scientists grist for developing new drugs. The object is to identify a biochemical “pathway” in the parasite that doesn’t exist in the human host, and then match it with a molecule that interrupts this pathway. That would yield a drug that stops the bug in its tracks but carries no side effects for the patient. Scientists think they’ve identified half a dozen pathways unique to the malaria parasite that constitute potential targets for new drugs.
Several such targets are located in one of the parasite’s organelles–the apicoplast–that contains genes otherwise found only in plants. Apparently, long ago the parasite’s evolutionary predecessor absorbed these genes from a species of plant. Although it lost many of them over the years–for instance, it no longer carries genes for photosynthesis–others came to be indispensable to the parasite’s metabolism. Now that scientists know about them, and know that humans don’t possess them, all that’s left is identifying molecules that negate these genes, disabling the apicoplast and killing the parasite. Scientists are especially keen to attack the parasite while it’s still in the liver, before symptoms are acute. They’ve identified several proteins associated with the liver stage and, if they can find a drug that neutralizes them, they may have a valuable new treatment.
Another strategy is to do a better job of attacking the mosquito that transmits the disease. Like the parasite, the malaria mosquito is exquisitely engineered for biting humans. Scientists found 19 “odorant receptors” in the mosquito’s genome that make the insect finely attuned to human scent: all 19 receptors are unique to the Anopheles gambiae. “These mosquitos have an exclusive preference for biting humans,” says Robert Holt, a molecular biologist at Celera Genomics and leader of the team that decoded the mosquito genome. He is now plumbing the bug’s genome for clues to how the mosquito develops resistance to pesticides by comparing its genes to those of other organisms who’ve developed resistance to the same pesticides. Holt thinks a new malaria-mosquito pesticide may emerge within five years.
A more sci-fi solution for disarming the malaria mosquito is to replace it with a test-tube version genetically engineered so that it cannot transmit Plasmodium falciparum to the people it bites. Researchers at Case Western Reserve in Cleveland, Ohio, successfully inserted a gene into a species of mosquito closely related to Anopheles gambiae, which caused it to produce a peptide that blocked transmission of a rodent version of the malaria parasite to laboratory mice. A problem with this approach is that the consequences of releasing a genetically modified insect into the wild would be difficult to foresee. For this reason, many experts are skeptical. Even if the scheme worked, the added gene might become “unstuck” in future generations of mosquitos, causing malaria to return with a vengeance.
As scientists delve deeper into the metabolic mysteries of the malaria parasite and mosquito, they’ll be taking the war against these formidable foes up a notch or two. To what degree the pests will rise to the occasion remains to be seen. “The malaria parasite is a complex pathogen. It is transmitted so often by so many different strains, and is constantly evolving as it goes from human host to mosquito vectors,” says Altaf Lao, a vaccine expert at the Centers for Disease Control in Atlanta, Georgia. “Some of the malaria genes are as complex as the whole genome of many viruses,” explains Alto. DDT, after all, is a fearsome chemical–it’s deadly to many creatures in trace amounts–and yet Anopheles gambiae has withstood decades of spraying, and has evolved resistant strains.
Malaria also has hubris and complacency working in its favor. In Latin America, malaria control was drastically scaled back in the early 1970s, even though people were still getting sick. The disease made a prompt comeback. In Brazil, infection rates rose throughout the 1970s and spiked in 1989 at 570,000 cases, and again in 1999 at 632,000. The mosquito outsmarted door-to-door spraying brigades by avoiding DDT applied to indoor walls and ceilings and instead biting workers in the fields. The infection rate eased only after Brazil began handing out insecticide-soaked bed netting to people in high-risk areas and establishing numerous local health clinics.
Will the pharmaceutical industry rush to develop all the potential wonder drugs scientists are so excited about? Not likely: there’s little money in it. Economist Jeffrey Sachs at Columbia University estimates that effectively controlling malaria worldwide would cost $2 billion a year–but only one tenth that sum is actually spent. Recently, funds have flowed a bit more freely into malaria research from governments and private foundations. The Walter Reed Hospital and drugmaker GlaxoSmithKline are working on a new, more powerful malaria drug, and perhaps 20 laboratory trials for vaccines are currently underway worldwide. But it’s not nearly enough. “Funding has gone from paltry to double paltry,” says David Alnwick, program director of the World Health Organization’s Roll Back Malaria Initiative.
Don’t hold your breath for science to solve these problems. At best, most of the fruits of malaria sequencing won’t come for decades, says Louis Miller, a researcher at the National Institute of Allergy and Infectious Diseases. “The most optimistic is 10 to 15 years for a really effective vaccine,” he says. “But that’s great. Malaria’s been out there for eons. It’s awful for the kids that are dying from it now, but at least the next generation will be protected.” Let’s give the scientists who labored for six years on the malaria-genome project their moment of glory. Then it’s time for the hard part: turning those brilliant insights into solutions that will help the likes of Nomthandazo Ngwenya.
