Malaria: Resurgence of a Deadly Disease

Malaria kills roughly twice as many people worldwide as AIDS, drugs no longer work against some strains, and mosquitoes in diverse parts of the United States now carry the disease.
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But Humphreys argues convincingly that this victory was not so much a triumph as a happy accident. She reminds us that the digging of ditches was a WPA make-work project, not a systematic effort to clean up malaria-ridden swamps, and quotes a malariologist who wrote at the time that "too often in the past, drainage ditches have been dug up hill, so to speak, by workers with no knowledge of engineering practices. Likewise, ditchdigging specialists have drained areas of little or no importance in malaria control." In the United States malaria had retreated from all but a few locales by 1942, the year the Public Health Service launched its anti-malaria campaign. Even in swampy New Orleans a malaria case that turned up in the early 1940s was rare enough to attract a crowd of curious medical students. Humphreys holds that the abrupt decline of malaria in the late 1930s came as a consequence not of ditchdigging and spraying but of the migration of vast numbers of people away from the swamps to the cities.

"It was prosperity, not massive public-health efforts, that caused the decline of malaria in the United States," Humphreys says. "That's something that's not terribly easy to duplicate in the developing world. History tells us that we can't generalize at all from the American experience. The truth is, we still don't know how to control malaria."

For the most part infectious-disease experts have come to agree that what seemed to work in the United States half a century ago will not work in the Third World today. In the tropics mosquitoes breed not just in swamps and ponds but everywhere -- in upturned soda bottles, discarded automobile tires, and animal footprints. Even if African nations had the money to drain swamps, doing so would not be enough. Large-scale spraying for mosquitoes is equally impractical in most areas, and even small-scale spraying is problematic. "Rachel Carson's legacy is not entirely positive," says Robert Gwadz, a malaria researcher at the NIH. "DDT is one of the more benign pesticides known." It is certainly among the cheapest. But it is banned or heavily restricted in most African nations, as in the United States, and the alternatives, pyrethroid insecticides, are expensive.

Even if insecticides were magically made available free to all, they would probably fail to solve the global malaria problem. The same chemicals that are used in small amounts to combat malaria are used in large amounts to keep bugs away from crops, a practice encouraged by the demands of agribusiness. Resistance to insecticides is growing rapidly, because insects have tremendous exposure to the chemicals and hence ample opportunity to develop protective tactics.

MALARIA FIGHTS BACK

EQUALLY troubling is the ability of the malaria parasite to develop resistance to drugs. Malaria has for centuries been a treatable disease. Quinine, an anti-malaria compound that is extracted from the bark of the South American cinchona tree, is one of the oldest effective pharmaceuticals in existence. Amazon Indians introduced Jesuit missionaries to the miraculous properties of the substance, and the Jesuits brought it home to Europe in the seventeenth century -- thereby, legend has it, saving the lives of many a malaria-stricken cardinal, and perhaps even a Pope or two. This so-called "Jesuit powder" is still useful in the treatment of acute falciparum malaria. But it is expensive and short-acting, has side effects ranging from dizziness to deafness, and fails to prevent relapses. Chloroquine, developed during the Second World War, killed malaria parasites and had none of the drawbacks of quinine, but resistance to it has spread throughout the world. A relatively new drug, mefloquine, a synthetic analogue of quinine, is expensive and is losing its effectiveness in many regions. U.S. doctors prescribe these drugs and others to prevent and treat malaria of various kinds.

Qinghaosu, a drug made from Artemisia annua, a cousin of wormwood which grows wild in fields and thickets across China, and a favorite of natural healers the world over, is showing the strain of overuse as well. Practitioners of traditional Chinese medicine have used qinghaosu to treat fevers for something like 2,000 years, though whether in its natural form it actually kills the malaria parasite is unclear. Like quinine, qinghaosu fails to prevent relapses of the disease, and may be neurotoxic. Gary Posner, who is the Scowe Professor of Chemistry at Johns Hopkins University, and his co-workers have synthesized a simplified version of the substance that Posner thinks may overcome these problems, but he has yet to find a drug company willing to develop it. "We have been contacted by several biotechnology companies," Posner says, "but the first question they ask is, 'Have you got a product yet?' Of course we don't. Taking this compound from the lab to the market would take from six to ten years and cost several hundred million dollars. You can't do it in a university laboratory."

Linda Nolan, a biochemist at the University of Massachusett s at Amherst, who has studied anti-parasitic plants in South America and elsewhere, argues that once a parasite has developed resistance to a drug, it is a fairly short step from there to resisting the entire class to which the drug belongs. This is why, she believes, chloroquine, mefloquine, and other drugs closely related to quinine are sinking fast. "What is needed is an entirely new class of drugs," she says. "You have to look everywhere -- in the sea, in the soil. You don't know until you look where you might find something that works." Richard Levins, the John Rock Professor of Population Science at the Harvard School of Public Health, agrees that we would do well to look to plants for insights into how to develop permanent resistance to pathogens. Plants use a spectrum of strategies to deal with predators, he says, and they never presume they have a problem licked. But scientists are also looking for ways to overcome drug resistance that don't involve lengthy trial-and-error procedures with wild plants.

A few years ago the Harvard researcher Dyann Wirth identified a protein on the membrane of the malaria parasite which helps to explain why the parasite develops resistance so quickly. The protein works like a nightclub bouncer, hustling undesirable anti-malaria drugs away from the interior of the cell. This mechanism, sometimes described as a protein "pump," is also found on the surface of cancer cells that do not respond to chemotherapy. In the case of malaria, the pump has a terrifying aspect, in that it allows the parasite to resist drugs it has never before encountered. Any drug that remotely resembles a drug the parasite "knows" to be unfriendly is, as one scientist put it, "spit out rather than sucked in."

"Unless you can reverse this pump mechanism, you are going to encounter resistance pretty consistently," Wirth says. "Right now we're trying to find a way around it." But some human cells contain similar pump mechanisms that fulfill such critical functions as preventing material in the bloodstream from going directly into the brain. What is needed, Wirth says, is a drug that works only on the malaria-parasite pump. "To find this we'd have to screen hundreds of thousands of compounds, and that requires the cooperation of a major drug company," she says. "Unfortunately, no major drug company in the world is involved in the research to develop new anti-malarials."

The dearth of new anti-malaria drugs has recently taken on a particularly urgent significance. The Thai-Cambodian border region harbors a variety of malaria that responds to no known drug. This densely forested territory has in the past decade or so been invaded by gem miners in search of rubies and emeralds, soldiers, and Cambodian refugees fleeing the Khmer Rouge. Virtually all these people come down with malaria, regardless of the precautions they take, and get very sick. Many of the refugees do not have access to medical care; some get well, and some die. But the miners try drug after drug, in an attempt to stay on their feet long enough to make their fortune before going home. This has encouraged the parasites to develop resistance, and this multi-drug-resistant malaria has spread from the border deep into Thailand and Cambodia, and as far as India, Bangladesh, and Nepal.

"Thailand has been the site where drug resistance gets its start," Dyann Wirth says. "In regions of high transmission there is resistance to all of the registered anti-malaria drugs except Artemisia, which has been recently introduced. There is evidence of multiple-resistant parasites in these regions."

Brazil is another cradle of drug resistance. Unlike Thailand, which has long been losing the battle against malaria, Brazil had greatly reduced incidence of the disease in the 1960s. But malaria returned in the 1980s, in a strain that is highly drug-resistant. Wirth told me of a town in the Amazon forest where the risk of getting malaria over the course of a year is virtually 100 percent. Gold miners here dig holes in the ground, pump them full of water, concentrate whatever gold they find with mercury, and sift through the resulting sludge. The mercury is terribly dangerous -- and so are the mosquitoes that breed in the muddy water. The Brazilian government is eager to develop this area, and offers land as a lure. Most takers come from coastal regions, and have never before been exposed to jungle malaria strains. Like the miners in Thailand, they get deathly ill. Their only recourse is mefloquine, but that may be simply a temporary solution. Mefloquine resistance was quick to develop in Thailand, and Wirth and her colleagues are grimly curious to see whether it develops just as quickly under similar conditions in Brazil.

At the conference in Dakar scientists exuded what I was told was an unusual level of optimism that the control of malaria, though not imminent, was at least possible. This hopefulness was inspired by the announcement of several new drug strategies and, more to the point, the development of a new anti-malaria vaccine. It is not the first vaccine to have been attempted; given the mercurial nature of the malaria parasite and the ubiquity of the mosquito that carries it, a vaccine is now widely considered the only realistic hope for gaining control of the disease. In a report titled "Vaccines Against Malaria: Hope in a Gathering Storm," published last year, a committee from the Institute of Medicine, a research organization chartered by the National Academy of Sciences, wrote, "Widespread application of a vaccine that can prevent the illness and death of malaria could be one of the most important advances in medicine, with the potential for improving the lives of hundreds of millions of people." It has not gone unnoticed by scientists that discovery of such a vaccine is the stuff of which Nobel Prizes are made, and competition in the field is fierce.

In the late 1980s Manuel Elkin Patarroyo, a flamboyant and charismatic Colombian immunologist, garnered headlines when he announced that he had developed a malaria vaccine, SPf66, that in a trial had protected monkeys and, to a lesser degree, Colombian soldiers from infection. A second trial in Colombia proved equally promising, and Patarroyo became a folk hero in South America, Asia, Africa, and even Europe, which showered him with praise and awards. But more recent field tests in Gambia and Thailand were disappointing. In Gambia the vaccine offered almost no protection, and in Thailand subjects given the vaccine seemed to have a slightly higher risk of contracting malaria than subjects given a control. Patarroyo, who donated the license for SPf66 to the WHO in 1995, remains adamant that his vaccine is effective. Howard Engers, the manager of the steering committee on vaccines for malaria at the WHO, told me that the agency is reserving judgment until the results of yet another trial, in Tanzania, are complete. He cautioned that the WHO is not sponsoring the Tanzanian trial, implying that it may be less reliable than earlier tests, but then hastened -- a bit nervously, I thought -- to pay his respects to Patarroyo. "Irrespective of the final outcome of SPf66," Engers said, "or of Dr. Patarroyo's apparently promising second-generation vaccines, it is clear that he and his collaborators have had a major impact on the malaria-vaccine-development field over the past ten years or so."

Not all scientists are impressed. At the meeting in Dakar several grumbled that what they saw as Patarroyo's grandstanding had in fact set the field back, by encouraging the erroneous idea that malaria had been cured. "After his announcement, the field crashed, because many governments assumed that the problem had been solved," says Carole Long, a malaria specialist in the Department of Microbiology and Immunology at Allegheny University of Health Sciences. Others hinted that WHO support of Patarroyo was due as much to intimidation as to the agency's faith in his science. Several mentioned Patarroyo's habit of accusing his detractors of being jealous racists resentful of a Third World upstart rising above his station.

"Patarroyo is a very talented, unique individual, but he's under very strong pressure and he tends to personalize things," says W. Ripley Ballou, the acting director of the Division of Communicable Diseases at the Walter Reed Army Institute of Research, who was involved in the test of SPf66 in Thailand. "Here's a guy on his own, with no FDA, no drug company, working out of an attic of an aging building, and he comes up with a vaccine that seems to protect thirty percent of people who get it. So then he builds a beautiful facility, puts a huge amount of money into a detailed characterization of his product, and puts it out there for others to test. And it turns out that in two really good trials SPf66 simply does not work. The devil is in the details."

Ballou has devoted the better part of his career to mucking around in the details of malaria-vaccine development. In January, The New England Journal of Medicine announced results from a vaccine trial that he and his group at Walter Reed designed in conjunction with scientists from the pharmaceutical company SmithKline Beecham. Volunteers were paid $600 to be injected with either the vaccine or a control, feasted on by malaria-carrying mosquitoes, and observed in a nearby hotel, where after seven days' incubation their blood was checked daily for parasites. Seven volunteers got the active vaccine, and the blood of only one contained malaria parasites -- evidence enough, Ballou says, to warrant a field test of the vaccine in Gambia. It got under way this past March.

But not even Ballou believes that the vaccine will prevent all children from getting malaria in Gambia, a densely forested sliver of West Africa floating in mangrove swamps and saline marshes. Gambia is where SPf66 and a long line of other vaccine candidates have met their Waterloo. The SmithKline vaccine was designed to counter a particular strain of malaria, not the mishmash of strains that occur in the wild. And it's not at all certain that the vaccine will stand up to repeated challenges: the volunteers at Walter Reed were infected once, but children in Gambia are infected up to three or four times a night. "This is an enormous human and scientific challenge," Ballou says. "Of course I hope it works, but I will be very happy if it fails and we understand why. This problem is really bigger than ourselves." Traditional vaccinology has depended almost entirely on making better antigens, on boosting the body's natural immune response. But in malaria the human immune response is incomplete and jagged.

"We've protected hundreds of thousands of mice against malaria, but we haven't learned to transfer that model to humans," Dyann Wirth says. "This may be a system where animal models don't teach us what's important for human disease." Richard Levins, of Harvard, says that by focusing on vaccines we are taking too narrow an approach. "Pathogens evolve; they learn how to hide in the central nervous system to avoid attack by vaccines. They change their surface chemistry regularly so that the vaccine cannot recognize them. And vaccines work only if they are used consistently. If the system breaks down, if there is a war or social unrest, vaccine programs fall apart."

Lamine Diawara also advocates a more nuanced approach, one that would contain malaria region by region, until it retreats into the background of everyday life in the tropics. "Malaria is our environment; it is part of what we are," he says. "To control it we must take care not to disturb the equilibrium, to respect the local ecology and customs, to work with human behavior as well as with science." Diawara believes that education would do much to stem the tide of the disease -- as would public-health measures such as the drainage of standing water and the judicious use of insecticides and drugs.

Pedro Alonso, a physician and an epidemiologist at the University of Barcelona, who oversaw the first SPf66 trials in Africa, explained to me how malaria was wiped out in Spain with just such a low-key approach. The Spanish Civil War, in 1936-1939, somehow prompted a resurgence of malaria in his country, and it hung on stubbornly into the 1950s. Pesticides were tried and they helped, but not enough. The Spanish stood back and reassessed the situation -- why this resurgence of malaria after war? What had been disrupted? They couldn't be sure what, but something had increased the mosquito population. The trick was to reverse the process. They stocked their ponds and lakes with gambusia, a fish that eats mosquito larvae. "Now Spain has an enormous number of gambusia," Alonso said, laughing, "but almost no malaria."

China's Hunan province, too, has beaten back malaria: its caseload fell from nearly a million in 1985 to 68,500 in 1993. No new drugs or vaccines were used; rather, a mixture of strategies was employed. Swamps were selectively drained, and malaria cases were quickly treated with both traditional and Western medicines.

But in the West early success in controlling infectious disease has bred arrogance and a belief in whopping big solutions -- vaccines and antibiotics that wipe out rather than contain. We know successful pathogens to be highly evolved and clever creatures, but we bluster about, attacking them as though they were the dumb, plodding aggressors that perhaps we ourselves are. When a microbe mutates around our onslaught, we go off in search of a bigger weapon with which to blast it. But like all re-emerging diseases, malaria has managed not only to dodge the bullets but also to turn the revolver back on us. Our attacks have made the parasite not weaker and less certain but more virulent. Controlling this disease requires vigilance, patience, and, to a certain degree, sacrifice -- there are places we might have to avoid. There are tradeoffs to be made, but so far we've shown ourselves reluctant to make them. Scientists pursue their quest for an effective vaccine or a more powerful drug while treasure hunters of another kind in Thailand and Brazil help the disease find a new foothold. Whether the scientific adventures will eventually pay off is uncertain, but for now there's no question that a price is being paid. Malaria, an ancient disease, a controllable disease, is spreading.

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Ellen Ruppel Shell is a professor and science journalist who teaches at Boston University. She is the author most recently of Cheap: The High Cost of Discount Culture. More

Atlantic contributing editor Ellen Ruppel Shell teaches at Boston University, where she co-directs the Graduate Program in Science Journalism. She writes on science, medicine, the media, economics, and sometimes even sports and the arts, and tends to focus on the underlying cultural and societal implications. She is the author most recently of Cheap: The High Cost of Discount Culture.
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