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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Waking up to Malaria

DEPENDING on one's perspective, the struggle to gain dominion over malaria can be seen either as a primer of the possible in infectious-disease control or as classic tragedy. All but obliterated in the developed world half a century ago, and suppressed in the Third World in the 1950s and 1960s, malaria has since returned in full force to North Africa, India, Southeast Asia, China, South America, and the Caribbean. Worldwide incidence of the disease has quadrupled in the past five years, and resistance to available drugs for prevention and treatment is growing rapidly. Nearly 40 percent of the world's population lives in regions where malaria is endemic, and millions more live in areas that are encountering the disease for the first time in decades. Europe has had outbreaks, and in the United States 1,000 to 1,200 cases annually have been reported in recent years. But the Centers for Disease Control and Prevention estimates that cases reported in the United States represent only about half the actual incidence. Every year approximately seven million American tourists and business people spend time in regions where malaria is endemic, as do military personnel and foreign visitors to the United States, and it is likely that thousands arrive here with malaria parasites in their bodies. As a consequence, locally transmitted malaria, absent from the United States for roughly thirty years, has returned. Since 1988 locally transmitted malaria has appeared in California, Texas, Michigan, Florida, New Jersey, and New York City. Anopheles mosquitoes -- members of the genus that carries malaria parasites -- are common almost everywhere in the United States and, for that matter, in most populated regions of the world.

Nonetheless, the United States has shown little interest in the problem. Malaria is transferable in blood, yet it is not screened for in the American blood supply. The country's Anopheles mosquito population has gone unmonitored for more than fifty years. "We just don't know the potential for transmission," says John Beier, a professor of tropical medicine at Tulane University. Temperature and humidity may well be among the most important factors in the rate of spread of the disease, yet we have only a vague notion of what effect, if any, climate change will have on malaria transmission -- if, for example, global warming can be expected to bring malaria and other mosquito-borne diseases north from Mexico. Most Americans seem to think the disease has been eradicated or, at worst, is confined to the tropics. In fact there are few places on earth that cannot sustain a malaria epidemic.

Dyann Wirth, a professor of tropical medicine at the Harvard School of Public Health, insists that Americans must stop thinking of malaria as purely a Third World disorder. "The official CDC line is that widespread malaria in the United States is unlikely," she told me recently. "But we could have mini-epidemics, established pockets of disease that would be very expensive to control." Vector-borne diseases -- diseases that are transmitted by way of a third organism, such as the mosquito -- have a much higher reproductive rate than other diseases and pass through a population much more quickly. "Each case of AIDS," Wirth says, "passes along, on average, two to ten additional cases of AIDS. A case of malaria can result in as many as a hundred more cases of malaria. So the multiplier effect is quite substantial." And in this era of tight government budgets there is ample reason to worry that erosion of our public-health infrastructure and the denial of affordable health care to recent immigrants and the poor will encourage the spread of malaria in the United States.

Last year Vice President Albert Gore told an audience at the National Council for International Health that emerging infectious disease was "one of the most significant health and security challenges facing the global community," and announced a policy on infectious-disease control that directed the United States to "work with other nations and international organizations to establish a global infectious-disease surveillance-and-response system." But his statement did not mention funding, and the war on emerging disease it proposes is well beyond the current means of any government research or health agency.

Although the U.S. government is the world's single largest supporter of malaria research, we spend relatively little on the problem -- roughly $40 million annually, most of it administered by the Department of Defense, the U.S. Agency for International Development, and the National Institute of Allergy and Infectious Disease. The Defense Department seeks to protect the U.S. military from acquiring malaria abroad, and focuses on short-term efforts to benefit soldiers. USAID is controversial among scientists, who complain that the agency has spread itself too thin, hiring consultants who, as one infectious-disease expert put it, "know a lot about economics but not a damn thing about disease." Since USAID funding takes into account particular strategic and political interests of the United States, malaria in Africa is for the most part not a priority. And NIAID, an organization with unquestioned scientific expertise, devotes less than one percent of its budget to malaria -- far too little to sustain a strong research base. The CDC also has a role to play. Stephen Morse, a virologist at the Columbia University School of Public Health, says, "The CDC is critical for world control of this disease, yet it's operating on a shoestring." Daniel Colley, who directs the Division of Parasitic Diseases at the CDC, agrees. "Most people assume that we're capable of doing considerably more than we can," he says. "The public-health challenges of malaria are enormous, and we're limited by manpower, time, and financing in our ability to tackle many critical tasks. In relation to the magnitude of the problem, support for research and control of tropical diseases is minimal in this country. Compounding this situation, parasitology has faded from the curriculum of many medical schools in the United States, so although in a global environment the medical community should know about this problem, it largely doesn't."

The international funding picture is equally dismal -- one scientist describes the total infectious-disease budget of the World Health Organization as "at best slightly larger than the budget of a major teaching hospital in Boston." Roughly $85 million a year of public-sector funds is spent internationally on malaria -- only about two cents for every reported case of the disease. As one adage has it, "Money is not a problem in malaria research, because, basically, there is no money." Stephen Morse warns that the lack of international attention to the disease amounts to sheer recklessness. "We have been trafficking in microbes -- albeit accidentally -- for a long time, and many of us are worried about our eroding infectious-disease surveillance-and-response capabilities," he says. "Internationally, funding is tenuous and in great need of improvement."

Eradication attempt

Still, sporadic attempts have been made to coordinate international efforts at controlling the disease. I witnessed one such effort, an international conference on malaria sponsored by the National Institutes of Health, the British Medical Research Council, and the French Institut Pasteur. It was a by-invitation-only affair held in a luxury resort hotel on the ocean about ten miles from Dakar. The President of Senegal, His Excellency Abdou Diouf, presided over the opening ceremonies, attended by a colorfully garbed entourage of ministers and ambassadors. President Diouf expressed his gratitude to the scientists for coming, and spoke gravely of malaria as one of the most terrible problems facing his nation, Africa, and indeed the world. Then he and his retinue left to a flutter of applause, and the session took on a Tower of Babel quality. Western scientists spoke of vaccine and drug development, of biotechnology, of manipulating and transplanting genes. African scientists spoke of a dearth of medical supplies and a lack of basic infrastructure, of bad roads and no refrigeration and a treatment population that thinks malaria comes from the sun. The one thing all parties seemed to agree on was that medical science has dismally failed to get a grip on the disease.

DEADLY, CAGEY, AND RESILIENT

MALARIA is caused by infection with the Plasmodium genus of protozoan parasite. More than a hundred species of this parasite exist, capable of infecting reptiles, birds, rodents, and primates. Four species infect human beings, the most common being P. vivax and P. falciparum. The most pernicious is P. falciparum. It is not unheard of for an African child to go to school in the morning and die of falciparum infection in the afternoon. Understanding this adds perspective to the public obsession with other fast-acting microbes, such as so-called "flesh-eating" bacteria and the Ebola virus. The 1995 Ebola outbreak in Zaire that inspired Hollywood and transfixed the world caused approximately 250 deaths over a period of six months. More than twenty times that many Africans die every day of malaria.

Malaria parasites have spent centuries adapting to life in the human body, and as a result have grown cagey. Unlike human immunodeficiency virus, or HIV, which both infects and is transmitted by human beings, malaria parasites keep their delivery system separate from their food supply -- they do not shoot the messenger. The parasites are transmitted to human beings through the saliva of the female mosquito, which is so efficient at this task that it is sometimes described as a flying syringe. Once injected, the parasites quickly retreat to the liver, where they mature and multiply. It is not until they re-emerge in the bloodstream and invade the blood cells that symptoms appear. By this time the parasites have reproduced thousands of times. They thrash about, popping blood cells, clogging blood vessels, debilitating their host, and in some cases killing within hours.

Like HIV and tuberculosis, malaria does not elicit what is called a complete immune response in human beings: we can be infected with these microbes repeatedly, or carry them for any amount of time, without developing a full resistance to them. Nor do we develop a protective immune response to these diseases, as we do for such infections as polio, measles, and smallpox. Whatever immune reaction we develop appears to occur deep in the cell, and is devilishly difficult to elicit.

Eluding containment "HIV, TB, and malaria are among the most important infectious agents in the world," says Harold Varmus, the director of the National Institutes of Health. "There are no effective vaccines against them, and all have the same property of establishing chronic infection without an effective immune response." Malaria is perhaps the toughest of all, because, as a parasite, it has far more genetic material than a virus or a bacterium has. Never yet has a vaccine been proved successful against a parasite, and malaria is a particularly difficult target for a vaccine, because in each of the several stages it goes through, it has the opportunity to take hold in the host.

Because it is so deadly, the malaria parasite has wielded surprising influence over the way human beings have evolved. Sickle-cell anemia, an excruciating and usually fatal genetically transmitted blood disorder, offers the most dramatic example. Historically, victims of sickle-cell disease, who have inherited the sickle-cell gene from both parents, were generally sick much of their lives and tended to die young, often before they had the opportunity to bear children. This should doom sickle-cell in terms of natural selection, which by definition selects for characteristics that ensure that an organism will live long enough to reproduce itself. But the sickle-cell trait, which occurs in people who get the gene from just one parent, is not lethal, and in fact confers partial protection against malaria. People who have the sickle-cell trait may get sick with malaria, but they are unlikely to die of it. In some parts of Africa a quarter of the population has the sickle-cell trait -- an almost incredibly high proportion considering that a double dose of the gene is fatal. The evolutionary fact that human beings have taken on a lethal blood disorder in exchange for partial protection against malaria shows the unprecedented power of the disease.

Malaria inspires such fear that forty years ago the World Health Organization targeted it for global eradication. The United States spent heavily on the campaign, in 1958 committing $23 million a year for five years to the WHO program. Worldwide investment in the project ran into the hundreds of millions of dollars, with some Third World countries kicking in 30 to 50 percent of their health-care budgets. The main thrust of the effort was the spraying of powerful, long-lived insecticides into the interior walls of homes. Workers tramped through villages in North Africa and Asia with spray guns loaded with DDT. The target was the Anopheles gambiae mosquito, which carried P. falciparum.

Hut after hut was sprayed, and untold legions of A. gambiae were ambushed. Malaria rates went down, and hopes for public health soared. But the optimism was short-lived. It soon became clear that spraying was most effective in areas that were only marginally malarious -- areas such as Egypt and southern Europe, where the parasite had only a slippery hold. Meanwhile, for complex reasons, mosquitoes where malaria was solidly endemic started showing resistance to the insecticides.

In 1969 the Global Eradication of Malaria Program was replaced with a global malaria-control strategy. But in 1975 reported malaria incidence was far higher than what it had been fifteen years earlier. Harold Varmus, of the NIH, recalls the impact in India as particularly dramatic. "When I was working there in 1966, I saw almost no malaria," he says. "But when I returned in 1988, there was a raging epidemic. This made a real impression on me. We thought we'd licked malaria in India, but of course we were terribly wrong."

The WHO now estimates that malaria kills as many as 2.7 million people worldwide each year (roughly twice as many as AIDS), and that it sickens as many as half a billion. Children infected repeatedly with malaria over a period of about five years generally develop a partial resistance that allows them to carry the parasite in their blood without getting deathly or even overtly ill. Adults develop this partial immunity too, in somewhat less time. But this does not mean that they can no longer be infected; it means only that their bodies have learned to keep the symptoms in check. Malaria parasites have a voracious appetite and in just a few hours can suck as much as a quarter pound of hemoglobin out of the red blood cells of an infected human being. Hundreds of millions of African children and adults are chronically infected with malaria, and are anemic much of the time. Bernard Nahlen, a physician who is studying malaria in Kenya, told me that one in twenty children in the villages surrounding his clinic are so anemic that were their blood tested in the United States, they would be rushed to a hospital for emergency transfusions. Another American physician in Kenya, Patrick Duffy, says that when he has treated Africans with drugs to clear their blood temporarily of malaria parasites, the patients report feeling as they have never felt before -- that is to say, well.

SOLUTIONS THAT AREN'T

ON the main road leaving Dakar through the savanna of western Senegal traffic thins and the landscape thickens with sorghum, melon, and peanut farms. Manioc sprouts in bushy clumps, and nomadic herders thread flocks of bony goats and long-horned cattle through clumps of mango and baobab trees. Lamine Diawara, a physician, an entomologist, and a commander in the Senegalese army, pulls our pickup truck over to ask directions from a group of people selling oranges by the side of the road. One of them, a man of about twenty in a tattered knee-length tunic and a headdress, swings first a canvas sack of peanuts and then himself into the bed of the pickup. Diawara shrugs and drives on. The truck he has borrowed to make the journey is finicky and slow; we pass horse-drawn carts but no cars. Dignified in his sharply pressed military uniform, Diawara is uncomfortable with silence, and his voice is soft but urgent. Since morning he has spoken of almost nothing but malaria. "Westerners think only of HIV," he tells me. "HIV is horrible, of course. But it is malaria that keeps Africa down."

Diawara is taking me to a village where he often comes to observe and treat patients. The village is a cluster of thatched huts some distance off the main road, on a dirt track that dissolves into a grassy path. Here most of the women have infants slung on their backs, as do some girls who appear to be as young as five. Young men relax in the shade while their wives pound sorghum and sort seeds. The children crowd Diawara, who strides off to seek the elders, five of whom emerge beaming from one of the huts, hands outstretched in greeting. Speaking in Woloff, Diawara asks permission to show me around, and they volunteer to serve as guides. I ask if they have been ill lately. The head elder nods, and says he has suffered from malaria four times this season. The others indicate that they, too, have been afflicted. We visit the village clinic, a cement-block hut hung with posters promoting "safe love" in English and Arabic. Inside there are no medical supplies, no equipment, and no lights. There are no medical personnel; a teenager trained in recognizing malaria symptoms comes in from time to time to hand out anti-malaria medications. This is the best that can be hoped for in rural areas, because anti-malaria drugs are costly; often there is no money for them. Another problem is that malaria is diagnosed not by its symptoms, which are ambiguous, but by checking for parasites in the blood, which requires a microscope. There probably isn't a microscope within miles of this place. When fever strikes in Africa, it is often assumed to be malaria, and if drugs are available, they are simply administered. A child may die of measles or meningitis while being treated for malaria.

I ask for a look inside a home and the head elder takes me to his. The single room is clean and cool, and a tightly made double bed fills most of the floor space. The only other object is a billowing mosquito net, whose corners are tucked neatly around the bedposts. Bed nets impregnated with insecticide are widely touted as a cheap and easy way to prevent malaria in the tropics. Many articles and even a book have been written advocating the use of bed nets, and the WHO devotes considerable space on its Web site to the health benefits of nets. I ask the elder if he uses his. He untucks the net, poses beneath it, and asks that I take his photo. Yes, he says, he uses the net. But still he gets malaria. He loses about two or three weeks a year to the disease. He says he is tired much of the time. The other elders nod, smiling. They, too, they say, are tired.

"Nets might help, but they will not cure the problem," Diawara tells me later. We are back in the truck en route to the nearby city of Thiès. "Bed nets reduce exposure, but they cannot stop it. Not all mosquitoes bite people in bed." I ask Diawara if he uses a net, and he says he doesn't. Nor, he presumes, does the elder who posed, or any of the people we just met in the village. "The elder wanted to show respect to a Westerner," he says. "The West brought the nets. But people here do not believe that they work, and most of us do not use them. Nets keep out the breeze, and this is a very hot country."

I learned another reason that mosquito nets are unlikely to solve Africa's malaria problem from Jean-François Trape, a French physician and malaria expert on the staff of the Laboratoire de Paludologie, in Dakar. Since the early nineties Trape has studied malaria transmission in two Senegalese villages, each about four hours' drive from Dakar. One of the villages, Dielmo, has a stream running through it, where Anopheles mosquitoes breed year-round. Malaria there is rampant, and children are never without parasites in their blood. The other village, Ndiop, has high malaria transmission only during the rainy season, which lasts about four months. Dielmo residents, exposed to an average of 200 infectious mosquito bites a year, experience an average of forty-three attacks of malaria from birth to age sixty. Ndiop residents, who get roughly ten infectious bites a year, average sixty-two malaria attacks. Trape explains this apparent paradox by pointing out that the villagers of Dielmo are more likely to have the bulk of their attacks during childhood, thereby boosting their resistance to the disease. Their bodies come to an uneasy truce with malaria, in which constant infection weakens but does not kill them. Trape argues that providing people with bed nets to ward off malaria in areas where it is highly endemic may in fact increase their risk of dying from the disease, by reducing but not eliminating their exposure. The gambiae mosquito can transmit the malaria parasite in a single bite. If the transmission rate is reduced to fewer than two attacks a year, a person may lose his or her partial resistance to the disease between bouts. Therefore, Trape told me, in areas where malaria transmission is reduced but not eliminated, adults get sicker and older children die at only a slightly later age than do their counterparts where the rate of transmission is higher. "I have two children, and I can tell you, as they get older, you invest in them more," Trape said. "In African culture people prepare for the death of an infant but not a ten-year-old. The nets in many cases simply delay the inevitable."

THIÈS is Senegal's second largest city, after Dakar, but by Western standards it's a village with sprawl. The center is small enough to cover on foot in about an hour, and most of the traffic is human. Goats and chickens poke through the streets, and children stare and wave. Diawara takes me to the Service de Lutte Anti-Parasitaire, which he directs. It is housed in a barrackslike brick structure surrounding an open courtyard where women sit, fanning flies away from buckets of fish. These are technicians' wives, who live here with their children while their husbands do fieldwork. Although Diawara has a wife and four sons in Dakar, he spends most weeknights here, sleeping on a bench in his office. The office is equipped with a computer that collapses from heat exhaustion each summer. A broken air-conditioner lurks near the ceiling. There are no screens on the doors or glass in the windows, but there is a giant-sized can of bug spray. On the wall is a map of Senegal, bristling with straight pins. The pins designate areas where mosquitoes have been trapped, dissected, and examined for parasites. From the dates on the pins I learn that Senegal has been trapping and dissecting mosquitoes for about thirty-five years. Given that most of the country is swarming with parasite-carrying insects, the point of this exercise eludes me.

Diawara introduces me to his head technician, a small, neatly made man of about sixty in a stained lab coat, who bows and pulls out tray after tray of mosquitoes. The mosquitoes were snared by the men I noticed lounging in the shade in the village we visited that morning. The men are paid three dollars a session to sit with their pants legs rolled up. Their exposed legs and feet are mosquito bait (malarious mosquitoes have a preference for the lower extremities). When a mosquito alights, the man traps it in a small glass vial. In the rainy season, when transmission is fiercest, a man can trap as many as 300 mosquitoes in an eight-hour shift. Up to one percent of these carry the falciparum parasite in their salivary glands.

Diawara sweeps a plastic cover from a microscope, slips in a slide, and focuses expertly to show me falciparum in action. What appears under the microscope at this moment looks relatively benign: the malaria parasite is stained a cheery red against the dimmer red of the infected cell. But I have seen greatly enlarged photographs of malaria parasites pouring from the ghostly white hulks of dead blood cells, like soldiers fleeing a scorched-earth spree, and the sight is frightening. Fierce and sometimes fatal anemia is only one consequence of such an attack. The parasite can alter human blood cells so that they adhere to blood vessels; in the case of cerebral malaria the infected cells can occlude capillaries to the brain.

I saw children with cerebral malaria in clinics near Dakar. In one clinic I visited, every child admitted was being treated for it. The head physician there, Mouhaumadou Fall, who is also the chief of pediatrics at the University of Dakar's medical school, explained that it was "pediatric strategy to always treat for malaria, even without proof." The children with full-blown cerebral malaria looked terrible. Their eyes were unfocused under half-closed lids, and they lay absolutely still. Scientists aren't sure, but they believe that cerebral malaria causes brain damage in about 10 percent of cases, and it is estimated that another 10 to 50 percent of cases result in death. But the disease is treatable if caught early enough. One fifteen-month-old at the clinic who just days before had undergone treatment was so lively that his mother joked about stuffing him into her pocket for safekeeping.

For complex reasons, women who have acquired partial resistance to malaria lose it during their first pregnancy, and tend to get very ill with the disease. They are more likely than the uninfected to die in childbirth, and there's about a 40 percent chance that the baby will have a low birth weight. Malaria can damage the brain and other vital organs, and cause heart failure, respiratory distress, kidney failure, bleeding disorders, and any number of other systemic breakdowns. A study recently conducted in Gambia suggests that almost any estimate of malaria deaths woefully understates the impact of the disease, because the control of malaria seems to bring about a radical reduction in mortality from all causes. The implication is that infection with the parasite greatly increases susceptibility to other infections and to malnutrition. Some scientists have gone so far as to cite malaria as a contributor in half of all childhood deaths in Africa.

Mamadou Kasse, the medical editor of Senegal's largest newspaper, Le Soleil, told me that Africans assume that the West considers malaria a necessary evil. "Malaria keeps Africa down, and down is where the rest of the world wants us to be," he said. "If this was a disease of the West, it would be gone." Kasse is not alone in his belief. Several Western scientists told me matter-of-factly that population control, not disease control, is USAID's central mission in Africa. As one scientist told me in a confidential tone, "I'd rather die of malaria than of starvation."

Indeed, many Westerners assume that infectious diseases like malaria, tuberculosis, and AIDS are simply the price that the Third World must pay for its population problem. But Jonathan Mayer, a medical geographer at the University of Washington, argues that just the opposite is true -- that in effect poor health exacerbates overpopulation. "It's fundamental in demographic transition theory that higher death rates lead to higher birth rates," he says. "Lots of kids die of malaria before age five, which means that people will have lots more kids to make sure some stay alive. As an economy becomes more developed, improved public-health measures do lead to a temporary increase in population: at first the birth rate stays stable and the death rate goes down. But in as little as twenty years the birth rate goes down as well. That's what happened in the United States and Europe during the latter part of the nineteenth century. We got rid of malaria here, and a whole lot of other infectious diseases, but we don't suffer from overpopulation."

BAD AIR

IT is unclear how long malaria parasites have infected human beings, but there is no doubt that the disease is an ancient scourge. Medical historians believe that it appeared with the introduction of agriculture, when the human population grew large enough to serve as a reliable reservoir for malaria parasites. The Chinese canon of medicine, the Nei Ching, which dates from about 2700 B.C., discusses the telltale symptoms of high fever and an enlarged spleen, and in their writings Aristotle, Homer, and Socrates describe cases of malaria. Hippocrates was the first to associate malaria incidence with proximity to stagnant water. The term mal'aria was coined in the sixteenth century by Italians, who insisted that the disease traveled by air. The medical microbiologist Robert Desowitz wrote in his outspoken review of infectious disease, The Malaria Capers (1991), that malaria was of particular interest to the English during Victorian times -- no surprise, given that at least a third of the hospital beds in their colonies were occupied by victims of the disease. The English carried P. vivax with them to Jamestown, and imported falciparum along with slaves from Africa. In this country malaria thrived in particular in port cities like Boston and New York, and in the South. A Scottish settler described his bouts with the disease thus: "I am now & then troubled with ye fever & ague wch. Is a very violent distemper here. . . . This place is only good for doctors & ministers." Malaria was among the most common reasons for hospitalization during the Civil War, with the two sides reporting more than 1.2 million cases between them.

Precisely a hundred years ago the British physician Ronald Ross proved that malaria is carried not by air or water but by mosquitoes -- a discovery for which Ross was awarded a Nobel Prize. The fact that mosquitoes were involved made the disease all the more frightening, because water could be purified but mosquitoes could not. Malaria was all but gone from the northern United States by the turn of the century, but it maintained a stranglehold on the South. In her forthcoming monograph "Water Won't Run Uphill: The New Deal and Malaria Control in the American South," Margaret Humphreys, a physician and medical historian at Duke University, compares the American South of the early 1900s to today's developing countries, with their colonial infrastructures, weak local governments, and pockets of extreme poverty where both health care and sanitation are minimal. Estimates vary, but there were certainly millions of cases of malaria a year in the South in the mid-1930s. In 1936 the Works Progress Administration hired 36,000 men to drain three million acres of swamp. After that initial push the WPA continued its work on a much smaller scale through 1942, when the Malaria Control in War Areas agency (the predecessor of the Centers for Disease Control) was formed. Soon thereafter the Public Health Service launched an eight-year, $50 million malaria-control program.

The program was an extension of the war effort -- the idea was to protect soldiers, and only incidentally civilians. The U.S. government had previous experience attacking malaria in the field: one of the most successful anti-disease campaigns of all time was waged in the Panama Canal Zone, where in 1904-1906 U.S. military engineers and "sanitary police" worked tirelessly to drain swamps and thereby vastly reduce the area of mosquito-breeding sites. This time the goal was to create a malaria-free zone around every military installation in the United States. American pharmacologists developed the anti-malaria drugs primaquine and chloroquine as an alternative to quinine, which at the time was being hoarded by the Japanese. Mosquitoes, officially dubbed "Public Enemy No. 1" by the Public Health Service, were pelted with insecticide bombs concocted by the Army. And DDT, itself a product of the war effort, was sprayed inside millions of American homes. (No matter that American mosquitoes seem to prefer the great outdoors.) The campaign appeared to pay off, and in 1953 America declared victory over Plasmodium.

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 the co-director of the Graduate Program in Science Journalism at Boston University. She is the author of Cheap: The High Cost of Discount Culture.

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