DISCOVER: Fighting the Parasite from Hell

Fighting the Parasite from Hell
Deaths from malaria are rising as older medicines fail
By Claire Panosian Dunavan
DISCOVER Vol. 26 No. 08 | August 2005 | Biology & Medicine

[I]Limbe, Haiti, July 1972: Another morning at Hospital le Bon Samaritain―the only medical outpost in a tropical valley with no paved roads, telephone, or electricity. From daybreak, patients filled the crude wooden benches of the waiting room. By midmorning, they also covered the floor. The scene was overpowering: Grandparents with rusty sputum and the rattle of tuberculosis; children with tattered clothes and broken bones; infants with swollen bellies, flaking skin, and mustardy diarrhea.

But one of these children was not just undernourished; she was unresponsive. I noticed her skin tone. Amid the rich brown faces of West African ancestry, she looked pale. Belle, a missionary nurse whose ancestry was pure Iowa cornfield, hurried over. She brushed a hand across the youngster's forehead, gently rocked her neck to check for meningitis, then pulled down her eyelids. They were bloodless.

"aper white! Hemoglobin's way down. Add fever and coma. What's your diagnosis?"

You're asking me? I thought, terrified. I was just a summer volunteer. I wouldn't start medical school for two months. In fact, after a few weeks in Haiti, I was wondering if I wanted to start at all.

"Quick!" Belle said. "Find Madame Toni and ask her for chloroquine while I track down Dr. Hodges. This is one wicked case of malaria."

Suddenly I "konprannéd," to borrow a verb from my meager Creole vocabulary. A lightbulb shone. The child's pallor was due to malaria parasites destroying her hemoglobin-rich red blood cells. Her fever and coma indicated the infection had invaded her brain. Didn't she need oxygen, a transfusion, a desperate ride over rutted roads to a better-equipped hospital an hour away? No. All she needed was for Dr. Hodges to snake a bitter dose of chloroquine down her throat. The girl was awake within hours. The medicine was magic.[/I]

I recently recalled that little girl and countless other children saved from certain death by chloroquine because I was reading about 80 U.S. Marines struck with falciparum malaria a few weeks after deploying to Liberia in August 2003. By day, the soldiers were clearing abandoned buildings on the steamy African coast. At night, according to Navy doctors who later investigated the cases, they slept in shorts and T-shirts on the roof. Their nighttime encampment without mosquito nets was a recipe for malaria. Worse, most of them forgot to take their weekly preventive medication, a modern-day relative of chloroquine called mefloquine.

Fortunately, prompt treatment aboard a hospital ship and in military intensive care units averted deaths among the 80 Marines, although a few experienced seizures, coma, and respiratory failure requiring ventilators. Today the average African child with severe malaria is not as fortunate. Although parents can buy chloroquine for pennies at almost any roadside stand (between 100 and 200 metric tons of chloroquine are consumed in Africa every year), the drug stopped working miracles decades ago. Effective alternatives are alien, unavailable, or unaffordable. Of the world's 1 million to 2 million malaria-related deaths each year, the majority occur among rural residents of the tropics living on less than a dollar a day. Unless better drugs arrive soon in their villages and towns, deaths from malaria will most likely double in coming years.

To understand why malaria is a world health crisis today, it's best to start with the pathogen: a single-celled [I]Plasmodium falciparum [/I] parasite that has been stowing away in humans for millennia. The microbe usually enters its host via the parasite-laden saliva of a female Anopheles mosquito. Minutes after she inserts her proboscis, threadlike organisms surf the human bloodstream, gain their beachhead, the blood-rich liver, and silently multiply. Seven to 10 days later, 10,000 to 30,000 descendants restorm the bloodstream, each ready to raid a red blood cell and siphon hemoglobin to fuel the birth of another 10 to 20 babies per cell. The end result? Every 48 hours, another round of breaking, entering, and breeding, accompanied by malaria's infamous fevers and chills. The cycle of transmission is sustained when a new mosquito bites an infected person and picks up more parasites.

Despite the parasite's prodigious growth in the human body, the ferocious onslaught doesn't always kill the infected person. Some people can better fend off malaria because they bear genetic mutations that hinder the ability of the parasite to grow within red blood cells (see "Good Genes Can Help," page 51). For most people who lack access to antimalarial drugs, the main line of defense is immunologic. In malaria-rich places like equatorial Africa and Haiti, the immune system is constantly pressured to make antibodies and fighter cells that reduce the amount of parasites in the bloodstream. As a result, many older children and adults keep their infections in check with an occasional "booster shot" from a malarial mosquito. Not that they escape. Repeated bouts of illness take their toll in anemia and debilitation. The economic losses attributable to malaria in Africa alone, including lost investment revenues, have been estimated at 1 to 4 percent of Africa's gross domestic product, up to $12 billion a year.

In a worst-case scenario, malaria-clogged blood vessels in the brain and other organs bring death within days, especially in youngsters, who have immature immune systems, and adults (like the Marines in Liberia) with no immunity to malaria. This explains how malaria still kills as many as a million children under 5 every year.

What the numbers don't tell is chloroquine's heroic 50-year record in preventing an even greater bloodbath.

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[CENTER] LIFE IN TWO HOSTS


Graphic by Nigel Holmes

The malaria parasite depends upon mosquitoes to transmit it from person to person (see diagram at right). Within the human host, the parasite develops into two forms. One form reproduces asexually within red blood cells, which then burst and release offspring to infect more red blood cells. These rounds of reproduction provoke malaria's characteristic fevers. The other form of the parasite reproduces sexually, does not cause symptoms, and is transmitted to mosquitoes. Malaria parasites belong to the Plasmodium genus and infect many types of mammals and birds.[/FONT][/CENTER]

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In medicine, great discoveries often have an inauspicious origin. Chloroquine is an example. Chemists at IG Farben in Germany originally synthesized the compound in 1934 and shared the formula with Winthrop Stearns, an American sister company. Then Farben chemists made a wrong turn: Mistakenly thinking the parent compound was toxic, they abandoned it for a weaker relative called Sontochin. As World War II loomed, communication between the pharmaceutical firms broke down, and almost a decade passed before French soldiers unearthed a stash of German-made Sontochin following the fall of Tunis. Knowing of America's desperate search for new antimalarial drugs (by then, the U.S. government and Winthrop scientists had screened roughly 14,000 candidate compounds), French military doctors shipped samples back to the States for further testing.

With just a few chemical modifications, Sontochin gained much greater potency, and chloroquine was born. But the exultation at Winthrop was short lived when researchers realized that the new cure was, in fact, identical to Sontochin's long-forgotten predecessor, already sitting on their shelf. The sad upshot for the Allies? Chloroquine production geared up too late for the drug to save lives during campaigns in the notoriously malarial Pacific and the Mediterranean. Within 20 years, mass chloroquine treatment, along with DDT spraying and other antimosquito measures, removed the threat of disease from more than 500 million people living in formerly malaria-ridden areas.

Despite choloroquine's smashing success, figuring out how it worked on a subcellular level took a lot longer to unravel. The first real clue was the drug's ability to concentrate in the food vacuole―or so-called acid stomach―of the malaria parasite. This specialized compartment is where the organism digests hemoglobin, releasing an iron metabolite called heme that is normally toxic to microorganisms. To avoid heme's damaging effects, malaria parasites convert it to an insoluble product, hemozoin, that stains their victims' internal organs a dark, rusty brown. Chloroquine controls the parasites by interrupting this heme detoxification step, exposing them to their own poisonous by-products. Because of the way it accumulates inside the parasite, the drug works even when it is present in extremely low concentrations.

By now, some parasites have evolved resistance to the drug: genetic adaptations that allow them to expel chloroquine from their food vacuoles 40 to 50 times faster than their drug-sensitive kin. They do this by making a lot more of a transport protein on the food-vacuole membrane that acts like a selective drug pump (multidrug-resistant cancer cells have evolved a similar mechanism to expel cytotoxic drugs). There may be a way to counteract this trait. Tests in the laboratory show that the parasite's ability to pump out chloroquine is inhibited by several different compounds: the calcium channel blocker verapamil as well as tricyclic antidepressants, phenothiazines, and antihistamines. But what works well in a test tube doesn't always prove a success in humans. Whether chloroquine-resistance reversers will someday be safe and feasible treatments is still a question.

Even in chloroquine's heyday, the drug's demise loomed. The earliest sightings of chloroquine-resistant parasites date as far back as the late 1950s and early 1960s. Clinical failures first surfaced along the Thailand-Cambodia border, in Colombia's Magdalena Valley, and in the nearby Lake Maracaibo district of southwestern Venezuela. A fourth resistant clone arose in New Guinea in the early 1970s. By the end of the 1970s, drug-resistant malaria strains―almost certainly from Asia―had made their way to Africa. Although we'll never know for sure how they got there, one theory is that they traveled as invisible cargo in migrant construction workers hired to lay railway track from Mozambique to the Democratic Republic of the Congo (formerly Zaire).

Meanwhile, back in Asia, chloroquine resistance was hardly invisible to the U.S. military. In the early phases of the Vietnam War, nearly 10 percent of American soldiers came down with malaria; many cases were due to drug-resistant parasites. With their first-line treatment failing, U.S. military doctors quickly moved to mefloquine, a potent replacement developed at the Walter Reed Army Institute of Research. Across the battle lines, Ho Chi Minh, faced with the same problem, appealed for help to then Chinese leader Chou En-lai. His timing couldn't have been better because it coincided with China's campaign to reassess plants once used in traditional medicine. That effort turned up the ancient Chinese herb qinghao. Like chloroquine, it had somehow eluded modern-day malariologists.

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GOOD GENES CAN HELP

In 1948 British biochemist and evolutionary biologist J. B. S. Haldane noticed that the distribution of populations with abnormal hemoglobin coincides with the distribution of malaria. Did genes for abnormal hemoglobin survive and spread, he wondered, because they protected against malaria infection? The best available evidence now supports Haldane's hypothesis. Sickle-cell anemia, for example, is a genetic disorder in which a single amino acid substitution creates hemoglobin S, a variant that results in blood cells that are inhospitable to the malaria parasite. In Africa people who carry one copy of this altered gene (so-called heterozygotes, who are relatively well despite their altered hemoglobin) are 90 percent less likely to die of falciparum malaria than those who do not carry it. Those who carry two copies of the gene must cope with a painful blood disorder that often causes early death. Despite strong selection against the sickle-cell gene, 10 to 20 percent of Africans are carriers. The gene is maintained in the population because carrying one copy improves a person's ability to survive malaria.

Another variant, hemoglobin C, also confers 90 percent protection against falciparum malaria in West Africa. In Southeast Asia, the variant hemoglobin E lessens the severity of falciparum malaria and decreases the susceptibility of red blood cells to parasite invasion. Other hereditary diseases of the red blood cells that protect against malaria include the thalassemias (disorders of hemoglobin's alpha and beta protein chains) and glucose-6-phosphate dehydrogenase deficiency, an enzyme defect that leads to red blood cell breakage during illness or following exposure to certain drugs.      ―C. P. D.[/FONT]


Map by Matt Zang

Despite ongoing efforts to eradicate malaria, it remains entrenched in many tropical regions. Cases of malaria are now rare in the developed world, but the United States battled the disease in the 19th century. Draining swamps and spraying areas with DDT helped eliminate the pathogen.[/FONT]

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Stop for a moment and think back to high school biology. If you learned about malaria even briefly, you probably remember that quinine, extracted from the bark of the cinchona tree of the Andes, was its earliest cure. Today there's a better candidate for malaria's oldest antidote: a woody shrub with silver-green fronds known in this country as Artemisia annua, or sweet wormwood, and in China as qinghao. Originally touted as a hemorrhoid treatment in 168 B.C., China's earliest record of qinghao's fever-fighting ability comes from a fourth-century [I]Handbook of Prescriptions for Emergency Treatments[/I]. In it, author Ge Hang advises febrile patients to "take a handful of sweet wormwood, soak it in a sheng [about 1 liter] of water, squeeze out the juice and drink it all." Quinine's botanical source, in contrast, was not officially recognized until the 17th century.

Now fast-forward from the fourth century 1,600 years. Charged with finding a new remedy for malaria, scientists working for Mao Tse-tung and Chou En-lai decided to test Ge Hang's ancient wormwood recipe in mice infected with a malarial strain that is lethal in rodents. In these experiments, the botanical tea performed as well as chloroquine and quinine. The researchers then isolated [I]A. annua's [/I] active ingredient (a crystalline compound called [I]qinghaosu[/I], or in chemical registries, artemisinin) and tested it in humans. In 1979 they finally published their findings in the [I]Chinese Medical Journal[/I]. The news caused barely a ripple until a 1985 Science article confirmed that qinghaosu had successfully treated several thousand Chinese malaria sufferers. Artemisinin's water-soluble derivative, artesunate, appeared to be more promising. Studies showed that patients comatose from cerebral malaria were restored to consciousness.

The rediscovery of the artemisinin class came at a fateful time for Southeast Asia, the original home of drug-resistant malaria. By the late 1980s, some Asian strains were impervious not only to chloroquine but also to sulfadoxine-pyrimethamine, a low-cost alternative to chloroquine, mefloquine, and quinine. Malaria deaths were on the rise. In Vietnam, for example, malaria mortality increased 300 percent between 1987 and 1990. Vietnamese health officials responded with bed nets, community health care, and annual malaria surveys. But their most potent weapon was artesunate. In one southern village, artesunate treatments lowered the proportion of residents with blood parasites from 42 to 4 percent in just five years. And on the Thailand-Myanmar border, using artesunate plus mefloquine stemmed the high rate of malaria infections and restored mefloquine to its previous efficacy.

In hindsight, the artemisinins' ability to wrestle malaria to the ground in parts of the Far East should have been no surprise. Unlike most other types of antimalarial drugs, artemisinins attack parasites in the sexual stage of their life cycle. Because they interrupt the proliferation that fuels the human-to-mosquito cycle, they are well suited to curb the spread of infection. They also extinguish malaria's prolific asexual forms faster than any other known treatment, drastically reducing total parasite biomass in the host. The chemical feature that enables this suppression is a bond between two oxygen atoms―an unstable peroxide bridge that releases a tiny barrage in the form of free radicals (unpaired electrons) that can fracture parasite proteins the way an F5 twister tears apart barns. The release occurs upon exposure to hemozoin, the dark granular digest of hemoglobin that accumulates in plasmodium-infected red blood cells.

Ironically, the artemisinins' chief virtue― speed―is also a weakness: The supercharged action translates to rapidly diminishing drug levels in the bloodstream. To compensate, a patient taking artemisinin alone must stay on it for seven days―a major disadvantage in places where an extra tablet or two of any medication can mean the difference between going hungry and eating dinner. On the other hand, combining the drug with a second agent that has a different mode of action, such as mefloquine, decreases the course to three days. The two-ingredient cocktail also offers protection against future resistance to artemisinin.

Many international experts and agencies―including the World Health Organization―have endorsed the strategy of coformulated artemisinin combination treatments in principle. But they cost about two dollars a course. Chloroquine costs just 10 cents a course. The investments in cultivating, manufacturing, and subsidizing the 300 million to 500 million yearly courses needed for Africa are in limbo. Meanwhile, other malaria researchers and funders are staking their hopes on synthetic peroxides designed to mimic natural extracts of [I]A. annua[/I]. Phase I clinical trials of the man-made compounds have begun, but there's no guarantee they won't reveal hidden side effects or toxicity. Even in the best-case scenario, new agents will not reach dying children for another five years.

In waging war against malaria, no weapon has proved perfect, no judgment completely unflawed. For the next stage,  it's worth recalling some wisdom from the native land of qinghao. Centuries before Ge Hang proclaimed its healing power, General Sun Tzu wrote in [I]The Art of War[/I]: "Now in war there may be one hundred changes in each step. But when one sees he can, he advances." The greatest pitfall in the battle against malaria is inaction.