Getting To Know The Enemy
In southern Zambia, scientists hunt the parasite and the mosquito that make malaria a fact of life and a persistent cause of death
Southwest of Lusaka, Zambia, the green woodland savanna runs to the horizon. Beneath a great blue African sky, the scrawling curves of the Kafue River slice the landscape. The endless expanse of low trees, grass and brush is interrupted only by the metal- or thatch-roofed huts of pounded-dust outposts, intersecting pale-red lines of dirt footpaths and the rare asphalt highway.
Millennia ago, across a more pristine African savanna, our ancestors first walked upright. First became human. And first encountered the Anopheles mosquito and the Plasmodium parasite. Intruding on our collective infancy, the mosquito and the parasite would unleash the scourge called malaria. The parasite attached itself to people so long ago that one malaria expert has said human beings were "recognizably malarious before they were recognizably human." Ruthlessly efficient and adaptive, Plasmodium has exacted a grievous toll on humanity, especially the very young. Today, malaria kills 1 million to 2 million people each year. The vast majority are children. Every 30 seconds, malaria claims the life of a child in Africa. Depending on the region, malaria causes sickness and death year round or flares seasonally. Regardless of timing, its symptoms are the same: Adults, with their partial immunity earned through the repeated malarial episodes of their youth, may suffer malaria's aching fatigue and soaring body temperature for days. The youngest children, however, burn with fevers and endure aching joints, bone-jarring chills and, sometimes, convulsions and death.
For the people of rural Zambia and for much of the rest of Africa, malaria remains a persistent fact of life.
"Malaria is a disease of tropical areas. It is not a disease of ivory towers," says Clive Shiff, an entomologist who first battled Anopheles mosquitoes in Africa a half century ago. So after the Johns Hopkins Malaria Research Institute (JHMRI) was launched in 2001 with a historic $100 million gift, Shiff, an associate professor of Molecular Microbiology and Immunology (MMI), and Diane Griffin, chair of MMI and JHMRI's director, began seeking a site in Africa for field research. They soon zeroed in on a small community in Zambia's Southern Province. A 380-kilometer (230-mile) drive from the capital of Lusaka, the isolated households of the Macha community are hidden among the savanna's brush. Malaria here is entirely dependent on the rainy season, which begins in November and usually lasts until June. In Macha, Griffin, MD, PhD, and Shiff, PhD, found just what they were looking for: a pristine tropical setting with endemic malaria and no active mosquito control programs, a district hospital with abundant clinical cases, and an Africa-based researcher committed to solving humanity's age-old malaria problem.
MALARIA IN MACHA
A red stethoscope looped around his neck, Phil Thuma walks into the one-story, red-brick Macha Mission Hospital. He passes a painting of a black Jesus thronged by joyous kids and heads down the long beige hallway to the children's ward. Thuma, the son of medical missionaries with the Brethren in Christ church, grew up in this rural community. After attending Temple University medical school in the United States, he returned in 1976 to work in the Macha Hospital. With his buzz cut, his wire-frame glasses and checkered button-down shirt, Thuma looks like an engineer. Impatient with problems. Committed to finding solutions.
"Afternoon, ladies," Thuma says, greeting the nurses in the children's ward. The large, battered room is crowded with hospital beds and steel cribs whose white paint chipped away long ago. Mothers and some fathers sit with their children. Conversation, cries and the sound of coughing echo off bare walls. Mosquito nets hang from the ceiling above each bed—their diaphanous tails knotted up during the day and unfurled in the evenings. Thuma's caseload for the day includes respiratory infections, skin infections and mild malnutrition. One boy, who fell from a tree, lies on his back in traction—both his legs held straight up by ropes and pulleys weighted with jugs of water. He will remain like this for six weeks.
"Milner!" Thuma says, recognizing a toddler standing in another part of the ward. A young boy, in a gray striped shirt and long navy blue shorts, holds a half-eaten hardboiled egg. Crouching down to the boy's level, Thuma asks if it's good. He speaks Chitonga, the local language. Bashful, Milner doesn't reply but looks back to his mother.
One thing missing from the ward on this afternoon in mid-January: malaria. When the disease rages (typically between February and May), sick children crowd the 45-bed ward, sleeping two to a bed. Thuma knows it's early in the season, and the malaria cases will soon come.
In the 1960s and early 1970s, government mosquito control programs held malaria to a minimal level. But as the country deteriorated economically, the programs faltered and disappeared. By the late 1970s, malaria was common but far from the number one cause of hospital admissions or child mortality. (That was malnutrition.) For the malaria cases they did see, the hospital physicians prescribed chloroquine, which quickly beat back the infection. During the 1980s, malaria cases increased rapidly. Then, in the late 1980s, chloroquine—the cheap, effective treatment for malaria—failed. Plasmodium had become resistant to the drug. "We used to get 40 cases per year of cerebral malaria in the mid-'80s," recalls Thuma, MD. "In '89, we had 120 cases of cerebral malaria. It has 20 percent mortality with good treatment. I was watching one to two kids die a day."
The seasonal outbreaks of malaria and the subsequent onslaughts of sick children forced Thuma, a pediatrician, to become a malaria researcher. "I tell people, God put African children on my heart," says Thuma. "This is my home area. And these are my kids."
So when Shiff and Griffin approached him, Thuma welcomed the opportunity to build a major field research site in Macha. "It's nearly like a dream fulfilled," says Thuma, who had carried on his own limited research for years through grant funding. Thuma quickly persuaded the Brethren in Christ church to set aside 16 acres it owned next to the Macha Hospital. The new collaborative research center, known as the Malaria Institute at Macha (MIAM), is sponsored jointly by JHMRI, Macha Hospital, the Zambian Central Board of Health and the Macha Malaria Research Institute, a non-profit organization founded by Thuma. By early 2005, MIAM officially opened. From the scrub and brush arose a laboratory building, staff and guesthouses, a satellite dish, a library/classroom, a vehicle maintenance facility and a water and electrical system.
"We don't just want to stay in the lab in Baltimore," says Griffin. "We really want to be able to move what we're doing from the basic science perspective into both testing and application in the field." She points to JHMRI's work in Macha as examples: the evaluation of a urine dipstick for quick malaria diagnosis (see sidebar, page 21), investigation of Plasmodium's ability to acquire drug resistance, studies of the short-lived human immune response to malaria, and entomological studies of Anopheles mosquitoes. By relentlessly probing different life stages of both the parasite and the mosquito, researchers hope to find weaknesses that can be exploited. The ultimate goal is to stop the disease, just as science has toppled smallpox, polio and others. The advantage JHMRI scientists enjoy in Macha: The researchers are hunting Plasmodium and Anopheles where they live.
ANOPHELES, BYTE BY BYTE
Doug Norris steers the white Toyota Hilux 4x4 pickup down a red-dirt, double-tracked road fringed with shoulder-high grass. Short, bushy miombo trees and brush dot the savanna. The truck lurches back and forth on the bumpy road. A mud-spattered red decal on the driver's side door proclaims MIAM and JHMRI. Norris, an MMI assistant professor, chats quietly with a couple of visitors and a fellow entomologist, PhD candidate Rebekah Kent. In the truck's bed, six MIAM employees—all young men—ride out the bumps. Norris recalls that on a previous visit, Kent rode in the back with the guys and had them shouting yee-haw! like bronco-busting cowboys.
After taking several forks in the road, Norris pulls the truck in front of a compound of brick huts, part of a community named Chidakwa. The Batonga people who live in the area typically live in isolated households of a half dozen or more huts. Each hut serves specific family members or a special purpose: the cooking hut, adult sleeping huts, children's sleeping hut, goat hut, grain storage hut and others. Some households have separate huts for the patriarch's different wives.
It is 6:35 a.m., a good time for "spray catches," which involve fumigating huts to catch the mosquitoes inside. Mosquitoes typically feed in the wee hours of the morning and then, gorged on blood that can double (or even quintuple) their weight, fly to a nearby vertical surface like a wall to digest. So just after sunrise is the best time to catch them with full bellies. The MIAM team also does "human landing catches," which require an intrepid individual to sit up all night in a dark hut and use a tiny aspirator to vacuum up live mosquitoes that land on his skin. The number of mosquitoes caught can be used to estimate the number of times a person is bit per night. (Kent will later estimate that in Chidakwa during February and March, there is an average of 1 bite per person per night by an Anopheles arabiensis mosquito. Nearby, in Lupata village, the average is about 3.5 bites per person per night.) The catches also help Norris and Kent determine the prevalence of mosquitoes infected with malaria. About 3 percent of the mosquitoes they've captured thus far were infective and transmitting malaria.
Spray-catch team foreman Harry Hamapumbu, wearing a baby-blue jumpsuit with a red MIAM patch, jumps from the truck with his five-member team.
"Mwabuka," they greet the household matriarch in Chitonga. The men enter a dimly lit hut and carry out some pots and pans. They ask a young woman to pull down strips of meat drying on low wooden rafters inside. They pull white sheets from a Philadelphia 76ers gym bag and spread them on the floor and a bed in a small adjacent room. Each room measures about 6 by 9 feet. They spray Doom Super insecticide in the hut and move on to the next hut. After 20 minutes, they return to see what has dropped onto the sheets. (A nice side benefit for the household: The fumigation kills flies and other annoying indoor arthropods.)
The spray catch represents a low-tech beginning to a decidedly high-tech scientific program that eventually will yield insights into the area's mosquito populations and the malarial threat. For each mosquito collected, the researchers will know the exact longitude and latitude where it was caught, its species, its genetic profile, the source of the blood meal (whether a human or a cow, or even a dog or chicken), and if it has the parasite in its midgut (indicating a recent infected blood meal) or its salivary glands (meaning it fed on an infected person a couple of weeks previously).
"That makes it a valuable little mosquito," says Norris, PhD, MS.
The information is plugged into geographic information systems (GIS) software to generate a detailed picture of Anopheles arabiensis, the mosquito believed to be the main vector (carrier) of malaria in Macha, and its cousin Anopheles funestus. Kent's research is gauging the seasonal intensity of malaria and the relative contributions of An. arabiensis and An. funestus to malaria transmission. She already knows that An. funestus seems to prefer permanent bodies of water like ponds, while An. arabiensis is more of a rainy-season opportunist, breeding in ruts in the road, cattle hoofprints or other divots when they fill with water.
Norris, meanwhile, is studying the genetic profiles of An. arabiensis to understand its population dynamics throughout a 2,000-square-kilometer area. He wants to know if An. arabiensismosquitoes are part of a single population there or divided into subgroups. Norris abandons entomological terminology for a moment to explain: "Do New Yorkers breed only with other New Yorkers or do they come down to Baltimore?" The insights can guide future control programs. How large of an area should control efforts target? If An. arabiensis mosquitoes could be eliminated in one village, for example, would its relatives likely just surge and fill the void?
For mosquito control programs, knowledge makes the difference between success and wasted effort. Some South African mosquito control workers, for example, recently learned that a particular population of An. funestus was not susceptible to a common insecticide that is considered deadly to anophelines.
THE NUMBERS GAME
In the Macha lab after an early morning spray catch, Kent is pinning an An. arabiensis to a small, Styrofoam-covered board. On a tiny label paired with each mosquito, Kent's minute script details when, where, how and by whom the specimen was collected. She is also teaching Hamapumbu and another local MIAM employee Kalizya Sinyangwe how to identify Anopheles mosquitoes. Kent notes the setae (hairs) and sclerites (plates) on a pinned mosquito and gives the specimen board to Hamapumbu and Sinyangwe to get a closer look. "The important thing," says Kent, "is to get familiar looking at the real thing versus the printed version." She points out the An. arabiensis'sspeckled legs and its distinguishing pale spot "in the third dark area of the first vein, towards the apex of the wing." She also notes that An. arabiensis lacks the shaggy mouth parts of some other anophelines.
"I feel so great because from the time I was small I never thought I would have something to do with entomology. I never thought I'd look at mosquitoes," says Sinyangwe, who like everyone else in Macha suffered frequent bouts of malaria in his youth. "It's very great for me."
Adds Hamapumbu: "I'm really glad to be part of this team, to wipe out this brutal, deadly disease."
Mosquito by mosquito, year by year, Norris and Kent are building a rich database of baseline information about An. arabiensis. Their work, made possible through JHMRI support, is the type of basic research that is difficult to get funded by outside organizations. "Funding agencies want to see background data, and we're getting the background data," says Kent.
The entomologists are also getting to know the enemy before new control methods and therapies are tested here. For Norris, the ultimate goal is not to kill every mosquito in the region, but just to shave a little time from the average mosquito's life. Even a few days could tip the dynamics of malaria transmission enough to stop the disease. Norris explains: About two or three days after a female mosquito is born, she mates and soon takes a blood meal. (The 50 to 100 baby mosquitoes in her "egg batch" need the nutrients to develop.) If her first blood meal was taken from a person infected with the Plasmodium parasite, about two weeks later the parasite reaches the mosquito's salivary glands. From there, it can be transmitted to another person. By now, it's day 17 or 18 of the mosquito's life. Under ideal conditions, mosquitoes live only 18 to 25 days.
If the mosquito's first blood meal could be postponed or her life shortened a little, no transmission. No malaria. No children dying. "You don't have to eradicate mosquitoes. You just have to get them to not live as long," says Norris. "It's a game of numbers."
A LASTING REPRIEVE?
Last year, the people of Macha were rejoicing.
Malaria, which had spread virtually unchecked every rainy season for two decades, suddenly became scarce. In 2005, just 159 children were treated at Macha Hospital for malaria; seven died. Just four years earlier, the numbers were dramatically higher: 1,600 children treated and 90 deaths. Phil Thuma, long familiar with Plasmodium's wily survival skills, wasn't ready to proclaim victory. But the Hopkins-trained physician allowed himself great hope.
The dearth of malaria cases coincided with the expanded use of a new artemisinin-based drug and droughts in 2003 and 2005, which drove down the mosquito population. Did the drug or the droughts cause the reduction in malaria?
Thuma had seen droughts before, but never such a drop in malaria cases. He places his hopes on the new drug, Coartem, which the hospital and clinics began prescribing in late 2003. Coartem and other artemisinin combination drugs are based on a Chinese herbal remedy and have replaced chloroquine as the treatment of choice for malaria. Community surveys that Thuma led in 2001 showed that 70 percent of children had the malaria parasite in their blood; today that figure is about 10 percent. "If 70 percent of people are carrying malaria, it doesn't take too many mosquitoes to transmit it," says Thuma. "If only 5 or 10 percent are carrying malaria, then it takes a lot more mosquitoes and a lot more bites to get back up to the same level. That's why I'm optimistic we're not going to go back to these high levels."
Entomologists, on the other hand, argue that malaria ebbs and flows with the mosquito population. More mosquitoes equals more malaria. During the 2005 drought, mosquitoes were hard to find. The MIAM team captured fewer than 100 An. arabiensis—about one per every 12 or 14 huts at peak season. Then the rains came back, and the mosquitoes flourished. In January 2006 alone, they found 250, an average of about one per hut.
Ominously, pediatric malaria cases began increasing at the Macha Hospital, from just a few in January to 25 in February and then 112 in March. Thuma remains optimistic; he's still seeing far fewer malaria cases than in years past. (In February 2003, there were 300 pediatric malaria cases.) If the fall in malaria cases were just a matter of the drought and lower numbers of mosquitoes, Thuma believes that the malaria cases would have popped back up to normal levels soon after the rains returned.
A couple years of good rains will likely resolve the debate. For now, the entomologists are sticking to the mosquito-malaria link. "If there are no mosquitoes, there's no transmission," says Shiff, an MMI associate professor. "Once the rains come, you have mosquitoes and transmission again. The mosquitoes are the heart of the problem."
ART OF THE POSSIBLE
Most researchers expect the fight against malaria to continue for years, if not decades. It is not a simple task. After all, the parasite has been with us since humanity's origins. "There are not going to be any easy answers," says Griffin. "You couldn't say, put all your money into X and you get a magic bullet. That was clear from the beginning. I think everybody has recognized it's going to be a complicated process. That's the reason we thought you need to attack the malaria lifecycle on a basic level from multiple fronts."
On the frontlines in Zambia, children—feverish, chilled and often near death—still come to the Macha Hospital. And to Phil Thuma. "I've always believed in having visions or goals that are nearly impossible to attain because if you aim lower, you're going to reach lower," says Thuma. "I would like to see malaria transmission go down to zero in Zambia, or at least in the Macha area."
He concedes eradicating malaria in Africa would be an immense task. Near impossible. After a moment, however, Thuma rallies his confidence and says, "But let's take one of the deans of the Hopkins School of Public Health—D.A. Henderson, the guy who eradicated smallpox. What if he said, 'Let's just get rid of smallpox just in this one local area?'
"I would maintain you have to think big. Maybe it's not realistic. Maybe it's not pragmatic, but your goal should be to get rid of malaria. Clearly, it will take a lot of resources, a lot of effort to get transmission down to zero, but I'm not willing to concede that it's not possible."