Mission Man

Soft-spoken by nature, Philip Thuma, MD, is humble in the extreme. It’s hard to get a rise out of the pediatrician. But there is one sure way: Ask him about the skeptics who admit that what’s happened in Macha is an extraordinary feat in malaria control—but dismiss it as a one-off, a statistical anomaly for which, they believe, it’s impossible to separate the scientist—Thuma—from the science. Never mind that the hospital his missionary father, Alvan, founded in 1957, and which runs almost entirely on Zambian government money (there is some church support, along with research dollars), is considered a first-rate institution. Or that during Philip Thuma’s time in Zambia, Macha Hospital, which services some 128,000 residents in a 35-km radius, has grown to 208 beds; and that the research facility he founded in 1997, the Malaria Institute at Macha, published 21 peer-reviewed articles within its first seven years of existence.

Despite these accomplishments, some raise an eyebrow at the fact that Thuma’s resume includes the words “missionary” yet lacks “PhD.” And they claim that Thuma and his work are intertwined beyond the point of unraveling, thus making the Macha experience useless elsewhere in malaria-ravaged, sub-Saharan Africa.

“Funders of malaria control research, a lot of them have come to Macha and they walk away saying, ‘This is great, but we don’t think this is reproducible,’” says the 60-year-old Thuma. “I obviously bristle at that, because I say, ‘we’re scientists. If something seems to work, instead of writing it off, don’t we instead analyze it and ask, ‘What are the key points?’ and then try to see which of those make a difference?”

To supporters and skeptics alike, one thing is clear: Philip Thuma is inextricably linked with the land and the people he serves. He is a doctor who is revered in his community, as was his father, before him. With a few exceptions—such as when he came to Johns Hopkins to complete his pediatric residency—he has spent the vast majority of his waking moments on these African plains (“Phil is an African. His life’s work is Africa,” says entomologist and Bloomberg School colleague Clive Shiff, who was born in what was then Rhodesia. “He’s as African as me.”)

One measure of Thuma's connection to Macha is revealed by the pain in his voice as he recounts malaria's lethal swiftness: "I have seen kids under five who are looking fairly normal one day, fever and headache the next day, by the third day they're in bed, and by the fourth day they might be dead," he says.

His lifelong commitment to the community's health has yielded unprecedented trust in Thuma and his work. In a culture where reverence can be measured by the number of babies named after a local hero, there are enough Thumas in Macha (Philip or Alvan, take your pick) to fill a phone book. "You walk in the bush, or stop by a hut, and everyone knows 'Thuma,'" says Greg Glass, PhD, a Bloomberg School microbiologist and professor in Molecular Microbiology and Immunology (MMI). "One time my tech, a jogger, got lost in the bush. He bumped into somebody and said, 'Take me to Thuma!' Well, they took him to Thuma, but it wasn't Phil ... it was some other guy, even farther out in the bush, named for Phil or Phil's dad. Fortunately he knew Phil, and got my tech back home."

The deep connections Phil Thuma has made, from the upper reaches of Zambia's Ministry of Health to generations of the poorest of Macha, take decades to establish. His hope: that the trust and communication that have taken root in Macha, nourished by the continuing scientific rigor that he has established, can be seeded elsewhere.

Diane Griffin was looking for a very special partner. It was 2001, and Griffin, MD, PhD, chair of MMI and the founding director of the Johns Hopkins Malaria Research Institute (JHMRI), knew that to do the work she envisioned for the Institute, she needed a living, breathing touchstone, an African field site that could serve as a wellspring for investigation, discovery and, ultimately, healing. A place where the presence of a community-oriented researcher would open the door to important projects (especially those that ask African subjects for bodily fluids such as blood) that often run into roadblocks among wary populations.

In Philip Thuma and Macha, she found that match. Alerted by colleague David Sullivan, MD, who had previously met and worked with Thuma, Griffin first met Thuma in Baltimore, during one of Thuma's stateside trips. She found they shared a mindset for ways of investigating malaria, and soon she visited Macha. Griffin discovered that Thuma's record keeping of malaria cases that came through his hospital was impeccable, giving her great confidence in his case numbers going back for years. And right next door to the hospital was a fledgling research lab, complete with something Griffin felt was absolutely vital for any sustainable control efforts: Zambian raised and trained technicians.

Thuma and Griffin soon found that, in hoping to better control malaria, they were both headed in the same direction ... back into the communities where the disease originated and continued to thrive. "Phil had exquisite records of malaria cases, but it was all hospital based and people were getting malaria out in the countryside," says Griffin. "The mosquito populations out there were totally unknown. The area hadn't been mapped. Everything was there to be done."

Even more enticing was the fact that, from an environmental viewpoint, Macha was virgin territory. While other African sites in Kenya and Mali had been pored over by a plethora of scientists, Macha, says Griffin, "was a brand new type of area of study, with seasonal [non year-round] transmission, no previous DDT spraying, no distribution of bed nets. Nothing had really been done to try and control malaria in the community before."

But even before JHMRI's imprint had been felt on Macha, the entire malaria landscape there changed. By 2004 the hospital cases had slowed to a trickle. On the surface, the cause was as simple as looking up at the cloudless skies: A severe drought had wiped out the mosquitoes' breeding sites. No mosquitoes = no malaria. But theoretically, that respite should only have lasted until the next rainy season. It came and went, but still the malaria stayed away.

Philip Thuma thought he knew why. It had everything to do with what had happened on the ground versus in the skies. Thuma had always sought better drugs for treating malaria. He knew that antimalarial drugs were often problematic, especially in adults who rarely died from the illness.

"In the days when we had quinine, we used to say that you're supposed to take seven days of it, but by day three, you were so dizzy and your ears rang so much that you usually couldn't function and you had to go to bed," recalls Thuma, who has contracted malaria numerous times. "In those early days, it was sometimes hard to separate out the symptoms of the disease from those of the drugs."

Things only got worse when malaria became resistant to chloroquine in the 1980s and '90s. Then, in 2003, the Zambian government made a strategic decision to spend big dollars on a new antimalarial medication, artemisinin combination therapy (ACT), which promised fewer side effects and the opportunity for malaria-stricken employees to return to work far sooner.

In Macha, Thuma discovered that ACT also held the potential to stop the disease. He got his Zambian government connections to procure for him large doses of the medication, which he and one of his first Hopkins hires, Zimbabwean Sungano Mharakurwa, PhD, delivered directly into the community. What they found astounded them. Before artemisinin, other antimalarials were capable of killing the parasite that caused the disease and its symptoms. But there's a stage to which the parasites can mature—a reproductive stage where they become known as gametocytes—that survived such previous treatment. Infectious gametocytes can persist for months in people with asymptomatic parasitemia. Seasonal mosquitoes die off, but come back in the next rainy season, and have a human source of the disease all ready to ingest.

Artemisinin stopped this process, knocking out both the blood-borne form of the parasite that causes clinical symptoms as well as the asymptomatic gametocytes. Aided by a relatively new field technology, rapid diagnostic testing, Thuma and company could quickly identify and treat malaria carriers with artemisinin—and do it right in their homes.

"We would take malaria smears every six hours, to count the parasites and quantify them," says Thuma, who had conducted similar tests during numerous previous drug trials held at his hospital. "Suddenly, with this drug, those parasites melted away faster than anything we'd ever seen."

Relying on a coterie of chiefs, medicine men and other influential community elders, Thuma and Mharakurwa, along with Zambian field workers they trained, visited every hut they could in 2003, testing asymptomatic people for gametocytes. Screening these unknowing carriers and offering them drug treatment was, by Thuma's own admission, a controversial choice. Some argued that parasites' presence in the body offered some immunity against serious cases of malaria. Eliminate the parasites and that potential protection is gone, but so is the chance of reinfection.

"People are taught about Typhoid Mary in medical school," says Thuma. "I talk about 'Malaria Mary'—though it's not just women. [My] example: If there's a parent in a hut with five or six kids, if the mosquito bites an asymptomatic parent, and then, after the 10- to 14-day incubation period, that mosquito bites their kid and the kid gets sick with malaria, you'll treat the kid at the hospital, the kid will go home, and the same thing will happen again because you've never found the source."

Thuma had found and treated the source. By 2004, cases at the hospital had plummeted, and malaria was on the ropes. The question for both Thuma and JHMRI had now shifted: What could they do to knock malaria down to the canvas ...  and keep it there?

 ome of the most important translational research in Macha didn’t happen in the lab, or the creeks and huts that dot the countryside, but rather on Philip Thuma’s veranda. It’s there at the end of a hard day’s work that some of the numerous JHMRI researchers and their Zambian counterparts gather. Ostensibly they come to eat—half of Thuma’s house is the communal kitchen for the compound (“My wife is chief cook and I’m head bottle washer,” he laughs)—but a few stragglers usually make their way to the porch as the sun goes down and the enemy, those damned mosquitoes, start pinging off the veranda’s enclosing screens. That’s the kind of omnipresent buzz that can turn thought into action. 

And so it has. Over the past six years, JHMRI researchers and postdocs have made numerous trips to Macha. By studying both Thuma’s work and greater Macha, they’re hoping to develop a transferrable one-two punch: Prove that there’s a way to knock down seasonal malaria to just a few cases, and then track those cases back to the homes where the disease was initially transmitted to treat asymptomatic patients who are parasite carriers. In and around this, investigate the effectiveness of control efforts such as insecticide-treated bed nets and mosquito larvae eradication programs.

Thuma says the largest body of publications in the 2004–2007 period came from mosquito vector expert Douglas Norris’s team, including then doctoral student Rebekah J. Kent. Kent collected 31 different mosquito species in Macha, discovering that one, Anopheles arabiensis, was the primary vector for transmission. “No one had studied mosquitoes in that part of Africa for many years,” says Thuma.

Thuma and his JHMRI colleagues understand the irony of what’s going on in Macha now. With malaria cases at an all-time low, some researchers and funders might be tempted to shift attention to other diseases. Clive Shiff, an MMI associate professor, says that would be a mistake on several fronts, noting that another mosquito malaria vector, An. funestus, was wiped out in the Macha area during the 2003 drought but could return in any given rainy season. On a more practical level, cash-strapped African governments could spend far fewer dollars if they attacked malaria when it was relatively quiescent—if they only knew where to look.

“None of the African countries where malaria is endemic can afford these long-term, high-cost control programs,” says Shiff, of the massive mosquito spraying and drug distribution efforts some health ministries have used in the past when malaria cases soared out of control. Moreover, he notes, “this is not a good time for donor countries to reach into their pockets and come up with another billion dollars.” Shiff’s goal? “[Find ways] of reducing the costs by about 80 percent, so you can focus at specific times of the year on critical parts of the population.”

Working with Thuma and parasitologist Mharakurwa, JHMRI’s faculty and several young Zambian scientists have made significant potential inroads to creating such efficiencies in Macha in just a few short years. Their efforts combine fieldwork with the latest communication and satellite technologies. Amplifying on the work of Doug Norris’ team, Greg Glass and Clive Shiff determined that An. arabiensis was particularly fond of breeding in clean streams of slow running water. They also learned An. arabiensis could only travel 450 meters from its birthplace to feed, an important factor in targeting control efforts aimed at humans.

Glass took the finding one important step further: He used satellite imaging and modeled the hydrology to elegantly map likely breeding sites (see sidebar). Armed with knowledge of the mosquito’s flying range, Glass drew concentric circles around these bodies of water to come up with a relative bull’s-eye of those most likely affected: people who lived or worked inside the ring. Shiff is pulling the treatment net even tighter: He and team members Aniset Kamanga and Gillian Stressman are finding and treating asymptomatic adults.

These findings were an impressive start at establishing some kind of controls that might be reproducible elsewhere. This past July, the National Institute for Allergy and Infectious Diseases (NIAID) designated JHMRI as an International Center of Excellence in Malaria Research (ICEMR), in part because of the Institute’s work with Thuma. Part of the multimillion dollar, seven-year ICEMR grant will strengthen the Macha collaborative, allowing Hopkins researchers to better share and implement their ideas with other ICEMR grantees studying endemic malaria in Asia, Latin America and the Pacific Islands.

JHMRI director Peter Agre says the money may allow the research in Macha to move more quickly into wider practice. “This is, I think, a big story waiting to unfold,” Agre says of Thuma and Hopkins’ work. Over the past decade, Macha “has led all the clinical activity in their district. They’ve gridded it via satellite technology, identified every hut, measured the hut, estimated the number of people living in the hut, identified the presence of water nearby—it’s all fully defined.” During the rainy season, Agre notes, researchers led by Zambians Aniset Kamanga and Petros Moono developed a cell phone text messaging system between mobile field clinics and JHMRI’s Macha data collection center to communicate and record who is diagnosed with malaria and where. After the rainy season, health care workers return to look for and treat carriers. “This may be the most important advance,” says Agre, a Nobel laureate. While looking for asymptomatic carriers may seem obvious in retrospect, he says, “people hadn’t done it because it required an investment. But now, with modern molecular diagnostic tests, we can identify who is carrying the parasite.”

Agre says that with the ICEMR grant, Macha—and what’s discovered there—will be juxtaposed against two other field sites; Nchelenge, Zambia, just a stone’s throw from the border with Democratic Republic of Congo, an area where epidemic malaria has never been controlled; and Mutasa, an area of Zimbabwe once under control but now devastated by the disease. “Macha is our reference point where malaria is coming under control, and Phil’s a principal in all our international activity [in Africa]. So we have a good series of viewpoints to establish whether the Macha experience can be transferred,” says Agre.

For his part, researcher Bill Moss, MD, MPH, believes that at least part of the Macha model will benefit other areas. Moss, who is investigating the epidemiology of symptomatic and asymptomatic malaria, gametocytemia and changes in immunity in Macha, says that while different regions may have different epidemiological features, the work done in Macha could yield more efficient, exportable control efforts. He points to Doug Norris’ investigations identifying vectors and their behaviors: when they like to feed (day vs. night), where (indoors vs. the fields), on whom (men vs. women, children vs. adults) and for how long (a quick rush at dusk vs. an all-night bite-a-thon). If it’s found that a vector bites during the day and outdoors, Moss says it might be less effective to distribute insecticide-laden bed nets for indoor use. Overall, says Moss, an Epidemiology associate professor, “I don’t think it will be a complete model that’s translatable from one area to another, but I would hope we could understand what the key factors are that you need to know in a particular area”—in order to arrive at the best package of malaria control interventions.

While investigations mature under the ICEMR grant, one thing is already clear to JHMRI’ers and Phil Thuma: The man’s mission can and will go on, perhaps long after he’s hung up his shingle. “He’s created capacity building,” Peter Agre says of Thuma’s little miracle in the middle of nowhere. Agre believes that Thuma’s model may convince Zambian health officials to go where they’ve rarely gone before: accelerating an academic track for homegrown PhD-level researchers—who bring a passion that comes from personal awareness of the devastating disease—and making sure they get paid a reasonable wage.

That’s the type of passion Phil Thuma can understand. Outsiders may see him as unique, but he insists he’s not. Well, maybe a little. “I’m like Don Quixote. I tilt at windmills. If there’s a problem, I’ll invest myself and work hard at it,” says Thuma. “I was raised by my Dad, who said, ‘You need to leave the world a better place.’”

Somewhere, you have to believe Alvan Thuma is smiling.