Thirty years ago, in the internal-medicine ward at the Hospital of the University of Pennsylvania, Thomas Wellems came face to face with his life’s work. He was a junior resident, a couple of years out of medical school, when several patients showed up at the hospital with malaria, which they’d caught while traveling in Africa. “And it was cerebral malaria, the kind that puts people in comas, puts them in the intensive care unit,” says Wellems, PhD’80, MD’81. “When I saw that, I said, ‘My god. This is just a terrible disease.’” A parasite that most Americans regarded as all but extinct suddenly became, for Wellems, an obsession. By the time his residency ended, he was waking up every morning thinking about malaria. “It was something that went to my bones.”

Like many of humanity’s deadliest diseases, malaria almost certainly predates us. Evidence from mosquitoes fossilized in amber suggests that the pathogen may be tens of millions of years old, and descriptions of malaria go back almost as far as the written word. In 2700 BC, China’s Nei Ching (The canon of medicine) outlined some of its symptoms; more than 1,000 years later, Sanskrit medical treatises connected fevers with insect bites; ancient Romans wrote about the disease arising from the swamps surrounding their city. Around 400 BC, the Greek physician Hippocrates documented malaria’s distinct stages, noting how its paroxysms rose and fell, how the illness progressed from chills to fevers, to sweats, to “crises.” Once widespread across the globe, malaria has withered civilizations and altered the course of wars. In the 17th century it hindered the settlement of the American colonies from Massachusetts to Georgia and laid waste to Europeans in Africa.

Quinine, the first large-scale drug to fight malaria, appeared in 1820, extracted by two French chemists from the bark of the Peruvian cinchona tree. Native Quechua—and later Spanish conquistadors and Jesuit priests—had used cinchona trees for centuries to treat malaria, grinding the bark into powder and mixing it with drink.

Quinine was effective, but its side effects could be brutal, and in 1934 another drug was developed, a cheaper, less toxic alternative called chloroquine. By the 1940s chloroquine had replaced quinine as the mainstay against malaria, and along with DDT—a powerful insecticide not yet known to be a dangerous pollutant—it became part of a worldwide campaign to eradicate the disease. “Chloroquine was the principal drug of the 20th century against malaria infections,” says Wellems, who now heads the Laboratory of Malaria and Vector Research at the National Institutes of Health. “And that knocked back malaria—gave it a reasonably good knock.”

Then came resistance. The first reports of chloroquine failing to clear malaria infections in some patients came out of Southeast Asia and South America in the late 1950s. By then the parasite had been expelled from Europe and North America, but in other parts of the world it remained a persistent, prevalent threat. In 1978 the mass campaign to rid the world of malaria “just stopped,” Wellems says, abandoned in part because of widespread resistance to chloroquine. Infection numbers began to creep back up to where they are now: the World Health Organization puts the number of malaria cases at 250 million per year. Wellems estimates it’s higher, between 300 million and 500 million. “The numbers are so big they’re hard to get a good handle on,” he says. His estimate of yearly deaths, one million, stands at the upper edge of the Centers for Disease Control’s range; the WHO puts the number of deaths at 655,000. “You’ll find opinions vary among epidemiologists,” Wellems says.

A few years after the campaign to eliminate malaria was suspended, those sick patients arrived at the Philadelphia hospital where Wellems was a second-year resident. He’d never encountered malaria up close like that, never seen with his own eyes how it could devastate the human body. Malaria often begins with flu-like symptoms and jaundiced skin, but untreated it can cause central nervous problems, liver and kidney failure, shock, coma, death. “Full-blown malaria can happen within a day, from a fever to a person being in serious trouble, prostrate, and going into coma,” Wellems says. “I’ve got a deep respect for this disease.”

Already, he had crossed paths with malaria in the library and the laboratory—as a PhD student at Chicago, Wellems studied the crystals and fibers of hemoglobin structure, especially in sickle cell disease and in sickle cell trait, a genetic mutation of one hemoglobin allele, common in places like Africa, South America, and Southeast Asia, because it offers an evolutionary adaptation against malaria. “In malarious areas, a child under five without access to medicine has about a 25 percent chance to die from malaria,” Wellems says. “That’s the mortality rate. But a single mutation in the hemoglobin confers a resistance, about 90 percent resistance, to deadly malaria.” Children with the sickle cell trait are 30 percent more likely, he says, to survive an infection.

Originally Wellems thought he might study malaria for better insight into sickle cell hemoglobin, “but that was backwards, wasn’t it?” In 1984 he took a research fellowship at the National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. One of his first projects was an unsolved—and seemingly unsolvable—mystery, which would consume the next 16 years of his life: chloroquine resistance.

In the early 1980s, chloroquine resistance wasn’t so much a mystery as a black hole, into which scientists hurled one vanishing theory after another. “You can go back to that period and look at the literature, and you’ll see dozens of ideas about how chloroquine was working and how the resistance mechanism might be operating,” Wellems says. Malaria grows within red blood cells. “So, biochemically and physiologically, the experiments to work with the parasite were very difficult. It’s buried within membranes within membranes, because it’s an intracellular parasite. And you couldn’t get many of them out using the techniques at the time, so there were issues of contamination and purity. People had come to dead ends.”

That predicament reminded Wellems of Max Perutz, the molecular biologist who in 1937 set out, using X-ray crystallography, to decode the structure of hemoglobin, the protein that carries oxygen and carbon dioxide through the bloodstream. It was a bewilderingly difficult task—scientists had used X-ray crystallography to decipher the structure of inorganic compounds like table salt, a molecule composed of only two atoms. But living proteins like hemoglobin, with their complex tangles of atoms, stymied them.

“It was a marvel … to read Perutz’s assessment of the hemoglobin structure problem as a possibly forlorn undertaking,” Wellems said in a 2009 address to the American Society of Tropical Medicine and Hygiene, of which he was then president. The talk, titled “Optimism, Persistence, and Our Collective Crystal Ball,” cited a paper Perutz published in 1948, when he was still more than a decade away from a solution. “He had no clear route yet to the protein structure—in fact, his model at that time would prove wrong,” Wellems said. But Perutz kept going, inching along his tenebrous path. At last, in 1959, he uncovered hemoglobin’s structure, a breakthrough that opened the world of proteins, the basic machinery of living organisms, to science.

As Wellems stood at the foot of his own mountain in the mid-1980s, his climb must have seemed no less steep than Perutz’s, his path no less murky. He wanted to figure out how chloroquine resistance worked, which gene within Plasmodium falciparum—the most fatal form of malaria—enabled it to repel the drug, and how. But the scientific tools required to do all that didn’t yet exist. “At that time it was just a glimmer,” Wellems says, “but it had such promise and such potential power that I was totally captivated.”

His plan was to engineer genetic crosses of the parasite, breeding a resistant strain with one that still responded to chloroquine, an experiment he expected would reveal the inheritance of the resistance, its genetic locus within the parasite. Without advanced genetic techniques, he would have to complete the malaria parasite’s full life cycle: introducing it into mosquitoes and then into chimpanzees, and finally recovering the crossbred malaria progeny from the chimpanzees’ blood. “And just like Gregor Mendel, and the Drosophila fruit fly people, and the yeast people, look at the progeny of that cross, map the different drug-resistant response types that come through, and then find the genes that control those response types.” Old-fashioned genetics mixed with contemporary molecular biology.

“It was a dream far on the horizons,” Wellems says. “We didn’t even know the number of chromosomes yet in the parasite. That’s how primitive genetics was. But it sure seemed possible.”

It was. In 1987 Wellems had the beginnings of the cross between the sensitive and resistant parasites. It would take another 13 years to identify the gene: a transporter called ​­PfCRT, which carries chloroquine molecules out of the parasite’s digestive vacuole, reducing its concentration. Wellems published the findings in 2000. Along the way he and his fellow researchers had to sort out several problems—how to clone the parasite and separate its chromosomes, how to build detailed genetic maps and search through the genes. And all the while, genetic and biological technology was galloping forward, catching up. Says Wellems, “It’s been a golden era.”

Since the discovery of PfCRT, scientists have been looking for ways to modify chloroquine’s structure so that it’s easier for the drug to elude the transporter gene’s clutches. “We call it ‘exploring chemical space,’” Wellems says. Meanwhile, he’s focused on other drug-resistance problems that have “blossomed.” One is chloroquine resistance in Plasmodium vivax, malaria’s less-virulent form, which is debilitating but less often deadly. During World War II, relapses of vivax malaria plagued American servicemen stationed in the South Pacific, and almost a century earlier the same disease had met homesteaders on the American frontier as they pushed westward. “Vivax was responsive to chloroquine longer than falciparum was,” Wellems says, but in the past 20 years, and especially the last ten, chloroquine resistance has spread. Wellems is part of the effort to unravel the reason why. “As the devil would have it, the vivax resistance mechanism is different from the mechanism in falciparum.” And because vivax can’t be grown in vitro, building the genetic cross to find the genes involved in resistance, Wellems says, “may take us another ten or 15 years.”

At the same time, he’s working on emerging resistance to ACTs—artemisinin-based combination therapies—a group of drugs derived from the herb Artemisia annua, or sweet wormwood, which herbalists in ancient China used to treat fevers. In the 1970s Chinese scientists extracted the antimalarial compound artemisinin from the plant, and ACTs now replace chloroquin. “I think every major malarious country today recommends ACTs as first-line therapy,” Wellems says. The bad news: in Southeast Asia, especially Thailand and Cambodia, some malaria strains have stopped responding to the drugs. “So we have an emerging threat, and a pretty big one,” Wellems says. “If we lose ACTs, malaria control and elimination programs stop dead in their tracks. And we don’t have an effective backup drug.” Losing chloroquine “was a huge blow. This’ll be a double blow.”

Wellems is also engaging would-be Perutzes in medicine’s fight against malaria. Since 1999 he has served almost continuously on the advisory council for the Medicines for Malaria Venture (MMV), an international partnership between pharmaceutical companies and myriad public entities: government labs, university labs, nonprofits, NGOs. The idea is “to identify drugs for malaria that might otherwise not be brought into development,” he says. Scientists from university labs, medical institutions, and biotech companies from across the globe come to the MMV seeking support for drug development projects. Once a project is funded, the MMV regularly evaluates its progress, following every step along the way, until the drug is brought to market or discontinued, a process that takes years. “You can imagine what happens with a lot of these drug candidates,” Wellems says. “It’s a large gauntlet that they must go through. And there’s attrition all along the path. So you’ll see that 90, 99 percent of these candidates lose their way and fail.” In the remaining 1 percent, of course, there is hope for saving millions of lives.

After almost 30 years chasing malaria from continent to continent and chasing its genes from lab culture to lab culture, Wellems says the most science can hope for is to stay one step ahead of the bugs. “It’s like an arms race, or tit for tat, or thrust and repartee,” he says. “The organisms we’re dealing with, they almost seem to have a collective intelligence about them.” Sometimes, he says, in the fog of exhaustion at the end of his workday, “I almost imagine that they’re figuring out the way they’re going to deal with our latest efforts. They’re in their laboratories too.”

Read “The Picture of Health” to learn more about Adam Nadel’s (AB’90) and his work.