Although humans share most of their genes—and many analogous diseases—with chimpanzees, these close relatives are not likely to blame for the menace of human malaria, according to new genetic research.

Malaria kills some one million people worldwide each year and sickens another 350 million to 500 million. In recent years the origins of this disease, the most common and deadly form of which is from the protozoan parasite Plasmodium falciparum carried by the Anopheles mosquito, had been winnowed down to the chimpanzee.

But after a new molecular analysis of more than 2,500 primate droppings sampled in central Africa from primarily wild chimps (Pan troglodytes), bonobos (Pan paniscus), eastern gorillas (Gorilla beringei) and western gorillas (Gorilla gorilla), a team of researchers has concluded that the modern human P. falciparum has its closest correlates in a variety found in western gorillas, not chimpanzees.

"When we first saw it, it was a surprise," says Beatrice Hahn, a professor of medicine and microbiology at the University of Alabama at Birmingham and co-author of the new paper, which was published online September 22 in Nature. (Scientific American is part of Nature Publishing Group.)

Although the findings contradict a 2009 report published in Proceedings of the National Academy of Sciences co-written by Nathan Wolfe, a visiting professor of human biology at Stanford University, he is excited about the results.* "It's nice to have higher resolution," he says. His group had not examined gorillas as a possible point of origin, and he notes that the new work "helps to push the field forward."

One bite
The new research proposes that the human P. falciparum malaria parasite variety emerged from a single cross-species transmission event.

This single-bite theory "would suggest that there is a hurdle to go from apes to humans," Hahn says. And because in many places humans and primates live in close proximity, a more easily crossed barrier would likely have given rise to novel human infections on multiple occasions, she explains.

But the findings do not rule out the possibility that less harmful primate varieties of Plasmodium are making their way into the human blood stream from time to time. "Are there transmissions going on on a lower level that we don't recognize?" Hahn asks. She suggests that many of these infections might have avoided detection because they do not infect other humans. And with standard clinical diagnostic practices, most of which are based on laboratory slide analysis, "you wouldn't be able to identify" great ape varieties of malaria, Wolfe points out. It is likely that most Plasmodium species "would look pretty similar" under the microscope, he says, noting that scientific studies typically rely on genetic analysis that provides a much higher level of species-specific detail.

New burdens
One of the big debates about the origins of malaria in recent years had been whether the parasite emerged in human populations—and then spread to great apes—or whether it had been in human and great ape lineages for eons, Wolfe says. The new paper "cements the great ape origin of human malaria," he says. But it throws a wrench in the time line of human malaria's origin.

"We really don't know how fast or slow Plasmodium parasites evolve," Hahn points out. Previous analyses of chimpanzee malaria parasite Plasmodium reichenowi had suggested the human variety P. falciparum likely split off some seven million to five million years ago. The new findings suggest that the human variety likely emerged less than 300,000 years ago (and possibly as recently as 5,000 years ago), she says.

The landscape of human malaria might also be a clue to its age. "Despite the fact that there's so much human malaria, there's a remarkably limited diversity of human malaria parasites," Wolfe says. He suggests that with explosive human population growth, the opportunistic parasite "expanded with us." The picture of malaria species diversity in chimpanzees and gorillas looks very different. "There's a jumble of relationships between these parasites in chimpanzees and gorillas," he says. The new analysis found at least nine closely related Plasmodium species in wild chimpanzee and western gorilla populations. This pattern, he notes, is similar to what researchers are uncovering about various types of HIV, which is now thought to have originated from both chimps and gorillas.

Diversity in droppings
Hahn and some of her co-authors are relatively new to the malaria field. She came to work after studying simian immunodeficiency virus (SIV), the closely related primate version of HIV. Her research showed that contrary to popular assumptions SIV was increasing mortality in many chimpanzees, so she and a team of researchers set out to find any comorbidities that might increase these infected primates' risk of dying. Malaria, although apparently less pathogenic in other primates, seemed an obvious choice.

Once she and her team got wind of a study showing that malaria parasites could be isolated and genetically analyzed from animal droppings, "we knew we were in business," Hahn says.

Stocked with shelves of frozen primate feces, the group is ready to move on to study the origins of Plasmodium vivax, another human malarial parasite, which is found in Latin America and Asia in addition to Africa.

New genetic research will help narrow down genes involved in malarial transmission and allow researchers to compare and contrast genetics in humans and apes. Simple trends of pathology, too, will be important to uncover, Hahn notes, such as whether ape infants are also more susceptible to malaria and whether the parasite causes pregnancy complications, as it does in humans.

The long-sought goal of malaria eradication could have unintended impacts on the parasite's evolution, however. If most current forms of the human malaria parasite are eliminated, "it's possible we open a niche for other parasites to move in," Hahn points out. That type of emergence "can have a major public health impact," she says. And the ever-growing list of known primate parasite species might mean future infection possibilities are greater than we had previously realized. "The diversity of the existing natural reservoirs makes the possibility that there are parasites that can jump into humans" greater, Wolfe says.

But just knowing the number and names of species in the wild will not likely halt future epidemics. "It is probably simplistic to think that describing what is out there in nature will permit disease emergence to be forecast with any accuracy," Edward Holmes, a biologist at the Center for Infectious Disease Dynamics at The Pennsylvania State University, wrote in an essay published in the same issue of Nature. That predictive shortcoming is in large part because "successful emergence also depends on aspects of pathogen genetics and epidemiology," he noted.

Nevertheless, Hahn notes, "It's important to understand how these microbes probe constantly to potentially colonize new hosts." Just like any other species, she says, "they want to survive."

*Correction (9/24/10): This sentence was edited after posting. It originally stated Nathan Wolfe's title as professor of epidemiology.