The malaria parasite has been studied for decades, but surprisingly, little is known about how it behaves in humans to cause disease.
In a groundbreaking study published November 28 in the advance online edition of Nature, an international research team has for the first time measured which of the parasite's genes are turned on or off during actual infection in humans, not in cell cultures, unearthing surprising behaviors and opening a window on the most critical aspects of parasite biology.
That insight springs from the genomic analysis of parasites in their natural state, derived directly from patients residing in Senegal, and also from the researchers' use of innovative computational approaches to interpret their results. These computational methods helped to identify three distinct biological states of the malaria parasite: an active growth-based state, a starvation response and an environmental stress response, presumably related to the body's inflammatory response to the parasite. This physiological diversity was previously unknown and may help explain the widely varying course of the disease in different patients, from mild, flu-like illness to coma and even death.
“For the first time, we have glimpsed the biology of the malaria parasite in one of its most important environments — humans,” said co-senior author Aviv Regev, a core member of the Broad Institute of MIT and Harvard and an assistant professor of biology at MIT. “Our unique computational approach holds promise not only for understanding the malaria pathogen, but likely other important microbes as well.”
“This work illustrates the true power that comes from developing the right computational methods and applying them to important biomedical problems,” said co-senior author Jill Mesirov, director of Computational Biology and Bioinformatics at the Broad Institute of MIT and Harvard. “Even more importantly, it reflects scientific research at its best — a global effort that brings together clinicians and researchers with diverse expertise, working directly with patients in areas hardest hit by disease.”
In its natural state, the malaria parasite, Plasmodium falciparum, leads a complicated life. It proceeds through a series of distinct developmental stages both in humans and in mosquitoes, the main vector for disease transmission. Malaria researchers typically circumvent this complexity by studying the parasite in cultured cells. Yet in this artificial setting, few differences have been found in the genes that are turned on or off in various strains of P. falciparum. That uniformity is surprising, because it fails to explain the drastically different courses experienced by malaria patients.
To explore the basis for these differences, first author Johanna Daily, an infectious disease physician at Brigham and Women's Hospital, assistant professor of medicine at Harvard Medical School, and a researcher at both the Harvard School of Public Health and the Broad Institute, set out to observe P. falciparum in its natural environment: the human circulation. Using small samples of blood collected from more than 40 malaria patients in Senegal, Daily and her colleagues worked meticulously to devise a method for isolating genetic material from parasites, allowing them to determine which of the nearly 6,000 P. falciparum genes are switched on or off during infection in humans. Importantly, all of the patients involved in the study harbored similar-looking parasites, yet their symptoms varied widely.
These clinical research efforts were led by Professor Souleymane Mboup and Dr. Daouda Ndiaye at Cheikh Anta Diop University. “This project would not have been possible without the dedicated work of our collaborators in Senegal,” said co-author Dyann Wirth, a professor and chairman of the department of immunology and infectious diseases at the Harvard School of Public Health and the co-director of the Broad Institute's Infectious Disease Initiative. “We are grateful to them and to the many malaria patients who generously volunteered to participate in this study.”
From the parasites in patients' blood, the researchers simultaneously measured the activity level, or “expression”, of every P. falciparum gene. Co-author Elizabeth Winzeler, an associate professor at The Scripps Research Institute, led this aspect of the study. “The ability to look across the parasite's entire genome was essential,” said Winzeler. “We uncovered extraordinary things about parasite biology — things we could not have even imagined.”
Winzeler, who is also head of malaria research at the Genomics Institute of the Novartis Research Foundation (GNF), where much of the genomic work was performed, is grateful that organizations like GNF choose to encourage these types of high-risk studies. “We are especially excited about using these observations to guide our drug discovery efforts,” she said.