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By Carol Schmidt, MSU News Service

BOZEMAN – A team of Montana State University mathematicians has made a key contribution to new research that indicates that malaria parasites operate on their own internal time “clock” rather than being triggered by the circadian rhythms of their host.

Tomas Gedeon, professor of mathematics, Bree Cummins, assistant research professor of mathematics, and Robert R. “Riley” Nerem, a former graduate student in the MSU Department of Mathematical Sciences, provided mathematical tools to analyze data for the research team. The results of the team’s research, which uncovered internal rhythms in malarial parasites, will be published in the May 15 issue of the journal Science. Steven Haase, a biology professor at Duke University, was senior author of the article, "An Intrinsic Oscillator Drives the Blood Stage Cycle of the Malaria Parasite, Plasmodium Falciparum.” The research may have implications to better treat the deadly disease.

Gedeon said science has long known that malaria’s telltale cycles of fevers and chills are caused by successive broods of parasites that attack and then multiply in sync inside red blood cells, bursting out in unison every 40 to 48 hours.

The research found that, in four strains of the parasite, that pattern — described in the paper as having the regularity of a metronome — does not rely on time cues from the host. Rather, the pattern is coordinated by genes within the parasite, a sort of timekeeping mechanism that ticks of its own accord and causes thousands of parasite genes to ramp up and down at regular intervals.

Gedeon said the long-term goal of the research is to disable these “clock” genes in malaria, which may help combat the mosquito-borne disease, which has proven increasingly resistant to existing drugs.

Cummins, who helped develop the mathematical models used by the team, said the finding is exciting because of its possible applications, which may help patients better overcome the malarial clock.

“What that means is the parasite would burst out of the blood cells asynchronously, and the immune system could mop them up without terrible malarial fevers,” she said.

Haase wrote that the research’s applications could lead to new drugs to treat the disease, which threatens half the world’s population. According to the Centers for Disease Control and Prevention, in 2018 an estimated 228 million cases of malaria occurred worldwide, killing 405,000 people — mostly children in Africa. About 2,000 cases of malaria are diagnosed in the U.S. each year, according to the CDC.

Gedeon said the work that resulted in the paper began with another longer-term study by the Defense Advanced Research Projects Agency, or DARPA. The research team has studied periodic processes in living organisms since 2012, eventually leading to the examination of the oscillating rhythms in malaria because the causes of the timing of the symptoms of the disease were not understood.

The work published in Science examined data gathered from four strains of malaria at Walter Reed Army Medical Center. The red blood cells were examined in petri dishes and were, therefore, removed from the host’s circadian rhythms. A parallel study published in the same issue of Science looked at the disease in mice.

The researchers noted that, even without cues from a host, all the parasites within a given strain kept in step. Roughly 90% of the genes they examined appear to be clock-controlled, rising and falling in a predictable fashion, and with a sequence of gene expression that repeats itself, over and over.

Haase said that the team is now looking into whether there is crosstalk between the malaria parasite and the rhythms of the cells of the human immune system.

“If we can figure out if and how the malaria parasite synchronizes the ticking of its clock with that of its host,” Haase said, “we might be able to disrupt those signals and help the human immune system better fight these invaders.”

Cummins said next steps also include analyzing the clocks in more strains of malaria.

“We have a way to go,” Cummins said. “We know there is an internal clock but don’t know what the parts are made of. The next steps will take massive amounts of data as we see what is important in the parasite.”

Gedeon credited Cummins and Nerem with developing the algorithm that helped analyze the gene expression oscillations in the parasite. Nerem, also a co-author of the paper, is currently a doctoral student in physics at the University of Calgary.

Elizabeth Burroughs, head of MSU’s Department of Mathematics in the College of Letters and Science, said that Cummins and Gedeon have been at the forefront of mathematical modeling of biological systems for a long time.

“The current environment has heightened public awareness of how mathematical modeling contributes to scientists’ and physicians’ understanding of and management of diseases that affect human health. I’m really proud of how Dr. Cummins and Dr. Gedeon are tackling the worldwide problem of malaria through their modeling work,” Burroughs said.

In addition to DARPA, the research cited in the paper is supported by the National Institutes of Health and the National Science Foundation.