Pitted Against Parasites

In his fight against a pathogen that shares much of our biology, James Morris is developing a creative way to turn a parasite’s own evolutionary adaptations against itself.

By Jill Sakai
Photography by Craig Mahaffey ’98

Seen through a microscope, the tiny creatures twirl and twist, their whiplike flagella keeping the beat of their graceful dance. But that elegance belies the threat they hold. These single-celled marvels are Trypanosoma brucei, the African trypanosome, and if they were to get into your bloodstream, they would trigger muscle aches, chills, confusion and — if not caught in time — death.

Transmitted via the bite of an infected tsetse fly, T. brucei causes sleeping sickness and threatens millions of people, mostly in sub-Saharan Africa. Existing treatments require two weeks of intravenous drug administration with toxic side effects. But without treatment, the infection is lethal.

James Morris sees both the biological allure of the parasites and the potential for a better way to kill them. As a Clemson professor of genetics and biochemistry, he is studying these creatures with an eye toward developing an easier, safer and more effective treatment.

KNOW YOUR ENEMY

Targeting a pathogen is rarely simple. Researchers must first identify a biological strategy to block, cripple or kill the pest, then find a chemical compound able to carry out the desired attack — and, critically, that can then be formulated into a medicine.

But T. brucei poses an additional challenge. Unlike bacteria and viruses, trypanosomes are eukaryotes, which means that their cells are built and organized much like those of animals. It also means that we have a surprising amount in common, biologically, with this single-celled wiggler.

“Our challenge is that we, and other mammals, share a lot of features with the trypanosome,” explains Morris. “We share a lot of biochemical and cellular pathways. So you have to be careful, as you might imagine. Targeting one of those organisms and one of their pathways — without hitting the host — becomes a big challenge.

“It’s sort of like fighting cancer [in that] you have to kill the parasite or fungus before you kill the host,” Morris says.

Finding potential ways to attack eukaryotes, then, requires a delicate touch. Fortunately, Morris is in good company. As part of Clemson’s Eukaryotic Pathogens Innovation Center (EPIC), a unique, collaborative facility that brings together researchers targeting pathogens as diverse as amoebas and fungi, he is surrounded by colleagues who share some similar challenges and strategic approaches.

And in the process, he’s finding a way to turn an unusual aspect of the parasite’s own biology back on itself.

James Morris sees both the biological allure of the parasites and is studying these creatures with an eye toward developing an easier, safer and more effective treatment.

PARALLEL LIVES

T. brucei splits its life cycle between two hosts: a mammal such as a human or a cow, and a tsetse fly. The mammal-dwelling form multiplies in the bloodstream and spreads throughout the brain and other organs. When a tsetse fly bites an infected mammal to get a blood meal, it sucks up the parasite as well. The trypanosome divides in the insect gut, then makes its way into the bug’s saliva, ready to hitch a ride to a new mammalian host when the fly gets its next meal.

The two hosts present very different physical living environments. Imagine being suddenly sucked from a host in the American Southeast and spat out into the Arctic tundra. Different surroundings, different climates, different strategies needed for survival. But this parasite has evolved to adapt to the abrupt shift by assuming different forms tailored for each host.

One crucial environmental difference is blood sugar. Mammals have a relatively high level of glucose in their blood; tsetse flies have almost none. And sugar equals energy. Glucose is the primary energy source for the mammal-dwelling form of the parasite. When the trypanosome is slurped into the fly gut, the sudden absence of sugar is what triggers a quick switch into its insect-adapted form, which dines on a diet of bug amino acids instead.

It’s an impressive evolutionary adaptation. But what’s more, it’s an opportunity the researchers can exploit, Morris says. If, in a mammal, the researchers can find a way to make the parasite think it’s in an insect, they may be able to trick it into assuming the wrong form — and dying. A compound that can accomplish that in an infected person has the makings of a powerful treatment, he reasons.

“If you block glucose uptake, the parasite might perceive that as, ‘Hey, there’s no glucose around!’ and then fire off the developmental program to assume the insect stage in the blood, which would be very bad for the parasite,” Morris explains. “So it’s a win-win: You either starve them … or you force them to become a stage that can’t live in the mammal.”

This has become a cornerstone of his research program: targeting T. brucei’s ability to access glucose, in search of a new kind of anti-parasite treatment.

EXPANDING THE TOOLBOX

Currently, little is known about how trypanosome detects nutrients in its environment, nor how it uses that information to trigger the change between mammal- and insect-dwelling forms.

Trypanosome researchers have long recognized glucose as an important target, says Kenneth Christensen, a former Clemson professor of chemistry who is now at Brigham Young University. But the tools to study glucose systems — especially in living cells — have been limited. Christensen is now collaborating with Morris to develop novel ways to identify molecules that interfere with the parasite’s ability to get the sugar it needs.

Christensen helped create a set of biosensors that give a fluorescent readout of glucose levels in the parasite. By positioning sensors in different structures within the trypanosome, he and Morris can develop a nuanced view of how glucose moves through the cell. They also recently published a powerful screening assay that can rapidly scan thousands of living cells using a technique called flow cytometry.

Together, the new tools are driving a large-scale search for potential drug compounds that can disrupt glucose uptake in T. brucei or another widespread parasite called Leishmania. So far, the team has screened more than 25,000 small molecules. “We’ve found a few compounds that are potent against both trypanosomes and Leishmania, which is exciting.” Morris says, “Now, we have some work to do.”

“There’s an excitement in resolving some of the unknown out there,” he says. “There are certainly hurdles we have to overcome, but I think so far we’re off on the right foot.”

FROM DISH TO DRUG

The path from a promising hit in a molecular screen to a usable drug is long and often bumpy, Morris says. From their screen, they pick out compounds that block glucose uptake, then select those that, at a reasonable dose, also kill trypanosomes. These top contenders move on to the next step, being shaped into something that can be given as a drug.

For that, Morris turns to another of his collaborators, Jennifer Golden at the University of Wisconsin–Madison. As a medicinal chemist, Golden specializes in building molecular structures with the qualities necessary to be used as medicine.

“Compounds typically have to have a balance of different characteristics to make them a drug,” Golden explains. They must be potent, stable and soluble. They must maintain the desired biological activity. And they must be able to reach and act in the correct place in a patient’s body without being broken down or causing unwanted side effects along the way.

The best candidates that emerge from a screen are Golden’s raw material. She strips them down to identify the essential bits of the molecular backbone that give it the desired anti-parasite activity. Then she builds them back up by adding chemical groups with the needed drug qualities. “It’s an art of manipulating the structure, piece by piece, until you get to an entity that has all of those balanced parameters,” she says.

With their tools in place, the collaboration is poised to push the research to the next level. The combination of so many complementary skillsets should allow them to tease the process apart and look more precisely at where each compound interferes, Morris says, as well as begin to home in on individual proteins and genes of interest.

“There’s an excitement in resolving some of the unknown out there,” he says. “There are certainly hurdles we have to overcome, but I think so far we’re off on the right foot.”

Jill Sakai is a freelance writer in Wisconsin.

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