Michael Glenwood

A Double Dose of Hope

Story by Melissa Hendricks

On an autumn morning in his lab at the Johns Hopkins Malaria Research Institute, Jürgen Bosch gets down to work.

He removes a pencil-sized metal wand from its case and places it on his lab bench to the left of a light microscope. He hoists a heavy container of liquid nitrogen and pours some into a foam dish. Fog billows from the frigid liquid. Then he sets a plastic laboratory dish underneath the microscope’s lens. The dish is divided into 96 wells.

Bosch takes a seat, interlaces his fingers and stretches out his arms so that his knuckles crack. “Okay,” he says. “Now comes the fun part.” He wheels his chair in close to the lab bench, picks up the wand and peers into the microscope.

Jürgen Bosch’s drug by design and David Sullivan’s brute force approaches could not be more different, but they may soon converge.

The object of his attention?

A protein crystal, about one ten-thousandth of a meter long, delicate and brittle. The protein comes from the malaria parasite Plasmodium. Bosch, PhD, an assistant professor of Biochemistry and Molecular Biology, is studying the structure of this protein and others like it to design new malaria drugs. This work involves growing crystals in laboratory dishes, and then plucking individual crystals from the dishes and flash freezing them in liquid nitrogen.

Through the lens, two crystals come into view, floating in their salt/sugar bath. They resemble rectangular blocks but with more sides. Bright streaks of green and red light reflect off their mirrored surfaces.

Slowly, Bosch angles the end of the wand toward the crystal. At the end of the wand is a fine nylon loop visible only under magnification. Bosch gingerly moves the wand to bring the loop directly over one crystal. He allows it to hover there a moment, until the surface tension of the fluid in the loop sucks up the crystal.

“Got one.”

An Elusive Foe

Antimalarial drug research has had lifesaving success stories. Scientists have generated several highly effective agents for treating or preventing the disease—including chloroquine and pyrimethamine-sulphadoxine, and, most recently, chemical derivatives of the plant-based drug artemisinin.

However, resistance to popular antimalarials such as chloroquine has rapidly spread worldwide, and there have been reports in some regions that the artemisinin derivatives are taking longer to clear the parasite from the body (not true resistance but enough to vex health officials). And no one has produced and marketed a new class of antimalarial in 15 years.

There are 225 million clinical cases of malaria each year. The most deadly parasitic disease, it causes nearly 800,000 deaths per year—and the majority of those deaths occur in young African children. Malaria accounts for approximately one out of five child deaths there.

With the looming specter of drug resistance reducing treatment options even further, scientists are seeking new drugs to add to the malaria medicine chest.

At the Bloomberg School, two  scientists are employing radically different strategies. Jürgen Bosch is using a relatively new strategy called structure-based drug design. He makes crystals of different protein components of Plasmodium and uses a technique called X-ray crystallography to determine their structure. Using the structure as a sort of cast for a mold, he then designs small molecules that will fit in certain gaps, grooves or crevices of the proteins, bind there and inhibit the parasite.

His colleague David Sullivan, MD, associate professor of Molecular Microbiology and Immunology (MMI), is using more of a brute-force approach: Pull a drug off the shelf, aim it at the parasite and see if it kills.

While the two schemes differ significantly, they also have something in common: Both look great on paper, but neither comes with a guarantee that it will work against an opponent that has eluded medicine time and time again