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Image courtesy of USAD
New solutions crystallize for malaria research
by Niki Boyd
This year, malaria will infect at least 300 million people; of these, more than 1 million will die. Anopheles mosquitoes transmit malaria by releasing the parasite into a person's blood. Within six days, an infected person can experience chills and fever; in severe cases, seizures, kidney failure, a coma, or death. More and more countries are plagued with strains of malaria resistant to antimalarial drugs. Consequently, after a decade, these drugs can become obsolete. "The malaria parasite is extremely adaptive - it adapts so that it can survive" says Dr. Scott Bohle, a chemistry researcher studying antimalarial drugs at McGill University.
During the 17th century, Italian physiologists discovered that patients who died of bad air, "mal aria", had organs spotted with dark pigment. This black, crystalline powder is known as malaria pigment. It is made by the parasite from molecules in the host's blood called haem. "Haem is toxic to the parasite so it must be converted to malaria pigment for the parasite's survival," says Bohle. In the 1980s, scientists recognized that antimalarials kill the parasite by preventing the formation of this pigment. Exactly how this occurred was anybody's guess, which made development of new antimalarials a daunting task.
Dr. Bohle believed that the key to understanding this problem lay in uncovering the structure of the malaria pigment. This pigment is every chemist's nightmare. "It is hard to isolate, poorly suited for structural experiments, and incredibly difficult to dissolve," says Bohle. His solution was to show that malaria pigment and an easier to work with synthetic compound were identical, then identify the structure of the synthetic compound. Bohle used a technique called powder diffraction which directs intense X-ray radiation towards a crystalline powder to understand the shape of the crystals. For a powerful enough X-ray source, he travelled to Brookhaven National Labs in New York. Competition is fierce for use of the light source - "beamtime" as it is called. In a cinematic turn, a hurricane caused a power blackout the afternoon Bohle was to start his experiment; the radiation source returned at 5:00 a.m. the next morning leaving Bohle a mere six hours of beamtime.
Bohle raced against the clock to finish the experiment and his results challenged some deeply entrenched theories in his field. Scientific dogma held that malaria pigment was made of repeating units of haem - in essence, a polymer. Bohle was able to show that malaria pigment is not a polymer at all, but simply two haem units - a dimer - joined together.
How has this helped in understanding how antimalarials work? Bohle's collaborators from the Washington School of Medicine in St.Louis have shown chloroquine, a well-known antimalarial, attaches onto malaria pigment crystals preventing their further growth. This causes the buildup of haem which leads to death of the parasite. Through Bohle's work, we now know exactly how this drug binds onto the surface of malaria pigment; more importantly, knowing the structure of this pigment makes it much easier to develop new antimalarials.
Bohle is optimistic about the future of malaria research. The genome of the parasite was published last year, opening the field to a slew of new researchers. This sets up a rich collaborative environment for veteran antimalarial researchers like Bohle, who plans to work in conjunction with molecular biologists at MacDonald campus to attack the problem from a different angle.
Dr.Scott Bohle is funded by NSERC and the Burroughs Wellcome Foundation