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To study the function of PfEMP-1 in malaria infection, Schofield needed a parasite with an inactive form of the molecule to compare its effects on the immune system with those caused by unaltered protozoa. Schofield collaborated with Cowman, a parasite molecular biologist who had been studying the biology of PfEMP-1, to design his experiment.
“Alan's always been interested in gene function and knocking genes out and knocking them in to examine the contribution of the different parasite molecules,” says Schofield. PfEMP-1 had been difficult to investigate because every malaria parasite contains 50 to 60 slightly different alleles, or variants, of the gene that encodes PfEMP-1. The protozoa's ability to switch these gene variants on and off allows it to escape detection by the immune system.
Cowman could not knock out all 60 genes. He did, however, engineer a P. falciparum mutant that switched off all PfEMP-1 expression.
Schofield exposed isolated adult white blood cells to unmodified, or wild-type, protozoa, and to Cowman's mutant P. falciparum. The mutant protozoa prompted a normal inflammatory immune response while the wild-type protozoa down-regulated INF-gamma and remained undetected by the host immune system. Schofield and Cowman published their results in the August 2007 issue of Cell Host and Microbe.
Next, Schofield intends to identify PfEMP-1's receptor in white blood cells. Then he hopes to design a field study that examines the response of white cells to wild-type P. falciparum or Cowman's mutant protozoa in children with different levels of susceptibility to disease. Schofield will incorporate this study into his ongoing program at the Papua New Guinea Institute of Medical Research.
At the Institute, Schofield's team works both on hospital-based studies with patients and on a longitudinal, population-based study with a group of children in Papua New Guinea. The researchers look at genetic variation within the group to learn how it might affect the children's immune function and their risk of developing malaria.
Schofield has been studying malaria for nearly three decades, since he was 21 years old. He says that he's kept his focus because of malaria's widespread impact. Although there is practically no malaria in Australia, the disease thrives in neighboring countries—along with Papua New Guinea, it is epidemic in Indonesia and East Timor. “That's one of the motivations,” adds Cowman, “It's a big problem. But also, scientifically it's incredibly interesting.”