An innovative new technique could finally lead to an early diagnostic test for diseases such as Bovine Spongiform Encephalitis (BSE), or "mad cow", and its human counterpart, variant Creutzfeldt-Jacob Disease (vCJD). Researchers say the results in lab animals, while encouraging, need to be replicated and note that competing tests are also under development.
BSE, vCJD, and several other neurodegenerative diseases are believed to be caused by so-called prion proteins, which can occur in two forms: the normal variety, called PrPc, and a misfolded variant that forms clumps in the brain (PrPSc). The diseases are infectious, most researchers think, because PrPSc has the peculiar ability to impose its abnormal folding on PrPc. So far, scientists can only detect prion diseases in the brain, after death. The problem is that levels of prions circulating in blood plasma are extremely low, so any test would need to be exquisitely sensitive.
In previous studies, Claudio Soto and colleagues at the University of Texas Medical Branch in Galveston had shown that they could amplify these minute amounts of prions in a cyclical process reminiscent of the way the polymerase chain reaction amplifies DNA (ScienceNOW, 21 April). The researchers added normal prion proteins to a sample in the test tube, let the misfolded proteins "convert" the normal ones, broke up the resulting clumps with a sound pulse, and then repeated the process over and over until the PrPSc became detectable with ordinary methods. In a new study published online this week in Nature Medicine, Soto and his colleagues show that a vastly optimized and automated version of their test correctly identified 16 out of 18 prion-infected hamsters, without false positives in a control group of 12 uninfected hamsters.
Perluigi Gambetti, who directs the National Prion Disease Pathology Surveillance Center at Case Western Reserve University in Cleveland, Ohio, has a few criticisms: The hamsters were infected by injecting the protein directly into the brain, for instance, which is "like creating a stab wound" through which protein may have entered the blood stream. Still, "this is a breakthrough," he says.
Replication is needed, says Paul Brown, a retired prion researcher at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. Other labs have had trouble achieving the prion amplification levels reported by Soto's group in previous papers, he says: "There's some nervousness about that." Soto acknowledges there were difficulties with replication at first but says these have largely been overcome.
Several competing tests are in the works as well, adds Jean-Philippe Deslys, who heads the Prions Research Group at the Atomic Energy Commission in France. Deslys says he has seen data on two promising ones that will be presented at an upcoming meeting. "It's really too early to say which test will be the best one," he says.