Prions, the misfolded proteins that can wreak havoc on the brain, are slowly surrendering their secrets. First identified in the late 1980s as the culprit behind mad cow disease (Creutzfeldt-Jakob disease in humans), investigators have spent the past 25 years trying to determine how these agents can turn an orderly cellular network into a tangled mess full of holes.

A research team at the University of Alberta has shed new light on this process, thanks to some advanced imaging technology. Holger Wille, an associate professor of biochemistry, and his colleagues have employed a technique known as cryo-electron microscopy to reveal the structure of prions in unprecedented detail. What they found was a key distinction in the sheet-like structure of the helical peptides that make up infectious prions, which lacked a capped edge. That means when healthy prion proteins encounter the edge of this structure, they can then acquire the same misfolding, along with the potential to continue spreading this change.

Although the mechanics sound straightforward, visualizing them has taken considerable effort. Electron microscopy has long been a workhorse technology to achieve high resolution of inorganic specimens but complex organic targets break apart under the bombardment of electrons used to produce the image. Only in the past few years has a new approach made it possible to reduce the number of electrons passing through a target and still obtain useful data. 

By flash-freezing a sample, proteins or other organic specimens are not stained or fixed but retained in what should be their natural state. As few as 10 electrons per square angstrom are passed through the target, which until recently has hardly been enough for a couple-charged device to assemble a coherent picture. However, complementary metal-oxide chips have transformed these digital cameras into direct electron detectors that can now capture almost every last information-carrying electron. “Cryo-electron microscopy is gaining a lot of attention as a structural biology technique because we can now reach atomic resolution,” says Wille.