When a sheep scrapes itself against fence posts, grinds its teeth and shakes its head, and finally stumbles and falls, the diagnosis is clear: it has scrapie, a deadly degenerative brain disease that is endemic in European flocks. The suspected cause of scrapie is as strange as the symptoms. Like several closely related diseases--mad cow disease, for instance, and Creutzfeldt-Jakob disease and kuru in humans--scrapie has been attributed to tiny infectious particles called prions. And prions, unlike viruses or bacteria, are believed by many researchers to be nothing but proteins: they appear to contain neither DNA nor RNA, the stuff of genes and of procreation. So how do prions reproduce and spread the disease? Researchers at the National Institute of Allergy and Infectious Diseases (NIAID) and at MIT may have found a solution to this decades-old puzzle. Prions, they say, seem to reproduce through a kind of evangelism: they convert harmless proteins into more prions.
Prions have been known for some time to be deviant versions of a harmless protein that is found on the surfaces of most mammalian cells, and particularly in the brain. (It may be involved in signaling between nerve cells.) The two forms of the protein consist of the same chain of amino acids folded in different ways. In the normal protein the amino-acid chain is coiled into delicate helices; that protein dissolves in water and is easily broken down by enzymes. Prions, in contrast, consist mostly of sticky, pleated sheets that don’t dissolve in water, aren’t broken down by enzymes, and tend to clump together inside a cell. Eventually they kill the cell, perhaps by simply blocking its molecular traffic.
In the process, say biochemist Byron Caughey of NIAID and his colleagues, the prions recruit the normal protein to their cause. The researchers showed as much through a simple experiment. First they tagged the normal protein with a radioactive label. Then they mixed it with unlabeled prion protein isolated from scrapie-infected hamster brains. After two days’ incubation, they added an enzyme that digested all the normal protein in the mixture, leaving only prion proteins. But some of those prion proteins were evidently new converts: when exposed to a fluorescent dye, they made it glow--indicating that they carried the radioactive tag Caughey’s group had originally put on the normal protein.
How does a prion corrupt its counterpart? In Caughey’s somewhat speculative scenario, the prions are like flat bricks that form a wall inside a cell, and the normal protein is a brick bent in the middle that wouldn’t ordinarily fit in the wall. But the normal protein is flexible--it can bend back and forth. Now suppose you have this brick wall of flat prion molecules, and there’s a nice open slot, says Caughey. And this flexible bent brick comes down and contacts that site, which is probably sticky. That bent brick is flexing back and forth between the bent state and the flat state. But as soon as it flops into the flat state, its contacts with all the bricks around it will hold it there. The new prion is far less vulnerable to degradation by enzymes than is the normal protein. Once you lay it in the brick wall, says Caughey, you could hit it with a sledgehammer all you want and it will remain totally untouched.
The brick-in-the-wall scenario is unproved, of course; Caughey still needs to show, for instance, that his converts are full-fledged prions that can themselves convert more proteins. But the scenario at least offers one explanation of how prions might cause disease without violating the laws of biology--and also how they manage to be involved in both genetic and infectious diseases. In the case of an inherited disease like Creutzfeldt-Jakob, the first crusading prion is made inside the body; it’s produced by a genetic mutation that may simply make the normal protein more likely to flip into the pathogenic prion form. But the first prion may also be an infectious agent that comes from the outside, as in the case of the mad cow epidemic that struck Britain in the mid-1980s. That scourge was traced to something the cows ate: a protein supplement that included the remains of scrapie-infected sheep.