Prions: When Proteins Attack

(Wired) In the novel Cat’s Cradle, an eccentric scientist develops a substance called Ice-9 that crystallizes every drop of water it touches. Eventually, it freezes the world’s oceans. Now, 40 years after writer Kurt Vonnegut imagined Ice-9, researchers think his creation is the perfect analogy for the renegade proteins that destroy the brains of people infected by the human form of mad-cow disease.

Once prion diseases infect a body, the proteins change shape and, with a kiss of death, turn their neighbors into clones of themselves. Clumps of misshapen proteins form, overwhelming neurons and poking holes in the brain. Death is inevitable.

This much scientists know. And this much is nearly all they know. Despite decades of study and high-profile outbreaks among beef eaters and cannibals, researchers are still mystified by the workings of a small group of diseases that turn prions — normally benign proteins present in all human brains — into killers.

“These are highly unusual diseases in many ways, and there are still a lot of questions, about everything from their long incubation period to the question of the actual infectious agent itself,” said Stephen S. Morse, director of the Center for Public Health Preparedness at Columbia University. “This is compounded by the difficulty of studying this.”

Part of the problem is that prion diseases don’t fit into the usual categories of infectious illness. Normally, diseases from the outside world set up shop in our bodies after we come in contact with a bacteria (strep throat), a virus (AIDS) or a fungus (athlete’s foot). Once an infection begins, our immune systems swing into action, and often we realize we’re sick because our lymph nodes swell up, our noses run or our digestive systems get temperamental.

Not so with prion diseases. Researchers haven’t found a single germ or bug that causes them, and the immune system appears to snooze right through the infection. “Prion diseases seem to represent a whole new class of infectious agent,” said Byron Caughey, an investigator who studies prions at the National Institutes of Health.

Prions (pronounced PREE-ons) are one of countless types of proteins found in normal cells, and are at the center of the mystery. Scientists, who identify proteins by their shapes and molecular structures, know the job descriptions of many of them: Some act like bricks in the structure of a cell, while others help cells carry out chemical reactions or communicate with other cells. Prions appear to be important since there are so many of them in our brain cells, but, like the boss’ son-in-law, their role in the whole organization is unclear.

In fact, one British researcher found that genetically modified mice without prions look and act exactly the same as other mice. “You can’t talk to a mouse, and maybe it’s lacking in some function, but as far as (the researcher) could tell, the mouse was perfectly normal,” said David Eisenberg, who studies prions at the University of California at Los Angeles.

“But it could be that the tests one could perform on the mouse aren’t sensitive enough to reveal the differences,” he said.

There was an important difference, though: Without prions to call their own, the mice couldn’t come down with prion disease.

People, of course, aren’t so lucky. At least two kinds of prion disease infect humans who eat the wrong thing — variant Creutzfeldt-Jakob disease, apparently caused by eating meat from cattle infected with mad-cow disease, and kuru, which infected members of a New Guinea tribe of cannibals. It’s not clear how infected prions make their way from food to the brain of a victim.

But you don’t have to chow down on a Quarter Pounder or your second cousin to become ill. So-called sporadic Creutzfeldt-Jakob disease, the most common type of prion disease, seems to develop on its own. Like its sister illnesses, it’s invariably fatal, striking an estimated 200 Americans each year. By contrast, the variant Creutzfeldt-Jakob disease linked to mad-cow disease has killed 153 people, almost all from Britain, since it was first discovered in 1995.

Once a human is infected with Creutzfeldt-Jakob disease, the renegade prions rampage through the brain, changing the shapes of other prions so they can no longer be “recycled” by cells. Surrounded on the inside and outside by globs of prions, brain cells collapse, perhaps by killing themselves through an internal suicide program. As this happens, the brain under a microscope begins to look like Swiss cheese or a sponge, full of holes. (Hence the name “spongiform,” which describes several types of prion diseases in people and animals.)

In humans, symptoms begin to appear, frequently beginning with depression or psychosis and leading to difficulty walking, strange body sensations and involuntary movements. Before they die, patients lose the ability to move and speak.

There are no simple tests to diagnose prion diseases. As with Alzheimer’s disease, which attacks the brain in a similar fashion, the only ways to confirm infection are through dissection of the brain after death or a risky brain biopsy.

Tests would be moot anyway, because there’s no cure or therapy available to treat a sick person. Like a small number of illnesses known as slow viruses, prion diseases lurk in the brain for years or even decades before anyone notices symptoms. The incubation period is thought to be six to 12 years for people who eat infected beef, perhaps because it takes time for the infected cow prions to adjust to humans, and as many as 40 years for kuru; long periods between infection and illness makes it especially hard to study prion diseases in laboratory animals.

Despite all the obstacles, the future of prion research isn’t entirely grim. In an intriguing twist, malformed proteins themselves are emerging as something less than verifiable villains. Last month, researchers announced that they’d discovered a protein in sea slugs and yeast that acts like deadly prions, but seems to have something to do with memory, not disease.

Scientists, meanwhile, are searching for ways to create a vaccine for prion diseases, a seemingly tough task considering that the infections don’t engage the immune system. Researchers also hope to develop screening tests to allow doctors to intervene with medications — although no one is sure what they would be — before the damage is done.

“We’re finding many drugs to test, and we’re hoping that will accelerate us greatly toward something that will work,” said Caughey of the National Institutes of Health. “But there’s no guarantee, and we’ve presumably got a long way to go.”