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Prions are proteins. They are infectious. And they can outlive the garden-variety pathogen.

     


One Heretical Hypothesis
The rise of mad cow has caused an explosion of research into the TSEs (Want The Why Files guide to mad-cow lingo?). The causative agent has some remarkable properties.

It's tiny, able to pass through a filter that stops most viruses.

It's tough, able to survive thermal, radiation and chemical treatments that kill bacteria and viruses.

It's not a nucleic acid. Nucleic acids are the basic component of DNA and RNA, the chemicals that carry life's genetic code. Viruses, bacteria, and just about every other infectious agent contain either DNA or RNA.

beta amyloid protein Prions are sometimes compared to beta amyloid protein, which form brain insoluble plaques in Alzheimer's disease. In its normal, soluble shape, amyloid protein causes neither plaque nor disease.
Courtesy Manuel C. Peitsch, Glaxo Institute of Molecular Biology, Geneva, Switzerland.
In 1982, Stanley Prusiner, a biochemist at University of California at San Francisco, suggested a radical idea: the agent was a rogue protein -- a "prion." Unlike all agents known to cause infectious disease, this agent contained neither DNA nor RNA.

Proteins are huge, complex molecules whose function is heavily influenced by shape. Prusiner hypothesized that normal prions twist into a shape that both causes disease and, chain-reaction fashion, distorts other prions into a new shape, which has new and dangerous properties.

Many biologists deemed the hypothesis heresy. Proteins are workaday molecules that reflect genetic coding; a response to, not a carrier of, information. And since proteins don't reproduce, how could they "multiply" and cause disease?

Don't blame a virus
As virologists searched in vain for a viral explanation for the disease, Prusiner and his colleagues gradually built their case. Today, although a few scientists consider prions a marker rather than a cause of TSEs, the prion hypothesis is well accepted. "It's becoming really clear that the agent is this abnormal protein; it's not formally proven but almost all the data we have supports this idea," says Judd Aiken, a TSE researcher at the University of Wisconsin-Madison. He says most scientists "are proceeding on the assumption that abnormal prions are the sole cause of disease" in TSEs.

However, plenty of basic questions remain: Although normal prion sits on the surface of cells in the nervous and immune systems, its function is unknown -- Aiken suggests it may be involved in binding metals to cells. And exactly why "good" proteins distort into "bad" remains to be tracked down.

Still, lots has been learned about prions and TSEs in the past few years.

Latest research

Neurologist John Collinge at St. Mary's Hospital in London recently reported that mice which received prion-infected extracts of mouse brain had diseased prions in their brains, even though they did not appear ill. The mice infected other mice, satisfying one of the Koch postulates on the causation of disease. (Want to jump ahead for coverage?) While some observers deemed it not cricket to extrapolate from rodents to larger animals, the study did raise the danger of "silent carriers" of TSEs (see "Experts Downplay..." in the bibliography). Independent prion scientist Tom Pringle likened the situation to Typhoid Mary, an English woman who spread the disease even though she didn't have symptoms.

Dutch veterinary pathologist Lucien van Keulen used an immune-marking technique to map scrapie infection in sheep. After five months, prions accumulated in lymph tissue and nerve fibers in the small intestine. After 10 months, nerves serving other organs were affected. By 17 months, the spinal cord was involved, and by 26 months, the animal was dying of scrapie (see "Prions: A Lone Killer..." in the bibliography).

Prions can change for the worse over time. Aiken, for example, passed a mink TSE, identified by the late University of Wisconsin-Madison virologist Richard Marsh, through hamsters, and found that the agent acted faster in successive generations. The first hamsters to receive the mink TSE generally outlived the disease, which took hundreds of days to incubate. When brain material from those hamsters was injected into other hamsters, the disease struck faster. By the third generation, there was a "tremendous shortening -- it has adapted to the new species," Aiken says. Why did it take two to three passages for the agent to stabilize? Because, as Marsh had suggested years ago, two strains of prions existed in the first passage, with the long-incubation prion predominating. After a couple of generations, however, the faster-acting prion grew dominant (see "Adaptation and Selection..." in the bibliography).

French researchers showed that two sections of aberrant prion killed mouse nerve cells by disturbing the cell membrane (see "Neurotoxicity of..." in the bibliography).

New research into the inherited form of CJD shows that aberrant protein causes massive apoptosis -- programmed cell death -- in the cerebellum (see "Accumulation of Protease..." in the bibliography).

The prospects for treating TSE seem to be improving. Knowing that prions replicate in immune cells early in the disease could allow early treatment, according to French neurovirologist Dominique Dormont. Drugs that affect immune cells have improved survival among rodents experimentally infected with scrapie or BSE (see "Prions: A Lone Killer... " in the bibliography). However, Aiken cautions that veterinary drugs that slow the onset of TSEs only work if used before symptoms appear, and the disease cannot be detected at that stage.

Why me worry?
We've stressed that neither BSE nor vCJD has been detected in the United States. Before you sign off, read the "glass is half-empty" side of the argument. And do check this photo essay of a CJD victim.

Scientists are gaining new respect for the infectivity of aberrant prions. A recent British report indicated that a chunk of prion-laced meat as small as a peppercorn could infect a cow -- and that thousands of British cows were infected simply because cow feed was contaminated by pig feed while being handled in grain mills.

Furthermore, Marsh, at the University of Wisconsin-Madison, diagnosed dozens of cases of TSEs among farmed mink in Wisconsin in the 1980s. When he learned that the mink had been fed food prepared from "downer" cows -- cows that had died for unspecified reasons. Marsh concluded that the most likely cause of their illness was BSE among those cows.

Independent biologist Tom Pringle, who runs the Official Mad Cow Disease Home Page, sees plenty of reasons for concern. "I'd say it's just a matter of time before cases show up" in the United States, he says, through one of three mechanisms:

Being infected while living in England or Europe.

Using medical products made from European-derived animal products.

A home-grown eruption of BSE among U.S. herds, due either to contaminated feed, or a spontaneous appearance of BSE.

By insisting that the diseases have never been seen in the United States, Pringle adds, the industry and government have set a high standard that will guarantee panic if the diseases do appear.

But spread is the order of the day: the day before The Why Files spoke with Pringle, the London Sunday Times published a list of 70 countries that had received contaminated animal products from Great Britain, and the list included the United States. "In North America," Pringle says, the reaction among regulators and industry "has basically been denial. I feel a very powerful group has drawn a line in the sand -- just as the tide is about to come in."

And while the Centers for Disease Control and Prevention does fund an effort to detect BSE and vCJD, the budget is only $100,000, and the center receives only 40 percent of the nation's cases of CJD -- which could allow victims of the human version of mad cow to slip through the cracks.

We've not seen a guide to exactly what can carry CJD and what won't. However, prions mainly or entirely affect spine and brain tissue, and so the risk of eating whole cuts of meat, like steak, are far less than for hamburger, which is more likely to contain bits of tissue from central nervous system. There is no indication to date that milk is infectious.

One more reason to fret. What about prion disease among elk and deer?

 

   

 

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