‘Mad Cow’ Disease: Is It a Prion or a Virus?

At first, Carol Marie Vanetti had trouble walking. Then came the long pauses in her conversations. One day she became so dizzy a friend called 911.

The doctors sent her to UC San Francisco for tests.

The diagnosis: The 58-year-old retired Stockton school counselor had Creutzfeldt-Jakob disease, an ailment similar to the “mad cow disease” plaguing cattle in Great Britain.

In two weeks, she fell into a coma. In two more weeks, Vanetti was dead.

That was in April, on the heels of the scare in Great Britain in which some scientists attributed 10 deaths there to eating beef tainted with mad cow disease. Those cases have transformed Creutzfeldt-Jakob from an obscure, one-in-a-million disease to worldwide worry.

Until now, Creutzfeldt-Jakob--which annually strikes about 250 people in the United States, usually killing them within a year--had been primarily an intriguing enigma to researchers.

In the past couple of decades, the uncommon family of afflictions that includes mad cow and Creutzfeldt-Jakob diseases has unveiled what appears to be an unexpected and unique mechanism of transmitting illness.

According to current theory, the diseases are caused not by the usual suspects--viruses, fungi or bacteria--but by misbehaving proteins dubbed prions (pronounced PREE-ahns).

The diseases eat away at the brain, like an accelerated form of Alzheimer’s. Whatever causes the diseases is not very infectious but is very hardy, able to survive high temperatures, radiation and many harsh chemicals in the laboratory.

But researchers cannot explain how infectious prions supposedly travel from contaminated food in the digestive tract to the brain. They don’t even know what the normal functions of the prion proteins are.

If the puzzle’s remaining pieces fall into place, a Nobel Prize could await the man who put together the crucial portions of the current understanding: Dr. Stanley Prusiner of UC San Francisco.

Prusiner’s view, while widely accepted, is not without detractors. Another school of researchers maintains that the diseases are caused by viruses, just ones that haven’t been found yet.

“It’s all speculative,” said Yale University neuropathologist Dr. Laura Manuelidis of prions. “So far they haven’t come up with any positive data to show it’s correct.”

The mystery of these diseases dates back centuries to when farmers in Europe noticed some of their sheep and goats stumbling around. Because the animals constantly scraped against fences and trees, the farmers called the disease scrapie.

In 1959, William Hadlow of the National Institutes of Health noticed similarities between scrapie and kuru, which afflicted women and children of the Fore tribe in New Guinea. Both diseases perforate the brain tissue with microscopic holes.

A couple of years later, NIH researchers traced kuru to the tribe’s ritualistic cannibalism of the brains of deceased relatives. Experiments in which kuru-infected human brains were injected into the brains of chimpanzees caused similar microscopic holes to appear. Because kuru can lie latent for decades before symptoms appear, researchers called it a “slow virus.”

Over the years, scientists identified other “slow virus” diseases, including Creutzfeldt-Jakob and related disorders that strike mink, elk and mule deer.

Four facts, however, didn’t jibe with the notion of a virus causing these diseases:

* Even after being baked in the lab at over 500 degrees Fahrenheit, diseased brain tissue remains infectious. Most viruses fall apart at temperatures hotter than 140 degrees. Dipping the tissue in chemicals that usually dismantle a virus’s genetic code also did not stop the disease, nor did radiation.

* At least 10% of Creutzfeldt-Jakob cases appear to be inherited. It would be very unusual for a virus to target all of the members of certain families, while ignoring almost everyone else.

* Experiments indicated that the infecting particle was too small to be a virus.

* No one has found any of the genetic material a virus would contain. Bacteria, viruses and fungi all have either DNA or RNA, the blueprint information that allows them to reproduce.

It was these discrepancies that in 1982 led Prusiner to his novel hypothesis of a rogue protein. In the years since, Prusiner and his collaborators have built up a promising, but not conclusive, body of experimental evidence.

They have found the protein they believe responsible for the diseases. They have shown that this prion protein has a virtually unique property among proteins: It can take on more than one shape. How a protein works and what it does is largely determined by its shape.

In the normal configuration, the prion protein goes about its business in the brain in a quiet fashion (although the exact function of a normal prion has yet to be determined).

Certain people, however, possess a faulty gene that produces a slightly different prion protein, one much more likely to shift to a diseased, misfolded, shape.

With billions of cells in the brain, a handful of delinquent proteins would not be enough to cause much damage.

However, according to the theory, the prion proteins are capable of transforming their normal companions into their own deadly image. Two bad prions become four. The four become eight. And so on.

The process starts slowly, explaining the long delay between infection and symptoms. When the symptoms finally do reveal themselves, the geometric doubling of prions rapidly destroys the rest of the brain.

Except for the diseases’ devastating end effects, Manuelidis and other critics don’t buy the idea of rampaging proteins. “I’ve never known any infectious agent that doesn’t have [DNA or RNA],” Manuelidis said.

She points out there are viruses that can survive hot temperatures. The hereditary component may be a defect that makes some people more susceptible to the virus. And finding a virus within a brain cell is not an easy task. Not having found it is not proof it is not there, she says.

In mice genetically engineered to produce human and mice versions of prion proteins, injecting misfolded human prions did not trigger the disease. Prusiner and his co-workers now hypothesize that another protein--dubbed protein X--helps in the Mr. Hyde transformation.

The virus hypothesis, Manuelidis said, “is a lot simpler. . . . Clearly, people in the field have a variety of opinions.”

The prion proponents maintain that the critics, by poking at the details, are missing the larger picture: No known viruses can survive all of the conditions that prions can.

“For any one piece of data, she’s right,” said Dr. Fred Cohen, UC San Francisco pharmacology and medicine professor and one of Prusiner’s collaborators. “[But] if you take all the data put together, you can’t fit the viral model.” (Since an unflattering 1986 article in Discover magazine, Prusiner himself has rarely talked directly to the press.)

However these diseases work, they wreak horrible havoc.

They make microscopic Swiss cheese of the brain’s gray matter--holes a few hundreds of a millimeter in diameter and often widening by a factor of 10 in the final stages. Sometimes the diseased prions clump together on the brain’s cerebellum into tiny spiked balls that look like sea urchins.

Generally, Creutzfeldt-Jakob disease first announces itself through memory lapses, problems in speaking and emotional changes. “It’s the same thing that can occur with Alzheimer’s disease,” said Dr. Stephen DeArmond, another of Prusiner’s UC San Francisco collaborators.

The last six weeks of Carol Marie Vanetti’s life followed this pattern.

“At first she would know you, but it would be difficult for her to talk,” said her brother, Ralph Sanguinetti, who visited her two or three times a week. “Then she would be happy to see you and smile. At the end, she could not even recognize you. She deteriorated very rapidly--almost by the hour by then.”

The British cases deviated from traditional Creutzfeldt-Jakob disease in several important respects. The victims were young--on average, 27. Usually Creutzfeldt-Jakob strikes late in life, in the 50s or 60s. Under the microscope, the disease looked different, too. The spiked balls of protein showed up throughout the brain, not just the cerebellum.

“It’s a whole new variant,” DeArmond said.

Researchers on both sides of the prion debate hope they can resolve the prion versus virus question relatively soon.

At UC San Francisco, Prusiner and company are working to build the disease-causing version of the prion proteins from scratch. If they can show that pure proteins can cause the disease, that should answer the remaining critics.

“That’s the one thing that’s keeping Stanley Prusiner from the ultimate prize,” DeArmond said, referring to the Nobel for medicine.

At Yale, Manuelidis says she will disprove Prusiner’s ideas and find the virus “if God loves us. . . . If something is there, we have a shot at it in the next year or two.”

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How Mad Cow Diseases May Function

Creutzfeldt-Jakob and related diseases appear to be caused not by bacteria, fungi or viruses, but by renegade proteins called prions.

1. According to the theory, the prion protein can occasionally refold itself from its normal, useful form into a shape that causes the diseases.

2. The renegade protein then attacks other normal prion proteins and induces them to refold into the disease-causing shape.

3. The process continues, eventually building the renegade proteins to dangerous levels. The disease appears to attack the brain’s synapses, disrupting its ability to send messages back and forth.