KURT WUETHRICH
Steffen Schmidt  /  AP file
Kurt Wuethrich, a Nobel-prize winning professor at the Federal Technical Institute in Zurich, Switzerland, shows the prion proteins of humans and cows in this July 10, 2000 file photo.
By Chief medical correspondent for NBC News
updated 1/13/2004 8:33:38 PM ET 2004-01-14T01:33:38

Just what are prions?  You've probably heard they are the infectious agents that transmit mad cow disease among cattle and from cattle to people. You may have also noted the frightening description of proteins indestructible by heat, radiation and most of the techniques used for sterilization.

And now the latest news:  One kind of prion seems to make up a critical part of the mechanism our brains use to form memories. The first evidence for this startling connection appeared by coincidence in the prestigious journal Cell just one day after the U.S. government announced the discovery of the first mad cow in this country -- but more about memory later.

Much about prions remains unknown. They are responsible for almost three centuries of medical mystery that is still unraveling. Scientists have viewed them with intense curiosity ever since realizing they were the cause of a set of seemingly unrelated brain-destroying diseases among animals and people.

Scrapie, CJD and kuru
English farmers noticed the first of the prion-related diseases -- scrapie -- in the mid-eighteenth century.  Sheep with scrapie first go wild then attempt to rub off their wool and skin by scraping against rocks and posts until they eventually die, usually a few months after symptoms appear.

In the early 1920s, two German neurologists Hans Gerhard Creutzfeldt and Alphons Maria Jakob described the condition that bears their names (Creutzfeldt-Jakob disease or classic CJD) in which humans undergo profound psychological and physical degradation then certain death as portions of their brains disintegrate. The condition seems to strike about one in a million people in all cultures around the world for no apparent reason. Classic CJD is different from the similarly named disease known as variant CJD, which is transmitted to humans through eating contaminated beef.

In the mid 1950s, Dr. Carleton Gajdusek, an American physician, led a team of scientists studying the Fore people of New Guinea, some of whom suffered from a disease called kuru, which is very similar to CJD. The disease struck only those who ritualistically ate the brains and other organs of dead relatives.

By the early 1960s, scientists had realized that the brains of sheep with scrapie and humans with either kuru or CJD shared a similar sponge-like appearance. They also found that they could transfer all three diseases to laboratory animals by inoculating or feeding the animals portions of brain from an infected person or sheep.

A naturally occurring protein
But what was the agent that transferred the infection?  Experiments indicated it was pure protein, a finding that stood in stark contrast to biological dogma including the most modern molecular understanding. Biologists knew that diseases could be transmitted only by viruses, bacteria, parasites or some form of life that contains genetic material (DNA or RNA), allowing it to multiply in the infected host.

Opposition to the idea of an infectious protein was intense and the debate raged for years.  Stanley Prusiner of the University of California at San Francisco, who came up with the name "prion," offered the final proof in 1985. He showed that not only were prions the infectious agent involved in neurological diseases such as scrapie and CJD, they were a form of protein that occurs naturally –- and most of the time harmlessly -- in all mammalian cells.

What was the purpose of this natural prion?  No one knew, and for the most part prions appeared to be a curiosity responsible for a disease of sheep, a condition afflicting human cannibals, and a tragic but very rare disease that struck humans spontaneously –- at least most of the time.

Connection to human growth hormone
In 1974, a U.S. woman who had received a cornea transplant came down with CJD and research indicated the cadaver donor was the source of the infection. As a result, scientists learned that even though CJD arises spontaneously, once a person gets the disease their tissues become infectious. 

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This was another scientific curiosity to be sure, but still of little public health concern because CJD is so rare that one in a million adds up to only a few hundred cases a year in the United States.  But fear began to increase in 1985 — the same year as Prusiner’s genetic discovery -- when children who had received injections of human growth hormone began to get CJD. The growth hormone was extracted from the pituitary glands (a part of the brain) pooled from hundreds of human cadavers.

A total of 17,000 children worldwide, including 7,000 in the United States, were given the injections. At first there was enormous fear that they would all develop CJD, but to date only about 170 of those worldwide — 26 in the United States -- have been diagnosed with the disease. Still, many live in terror because the observations of the New Guinea cannibals and lab experiments prove that the incubation period for CJD can be decades. (Nowadays human growth hormone is genetically engineered and does not carry a danger of CJD.)

The arrival of mad cow
It was also in 1985 that the first mad cows appeared in Britain. Until then, no such disease had been known to exist in cattle.

There is little question that the animals got the disease (called bovine spongiform encephalopathy or BSE) by eating prions in the brain matter and other organs from animals boiled down as a cheap source of feed. But, to this day, researchers don’t know if the original source was scrapie from sheep or a spontaneous prion that appeared in the brain of a British cow and was then amplified through massive cattle cannibalism.

To researchers' best knowledge, scrapie in sheep had never naturally infected another species. This is why some British scientists and politicians assured the public that there was no danger from eating infected beef – assurances that lasted until the first cases of what is now called new variant CJD struck people who ate the meat.

As with concerns over human growth hormone, initial fears about the size of the mad cow epidemic seem to have been exaggerated. Some scientists predicted the number of human cases could be in the tens of thousands. The best estimate is that some 900,000 infected cows made it into the British food supply, but to date there have been only 143 cases of the human disease in Britain. Each is a tragedy to be sure, but those numbers provide some of the best reassurance about the scope of the danger in the United States where one mad cow has been found.

How prions transmit disease
But how does the prion transmit the disease? This is a puzzle with many of the pieces still missing. The key seems to be that most of the time the natural protein is folded into a tight ball, one of two shapes the proteins can assume. It is when the prion unfolds into the second, more linear form that it becomes dangerous.

When an unfolded prion touches one of the proteins in the folded state, the second one  unfolds setting off a chain reaction. One molecule after another unravels. It is similar to crystals of ice spreading through a glass of water as the water falls below freezing temperature. An unfolded prion that enters the brain of a person or animal that has eaten infected tissue sets off a massive process of unfolding that turns the entire brain into a spongy remnant of itself.

But the prions can also unfold spontaneously on their own. This seems to be the cause of classic CJD that strikes one in a million people worldwide.  As the transplant and growth hormone cases prove, a spontaneous case becomes infectious if a piece of tissue from the victim’s body finds its way into someone else's body. Thus, the best theory of how kuru arose in the Fore people of New Guinea was that a spontaneous case of CJD eventually spread though the tribe by cannibalism.

The ultimate purpose of prions?
Clearly prions did not arise during our evolutionary development for the sole purpose of destroying brains. That's where the new memory research comes in.

It turns out that the transformation from the folded to the unfolded state of prions makes for a perfect on-off switch. And right at the synapse -– the connection between nerve cells -- there is a kind of prion that seems to be switched on when a memory is created.

This is a new idea so far proved only in experiments involving sea slugs and yeast. But it is tempting to speculate that disease-causing prions are really memory-creating prions somehow gone amok. We don't know this for sure, but in dealing with prions it is important to remember that there is much we don't know.

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