From Jones and Bartlett, a book on Stem Cells from Dr. Ann A. Kiessling and Scott C. Anderson:

Selected Articles:

January 22, 2004

The Mad Cow Jumps Over the Moon

Mad cow disease has led to an extraordinary new view of learning and memory.

The genesis of our national mad cow obsession is a fascinating story of adventure, discovery, ghoulishness and even happy endings. The story starts in 1955 with young Carleton Gajdusek, ten years out of Harvard, who was constantly on the lookout for new and unusual diseases. He found a remarkable one in New Guinea, among a tribe known as the Fore (pronounced for'-ay).

This unfortunate group of natives was being wiped out by a disease they called kuru, which meant trembling, one of the first symptoms of this uniquely dire condition. As the disease progressed, the victim's speech became disrupted and their bodies started to spasm, as if hit by electric jolts. Near the inevitable end, in the most macabre manifestation of the disease, the victim became bed-ridden, convulsed with mirthless laughter. Finally, deep sores developed and they died in great misery. The progress was like a lottery; some died in 2 years, others took dozens.

At first, Gajdusek suspected a genetic disease, but rejected the hypothesis when he could find no familial patterns. Whatever kuru was, it paid no heed to heritage - it was an equal opportunity killer. Stranger still, there was no accompanying inflammation. The body was not fighting back at all. How could such a devastating disease completely elude detection by the immune system?

As diseases go, it was a standout, as awful and deadly as Ebola, but even more enigmatic.

Here Comes the Yucky Part

To solve the mystery, Gajdusek moved in with the tribe, learned their language and soaked up their lore. It was an eye-opener. The Fore, he would quickly learn, had a most unpleasant habit of eating their dead relatives. They consumed every morsel - including the brain, which was scooped out by the women of the tribe and fed to their hungry children.

Gajdusek did autopsies on some of these kuru victims and noticed that their brains were mushy. He made a serum from the brain tissue and injected it into monkeys. When they came down with a similar disease, he quickly recommended that the Fore tribe stop eating their relatives. In a few years kuru disappeared from the Fore, and thus from the face of the earth.

For Gajdusek's brilliance and tenacity, he was awarded the 1972 Nobel Prize for Medicine. Gajdusek wasn't able to identify the infectious agent, but he learned a lot about it. He found that it was tiny, even smaller than a typical virus. Most astonishing was how robust it was. He dosed it with disinfectants, zapped it with microwaves, soaked it in enzymes and cooked it, but still it remained infectious. No one had ever seen such an indestructible infectious agent, and it was quite sobering. Merely studying this disease started to look downright dangerous.

Other researchers started to notice that kuru seemed to have a lot in common with scrapie, a disease that affects the brains of sheep and goats, causing them to scrape against fences, among other anomalous behaviors. Similarities were also noticed to Creutzfeldt-Jakob disease (CJD), which causes telltale sponginess in the brain. All these diseases proved to be infectious. They were also inevitably lethal, communicated by a die-hard vector that never triggered the slightest immune reaction - not even a fever.

Around the time of Gajdusek's Nobel award demonstrating that it was possible to communicate a deadly disease by eating brains, British farmers decided to put animal tissue into their cattle feed. That included the brains of "downer" sheep - the ones who were too sick to stand up, often the victims of scrapie.

In 1982 Stanley Prusiner isolated the infectious agent of these diseases. Like Gajdusek, he tried to kill it using several antiseptic techniques. Neither DNA nor RNA could have withstood such an onslaught, which ruled out a living organism.

After eliminating every other possibility, he concluded that it had to be a mere protein, and he called it a prion (pronounced pree'-on), a mangled shorthand for infectious protein. An unusual protein, for sure, but nevertheless a purely chemical, non-living agent. Although this explanation fit the data, it didn't fit with the biological orthodoxy. For a disease to spread, it needs to copy itself millions of times over. How could a simple protein replicate itself?

Prions Aren't Really Bad, They're Just Folded That Way

As proteins are assembled from the genetic blueprint, they take on distinctive forms like ribbons or circular staircases that fold back on themselves, making secondary connections. There are thousands of different structures a given protein can assume without changing its chemical composition in the slightest. That structure in turn determines what its task will be. Change a protein's structure and you change its task.

Prions just represent a different way to fold an otherwise innocuous protein. Prusiner thought the new task of that prion was to convert their brethren. If you let a prion loose among the unconverted, they will stop what they are doing and take on the new form. In fact, they seem almost spring-loaded to assume the new position. Like a room full of mousetraps, tripping one is sufficient to set off the rest in a chain reaction.

The trouble is, the prion is tough. It doesn't get recycled like most of the other proteins in a cell. The prions are dutifully swept up and tossed into a cellular garbage can called a lysosome, but being virtually indestructible, they just build up until the lysosome bursts, killing the cell and spreading its lethal payload to neighboring cells. As this wave of destruction moves outward from the initial infection, spherical holes form, filled with the detritus of dead neurons.

That makes prions a formidable foe: they are indestructible, thus escaping the recycling fate of ordinary proteins. Worse yet, they are chemically identical to normal proteins, so they completely fool the immune system. By and large, we are defenseless against this insidious nano-invader.

In 1985, after feeding sheep brains to cattle for fifteen years, mad cow disease swept through England. Over 170,000 cows were infected, causing panic around the world and creating a huge economic loss for the British beef industry. Mad cow disease was quickly diagnosed as another prion infection. Those durable prions had hopped the species barrier with surprising ease.

In 1997, Prusiner was awarded the Nobel Prize for his groundbreaking prion work, but there were still many lingering questions. For one, prions are so utterly deadly that it's surprising they exist at all. A disease this dreadful either destroys its host or is conquered by some immune strategy. It was time for some hard thinking. What if, for instance, there is a legitimate use for prions? That might explain why the immune system tolerates them.

Our Story Takes A Sharp Turn

Far from the land of exotic diseases, on the well-groomed campus of Columbia University, Eric Kandel and his group were searching for an elusive quarry: the basic unit of memory. Whatever it is, they reasoned, it should be stable enough to last in the body for years - otherwise we would quickly lose our recall. Much had been learned from their favorite subject, the sea slug (which has accommodatingly large nerve cells), and Kandel won the Nobel Prize in 2000 for his pioneering work understanding how gene expression correlates with long-term memory. But they were looking for something more - a chemical robust enough to keep the genes locked into place.

In December of 2003, Kandel's group made a remarkable announcement. They believe they've found the chemical responsible for storing memory. Turns out, it's a prion.

Apparently this prion is activated by the tiny electrical jolt of a nerve impulse, and rather than setting off a damaging chain reaction, it leads to the growth of synapses, permanently enhancing a specific junction in the brain - otherwise known as forming a memory.

It may be that prions have an important role to play outside of the brain as well. They could provide the perfect ratchet to drive the clock of development. Through its ability to transmit information forward to another cell, it offers an independent scheme of inheritance, not involving any genetic material at all. That has implications for all of biology.

If prions guide development, might they also have a role in aging? Are prions one of the keys to regenerative medicine? These are fanciful speculations at the moment, but by any score, prions seem destined to have significance far beyond their ghoulish discovery in the brain-eaters of New Guinea.

Copyright © 2000-2014 by Scott Anderson
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Here are some other suggested readings about how the brain works: