January 22, 2004
The Mad Cow Jumps Over the Moon
Mad cow disease has led to an extraordinary new view
of learning and memory.
By Scott C. Anderson
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
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
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
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
For reprint rights, email the author:
Here are some other suggested readings about how the