What's all the fuss about prion diseases?
By Gary Raham
Correspondent
Human nervous system diseases caused by minute protein fragments called
prions (pronounced "pree-ons") include Creutzfeldt-Jakob disease, kuru,
Gerstmann-Straussler-Scheinker disease and fatal familial insomnia.
Yes, they are incurably fatal, and yes, families must watch loved ones
die slowly with a gradual loss of mental function, but only a few hundred
cases have been documented worldwide.
Contrast that to flu epidemics that can take millions of lives at a time.
Why get unduly worried about rare transmissions of prions between species,
as with the "mad cow" epidemic or recent concerns about chronic wasting
disease (CWD) in deer and elk? Why pour money into research on "one-in-a-million"
diseases?
The answer to the first question is easy: Prion diseases are scary. The
answer to the second is uniquely human: Prion diseases are weird and we
want to know why. Curiosity has been a fruitful human ally in the past.
Prion diseases challenge what we think we know about biology.
In the 19th century, Louis Pasteur demonstrated that human and animal diseases
don't arise spontaneously from dirt. Instead, microscopic creatures like
bacteria and viruses, each trying to ensure their own survival, invade
larger creatures to co-opt their resources. The invaded body rallies its
defenses in the form of antibodies, which attach to alien proteins, marking
them for destruction. Fever is a sign of the battle in progress.
Prion diseases don't cause fevers, sores or other obvious signs of infections.
Instead, they poke holes in brain and nervous tissue and sometimes leave
fibrous residues called plaques. Depending on the area of the brain affected,
symptoms vary, but usually involve tremors or shivering, loss of motor
control and dementia in humans.
Animal forms of the disease, like scrapie in sheep, were first described
in 18th century England. Scrapie occurred rarely and randomly. Transmission
between sheep was suspected in some cases, but inconsistent. Sometimes,
but not always, it appeared to pass from one generation to the next. The
disease vector also seemed to linger. Years after an episode of infection
it might reappear on the same farm.
In the 1920s, two doctors, Hans Creutzfeldt and Alfons Jakob, independently
discovered a human disease with symptoms that echoed those of scrapie in
sheep. Sporadic Creutzfeldt-Jakob disease (CJD) quickly became a medical
footnote and largely forgotten for many years.
Two French researchers, between 1936 and 1938, showed that scrapie could
be transmitted from sheep to sheep with inoculations of brain tissue, but
no causative microorganisms were found.
A cannibal tribe in New Guinea in the 1950s began dying of a strange malady
they called kuru. Slides of brain tissue showed the same spongy appearance
as that of CJD and scrapie. Kuru was evidently another spongiform encephalopathy
(SE) - the scientific term for such diseases. When the tribe stopped eating
the brains of dead family members, kuru disappeared.
In the 1960s, researchers demonstrated that scrapie occurred in several
strains. All SEs were hard to work with because there was often a long
period between infection and the appearance of symptoms. Research advanced
more quickly when scrapie was successfully transmitted to purebred strains
of mice. In general, a given disease couldn't pass between species - unless
those species were closely related. Chimpanzees could be infected with
kuru, for example.
During all this time scientists were learning more about genetics and the
biology of bacteria and viruses. Two generalizations seemed evident:
- Diseases are either hereditary or infectious, but not both.
- Diseases were caused by organisms playing out the instructions inherent
in their own genes (the nucleic acids DNA or RNA). CJD and other SEs became
the exception to these assumptions.
The causitive agent of scrapie, for example, survives radiation doses that
would destroy the nucleic acids (genes) of typical infectious organisms.
It resisted the high temperatures and formaldehyde treatment of standard
sterilization techniques. But it could be broken down by proteases - enzymes
that disassemble protein. How could a disease be caused by nothing but
a protein?
In the early 1980s, Stanley Prusiner coined the term prion to describe
such a protein. As the techniques of "gene reading" developed, the story
got stranger. Every mammal tested carries a prion gene that directs the
production of a prion protein that is normally affixed to cell membranes
in some way. Obviously, something happens to that protein to make it cause
illness.
Every protein is a string of subunits called amino acids arranged like
pop beads on a string. Because of the unique shapes and charges of individual
amino acids, each protein was thought to snap into a single unique 3-D
configuration that could explain all its chemical properties. Prions have
demonstrated, however, that the same protein can have several forms, some
much more stable than others. The disease-causing prion is not only an
ultra-stable variant, it can transform a normal prion protein into the
disease configuration on contact, mimicking the reproduction of a typical
parasite.
Cows became "mad" in the mid-1980s when they became infected through bone
meal containing sheep animal parts (including nervous and lymphatic tissue).
In 1996, 10 young Britons came down with a version of CJD believed to have
been contracted from eating cattle products. In North America a small percentage
of deer and elk have contracted chronic wasting disease. The question has
become can the (supposed) prion causing this disease cross the species
barrier to humans as well?
While this last question remains open, scientists are noting similarities
between known prion diseases and other neurodegenerative diseases like
Alzheimer's, Parkinson's and Lou Gehrig's disease. Aberrant, clumped proteins
are features in all of them. Someday human curiosity about prions may lead
to cures for these diseases and redefine, again, humanity's understanding
of a beautifully complex, intertwined and sometimes frightening biosphere.
References
Belay, Maddox, Williams, Miller, Gambetti, and Schonberger. "Chronic Wasting
Disease and Potential Transmission to Humans" in Emerging Infectious Diseases,
www.cdc.gov/eid, Vol. 10, No. 6, June 2004.
Prusiner, Stanley B. "The Prion Diseases" in Scientific American, Vol.
272, No. 1, January 1995.
Prusiner, Stanley B. "Detecting Mad Cow Disease" in Scientific American,
Vol. 291, No. 1, July 2004.
Schwartz, Maxime. How the Cows Turned Mad. Los Angeles: University of California
Press, 2003, 2004.
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