It all began long ago when a sheep rubbed up against its corral fence,or a tree trunk. So did a lot of other sheep in the flock; they rubbed sohard that they scraped the wool off their hide.

What made them do it? A baffling and swiftly fatal neurologicaldisease, aptly named "scrapie."

Then in 1976, a virologist named D. Carlton Gajdusek won a NobelPrize in medicine for discovering and describing a similar disorder intribes of human aborigines inhabiting the island of New Guinea. Theyate the brains of their forebears and their enemies, and duly died ofkuru, a "slow virus" infection that Gajdusek found similar to scrapie.

Changing times _ and tourism _ have put an end to kuru and itsanthropophagous etiology. Still with us, however, is Creutzfeld-Jakobdisease (CJD), marked notably by dementia, muscle spasms, ataxia,coma and early death. Once also attributed to a "slow virus," CJD isnow known as the first human prion disease. It affects one in amillion people.

CJD has a triple etiology: genetic, sporadic and infectious, eachcaused by a prion. Its inherited versions arise from one or anotherfamilial mutation of the human prion gene, which has been identifiedin the central nervous system and other tissues. Its function orfunctions remain a mystery. Sporadic CJD, as the term implies,occurs when a new mutation turns the normal prion gene defective.The proteins it then encodes are pathogenic. They cause CJD andseveral other human prion neuropathies, including bovine spongiformencephalopathy _ "mad cow disease."

CJD's infectious form is best known from the occasional cornealtransplant, which transmits the disease from a donor not suspected ofharboring the disease, and until a decade ago from human growthhormone harvested from cadaver pituitary glands.

Prions Stand Alone

"Prion" stands for "proteinaceous infectious particle." Unlike othermicroorganisms _ bacteria, fungi, viruses, viroids _ prions are suigeneris. Alone among these agents of disease, its genes harbor nonucleic acids, no known DNA or RNA, despite a decade of hotpursuit, and controversy. (See BioWorld Today, Feb. 10, 1994, p. 1.)

"The best examples," self-described "scrapiologist" Richard Bessentold BioWorld Today, "are viruses and bacteria. We can study thesequite well, and pinpoint the change in their nucleic acid base or basesthat gives rise to a different phenotype."

Bessen, a post-doc at the National Institute of Allergy and InfectiousDiseases' Rocky Mountain Laboratories in Hamilton, Montana, isfirst author of a paper in the current issue of Nature, dated June 22.Its title: "Non-genetic propagation of strain-specific properties ofscrapie prion protein."

Bessen observed that "The definitive experiment to demonstrate thata nucleic acid does not exist in prions has yet to be shown. But theevidence strongly supports the protein-only scenario. In this Naturepaper, what we've demonstrated is a prion protein from two differentstrains."

Those two strains of transmissible mink encephalopathy denote twopathological prion syndromes, HY and DR, in what approximateanimal stand-ins for CJD. The HY (for "hyper") animals, Bessensaid, "exhibit hyper-excitability, ataxia, head and body tremor. DR(for "drowsy") ones show progressive lethargy, almost narcolepsy;they just sleep."

HY and DR came to light, Bessen pointed out, only when hisLaboratory of Persistent Viral Diseases in Montana passaged inSyrian hamsters infective materials from mink. "Although the twodisease strains are infectious in nature," he pointed out, "they containthe normal hamster prion gene."

Such a phenomenon, he added, "is unusual and unprecedented. Theprecedent has always been, nucleic acid-to-protein. Here we seem tohave an example of where a protein can propagate itself, yet alsoexhibit strain differences, associated in the past only with nucleicacid differences."

His team's "hypothesis and speculation" account for the molecularbasis of those strain differences as "due to different structuralconformations of the same protein. These different molecularshapes," Bessen said, "are able to faithfully propagate themselves,which gives rise basically to the same protein with these distinctconformations."

That is, one strain with an alpha-helix structure; the other, a beta-pleated sheet. "The property of amyloid," Bessen pointed out, "is ahigh beta-sheet content," so prion proteins change to anamyloidogenic form.

This, however, he hastened to add, does not make Alzheimer'sdisease, in which amyloid plaques are a hallmark, into prion diseases."Alzheimer's disease is a distinct entity that has some similarities tothe scrapie diseases," he said, but its candidate pathological protein_ amyloid precursor protein _ is different.

Experiment Fulfills `No-Nucleic-Acid' Criterion

Here's how they went about construing this conversion:

"What we did," Bessen related, "was to partially unfold thepathological form of the HY and DR proteins and the normal form.We mixed them, let them refold, and treated them with an enzymethat partially degrades these proteins.

"The key thing," he emphasized, "is that the normal form of theprotein is sensitive to pretreatment with a proteinase enzyme,whereas the pathological form is resistant."

They then tagged the normal form with a radioactive molecule, mixedthis with a pathological version, treated both with protease, "thenlooked for the presence of a proteinase-resistant radioactive prion-protein molecule.

"And we found one," Bessen said.

This signified that the isotope-tagged normal form had converted to"something resembling the abnormal," without benefit of anyreplicated DNA or RNA, or other cellular machinery. "And thisconverted molecule retained the properties of each strain."

Bessen concluded: "This gives a possible explanation for theexistence of strains. If these proteins can self-propagate in a strain-specific way, you've fulfilled the criterion of not really needing anucleic acid in the process." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.