JOVANA
Explore Library Glossary Getting Started Three Levels Fields How it works Mission
Join the mission
Back to the library
Biology 1982

Novel Proteinaceous Infectious Particles Cause Scrapie

Stanley B. Prusiner

An infectious agent made of nothing but protein — a misshape that makes more of its own misshape.

Choose your version
In depth · the introduction

What if a disease could spread with no germ, no virus, no DNA at all — just a single protein folded into the wrong shape?

The big idea

Every infection we knew of — a cold, the flu, a bacterial wound — is caused by something carrying genetic instructions, DNA or RNA, that it copies to make more of itself. That was treated as a law of biology: to replicate, you need a genome.

Prusiner argued that one strange brain disease broke the law. The culprit, he found, was a protein — and proteins have no genes inside them. His answer to how it could possibly copy itself was as elegant as it was unsettling: the rogue protein is a normal protein of your own body, folded into a wrong shape, and that wrong shape is contagious to its neighbours. A misfolded molecule grabs a normal one and bends it into the same wrong shape; now there are two; then four. The disease isn't a thing that invades you so much as a shape that spreads through proteins you already had. He called the agent a prion.

How it came about

The trail began with horror stories: scrapie, which makes sheep itch themselves raw and stumble; kuru, a trembling death among the Fore people of Papua New Guinea linked to mourning rituals; and Creutzfeldt–Jakob disease in humans. All were transmissible, yet whatever caused them shrugged off radiation that shreds any virus. In the 1960s Tikvah Alper's experiments hinted the agent might have no genetic material at all, and J. S. Griffith sketched how a protein might, in theory, copy a shape.

Stanley Prusiner, a young physician-scientist in San Francisco, spent years grinding up infected hamster brains and purifying the active fraction, testing what destroyed it and what didn't. In 1982 he published the answer and the name. It was met with fierce resistance — many were sure he had simply failed to find a hidden virus — and the fight ran for over a decade before the protein-only picture won out. He received the Nobel Prize in 1997.

Why it mattered

Prusiner forced biology to admit a second way to inherit information. Genes are one way — a sequence of DNA letters. A protein's shape is another: a fold that can copy itself by bending its neighbours, no genome required. That reshaped how we think about a whole family of diseases, and it arrived in the public's life through catastrophe — the 1980s–90s "mad cow" epidemic in Britain, when prions jumped from cattle into people. Most importantly, the same self-spreading-shape idea now helps explain the far commoner scourges of Alzheimer's and Parkinson's, where misfolded proteins creep through the brain.

A way to picture it

Think of a row of standing dominoes. A protein is like a long ribbon that folds into a particular shape to do its job — imagine it folded neatly, like a made bed. A prion is the same ribbon crumpled into a bad fold. The eerie part is that the bad fold is pushy: when a crumpled protein touches a neat one, it forces the neat one to crumple the same way. One pushes over the next, which pushes over the next — a chain reaction of misfolding running through your proteins like dominoes toppling. That's why a tiny invisible speck of the bad shape can, given time, convert a whole brain's worth. Use the tool below to drop in a tiny seed and watch it take over.

An interactive graph: the fraction of misfolded protein over time rises as an S-shaped curve — a slow lag from a tiny 2% seed, then a steep takeover, then levelling off when nearly all is converted. One slider changes how fast proteins convert; another slides time forward. A row of symbols below shows normal proteins (open circles) flipping to misfolded ones (filled diamonds).

Where it sits

The prion is a strange cousin to the central story of this Library's biology. Watson and Crick (1953) showed life's instructions are written in DNA, and Crick's "central dogma" (1958) had information flow from gene to protein. The prion is the unsettling footnote: here, information rides in the protein's shape and copies itself without ever touching a gene. It doesn't break the dogma so much as sneak around it. And it ties back to Anfinsen's discovery that a protein's sequence normally dictates its fold — prions are what happens when a protein finds a second, catching, fold it was never supposed to take.

The original document
Original source text
Stanley B. Prusiner · Science, vol. 216, no. 4542, pp. 136–144 · 9 April 1982
The problem: an agent that breaks the rules
Scrapie — a fatal degenerative disease of the sheep brain, related to kuru and Creutzfeldt–Jakob disease in humans — is transmissible, yet its causative agent had defied two decades of effort to classify it. It is astonishingly resistant to ultraviolet and ionising radiation at doses that destroy any known virus, and to many treatments that damage nucleic acids. Prusiner sets out to determine, by purification and inactivation studies, what the agent is actually made of.
The evidence: a protein is required; nucleic acid is not found
Prusiner reports several converging lines of evidence. Procedures and enzymes that attack protein — and treatments such as alkali — reduce or abolish the infectivity, showing that a protein is required for the agent to infect. By contrast, five separate procedures aimed specifically at modifying or destroying nucleic acids fail to inactivate it. Across the purification, infectivity tracks with a protein fraction, while no nucleic acid large enough to encode that protein can be detected.
The proposal: a new word for a new thing
Because these properties set the agent apart from viruses, plasmids and viroids, Prusiner proposes a new term — "prion," for proteinaceous infectious particle — to name a small infectious agent that is resistant to the procedures that modify nucleic acids. The paper is careful and hedged: it lays out the protein hypothesis as the best account of the data, while noting that a small, well-shielded nucleic acid had not been absolutely excluded.
[ … ]
How a protein with no genome could possibly replicate is left open here. The mechanism that answered it — a misfolded protein templating the conversion of the normal form of the same protein — and the identification of that protein (PrP) and its gene came over the following years, and turned a contested proposal into the founding paper of an entire field. The complete article is available at the source below.
Stanley B. Prusiner · San Francisco · 1982