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Lab-made prions trigger mad cow symptoms

July 29, 2004 By Helen Pilcher This article courtesy of Nature News.

Result shows protein alone can act as infectious agent in disease.

Researchers have created a synthetic protein that makes mice display symptoms similar to those of mad cow disease.

The protein, called a prion, helps to resolve a long-standing debate on the cause of certain degenerative brain conditions, such as Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy (BSE) in cattle. Being able to manufacture the rogue protein in the lab may also aid the development of new therapies and speedy diagnostic tests.

Sporadic CJD, which accounts for 85% of prion diseases in humans, is thought to develop spontaneously. Researchers believe that healthy brain prions somehow become twisted out of shape and go on to trigger the production of more misshapen proteins. As the brain degenerates, patients lose the power of speech and movement. As there is no effective treatment, the disease is invariably fatal.

But there is controversy over whether a protein alone can trigger the disease. Many researchers believe that the infectious agent must also contain genetic material, such as DNA or RNA, in order to instruct the healthy proteins to turn bad.

To settle the point, Giuseppe Legname from the University of California, San Francisco and colleagues set out to make a synthetic prion protein, which they knew could not possibly contain DNA or RNA, to see whether it could trigger a BSE-like illness all by itself.

Shaping rogues

Creating the rogue prions from scratch was no mean feat. The researchers used bacteria to generate healthy-looking prion proteins and purified them. They shook these proteins until they changed their shape and resembled the twisted, unhealthy prions seen in diseased brains. Then the researchers injected the molecules into the brains of mice.

The mice developed BSE-like symptoms one to two years later, the team report in Science1. They became weak and shaky, and post-mortem analysis revealed that their brains were full of holes and rogue prion proteins.

Critically, when the mouse brains were ground up and injected into healthy rodents, they too became ill. This is the acid test for any prion disease, says Legname.

"The data show that infectious prions can be formed de novo from only protein," says prion researcher Surachai Supattapone from Dartmouth Medical School in Hanover, New Hampshire. The result should help to convince the sceptics who demanded proof from a chemical experiment that prions alone were sufficient to trigger the disease.

Prions in a test tube

"The finding represents a renaissance in prion biology," says Nobel laureate Stanley Prusiner, also from the University of California, San Francisco, who contributed to the research. Prusiner coined the term 'prion' and was the first to postulate the 'protein-only' hypothesis about infection. "For the first time, we can create prions in a test tube. We now have a tool for exploring the mechanism by which a protein can spontaneously fold into a shape that causes disease."

The discovery could speed the development of new drugs and diagnostic tests. At the moment, for example, it is only possible to confirm that a patient had the disease after he or she has died.

The research could also boost our understanding of other degenerative brain disorders, such as Alzheimer's and Parkinson's disease. In Alzheimer's disease, it may be that a protein called amyloid beta becomes misfolded and begins to clog up the brain. Mechanisms could be at work that are similar to those involved in creating rogue prions, says Legname.


  1. Legname G., et al. Science, 305. 673 - 676 (2004).


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