Mad Cow, Creation of a Prion  

Summary: For the first time, an artificial prion, or misfolded protein, has been created that can, by itself, produce a deadly infectious disease in mice. This is thought to occur in mad cow disease. This research, if corroborated, would provide strong evidence for the protein-only hypothesis, the controversial concept that a protein alone, without the help of DNA or RNA, can cause infectious disease.

Quote: "The finding represents a renaissance in prion biology. For the first time, we can create prions in the test tube, which will change the way scientists do experiments in the field. We now have a tool for exploring the mechanism by which a protein can spontaneously fold into a shape that causes disease." (Dr. Stanley B. Prusiner, whose laboratory did the research)

Comment: It is a curious irony that this work should have been published the same week as Francis Crick died. Dr. Crick assumed from the start that the genetic code was universal to all forms of life. Dr. Crick formulated the "central dogma" -- the view that the usual sequence of events is from DNA to RNA to protein. By contrast, Dr. Prusiner has postulated the prion -- the idea that proteins can go it alone. DNA and RNA are unnecessary to the prion.

Both Crick and Prusiner received the Nobel Prize. A Nobel Prize may not constitute proof that an idea is correct but in these cases it certainly confirms that both Francis Crick and Stanley Prusiner have had major impact on science and medicine.

Barbara K. Hecht, Ph.D.
Frederick Hecht, M.D.
Medical Editors, MedicineNet.com

Prion finding offers insight into spontaneous protein diseases

UCSF scientists are reporting what they say is compelling evidence that the infectious agent known as prion is composed solely of protein. Their findings promise to create new tools for early diagnosis of prions causing bovine spongiform encephalopathy, or "mad cow" disease, in cattle and Creutzfeldt-Jakob disease in people, they say. The researchers believe that their work may also help advance investigations of more common neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

The finding is reported in the July 30 issue of Science.

In the study, the researchers created a large fragment of the normal prion protein -- a harmless protein found in all mammals examined. They then folded this fragment into the abnormal shape that they suspected would give it the infectious properties of the prion. Next, they injected the folded protein fragment into the brains of mice genetically engineered to over express the same fragment, but with the shape of the normal prion protein. After a year, the mice developed prion disease and brain tissue from the inoculated mice was injected into wild-type mice that subsequently developed prion disease in about half a year.

"Our study demonstrates that misfolding a particular segment of the normal prion protein is sufficient to transform the protein into infectious prions," says the lead author of the study, Giuseppe Legname, PhD, UCSF assistant adjunct professor of neurology in the laboratory of the senior author, Stanley B. Prusiner, MD, UCSF professor of neurology and director of the UCSF Institute for Neurodegenerative Diseases.

"A great deal of evidence indicates that prions are composed only of protein, but this is the first time that this has been directly shown in mammals. The challenge in the last few years has been to figure out exactly how to demonstrate that prions are made entirely of protein."

Spontaneous prion diseases

The discovery that a small change in the condition of a cell can cause the development of a prion offers an explanation, says Prusiner, for the sporadic form of Creutzfeldt Jakob disease (CJD), which is responsible for 85 percent of cases of prion disease in humans (occurring in 1 or 2 people per million) and is believed to develop spontaneously. It also supports his belief, he says, that sporadic forms of prion disease are caused by prion strains that are different from the one causing bovine spongiform encephalopathy (BSE) in cattle in Britain. He says he thinks that sporadic BSE will be found in one to five cattle per million and predicts such numbers will be found with increased testing for BSE.

"The finding represents a renaissance in prion biology," says Prusiner. "For the first time, we can create prions in the test tube, which will change the way scientists do experiments in the field. We now have a tool for exploring the mechanism by which a protein can spontaneously fold into a shape that causes disease."

More broadly, he says, the advance may lead to similar changes in the way studies are conducted for other neurodegenerative diseases that involve protein misprocessing, including Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis. Each disease involves a particular protein that undergoes some form of misprocessing, in terms of a shape change, metabolism or degradation, or proteolysis. At this point, it is not clear which of these forms of misprocessing occurs in each disease, says Prusiner. However, as in prion diseases, the misprocessing involves a profound conformational change that most often occurs spontaneously.