UCSF’s Stanley Prusiner Named to Receive the 1997 Nobel Prize in Physiology or Medicine

By Jeffrey Norris

Stanley B. Prusiner, MD, 55, today was named to receive the 1997 Nobel Prize in Physiology or Medicine for discovering and characterizing an entirely new class of proteins, called prions, which cause several rare and fatal neurodegenerative diseases.

Prusiner is Professor of Neurology and Biochemistry and Biophysics at the University of California, San Francisco.

Prusiner's elegant work and seminal experiments, often conducted and presented in the face of skepticism and controversy, have proved revolutionary in establishing the cause of some of the most baffling diseases of the central nervous system.

The identification of an entirely new class of disease-causing pathogens that appears to replicate without genes is one of the most revolutionary conceptual advances in medicine and has opened a new era of biological research.  To set forth what many scientists considered to be the heretical idea that the transmissible agent in several rare neurodegenerative diseases is a protein, and not a slow-acting virus as had been generally thought, required great scientific and personal courage.

Among these diseases are scrapie, an infectious disease of sheep, and "mad cow" disease, an infectious prion disease responsible for an epidemic among cattle in Great Britain fed meat and bone meal contaminated with scrapie prions.  The most exotic infectious prion disease of humans is kuru, which was spread among New Guinea aborigines by ritualistic cannibalism.

In 1982, Prusiner proposed that the infectious agent causing scrapie, a neurodegenerative disease of sheep, is a mysterious pathogen which he named the prion, for proteinaceous infectious particle.

From the brains of scrapie-infected animals, Prusiner and his colleagues purified the prion (pronounced PREE-on), which appeared to be composed only of protein.  When Prusiner looked in the prion for a nucleic acid (DNA or RNA) that could direct the synthesis of progeny prions, he was unable to find one.

This discovery posed a conundrum that seemed to threaten the very foundations of modern biology, as nucleic acids are the building blocks of genes, the basic units of heredity found in all living organisms, including viruses.  These genes must be passed on to progeny in each generation.  Genes encode proteins which are the action molecules of life, controlling metabolism, movement and growth.  Yet prions, apparently lacking genes, multiply nonetheless.

Research conducted by Prusiner and his colleagues revealed that the protein of the prion was derived from a normal protein that is encoded by a gene found in all animals examined, including humans.  Prusiner called this protein "prion protein," or PrP.

In 1986, Prusiner and his colleagues substantially advanced prion research when they found that the tempo of scrapie in animals is controlled by the sequence of nucleic-acid building blocks in the gene encoding PrP.  Three years later, they reported that patients dying of Gerstmann-StrŠussler-Scheinker disease possess a specific nucleic-acid substitution, or mutation, in the PrP gene.  Slightly different mutations in the PrP gene were also found in familial Creutzfeldt-Jakob disease (CJD).

Next, Prusiner and his colleagues produced genetically engineered (transgenic) mice harboring PrP genes with the human disease mutation.  As a result of this genetic alteration, these animals spontaneously developed brain degeneration similar to that seen in scrapie after inoculation with prions.

The finding from these studies that prion disease can arise as a result of genetic alterations posed yet another riddle for those scientists who believed that scrapie, GSS and CJD are caused by slow-acting viruses, which are not transmitted across generations according to the laws of genetics.

The results of the experiments on genetically engineered animals led Prusiner to conclude that prion disease can be inherited as well as infectious, a truly unprecedented notion.

His ideas explained how prion diseases of humans can (1) arise spontaneously in some people, (2) be inherited by patients who have a family history of prion disease, or (3) be acquired by infection.

In a study that spanned almost a decade, Prusiner and his colleagues searched for the difference between the normal and disease forms of the prion protein.  They eventually discovered that the normal form of PrP is folded into a twisted corkscrew or helical shape, whereas the disease-associated form exists as a flattened sheet.

For several decades each protein has been thought to have only a single, natural shape.  Therefore, Prusiner, by demonstrating that the normal corkscrew form of the prion protein can change its shape into the disease-associated sheet-like form, again challenged another basic tenet of biology.  Shape is vital to a protein, because it determines protein activity.

Studies with genetically engineered mice over the past six years have revealed that the interaction of the normal, or "C" form of PrP, with the diseased, or "S" form, underlies the multiplication of prions.  The disease form of PrP seems to act as a template for the refolding of normal PrP into a second diseased PrP.

Prusiner emphasizes that prion replication is a complicated process. In a family with a history of inherited prion disease, two different "C" forms of PrP can exist in the same individual.  One "C" form of PrP is the normal, or as geneticists call it, the wild-type form and the other "C" form of PrP is a mutant one.  A mutation within the PrP gene programs the brain to produce mutant PrP in which one or more amino acids have been changed.  The amino acid substitution seems to destabilize the "C" shape of PrP and render it more susceptible to folding into the "S" form.  Among humans carrying a mutation of the PrP gene, nearly all will develop prion disease; whereas only one in a million with normal PrP become ill.

Using transgenic mice carrying artificial PrP genes, Prusiner and his colleagues also have begun to unravel the mysteries of the "species barrier," the obstacle that minimizes transmission of prion disease from one species to another.  The UCSF researchers have constructed artificial genes by embedding a segment of the PrP gene from the human or hamster within that of the mouse, and they have found the barrier is due to slight differences among species in the amino acid sequence of the prion gene.

Genetically engineered mice have also been used by Prusiner and his colleagues to investigate some of the processes that cause brain degeneration in humans.  The accumulation of the "S" form of PrP, sometimes as large clumps or plaques in the brain, seems to be responsible for the pathologic insults that the brain suffers as it undergoes degeneration.  From these and other investigations, Prusiner concludes that prion diseases are disorders of protein shape.

While Prusiner indisputably continues to be a leader in the study of neurodegenerative diseases, he credits the many years of hard work by his many talented colleagues for his success.  His own dedication to advancing investigations of all neurodegenerative diseases, including more common disorders such as Alzheimer's disease, Parkinson's disease and ALS (Lou Gehrig's disease), is widely recognized.

Prusiner was born in Des Moines, Iowa and received his undergraduate training and MD degree from the University of Pennsylvania.  He is the winner of numerous awards and honors including the Albert Lasker Basic Medical Research Award, the Potamkin Prize, the Wolf Prize, the J. Elliott Royer Award, the Ehrlich-Darmstaedter Award, the Gairdner Foundation Award, the Charles A. Dana Award and the Max-Planck-Forschungspreis.