MEDICINE

Prion Pioneer

STANLEY B. PRUSINER

In a January 1995 Scientific American article, Stanley B. Prusiner wrote:

"Fifteen years ago I evoked a good deal of skepticism when I proposed that the infectious agents causing certain degenerative disorders of the central nervous system in animals and, more rarely, in humans might consist of protein and nothing else. At the time, the notion was heretical. Dogma held that the conveyers of transmissible diseases required genetic material, composed of nucleic acid (DNA or RNA), in order to establish an infection in a host."

Today Prusiner, a professor of neurology at the University of California at San Francisco is hardly a heretic. He has won the highest accolade in science for his discovery of prions, tiny protein molecules that seem to cause a variety of slow acting--and inevitably fatal--diseases in animals and humans; the name is an acronym for "proteinaceous infectious particles." The Nobel Assembly at the Karolinska Institute cited Prusiner for "his pioneering discovery of an entirely new genre of disease-causing agents and the elucidation of the underlying principles of their mode of action."

According to the Nobel panel, prions are now firmly established as a group of pathogens along with other well-known infectious agents, including bacteria, viruses, fungi and parasites. In animals, they are seen to be the causative agent of scrapie, a disease of sheep, and bovine spongiform encephalopathy (BSE), the well-publicized "mad cow disease." In humans, prions are believed to cause kuru, a much studied disease of the Fore people in New Guinea, and several hereditary forms of dementia, including Creutzfeldt-Jakob disease (CJD), which affects about one in a million people.

Of Prusiner's numerous discoveries, possibly the most startling--and controversial--was that prions can reproduce without genetic material because they are forms of ubiquitous proteins found in humans and animals. Yet when he and his colleagues identified the first prion pathogen as a protein they knew there must be a gene somewhere that carried the DNA coding for its production.

In 1984 gene probe experiments found the matching sequences not in a virus or bacterium but in the genome of all mammals. The normal prion protein was an ordinary component of white blood cells (lymphocytes) and was found in many other tissues as well. Normal prion proteins are particularly abundant on the surface of nerve cells in the brain.

Then how do prions cause disease? Subsequent research showed that the prion protein could sometimes fold into a different and very durable conformation. Infectious prions with this configuration would set off a chain reaction that would convert normal protein to the deadly form. In some diseases, such as CJD, the pathogenic proteins are created by a genetic mutation.

Prusiner believes that it is the buildup of this abnormal protein in the brain that causes the damage responsible for the characteristic dementia of prion diseases. Regions within diseased brains have a characteristic porous and spongy appearance (evidence of extensive nerve cell death) and affected individuals exhibit neurological symptoms, including impaired muscle control, loss of mental acuity, memory loss and insomnia.

Some researchers remain skeptical of Prusiner's findings. Even so, his work has opened the door to developing treatments for prion diseases. Investigators are already seeking ways to block the activity or formation of the abnormal proteins. It may also have contributed to the understanding of more common dementia illnesses, such as Alzheimer's disease.