Presentation Speech by Professor Ralf F. Pettersson of the Nobel Committee at The Karolinska Institute, December 10, 1997.

Translation of the Swedish text.

Your Majesties, Your Royal Highnesses, Ladies and Gentlemen,

This year’s Nobel Prize in Physiology or Medicine has been awarded to Stanley B. Prusiner for his discovery of prions – a new biological principle of infection. What is a prion? It is a small infectious protein capable of causing fatal dementia-like diseases in man and animals. It has been known for approximately a century that infectious diseases can be caused by bacteria, viruses, fungi and parasites. All these infectious agents possess a genome, the hereditary material that provides the basis for their replication. The ability to replicate is essential for the manifestation of the diseases they cause. The most remarkable feature of prions is that they are able to replicate themselves without possessing a genome; prions lack hereditary material. Until prions were discovered, duplication without a genome was considered impossible. This discovery was unexpected and provoked controversy.

Although the existence of prions was not known until the work of Stanley Prusiner, many prion diseases have been previously documented. On Iceland, scrapie, a disease affecting sheep was first described in the 18th century. In the 1920s, the neurologists Hans Creutzfeldt and Alfons Jakob discovered a similar disease in man. During the 1950s and 60s Carleton Gajdusek studied kuru, a disease that was spread through cannibalistic rituals practised by the Fore people in New Guinea. Presently attention is focused on mad cow disease, which has affected approximately 170,000 cows in Britain. These diseases exhibit common pathologies. They are inevitably fatal due to the destruction of the brains of infected individuals. The incubation times may last for several years, during which the affected regions of the brain become gradually spongy in appearance. Gajdusek discovered that kuru and Greutzfeldt-Jakob disease could be transmitted to monkeys demonstrating that these diseases are contagious. In 1976, when Gajdusek received his Nobel Prize, the nature of the infectious agent was completely unknown. At this time, these diseases were assumed to he caused by a new unidentified virus, termed a slow or unconventional virus. During the 1970s, no significant advances regarding the nature of the agent were made, that is, not until Stanley Prusiner took on the problem.

Prusiner set out to purify the infectious agent, and after 10 years of hard work he obtained a pure preparation. To his great surprise, he found that the agent consisted only of a protein, which he named prion, a term derived from proteinaceous infections particle. Strangely enough, he found that the protein was present in equal amounts in the brains of both diseased and healthy individuals. This discovery was confusing and it was generally concluded that Prusiner must have arrived at the wrong conclusion. How could a protein cause disease if it was present both in diseased and healthy brains? The answer to this question came when Prusiner showed that the prion protein from diseased brains had a completely different three-dimensional conformation. This led Prusiner to propose a hypothesis for how a normal protein could become a disease-causing agent by changing its conformation. The process he proposed may be compared to the transformation of Dr Jekyll to Mr Hyde – the same entity, but in two manifestations, a kind innocuous one, and a vicious lethal one. But how can a protein replicate without a genome? Stanley Prusiner suggested that the harmful prion protein could replicate by forcing the normal protein to adopt the shape of the harmful protein in a chain reaction-like process. In other words, when a harmful protein encounters a normal protein, the normal protein is converted into the harmful form. A remarkable feature of prion diseases is that they can arise in three different ways. They can occur spontaneously, or be triggered by infection, or occur as a consequence of hereditary predisposition.

The hypothesis that prions are able to replicate without a genome and to cause disease violated all conventional conceptions and during the 1980s was severely criticised. For more than 10 years, Stanley Prusiner fought an uneven battle against overwhelming opposition. Research during the 1990s has, however, rendered strong support for the correctness of Prusiner’s prion hypothesis. The mystery behind scrapie, kuru, and mad cow disease has finally been unravelled. Additionally, the discovery of prions has opened up new avenues to better understand the pathogenesis of other more common dementias, such as Alzheimer’s disease.

Stanley Prusiner,

Your discovery of the prions has established a novel principle of infection and opened up a new and exciting area in medical research. On behalf of the Nobel Assembly at the Karolinska Institute I wish to convey to you my warmest congratulations and I now ask you to step forward to receive your Nobel Prize from the hands of His Majesty the King.