1997 Nobel Prize in Physiology or Medicine β Prusiner, Discovery of Prions, Infectious Agents Without Genetic Material
What You Will Learn in This Article
You will understand the amazing fact that there are infectious agents that cause disease without DNA or RNA, but only with proteins. Stanley Prusiner overcame being treated as an academic heretic for over 20 years and revealed prions β a new concept of infectious agent in which a misfolded protein induces normal proteins to misfold and spreads infection. We will also explore how this discovery has expanded into the understanding of not only bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease (CJD), and scrapie (sheep), but also neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's diseases.
A Story Different from Common Sense β Disease Caused by Infection Without Genetic Material
The common understanding of infectious agents was as follows: Bacteria and viruses replicate themselves using their own DNA or RNA to cause disease. Without genetic material, it was believed that information transmission and replication are impossible, thus biological infection is impossible.
Prusiner's discovery overturned this common sense. The infectious agents causing scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeldt-Jakob disease (CJD) in humans were infectious particles composed only of proteins, without any genetic material. Prusiner named these particles prions (proteinaceous infectious particles).
The mechanism of action is dramatic. Normal cells contain PrPc (normal prion protein). If this protein is misfolded into PrPsc (scrapie prion), this misfolded form comes into contact with neighboring normal PrPc and causes the normal protein to also misfold. As a result, misfolded proteins accumulate explosively, destroying nerve cells. This causes sponge-like holes to form in the brain.
The key is a new form of information transmission. Information is transmitted not through DNA or RNA, but through the protein structure itself. A single misfolded structure causes neighboring proteins to take on the same misfolded structure. Self-replication is possible even without information.
In terms of computer science, this is like a self-replicating data destroyer. A single, incorrectly initialized data object comes into contact with neighboring normal objects and changes their state to match its own. Infinite spread. And these infected objects gather to form aggregates, paralyzing the system.
An example of how unconventional this concept was: When Prusiner first presented his findings in 1982, the academic community did not accept them. The belief that infection was impossible without genetic material was strong, and scholars regarded Prusiner as a "heretic in the scientific community" and advised him to stop his meaningless research. However, his belief and passion did not waver. Fifteen years later, his correctness was recognized with the Nobel Prize.
The Zeitgeist β The Year of the Korean Economic Crisis
1997 was the year of the beginning of the IMF foreign exchange crisis in modern Korean history.
In Korean history, on November 21, Vice Prime Minister Im Chang-yeol applied for bailout funds from the IMF β amounting to $21 billion. Korea's national credit rating plummeted, and large corporations went bankrupt one after another. A moment of practical failure for the Kim Young-sam administration. On December 3, an agreement was signed with the IMF. On December 18, Kim Dae-jung was elected president β the first opposition-ruling party change in constitutional history. A political transition in the midst of a crisis. On August 6, Korean Air Flight 801 crashed in Guam, killing 228 people. A failure of the aviation safety system.
In world history, on July 1, Hong Kong was returned to China β ending 155 years of British rule. On August 31, Princess Diana died in a car accident in the Alma Tunnel in Paris. Worldwide mourning. In February, the Roslin Institute announced the birth of Dolly the sheep, the first cloned mammal. In May 11, IBM's Deep Blue defeated chess world champion Kasparov β a milestone in AI. The spread of bovine spongiform encephalopathy in the UK and Europe reached its peak.
In this year of crisis and milestones, the Nobel Committee recognized Prusiner, who had endured 20 years of being treated as a heretic.
Stanley Prusiner β From Heretic to Nobel Laureate
Stanley B. Prusiner (1942β) is an American physician. He received his Ph.D. in medicine from the University of Pennsylvania in 1968 and has been a professor at the University of California, San Francisco (UCSF) since 1980.
In 1972, one of his patients died of Creutzfeldt-Jakob disease (CJD), which changed his life. When the brain of a CJD patient is autopsied, it is found to have sponge-like holes and an accumulation of strange proteins. The cause of this disease was completely unknown. Prusiner decided to investigate this mystery.
As a result of purifying this strange protein from the brains of experimental animals, he demonstrated that infection can occur with only pure protein, without any nucleic acid. Even after irradiating the nucleic acid, the infectious ability was maintained, but when treated with protein-degrading enzymes, the infectious ability disappeared.
When he announced the prion concept in 1982, the academic community's reaction was cold. Most scholars believed that infection without genetic material was theoretically impossible. Prusiner persisted in his research, despite the objections of those around him. Over the next 15 years, he continued to research the nature of prions and eventually elucidated the relationship between prion genes and normal protein (PrPc) and pathogenic protein (PrPsc). In 1997, he was awarded the Nobel Prize.
Prusiner's story is a symbol of the case where he stuck to his conviction, not yielding to the opinions of the majority of the academic community. Similar to the case of McClintock (1983 Nobel Prize) β a case where a discovery that went against academic common sense was recognized after many years.
Decisive Experiment β Normal Prion and Pathogenic Prion Interaction
The crucial picture revealed by Prusiner:
Normal cells also have prion genes, and the normal prion protein PrPc is produced from this gene and exists on the surface of nerve cells. This normal protein is mainly composed of alpha-helix structures.
The pathogenic prion PrPsc has the same amino acid sequence but a different tertiary structure. It has a structure mainly composed of beta-sheets. This different folding is the root of the pathology.
When infection occurs, PrPsc comes into contact with neighboring PrPc, causing the protein to fold into the same abnormal structure as itself. Self-replication occurs through structure alone, without information. PrPsc increases explosively in infected cells.
An experiment was conducted using mice that did not have normal prion genes, and it was found that these mice were not infected with prions. This proved that normal prion protein must be present as a target for infection. Attempts were subsequently made to create cows and sheep that lack normal prion genes through genetic engineering.
CS Framework β Self-Replicating Data Destroyer
If we reconstruct prion infection in the language of computer science, we get the following picture:
PrPc = Normal Data Object: Normal prion protein on the cell surface. Stored in a normal structure.
PrPsc = Infected Data Object: The same class, but in an incorrectly initialized (misfolded) state.
Infection Spread = State Corruption: When PrPsc comes into contact with PrPc, it changes the protein into the same state (corrupted state) as itself. This is an extreme case of a software anti-pattern β a single, incorrect instance comes into contact with other normal instances and destructively changes their state.
Aggregation = Extreme Memory Leak: Misfolded PrPsc aggregates together to form aggregates. The cells cannot remove these aggregates, and they accumulate. Eventually, the cells die.
Information-Free Self-Replication = Infection Without a Program: Self-replication of data structure without genetic material (code). This is different from computer viruses, which replicate themselves using execution code. It is an extremely unique form of infection that occurs only through the data state.
Inter-Species Infection = API Compatibility: The reason why prions of different species can infect is that prion proteins are evolutionarily conserved and have similar tertiary structures. This is a situation where the cell surface API of different species uses the same protocol.
Protein Misfolding Diseases = Extension of Prion Pattern: Alzheimer's disease (amyloid beta and tau), Parkinson's disease (alpha-synuclein), Huntington's disease (polyglutamine expansion huntingtin), and amyotrophic lateral sclerosis (TDP-43 and SOD1) have similar self-catalytic misfolding and aggregation mechanisms. This is a fundamental paradigm of neuropathology in the late 20th century.
Resistance = System Robustness: Prions are extremely resistant to heat and chemicals. They cannot be removed by ordinary sterilization methods. This is an extreme challenge in managing infectious agents.
Limitations of this analogy: Actual prion infection is probabilistic and is greatly influenced by genotype (polymorphism of normal prion genes). It is a more complex probabilistic system than simple deterministic state propagation.
Academic Impact β A Unified Picture of Neurodegenerative Diseases
Response to BSE Outbreak: In the 1980s and 1990s, bovine spongiform encephalopathy (BSE) spread in the UK, and variant Creutzfeldt-Jakob disease (vCJD) appeared in people who ate beef. This response maximized the social urgency of prion research. Establishment of international standards for meat and feed regulations.
Unified Understanding of Protein Misfolding Diseases: The aggregation of amyloid beta in Alzheimer's disease, the aggregation of alpha-synuclein in Parkinson's disease, and the aggregation of polyQ in Huntington's disease have a similar self-catalytic misfolding and aggregation mechanism as prions. This is a fundamental paradigm of neuropathology in the late 20th century.
Therapeutic Approaches:
- Protein aggregation inhibitors: Antibody therapies such as aducanumab (2021) and lecanemab (2023) target amyloid beta in Alzheimer's disease.
- Small molecule stabilizers: Stabilize the normal protein structure to prevent misfolding.
- Aggregation decomposition: Activate autophagy to remove aggregates.
- Gene silencing: Use siRNA and antisense oligonucleotides to inhibit the expression of prion-related genes.
Improved Diagnosis: Methods for detecting prions in cerebrospinal fluid (RT-QuIC, etc.), specific MRI patterns for early diagnosis of CJD.
Korean Impact: Although there have been no cases of BSE in Korea, there have been related social debates, such as the 2008 resumption of US beef imports. Prion research in Korea is being conducted at Seoul National University, Yonsei University, and Hanyang University.
Why is it important?
Prusiner established that "infection can occur without the transmission of information."
Expansion of the concept of pathogens. He added a new category to the concept of pathogens, which was established in the early 20th century with bacteria and viruses. Prions are pathogens that can complete an entire infection cycle without their own genetic material.
Unified understanding of neurodegenerative diseases. The prion's autocatalytic propagation concept provided a new perspective, prion-like spreading, to the fundamental understanding of Alzheimer's, Parkinson's, and Huntington's diseases. This is a fundamental concept in 21st-century neuropathology.
The final recognition of an academic hereticβsimilar to McKlintock's story. This is a case where a discovery that directly challenged academic common sense withstood the test of time and was eventually recognized. Science reaches the truth not through majority rule, but through the accumulation of empirical evidence.
After this award, the trends in neuropathology and protein aggregation research continued as follows:
- 2004, Axel and Buck β Olfactory receptors
- 2013, SΓΌdhof, Rothman, and Schneeman β Intracellular transport regulation
Clinical applications of this discovery:
- Diagnosis and surveillance of CJD and BSE: Establishment of international standards
- Alzheimer's treatment: Aducanumab and Lecanemab (targeting amyloid)
- Parkinson's research: Targeting alpha-synuclein aggregates
- Autophagy activation therapy: Future target for neurodegenerative diseases
β Previous: 1996 β Doherty and Zinkernagel β Next: [1998 β Batch 8 in progress]