How does a Nobel Prize winner, the mystery of Alzheimer’s Disease, and a rare brain ailment caused by cannibalism become part of the same story?
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In
1997, Dr. Stanley Prusiner won the Nobel Prize in Medicine and Physiology for
the discovery of the cause of Creutzfeld Jakob encephalopathy, a rare brain
disease caused by an infectious particle known as prion. The Prion particle is
also the cause of the Kuru disease, an ailment first observed among a tribe in
New Guinea, who practice cannibalistic rituals. Members of this tribe ate the
brains of the deceased as a result of their spiritual beliefs. Kuru disease is
characterized by the presence of tremors and other neurological symptoms.
In
recent years, medical scientists have discovered that the same type of
mechanism, a prion-like phenomenon, might also be related to the cause of
Alzheimer’s disease. Scientists have demonstrated that molecules derived from
amyloid-beta behave in a prion-like fashion. Last year, Cold Spring Harbor
Laboratories published a seminal review article by Dr. Stanley Prusiner
entitled “Amyloid-beta Prions and the Pathobiology of Alzheimer’s Disease” (see
sources below). In the article, Dr. Prusiner clearly explains how these
prion-like molecules are related to the cause of Alzheimer’s. Today, prions are
defined as alternative protein conformation capable of self-propagation.
Indeed, prion particles are infectious. They encipher their own replication
blueprint without the use of a genetic code. It is defined as protein-only
inheritance.
This
month, French scientists from Sorbonne
Université in Paris have published an article on the journal “Current Opinion
in Neurology” (article in press, see reference below) discussing the body of
evidence in the medical literature supporting the prion hypothesis as the cause
of Alzheimer’s. As Dr. Stanley Prusiner’s medical hypothesis gains acceptance
among medical scientists today, it almost becomes imperative to review the
history behind Dr. Prusiner’s eureka moment.
The Discovery of the Prion and The
Scientific Controversy that Ensued Afterward
In
1997, the Medicine and Physiology Nobel Prize Ceremony became vindication for a
maverick scientist who was marginalized by the scientific community for almost
15 years. The winner of the highly rewarded prize that year, Dr. Stanley
Prusiner, had been previously criticized for postulating a medical hypothesis
that challenged at the time one of the most important dogmas in biology. Back
then, it was widely accepted by the scientific establishment that the flow of
genetic information is based on the genetic code. Information flows from
nucleic acids, DNA and RNA, to proteins. The problem was that the Prion
particle did not contain any nucleic acid. With zero content of DNA or RNA, how
was it possible that Prions were infectious? Scientists were in disbelief.
On
his paper published on the journal “Science”
in 1982, Dr. Prusiner claimed that the Prion particle, the infectious agent
that caused Creutzfeld Jakob disease, consisted of only protein, with zero
nucleic acid content. The scientific community did not believe Dr. Prusiner’s
findings. His medical hypothesis was rejected by most of his peers. Without any
nucleic acid content, a particle cannot be infectious, they sternly claimed. It
is not feasible as there is no genetic information within the Prion particle,
the medical community thought at the time. As a result of the discrepancy, the
work of Dr. Prusiner’s laboratory lost credibility, as scientists and experts
claimed that Dr. Prusiner’s team have failed to identify the presence of nucleic
acid in a Prion. The culprit of the infection had to be a nucleic acid,
scientists thought then. They were confident that the nucleic acid had gone
undetected by Prusiner’s team, maybe because it was in minor quantities.
Dr.
Prusiner denied those claims, as he sternly continued to support his medical
hypothesis:
The Prion particle consists
of only protein with two main properties:
- prions
exist in two main conformations (“sick conformation with propensity to generate
oligomerization or formation of aggregates, and normal conformation, which
remains monomeric (single protein, without aggregation));
- The
prion conformation (“sick” form of the protein) can propagate itself by
converting the normal conformation of the protein into prion by physical
contact.
The
controversy made Dr. Stanley Prusiner a pariah of the scientific community.
Organizers of medical conferences and meetings did not want to invite him, and
rumors of many kinds on the origin and quality of his work grew.
Cannibalism and the Infectious
Prion
Kuru is a rare, fatal brain disease caused by “funerary cannibalism”. The disease spread among the people of Papua New Guinea, an Oceanian country, where relatives consumed the bodies of the deceased. Their belief was that a “life force” of the dead will return to them. The spread of Kuru started in the region in the 1920s, becoming an epidemic lasting until 2009. Kuru disease is characterized by body tremors. The word “Kuru” derives from the Fore (a language spoken in Papua New Guinea), and the word “kuria” (shaking), used to describe the tremors caused by this illness. Kuru is also manifested with uncontrollable laughter, which gives the ailment another name, “laughing sickness”.
Prion, Kuru and
Cannibalism
Among the people of Papua New Guinea, the incidence of Kuru was the highest among those that ate the brains of the deceased. It was demonstrated that Kuru is caused by prion particles, which have their highest concentration in the brains of the sick. The same prion particle, discovered by Dr. Stanley Prusiner, which causes Creutzfeldt-Jakob disease, it is also the causative agent responsible for the Kuru epidemic. Like all neurodegenerative diseases caused by prions, including Alzheimer’s, Kuru is incurable at present.
Prion-Like Transmission and
Alzheimer Disease
Alzheimer’s
disease is the main cause of dementia, memory loss, and cognitive decline in
elderly patients. The illness’ symptoms start gradually, but worsen quickly
later on, severely affecting a patient’s thinking capacity and behavior. The
brain of Alzheimer’s patients shows significant damage, with remarkable loss of
neurons, as the overall brain size shrinks.
After
two decades of intense basic and clinical research, a new hypothesis to explain
the mechanism responsible for Alzheimer’s disease has emerged. Based on results
obtained from multiple experimental models, it has been demonstrated that
amyloid-beta, the same protein molecule forming aggregate deposits in the brain
known as “amyloid-beta plaques”, gives rise to smaller peptides known as “toxic
oligomers”, which behave in the same fashion as a Prion particle. These
prion-like molecules have been shown to be responsible for the toxic effects
responsible for killing neurons in the brain of Alzheimer’s patients. An
amyloid-beta toxic oligomer or “amyloid-beta prion” acquires an aberrant
conformation (shape) and it is capable of converting normal oligomers into
disease causing “amyloid-beta prions”. These prions are capable of propagating
the disease from neuron to neuron, which gradually results in neuronal loss and
memory impairment. This type of transmission is similar to what occurs in the
brain of patients suffering from Creutzfeldt-Jakob and Kuru diseases.
Despite the significant
progress made to identify the cause of Alzheimer’s disease, finding a cure for
this illness remains today as one of the most difficult challenges for the
biotechnology and pharmaceutical industries. It is common belief among experts
that a “disease-modifying drug therapy” for Alzheimer’s patients has the
potential to become the largest blockbuster medicine in the history of the
industry. Thus far, all attempts to develop such a candidate medicine have
resulted in clinical trial failures. Experts believe that the main obstacle to
finding a cure has been not knowing what causes this terrible illness.
