I first became interested in Prions when I met Carlton Gajdusek at a Pauling Institute meeting held at the Stanford Court Hotel on Nob Hill in 1986. Gajdusek was the most unassuming Nobel Prize winner (1976) I ever met, perhaps a couple of notches below Linus Pauling who was there also. So was Becki. Gajdusek’s interest in scientific endeavors started with entemology much like Darwin. In 1957 he went to New Guinea to study child growth and development in primitive cultures. He came away with the discovery of kuru, a debilitating neurological disorder among the primitive tribal natives of New Guinea who ate the brains of their victims. Gadjusek could not identify the infectious agent such as a virus or bacterium that caused kuru. Two things that I can think of that came out of Gajdusek’s discovery were the erradication of kuru in New Guinea because of the ending of cannabalism and the ending of the practice of feeding animal tissues and bone meal to livestock. Stanley Prusiner coined the term “prion” in 1982 and received the Nobel Prize in 1997 for demonstrating that the prion was an protein that were all have that becomes “infectious” when mutated or misfolded. This was a hard concept for the scientific community to embrace which makes it even more fascinating.
A compelling case was built for the infectious prion protein when a ‘new variant’ prion (nvCJD) was found in human victims of Creutzfeld-Jacob Disease during the outbreak in England in the mid 1990’s. This variant prion was found to be structurally related to the BSE prion that was linked to the mad cow disease outbreak in England almost a decade earlier. But nvCJD was distinguishable from the spontaneous prion that is linked to classical CJD because the nvCJD prion had a different abnormal fold than the classical prion. There are other epidemiological features of the nvCJD prion that suggest its transmission from the BSE cattle. First, the BSE outbreak in cattle was followed by a similar localized outbreak of nvCJD in humans a decade later. Also, the average age of these Bristish victims was 36 years, much younger than the rare spontaneous CJV victims. The development of CJD in young people argued for an external infectious source of the disease rather than a protracted spontaneous development of the disease. Cloning and sequencing of the gene for the normal endogenous PrP protein revealed the existence of two different polymorphic forms in humans. One of the two allelic (polymorphic) forms of PrP contains the amino acid, methionine (M), at position 129 in the amino acid chain of PrP instead of valine (V) at that position due to an inherited mutation of at least one of the two possible PrP alleles. All victims of the nvCJD outbreak were from only one of the three possible human populations, those who carried the MM genotype (a methionine encoded at position 129 in both of their inherited PrP alleles). No incidence of nvCJD has been found in people with the VV phenotype or the MV phenotype, indicating, as of yet, that they are not susceptible to the ingested BSE prion. However, it was possible at the time that incubation periods may just be much longer for people with the VV or MV phenotypes.
Different populations of people have been examined for frequencies of occurrence of the normal MM phenotype that is associated with the rapid and early on-set of CJD. These frequencies ranged from 43% of a Caucasian population in one study to 50% of the French and 57% of the Turkish population in two other studies. Thus, a significant portion of the human population appears to be resistant to the fast onset of CJD. While rigorous proof of the direct link of the prion protein to “prion disease” is missing, it’s hard to ignore the rest of the story in favor of the prion protein as the etiologic agent of these diseases.
