Accidents happen. Even in laboratories where safety is a priority they occur despite our best (and sometimes not so best) efforts to keep ourselves and our co-workers protected from injury and disease. Scientists working with infectious agents are particularly at risk even though there are numerous physical and procedural requirements in labs to ameliorate the risk. Still, when accidents do occur there must be a reevaluation of all operations to identify and eliminate the source of danger as was recently announced for five institutions in France that study prion diseases. At one of the five institutions, a lab worker died in 2019 from a prion disease called variant Creutzfeldt-Jacob disease (vCJD); this prion also causes mad cow disease. The French worker cut herself with forceps that had been used to dissect prion-infected mouse brains, thus introducing this untreatable agent into her body. Tragically, another worker at the same facility was diagnosed this year with Creutzfeldt-Jacob disease (CJD) symptoms leading to a moratorium on prion studies at all five institutions while safety standards are reviewed. However, CJD can occur spontaneously so this second case may not be lab acquired. Unfortunately, the prion that causes spontaneous CJD can only be distinguished from the laboratory prion that causes vCJD by a postmortem examination of brain tissue. Therefore, the research was halted to ensure that best practices are in place and being followed.
Prions are a strange and unique type of infectious agent that are not viruses nor living organisms like bacteria, yeast, fungi, and parasites. Instead, prions are a defective version of a normal cellular protein called PrPC (prion protein cellular form). Normal (wildtype) PrPC is found on the surface of cells throughout the body but with a heavy concentration in the brain. While its normal physiologic function is still not precisely understood, PrPC is an important protein that has been linked to a variety of processes from neurological function to immunity. All proteins normally fold into very specific 3-dimensional shapes that are essential for their function. On very rare occasions, a molecule of PrPC protein in an individual may spontaneously misfold into an abnormal shape called PrPSC. PrPSC is highly dangerous because it is a self-propagating molecule. The first PrPSC that forms binds to a normal PrPC molecule and causes the normal protein to refold into the abnormal PrPSC form. Now, these two PrPSC molecules each bind to a normal PrPC molecule and converts them to the PrPSC form. This process goes on and on as one PrPSC becomes 2, then 4, then 8 and keeps doubling. Slowly over several years, the PrPSC builds up in the brain and eventually causes the fatal and untreatable neurological degeneration that we call CJD. Spontaneous CJD occurs in about 1 in every million people each year.
CJD can also occur in a familial form. In these affected families, there is a mutation in the gene for PrPC that causes an amino change in the PrPC protein. This mutant protein has an increased propensity for misfolding into the PrPSC form so the odds of CJD occurring are higher in carriers of the mutant gene than in individuals with the wildtype PrPC gene. Still, to initiate the disease requires the random initial misfolding event which may never occur in some carriers. Thus, even in affected families, not everyone with the mutant gene manifests the disease.
vCJD results from ingesting meat from animals with PrPSC or from laboratory accidents. The prion form that causes vCJD and mad cow disease is particularly dangerous because it is very effective at converting normal PrPC to PrPSC. This results in a disease that progresses faster and gives a somewhat different brain pathology than seen with sporadic CJD. The molecular basis for these differences between vCJD and typical CJD is still poorly defined as is our overall understanding of the PrPC protein and all its disease-causing versions. Horribly, as with CJD, once symptoms manifest for vCJD or any other prion disease, the illness is untreatable and always fatal. Much further scientific study is needed to develop approaches for stopping the PrPS to PrPSC progression and for treating people once symptoms appear. However, this field can only move forward with scientists willing to work with this dangerous agent, and these intrepid pioneers deserve our respect and appreciation.