Everyone is familiar with infectious disease — the yearly influenza virus that changes strains every winter, the viral or bacterial onset of food poisoning, fungal ringworm at the gym — we have all been infected by a microbe at some point in our lives.
Transmission of infectious agents (called pathogens) occurs through direct contact, via airborne suspension, through sexual intercourse, blood, or other body fluids, or fecal-orally (typical of poor hygiene or sanitary practices).
While not all microorganisms cause disease, those associated with contagious infection typically follow Koch’s Postulates, four principles proposed by the German physician Robert Koch in 1890:
- The microorganism must be found in abundance in all organisms suffering from the disease, but should not be found in healthy organisms.
- The microorganism must be isolated from a host containing the disease and grown in pure culture.
- Samples of the microorganism taken from pure culture must cause the same disease when inoculated into a healthy, susceptible animal in the laboratory.
- The microorganism must be isolated from the inoculated animal and must be identical to the original organism first isolated from the originally diseased host.
As medicine advanced throughout history, it was clear that exceptions to these principles exist. Asymptomatic infection was noted in cholera patients even during Koch’s time, and is still a feature of many infectious diseases today, including HIV and Hepatitis C. Not everyone exposed to a pathogen may advance to disease, due to genetic immunity or acquired resistance from vaccination or previous exposures. While Koch’s Postulates do not support causality between a pathogen and disease, the principles have been “modernized” to account for advances in the medical research field and the ability to sequence pathogenic DNA or RNA material.
Yet, there is a pathogen that still seems to break all the rules: the prion. With its name derived from “protein” and “infectious,” the discovery of the prion earned Stanley Prusiner the Nobel Prize in Physiology/Medicine in 1997.
While a neurology resident, Prusiner admitted a patient diagnosed with Creutzfeldt-Jakob disease (CJD), a disease that rapidly causes dementia and impaired muscular coordination. At the time, CJD was thought as result of a “slow virus” which caused infection but didn’t elicit an immune response. Prusiner was fascinated with this so-called viral disease, and began to extensively research scrapie, a similar neurodegenerative disease in sheep and goats.
Viruses have been the subject of the “alive-or-not” debate for some time; you can even weigh in with your opinion on the poll over on self-proclaimed “Earth’s virology professor” Vincent Racaniello’s blog and see the current results. The structure of a virus consists of a protein capsule which acts as a vessel for the infectious genetic material inside. viruses cannot act on their own, they need to hijack the molecular machinery of a living cell in order to assemble and replicate. Prusiner’s scrapie research demonstrated that the “slow virus” thought to be responsible could not possibly be a virus—the data came back positive for protein material but there was no DNA or RNA present in the purified samples! The Nobel winner’s findings are still debated today, though no nucleic acids (the building block for genetic material) have yet been identified in any prion disease.
Prions are proteins that can misfold into an irregular structure, making it transmissible to other prion proteins. In mammals, the protein PrP exists in a normal configuration, denoted PrPC (the “C” stands for cellular). However, when the protein is misfolded and infectious, the warped state is denoted PrPSc, “Sc” in reference to scrapie.
These prion diseases are now classically known as transmissible spongiform encephalopathies (TSEs), due to the sponge-like appearance of degrading brain tissue. TSEs also include bovine spongiform encephalopathy (BSE, or more commonly known as “mad cow disease”) and chronic wasting disease in deer and elk.
In the 80’s, “mad cow disease” became a well-known epidemic, as BSE-tainted beef made its way into human consumption. Patients were officially diagnosed with “new variant Creutzfeldt-Jakob disease,” or vCJD, to differentiate the infection from the genetically acquired disease. Though cows are herbivores, it is believed that transmission between animals (and ultimately to some humans) was caused by the addition of meat and bone meal—a byproduct of meat production—into the cattle’s food supply. This cannibalistic cycle allowed the infectious prion to spread.
Cannibalism also played a central role in the spread of a prion disease called kuru. The Fore tribe in Papua New Guinea had a history of cannibalistic funeral practices, in which they would consume the deceased in order to acquire their “life force.” Curiously, anthropological studies beginning in the 50’s showed that infection rates were significantly higher in women and children. This was because men of the tribe would partake of the warriors and leaders that had passed, in addition to getting the “good meat”—such as large muscles and the heart—from the bodies. The women and children fed on the ill and the elderly and consumed the leftover body parts, including the brain (where infectious prions are most concentrated). Kuru continued to plague the Fore tribe until the last infected person died in 2005.
A recent study published in Nature reported that a newly discovered genetic variant of the PrP gene prevented some members of the Fore tribe from acquiring kuru. A normal protein, such as PrPC is built from a chain of biological units called amino acids. In the common PrPC variant, the 127th unit in the chain is an amino acid called glycine (G). The new variant, called G127V, retains the function and shape of PrPC, with valine (V) replacing glycine as the 127th unit.
Asante et. al. created transgenic lines of mice—meaning they bred in genetic material coding for a gene of interest—for these PrP variants. They discovered that the mice with the G127V variant were resistant to the misfolding effects of the infectious PrPSc prion that causes kuru. Additionally, it was resistant to the transmission of CJD.
This research provides clues about the genetic evolution of resistance in a natural population during an ongoing epidemic. If cannibalism wasn’t abolished, would the Fore people eventually have rid themselves of kuru due to genetic resistance? What does it tell us about other genetically acquired neurodegenerative diseases such as Alzheimer’s and dementia? We need researchers like Stanley Prusiner, who are willing to think outside of the established rules to make new discoveries—who knows, a Nobel Prize might be waiting at the end.
Featured image of Mad Cow by Michael Thompson licensed under CC BY SA 3.0.
Pandemic Board Game image by flickr user Cole Camplese licensed under CC BY 2.0.
Brain histology image (public domain) from the U.S. Dept. of Agriculture – Animal and Plant Health Inspection Service by Dr. Al Jenny.