Prions, the Silent Saboteurs

The world is teeming with biological assassins. They lurk everywhere—in secluded forests, homes, and even within your body. Some stalk silently, striking when backs are turned. Others, like viruses, infiltrate and hijack their targets. Their motive is clear: survive and reproduce. Yet, prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are inexplicable and claimed over 500 lives in the United States in 2023, according to the Centers of Disease Control and Prevention.

Prions, nonliving pathogens, have baffled scientists since the 1920s, when German neurologists Alfons Jakob and Hans Creutzfeldt first described brains riddled with Swiss-cheese-like holes, alongside memory loss and personality shifts. The culprit wasn’t a parasite or virus, but a rogue protein.

Even if we don’t fully understand what makes prions tick, scientists are working to fight back using cutting-edge tools, and perhaps a little CHARM.

A look at prions

Prion diseases are as bizarre as they are deadly. They stem from a misfolded, scrambled version of a cellular prion protein (PrPc), which is found mostly in nerve cells. The danger? Once one PrPc protein misfolds, it convinces others nearby to do the same, triggering a domino effect of destruction. 

Even stranger, scientists still aren’t sure what normal PrPc even does. Lab animals, like mice, missing the gene live normal lives. Yet it’s found in high levels in many cells. As Professor Neil Mabbott, a specialist in prion disease at the University of Edinburgh’s Roslin Institute, puts it, “It must be doing something.”

Mabbott studies scrapie, a prion disease in sheep and goats that doesn’t infect humans but behaves similarly to human versions. It’s a safer model for studying diseases like Creutzfeldt-Jakob disease (CJD), which causes memory loss, stiffness, vision problems, and fatigue in people. 

Prions can wreak havoc in three ways: through inherited mutations (familial CJD), ingestion of contaminated meat, or chillingly, by appearing spontaneously (sporadic CJD) for reasons we don’t yet understand.

Mabbott’s work focuses on how prions spread after being eaten, like during the foodborne outbreak of variant CJD linked to infected beef primarily in the United Kingdom in the 1980s and 1990s. When contaminated meat, typically brain or spinal tissue, is consumed, prions slip through the gut using the immune system’s structures meant to monitor for pathogens. They deceive the body’s defenses, settle in immune tissues like the spleen and lymph nodes, and multiply quietly. Because they originate from a native protein, the immune system doesn’t flag them as threats. 

What follows is a neuroinvasive assault. Prions infiltrate nerves near the gut and begin their climb up neural highways, mainly the spinal cord or vagus nerve, toward the brain. It’s a slow-motion relay race that can take up to five years from infection to symptoms. 

Once in the brain, the pace quickens. Prions pile into sticky, insoluble masses that block brain function. The brain becomes a toxic wasteland. “You see lots of white holes,” Mabbott says of CJD brain scans. Neurons become swollen or damaged. “You can lose up to 50% of those nerves.”

From investigation to intervention

While Mabbott untangles how prions invade, others are working to stop the problem at its root. One is Edwin Neumann—a Ph.D. candidate in biological engineering at the Massachusetts Institute of Technology—who’s taking a new route: epigenetic therapy. 

“I came to Boston… because I was… interested in the biotech industry… particularly gene therapy,” Neumann says. Prions became his focus later because they were the perfect target for this type of intervention.

Unlike traditional gene editing, which rewrites DNA, epigenetic therapy controls how genes are used. “It’s like a conductor,” he explains. Epigenetics decide which ones play, and when.

This approach matters because the gene that codes for PrPc, called PRNP, is in everybody’s DNA. We’re born with it. 

Neumann’s lab uses a molecular tool called CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase), which reaches the brain and silences specific genes, like PRNP, by triggering a chemical process called DNA methylation. 

“[It’s] like in a wildfire… removing burnable foliage… around the fire to prevent it from spreading,” Neumann says. CHARM is like a controlled burn; it removes the proteins, so prions can’t spread.

What makes CHARM so promising is how efficient it is. “The way CHARM [works] is by leveraging the [cell’s own] machinery,” he explains. Our cells already produce gene-silencing proteins, but they don’t normally act unless all the right pieces are in place. CHARM brings those pieces together to get the job done.

With prions’ eerie ability to evade the immune system, and no existing cure, this kind of therapy might be our best shot. The idea is simple: no protein, no prion, no problem.