Prions have never played by the rules. They aren’t viruses or bacteria. They’re simply proteins folded into the wrong shape, and that structural mistake can cause devastating problems.

As Alison Armstrong, PhD, global head of scientific & regulatory consultancy, BioReliance Contract Testing Services, Merck KGaA, Darmstadt, Germany, puts it: “Prions are infectious forms of naturally occurring proteins that can alter healthy proteins and lead to neuronal cell death.” As she adds, “They present a potential health risk through animal-to-human transmission, although human-to-human transmission is rare.”

One prion can trigger a chain reaction, coaxing neighboring proteins to misfold too, and the damage spreads through the brain like a rumor nobody can stop. Prion diseases are called transmissible spongiform encephalopathies (TSEs), and they include bovine spongiform encephalopathy (BSE), better known as mad cow disease, and Creutzfeldt-Jakob disease (CJD). Once symptoms of CJD appear, a person’s decline is often fast, and it is always fatal.

For scientists, drug developers, and biomanufacturers, that strange biology creates a second, more practical problem: prions are brutally hard to eliminate, detect, and study.

“For products with a risk of prion contamination, purification processes must be able to eliminate the pathogen,” Armstrong says. “Because methods for directly detecting prions in raw materials are limited by sensitivity, prion-clearance studies have become an industry-standard approach for demonstrating that downstream purification steps can remove or inactivate transmissible spongiform encephalopathy agents.”

Unique infectious agent

Human prion diseases are exceedingly rare. CJD is the most common, and variant CJD (vCJD)—historically linked to eating beef from cattle infected with BSE—is rarer still. Only four vCJD cases have ever been reported in the United States, all in people believed to have been exposed abroad, but rarity doesn’t mean the risk disappears.

Acquired prion disease can, in unusual circumstances, follow medical procedures involving contaminated equipment or human tissue. That possibility also looms over pharmaceutical manufacturing, particularly wherever human- or animal-derived materials enter the production line.

“Industry and regulatory authorities address these challenges through risk assessment and controls around animal-derived materials used in biologics manufacturing,” Armstrong says. “A TSE risk assessment typically evaluates factors such as the animal species, tissue source, country of origin, tissue classification, manufacturing controls, and sourcing from countries with negligible or controlled BSE risk. These measures, combined with appropriate manufacturing and quality controls, help mitigate the risk of transmissible prion diseases.”

For biological products carrying any plausible contamination risk, manufacturers can use prion-clearance studies to test whether individual purification or manufacturing steps actually remove or inactivate prions. Researchers deliberately spike scaled-down versions of a production process with prion material, then measure what’s left afterward.

Texcell, for instance, describes seeding prion material into crude starting material or mock manufacturing vessels, then tracking removal or inactivation through each subsequent step. Similar studies check whether cleaning procedures between production batches actually destroy prion protein left behind on equipment.

On paper, it sounds simple: put prions in, run the process, see what comes out. Measuring that convincingly is another matter entirely.

The measurement problem

A clearance study is only as trustworthy as the assay behind it.

ViruSure, whose staff have worked in prion safety since the BSE crisis of the 1990s, relies on the hamster-adapted 263K scrapie strain for many of its studies—a model it describes as accepted by regulatory authorities. The company runs quantitative Western blot assays to check whether manufacturing steps remove or inactivate prion protein, alongside in vivo bioassays for determining prion titer.

Animal bioassays remain the benchmark, but they are slow, expensive, and nearly impossible to scale. And an assay built on rodent-adapted prions isn’t a stand-in for rapidly experimenting on the real, infectious human thing.

That distinction matters most in drug discovery. A compound that performs beautifully against an experimental prion model has no guarantee of working against actual human disease.

A new experimental system might finally close that gap.

Making human prions grow in cells

Parmjit Jat, PhD, a professor of molecular biology at University College London, and his colleagues report developing EKV cells: a humanized mouse-cell model capable of supporting robust, indefinite propagation of sporadic CJD (sCJD) prions.

That solves a problem that has dogged the field for decades. As Jat and his co-authors put it, research into human prion biology and therapeutics “has been severely constrained by the inability to propagate human prions in dividing cells,” leaving scientists dependent on “costly and slow animal bioassays.”

The team reports that EKV cells reliably generate high-titer infectious sCJD prions. Lysates from those cells triggered lethal prion disease in humanized mice that was clinically and neuropathologically indistinguishable from disease caused by sCJD-infected human brain tissue, which gives a strong signal that the model is capturing the real thing, not a rough approximation of it. Using the cell line, the researchers built the Human Prion Assay (HPA) which quantifies sCJD infectivity with sensitivity they report as comparable to the gold-standard mouse bioassay.

The crucial difference is time. The HPA compresses the experimental timeline “from years to weeks,” the scientists note.

A renewable, cell-based model makes experiments more reproducible and far more scalable. Instead of leaning entirely on infected brain tissue or months-long animal studies, scientists can now investigate disease mechanisms and screen candidate therapies directly against infectious human prions.

It also hands researchers a faster route to arguably the most important question in the field: Can an established prion infection actually be cleared, once it has taken hold?

To show the platform could actually screen drugs, Jat’s team dosed infected cells with ICSM18, an anti-prion protein monoclonal antibody previously shown to work against nonhuman prions. The result was potent, dose-dependent clearance of human PrPSc in infected EKV cells. An isotype control antibody, used as a check, did nothing.

These scientists point out that earlier therapeutic screens built on murine prions turned up compounds like quinacrine that later failed in human trials. Infected EKV cells, by contrast, could support high-throughput screening of small-molecule inhibitors against genuine infectious human prions from the start.

The gap between a years-long assay and one that produces answers in weeks could reshape the scale of that screening. More compounds, more concentrations, more shots on goal become experimentally realistic. Failures get weeded out sooner. Promising candidates move faster.

Attacking from another direction

As some researchers build better models, others are widening what counts as a viable drug target in the first place.

Most therapeutic strategies have focused on blocking the conversion of normal cellular prion protein, PrPC, into its pathological form, PrPSc. Scientists at the laboratory of prion biology at the Scuola Internazionale Superiore di Studi Avanzati in Italy tried something different: reducing prion burden without touching either protein directly.

Their strategy grew out of an observation that the protease inhibitor SERPINA3, also known as SerpinA3n, is upregulated during prion disease. The researchers identified a small molecule, ARN1468, that inhibits those serpins and reduced prion load in chronically infected cells.

That compound’s low bioavailability, however, ruled out in vivo studies in prion-infected mice. Even so, the work is proof of concept that a drug can target the biological machinery around prion accumulation rather than the prion protein itself. The researchers call it “a novel and effective approach to the treatment of prion disease.”

That broader strategy could become especially useful once paired with scalable, human-relevant experimental systems. Researchers could investigate not just molecules that physically bind prion proteins, but the cellular pathways that decide whether misfolded proteins accumulate, persist, or vanish.

Breaking the bottleneck

Prion clearance in biomanufacturing and therapeutic drug discovery can look like two unrelated fields. They aren’t. Both are wrestling with the same core problem: scientists need a reliable way to prove that infectious prions have actually been removed.

For manufacturers, that means stress-testing purification and cleaning processes and quantifying how well they eliminate a remarkably resilient contaminant. For therapeutic researchers, it means building systems where a genuine human prion infection can be established, measured, and cleared, rather than approximated.

Prions remain exceptionally difficult targets. The distance between clearing PrPSc in a dish and treating a patient with a rapidly progressive, fatal neurodegenerative disease is enormous, and new cell assays will complement rather than replace rigorous animal and validation studies.

But the tools available to scientists shape the questions they can realistically ask. For decades, prion research has been bottlenecked by exactly that—the sheer time and difficulty of studying the pathogen at all. Human prions resisted scalable propagation, infectivity studies leaned almost entirely on animals, and drug candidates built on nonhuman models kept failing to translate. A system that can propagate, quantify, and experimentally clear genuine human sCJD prions would change that math.

The most important advance here, then, might not be any single antibody, small molecule, or assay. It’s the possibility of a faster experimental loop—one where scientists can generate human prions, measure them, challenge them with candidate treatments, and get an answer within weeks instead of years.

For one of biology’s most stubborn infectious agents, simply making the experiments faster might turn out to be one of the most powerful forms of progress available.