In 1996, the British government announced that ten suspected cases of Creutzfeld-Jacob disease (CJD), a degenerative brain disorder, were caused by the consumption of beef products that harbor mad cow disease [1]. This news not only prompted the EU and Japan to institute a ban on British beef products, but also redirected the attention of the scientific community to the bizarre infectious agent responsible for causing these similar and devastating diseases (mad cow disease in cattle and CJD in humans). This infectious agent, called the prion, is responsible for causing a group of fatal neurodegenerative diseases in mammals referred to as transmissible spongiform encephalopathies (TSEs) [2]. In these diseases, prions cause holes to form in the brains of the affected individuals, giving the brain a sponge-like appearance, hence the term spongiform. Affected individuals develop progressively worsening dementia and eventually die. Another example of a prion disease in humans is the Kuru disease in Papua New Guinea, which spreads among tribal people when they eat the brains of deceased relatives during funeral rituals. Prions cause fatal diseases in sheep as well, such as sheep scrapie, and it is believed that sheep may have transmitted the first prions to cows.

The discovery of an infectious protein

Scientists have been trying to identify the cause of these fatal “sponge-like” brain diseases since 1967 but had limited success. Whatever was causing these diseases was infectious, and could spread from human to human, like in Kuru disease, but also between different species (e.g. cows to humans). Scientists initially thought of the usual suspects, namely viruses and bacteria, as these agents are known to spread among individuals and, in some cases, between species. However, scientists could not kill this infectious agent the way one would kill viruses or bacteria. For instance, heat and UV radiation kill viruses and bacteria by destroying their genetic material, which is crucial to their existence. However, this mysterious infectious agent was resistant to heat and UV radiation and continued to spread as if nothing had happened to it, strongly suggesting that it was neither a virus nor a bacterium. This is why infected beef is still not safe to eat even after cooking it at very high temperatures.

A breakthrough came in 1982, when Stanley Prusiner from the University of California, San Francisco found that the infectious agent causing TSEs was actually a single protein. He called this protein “prion”, which means infectious protein. His discovery was initially met with great skepticism among the scientific community, as most scientists did not believe that proteins could be infectious. Despite all the criticisms, Prusiner went on to discover that the prion protein is native to many mammals, including humans, meaning that we naturally harbor this protein inside our bodies! Prusiner’s groundbreaking discovery won him the Nobel Prize in Medicine in 1997 [3].

If the prion protein exists in all of us, then why don’t we all have TSEs? It turns out that the protein is normally present in a harmless form called PrPC. Despite much work, scientists still are not sure what PrPC normally does in the body. However, what is special about this protein is that it can change from its normal shape into a misfolded shape (the prion form, named PrP-scrapie (PrPsc)) that can resist the harsh treatments that normally destroy proteins. In the prion form, the proteins aggregate, or clump, together and lead to brain damages by killing the neurons (brain cells) that harbor such aggregates. These aggregate protein clumps are also infectious and can spread to nearby cells and even to different individuals.

But how can proteins replicate and spread (a process which normally requires genetic material like DNA) on their own? It turns out that prions replicate by recruiting the  normal PrPC proteins to the ends of the aggregates and forcing it to adopt the  prion conformation as well.  In this way, the prion aggregates will grow larger and larger over time (see Figure 1). When they get too large, they usually break into smaller aggregates, which can then go on to grow at the cost of the normal protein. This ability to corrupt the normal protein in the cell makes these prion aggregates infectious. A topic of ongoing research is the cause of the initial conversion of the protein, from its normal shape into prion.

Figure 1. A schematic of the two possible states of a prion protein. On the left, the protein is in its normal shape (PrPC). In this state, the protein carries out a certain function in the cell. In the middle, the protein has converted to the aggregated prion form (PrPSC). Prions have the ability to recruit normal PrPC proteins to the ends of the aggregates and convert them to prions as well. The aggregates grow larger in this way and when they get too big, they will break apart into smaller aggregates, which then convert even more normal protein to prions. 

Making a lasting impression

Despite their bad reputation, recent research has shown that there is more to prions than initially thought. First, prions can be found in our primitive relatives, yeast and fungi, suggesting that they accompanied us during evolution. Also, not only do prions not kill the yeast cells that harbor them (contrary to what happens in mammals), but in harsh environments they even help yeast survive. For instance, research has shown that yeast strains that can form prions are more resistant to antifungal drugs or heat/chemical stress than strains that cannot form prions [4].

Prions could be beneficial in higher organisms as well, having been implicated in the process of memory formation.  Neuroscientists have always been intrigued by our ability to form memories, and many believe that memories are encoded in the connections between neurons, called synapses. When we encounter an experience, neurons communicate with each other, strengthening their existing connections and establishing new ones, and this process is crucial to memory formation.

The “happens once and persists” feature of memory is loosely reminiscent of prions (once they form, they persist in the organism), and research in sea slugs has shown that there is a protein in the brain that behaves like a prion. This protein, called CPEB, can respond to an experience and facilitates the formation of synapses for storing the newly formed memory. CPEB is an unusual protein in the sense that it has the ability to form aggregates and replicate itself, just like a prion. However, unlike prions, CPEB does not cause neuronal death [5,6]. Researchers think that this prion-like behavior of CPEB may be important to its role in memory formation. Specifically, they think that in response to experience, this protein switches from its normal shape into the prion-like shape, which is better at making connections with nearby neurons and thus establishes memory in the brain.

So what should we make of prions-are they our friends or are they here to harm us? While more needs to happen, recent research suggests that we should keep an open mind and consider that there might be more to prions than a “spongy brain”.

Entela Nako recently finished her doctoral work in the Molecular and Cellular Biology Department at Harvard University.


[1] Center for Food Safety. Timeline of Mad Cow Disease Outbeaks <a href=”” target=”_blank”></a>

[2] Prions: On the Trail of Killer Proteins (Learn Genetics) <a href=”” target=”_blank”></a>

[3] The Nobel Prize in Physiology or Medicine 1997. Stanley B. Prusiner <a href=”” target=”_blank”></a>

[4] Prions play powerful role in the survival and evolution of wild yeast strains. <a href=”” target=”_blank”></a>

[5] Science Daily. Prion Leaves Lasting Mark On Memory <a href=”” target=”_blank”></a>

[6] Prions in Long-Term Memory <a href=”” target=”_blank”></a>


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