Life of Prion

Or What Links Cannibalism to Foot and Mouth Disease?

Simona Zahova | 3 APR 2019

A peculiar group of proteins, prions, have earned a mythical status in sci-fi due to their unorthodox properties and unusual history. These deadly particles often play a villainous role in fiction, appearing in the Jurassic Park franchise, and countless zombie stories. Even putting apocalyptic conspiracies aside, prions are one of the wackiest products of nature, with a history so remarkable it needs no embellishment. Tighten your seatbelts, we are going on a journey!

Our story begins in Papua New Guinea, with the Fore tribe. The Fore people engaged in ritualistic funerary cannibalism, consisting of cooking and eating deceased family members. This tradition was considered necessary for liberating the spirits of the dead. Unfortunately, around the middle of the 20thcentury, the tribe experienced a mysterious deadly epidemic, that threatened to wipe them out of existence. A few thousand deaths were estimated to have taken place between the 50s and the 60s, with the diseased exhibiting tremors, mood swings, dementia and uncontrollable bursts of laughter. Collectively, these are symptoms indicative of neurodegeneration, which is the process of progressive death of nerve cells. Inevitably, all who contracted the disease died within a year (Lindenbaum 1980). The Fore people called the disease Kuru after the local word for “tremble”, and believed it was the result of witchery.

Meanwhile, Australian medics sent to investigate the disease reported that it was psychosomatic. In other words, the medics believed that the tribe’s fear of witchcraft had caused massive hysteria that actually had an effect on health (Lindenbaum 2015). In the 60s, a team of Australian scientists proposed that the cannibalistic rituals might be leading to the spreading of a bug causing the disease. Since the Fore tribe learned about the possible association between cannibalism and Kuru, they ceased the tradition and the disease rates drastically reduced (Collinge et al. 2006). However, the disease didn’t disappear completely, and the nature of the mysterious pathogen eluded scientific research.

Around the same time, on the other side of the globe, another epidemic was taking place. The neurodegenerative disease “scrapie” (aka “foot and mouth disease”) was killing flocks of sheep in the UK. The affected animals exhibited tremors and itchiness, along with unusual nervous behaviour. The disease appeared to be infectious, yet no microbe had been successfully extracted from any of the diseased cadavers. A member of the agricultural research council tentatively noted that there were a few parallels between “scrapie” and Kuru (Hadlow 1959). For one, they were the only known infectious neurodegenerative diseases. More importantly, both were caused by an unknown pathogen, which eluded the normal methods of studying infectious diseases. However, due to the distance in geography and species between the two epidemics, this suggestion didn’t make much of a splash at the time.

The identity of this puzzling pathogen remained unknown until 1982, when Stanley Prusiner published an extensive study on the brains of “scrapie” infected sheep. It turned out that the culprit behind this grim disease wasn’t a virus, a bacterium, or any other known life form (Prusiner 1982). Primarily, the pathogen consisted of protein, but didn’t have any DNA or RNA, which are considered a main requirement for life. To the dismay of the science community, Prusiner proposed that the scrapie “bug” was a new form of protein-based pathogen and coined the term “prion”,short for “proteinaceous infectious particle”. He also suggested that prions might be the cause not only of scrapie, but also of other diseases associated with neurodegeneration like Alzheimer’s and Parkinson’s. Prusiner was wrong about the latter two but was right to think the association with “scrapie” would not be the last we hear of prions. Eventually, the prion protein was confirmed to also be the cause of Kuru and a few similar diseases, like “mad cow” and Creutzfeldt-Jacob disease (Collins et al. 2004).

Even more curiously, susceptibility to prion diseases was observed to vary between individuals, leading to the speculation that there might be a genetic component as well.  The mechanism behind this property of the pathogen remained a mystery until the 90s. Once biotechnological development allowed the genetic code of life to be studied in detail, scientists demonstrated that the prion protein is actually encoded in some animal genomes and is expressed in the brain. The normal function of prions is still unclear, but some studies suggest they may play a role in protecting neurons from damage in adverse situations (Westergard et al. 2007).

How does a protein encoded into our own DNA for a beneficial purpose act as an infectious pathogen? Most simply put, the toxicity and infectiousness only occur if the molecular structure of the prion changes its shape (referred to as unfoldingin biological terms). This is where heritability plays a part. Due to genetic variation, one protein can have multiple different versions within a population. The different versions of the prion protein have the same function, but their molecular architecture is slightly different.

Imagine that the different versions of prion proteins are like slightly different architectural designs of the same house. Some versions might have more weight-bearing columns than others. Now let’s say that an earthquake hits nearby. The houses with the extra weight-bearing columns are more likely to survive the disaster, while the other houses are more likely to collapse.

What can we take away from this analogy? A person’s susceptibility to prion diseases depends on whether they have inherited a more or less stable version of the prion protein from their parents. In this case, the weight-bearing column is a chemical bond that slightly changes the molecular architecture of the prion, making it more stable. Different prion diseases like Kuru and “scrapie” are caused by slightly different unstable versions of the prion protein, and their symptoms and methods of transmission also differ.

Remarkably, a study on the Fore people from 2015 discovered that some members of the tribe carry a novel variant of the prion protein, that gives them complete resistance to Kuru (Asante et al. 2015). Think of it this way: if people inherit houses of differing stability, then some members of the Fore tribe have inherited indestructible bunkers. Evolution at its finest! It isn’t quite clear what is the triggering event behind the “collapsing” or unfolding of prions. Once a prion protein has unfolded, it leads to a domino effect, causing the other prions within the organism to also collapse. As a result, a bunch of unfolded proteins accumulate in the brain, which causes neurodegeneration and eventually death.

One explanation of why neurons die in response to prions “collapsing” is that cells sense and dislike
unfolded proteins, triggering a chain of events called the unfolded protein response. This response stops all protein production in the affected cells until the problem is sorted out. However, the build-up of pathogenic prions is an irreversible process and it happens quite quickly, so the problem is too big to be solved by stopping protein production. In fact, it is a problem so big that protein production remains switched off indefinitely, and consequently neurons starve to death (Hetz and Soto 2006).

We have established that prions are integral to some animal genomes and can turn toxic in certain cases, but how can they be infectious too? Parkinson’s and Alzheimer’s are also neurodegenerative diseases caused by the accumulation of an unfolded protein, but they aren’t infectious. The difference is that prions have a mechanism of spreading comparable to viruses or bacteria.  One might wonder why one of our own proteins has a trait that allows it to turn into a deadly pathogen. Perhaps this trait allowed proteins to replicate themselves before the existence of DNA and RNA. Or, in other words, this might be remainder from before the existence of life itself (Ogayar and Sánchez-Pérez 1998).

To wrap things up, prion diseases are a group of deadly neurodegenerative diseases that occur when our very own prion proteins change their molecular structure and accumulate in the brain. What makes prions unique, is that once they unfold, they become infectious and can be transmitted between individuals. The study of their biomolecular mechanism has not only equipped us with enough knowledge to prevent potential future epidemics, but also offers an exciting glimpse into some of the secrets of pathogenesis, neurodegenerative diseases, evolution and life. Most importantly, we don’t need to worry about the zombies anymore. Let them come, we can take ‘em!

Edited by Jon Fagg & Sophie Waldron


  • Asante, E. A. et al. 2015. A naturally occurring variant of the human prion protein completely prevents prion disease. Nature522(7557), pp. 478-481.
  • Collinge, J. et al. 2006. Kuru in the 21st century—an acquired human prion disease with very long incubation periods. The Lancet367(9528), pp. 2068-2074. doi:
  • Collins, S. J. et al. 2004. Transmissible spongiform encephalopathies. The Lancet363(9402), pp. 51-61.
  • Hadlow W.J. Scrapie and kuru. Lancet. 1959:289–290.
  • Hetz, C. A. and Soto, C. 2006. Stressing out the ER: a role of the unfolded protein response in prion-related disorders. Current molecular medicine6(1), pp. 37-43.
  • Lindenbaum, S. 1980. On Fore Kinship and Kuru Sorcery. American Anthropologist82(4), pp. 858-859.
  • Lindenbaum, S. 2015. Kuru sorcery: disease and danger in the New Guinea highlands. Routledge.
  • Ogayar, A. and Sánchez-Pérez, M. 1998. Prions: an evolutionary perspective. Springer-Verlag Ibérica.
  • Prusiner, S. B. 1982. NOVEL PROTEINACEOUS INFECTIOUS PARTICLES CAUSE SCRAPIE. Science216(4542), pp. 136-144. doi: 10.1126/science.6801762
  • Westergard, L. et al. 2007. The cellular prion protein (PrP C): its physiological function and role in disease.Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease1772(6), pp. 629-644.

My reflections on studying Parkinson’s Disease

Dr. Lucia Fernandez Cardo | 18 JUN 2018

Parkinson’s disease (PD) owes its name to Doctor James Parkinson, who in 1817 described the disorder in his manuscript “An essay on the shaking palsy”. It has been 200 years since we began to study this disease, and despite the advances in understanding, we are still far from finding a cure.

PD is the second most common neurodegenerative disorder affecting 1-2% of the worldwide population. The pathological hallmark is the loss of dopaminergic neurons in a very small part of the brain called the Sustantia nigra, and the presence of protein depositions called Lewy bodies (Spillantini et al., 1997). The loss of dopamine leads to a number of motor symptoms: bradykinesia (slowness of movement), rigidity, resting tremor, and postural instability. For the clinical diagnosis of PD, the patient must present bradykinesia plus one of the other three signs. Along with these motor signs, some non-motor symptoms are often present, amongst them anxiety, depression, dementia, sleeping disturbances, intestinal problems or hallucinations (Postuma et al., 2015).

PD can be due to both genetic and environmental risk factors. 10-15% of the cases are described as familial PD with a clear genetic origin (mutations in SNCA, LRRK2 or Parkin genes are the main cause), the remaining cases are considered ‘sporadic’ or ‘idiopathic PD’ and are due to a possible combination of multiple genetic (risk polymorphisms) and environmental risk factors (toxins, exposure to pesticides, side effects of drugs, brain lesions, etc.) (Billingsley et al., 2018; Fleming, 2017; Lee & Gilbert, 2016).

In my experience, researching PD is something that I find challenging, but also motivational and rewarding. Every 11th of April (James Parkinson’s birthday), the regional and national associations of PD patients and their relatives have a day of celebration. They obviously do not celebrate having the disease, but celebrate being together in this battle and never giving up. This day they put aside the pain and the struggling, and celebrate that they are alive by gathering together, laughing, eating, and dancing.

When I was doing my PhD dissertation, I was lucky to be invited to this celebration as part of a group of scientists working on PD. Our group study the molecular genetics of PD, amongst other disorders, and my thesis was focused on studying genetic risk variants in sporadic patients. I will never forget how nervous I was, having to deliver a very brief talk, explaining the genetic component of PD and our current projects at the time. Some years later, though they may not remember me, I still clearly remember the smiling faces in the audience and the cheering and nice words that were said after I finished. Perhaps they did not grasp the most technical concepts, but for them, the mere fact of knowing that there were people researching their disease, working on understanding the mechanisms, and fighting to find a cure, was more than enough to garner many thanks and smiles.

Sadly, there is not yet a cure for PD, but medications, surgery, and physical treatment can provide relief to patients and improve their symptoms. The most common treatments (e.g.  levodopa, dopamine agonists, MAO-B inhibitors) all restore the dopamine levels in the brain (Fox et al., 2018). Levodopa is usually the most successful treatment but the side effects, appearance of dyskinesia (involuntary movement) and fluctuations in the effectiveness can be an issue with long term use. Some patients can be candidates for a very successful surgery treatment called Deep Brain Stimulation (DBS) which involves the implantation of a neurostimulator, usually in the top chest area, and a set of electrodes in specific parts of the brain. The electrical pulses stop the over excitation in the brain and the reduction of motor symptoms is astonishing. Follow the links below to check out some videos of the effects.

Despite the treatments, these people can struggle daily due to the difficulty of finding the right drug combinations, the on and off phases of the medication, or the issues of carrying an internal battery to control the electrode pulses in their brain – and this is not even mentioning the possible non-motor symptoms of the disease. After spending a whole day with them I felt overwhelmed by their energy and good sense of humour and definitely saw things from a different perspective.

Finally, I just want to say that getting the chance to meet real people who have the disorder can be so important for us scientists. It helps to remind us why we dedicate so much of our lives researching a disorder. It is why during the hardest moments of failed experiments, struggling with new techniques, and so many extra hours of work, we can keep on going and will not give up. We do it so that we can see patients smile and keep up their hopes that we will one day find a cure for a disease as debilitating as PD.

Edited by Sam Berry & Chiara Casella


If you are interested in learning a little bit more about PD and helping us to demystify this disease, here is the link to some useful websites:

Killing cancer with your brain!

Oly Bartley | 9 MAY 2016

It is predicted that in the UK over one thousand people will be diagnosed with cancer every day this year Statistics Fact Sheet, 2015). Those unlucky enough to develop the most common form of brain cancer (Glioblastoma) will typically only survive 12 to 15 months (World Cancer Report, 2014). But what if you could kill the cancer with your brain? Unfortunately, I don’t mean cancer-fighting psychic powers (I know, the picture of Jean Grey is misleading… it was a cruel hook!). Instead, I’m referring to a new use for neural stem cells (NSC), to do the job of tracking and killing down cancerous cells for us. Believe it or not there are scientists working on such an intervention, and a new paper (Bagó et al., 2016) published last month in Nature Communications describes an exciting advancement that could help bring this strange therapy to a cancer clinic near you.


An example of a Glioblastoma

NSCs are unusual for various reasons, but of particular interest here, they’re able to migrate through the brain towards tumorous cancer cells. By engineering these cells to also secret anti-cancer molecules, they become natural cancer hunters capable of both finding and killing tumorous cells. This has been demonstrated as an effective therapy in various pre-clinical models, but the difficulty has been finding a good cell source to move this concept into clinics. Ideally we need something autologous (to stop our immune systems killing the NSC) and readily available. Unfortunately, the naturally occurring NSCs we all have exist deep within our brains (making them hard to obtain), and haven’t been genetically modified to secrete those important anticancer molecules (they’re not natural cancer killers).

Previously, scientists have wondered if we could make our own NSCs for this treatment by using induced Pluripotent Stem cells (iPSC). To learn more about iPSCs watch this short video:

iPSCs seem like they would be ideal because they are easy to get hold of (we can grow them from a skin sample), genetic modification can be made during the initial generation process, and they can be autologous to the patient. However, labs that have transplanted NSCs grown from iPSCs into the brain frequently report that iPSCs also have a really REALLY frustrating tendency to become cancerous tumour cells… and you’re not going to fix brain cancer by sticking more in there!

So what’s different about this paper? Simple; they used transdifferentiation. What the heck is transdifferentiation? I’m glad you asked. It’s a method similar to iPSC generation, except that instead of reprogramming cells to a pluripotent state, you reprogram them directly into the cell type you want. In this case they took fibroblasts (skin cells) and transdifferentiated them into NSCs, and named these new cells induced neural stem cells (iNSC). Crucially, these iNSC don’t seem to have the same tendency to become cancerous, yet they retain all those benefits of iPSCs outlined above! The researchers found that by injecting these iNSC into mice with glioblastomas, their survival increased between 160%-220%!

The iNSCs aren’t ready for clinics yet. For instance, one problem the paper outlines is that their iNSCs need a structure to help target the right parts of the brain, because otherwise they wander off before they’ve killed all the cancer. But, because these cells work so well, the scientists are confident the work only needs refinements*, so maybe one day in the not too distant future we can expect to be killing brain cancers with our brains!**


  • Bagó, J.R., Alfonso-Pecchio, A., Okolie, O., Dumitru, R., Rinkenbaugh, A., Baldwin, A.S., Miller, C.R., Magness, S.T. and Hingtgen, S.D. (2016) Therapeutically engineered induced neural stem cells are tumour-homing and inhibit progression of glioblastoma. Nature communications7.
  • Statistics Fact Sheet, 2015, Macmillan Cancer Support
  • World Cancer Report, 2014, World Health Organisation

*Of course, ‘refinements’ usually translates to another decade or two of work.

**Disclaimer: This statement is technically true, though your ‘cancer killing brain’ might actually be skin cells that have been turned into genetically modified brain cells. 😉 TECHNICALITY!