A Stubborn Pathogen

The classroom poster of the scientific method dictates that one should construct a hypothesis or two.

All right, here are mine:

Zombies are either incredibly stupid… or incredibly brave.

Biological Origami

Proteins catalyse and facilitate the major majority of reactions occurring in an organism, including the synthesis of more proteins. Additionally functioning as structural units for organs like the skin and muscles, proteins draw their broad versatility from the fact that there are simply millions of them. Each one’s structure is tailored to a function or system of functions. There are, at most, four main levels of structure to any protein. They describe the bonding of the amino acids which make up the protein, as well as how parts of the protein interact with and attract each other to fold in various ways and maintain a 3-dimensional structure. For some reason, be it genetics, contaminated food, or sheer chance, this folding can sometimes go haywire. If it does, the protein becomes dysfunctional or possibly even harmful. Most of the time, cells can remedy this issue in various ways, either by trying to refold the protein, using enzymes called proteases to degrade and recycle it, or by committing cell suicide (apoptosis) as a last resort. In some exceptionally rare cases like Huntington’s Disease, the misfolding of a protein can spell an organism’s death.

An image of the CI-2 protein before and after folding. Cell machinery can help fold amino acid chains into 3-dimensional proteins.

Prions Discovered

Proteinaceous Infectious Agent. Rolls right off the tongue…and into destructive clusters in both human and bovine brains. Fortunately (for humanity), Professor Stanley B. Prusiner discovered both of these things, which is — respectively — why he came up with the term ‘prion’, pronounced pree-on (short for proteinaceous infectious, with some letter swapping), and why he won a Nobel Prize.

Let’s go back a bit.

The famous discovery of prions dates back to 1982. Up until that point, neuroscientific research had been desperately attempting to isolate and classify an unprecedented biological agent that had been silently wreaking havoc among the sheep population for the past three centuries. Causing what appeared to be rapid onset dementia, loss of nervous system functionality, and death within a few months, the disease was dubbed “scrapie” after infected sheep who would try to scrape against objects for balance and support. The only way to definitively confirm this diagnosis was a post-mortem examination of a sheep’s brain, upon which one would be confronted with a terrifying sight similar to this:

Diseased (Stained section of bovine brain infected with BSE)
Normal (Stained section of normal human brain)

The agent left thousands of microscopic cysts, destroying millions of neurones in its wake. This spongy appearance is medically described as “spongiform encephalopathy”.

Up until Dr Prusiner’s breakthrough, the agent was presumed to be a virus or viroid. Due to its unexpected behaviour, it was referred to as an “unconventional virus” or “slow virus”. Consensus was brittle, and confusion abounded. One thing remained certain: this agent was extremely small.

But something just didn’t add up.

By definition, a virus or viroid would have contained genetic material. However, previous attempts to extract any genetic material from the scrapie agent had entirely failed. This wasn’t the only red flag, but it was intriguing. As well as this, the agent had displayed extreme resistance to sterilisation by ionising radiation, something uncharacteristic of genetic material. It was pretty resistant to heat (required temperatures of more than 200°C for multiple hours to be destroyed), which was extremely unlike genetic material. To top it all off, it failed to elicit any immune response from its victims. All of this led Dr Prusiner to postulate that the mysterious agent behind scrapie was a rogue group of proteins, giving rise to the now widely accepted prion theory.

The BSE Crisis of the ‘80s/90s

In 2004, the UK’s National Health Service introduced a (currently active) policy forbidding anyone who had ever received a blood or blood product transfusion in the UK after January 1980 from becoming a blood donor. About a decade prior to the implementation of this policy, the British agricultural sector had been confronted with the worst of a vexing and proliferating medical threat within its livestock: mad cow disease, or bovine spongiform encephalopathy (BSE). What started off as a mysteriously tremoring cow in West Sussex turned into thousands of nervous, aggressive, uncoordinated cattle who produced less milk, all rapidly deteriorating and dying within a few months of the first symptoms. Unbeknownst for now, patient zero’s feed had included the remains of scrapie-infected sheep.

In 1987, BSE was confirmed to belong to this new class of prion-related spongiform encephalopathies.

Laboratory experiments around 1990 started to show that BSE could infect mice. Neuroscientists surely thought that if BSE could infect mice, who shared a similar neurological architecture to humans, there was a chance that humans were within BSE’s sights. Medically, this raised a dilemma. After all, Creutzfeldt-Jakob Disease, Gerstmann-Sträussler-Scheinker Disease, and kuru to name a few were other established human encephalopathies that left their victims with hole-riddled brains.

For now, things seemed to be controllable. The disease did not seem to have crossed the “species-species barrier” out in real life and, much like scrapie, was contained within its original species. Just in case, things like bovine offal (organs) were banned from public consumption.

By 1993, 120,000 British cows had been diagnosed with this inexplicably fatal disease, 1000 more deaths per week being added to a perturbing tally. However, thanks to safeguards that were progressively added against animal feed, it started to decline within the same year. Around the same time, Dr Prusiner and his team expanded on prion theory, publishing evidence that prions already existed in healthy sheep, but that differently folded forms of the same proteins were associated with scrapie.

But all was not well just yet.

In 1991, the UK’s Chief Medical Officer had been succeeded by a new Officer. Up until 1995, both had repeatedly maintained that eating beef was perfectly safe for humans. Unfortunately for the two of them and the eventual two hundred plus victims of a novel variant of the known Creutzfeldt-Jakob disease (CJD), they were dead wrong. Cooking temperatures and durations were never remotely enough to destroy or inactivate prions. The spring of ‘95 concluded with the death of 19-year old Stephen Churchill from what appeared to be CJD. For a disease associated with older people, this was extremely peculiar. Suffering from dementia and a twitching body, Stephen had stereotypical symptoms of CJD. Stephen’s family had to helplessly watch on as their son devolved into being unable to dress himself. Within months, prions condemned a 19-year old to a nursing home’s life. On post-mortem examination, it was made certain that Stephen had spongiform encephalopathy. However, Stephen’s first symptom was psychiatric illness, highly unusual for regular CJD. While other CJD patients would have started to lose their memories and become increasingly confused, Stephen became depressed and had hallucinations. Moreover, his brain’s electrical activity didn’t match previous CJD patients. Stephen was finally diagnosed with “new-variant Creutzfeldt-Jakob disease” (now known as vCJD). The mallet was caressing the alarm bell now, toying with it. With its final determining strike, the floodgates to a multi-billion pound economic disaster would open.

Between Stephen’s passing and 1996, research linked vCJD cases to BSE with high certainty. A possible factor in this was that the analysis of Stephen’s brain proved to be doubly weird. Protein clumps/plaques were observed, already not common in CJD, surrounded by a floral arrangement of holes, which was unseen in CJD…but seen in people infected with kuru. In 1976 a Nobel Prize had been won for the discovery that kuru was due to cannibalistic practices within a tribe in Papua New Guinea. The UK’s Spongiform Encephalopathy Advisory Committee publicly announced this. What ensued was the culling of 4.4 million cattle to try to stop the disease. Global and individual bans on British meat were set in motion, some of which, like Japan’s, were only lifted as late as 2019. In addition, many agricultural and blood donation protocols were globally implemented, with stringent emphases on the brain and spinal cord.

What we know now

While many, both humans and animals, unfortunately lost their lives and loved ones to the relentless deterioration that comes with vCJD, we’ve learnt a lot in the process. We now know that Protease Resistant Prions, or PrPs, already exist in healthy humans in an uninfectious form. We’re not exactly certain on what they do, but we’re trying to figure that out. We know that if prions misfold or misfolded ones are introduced, they act as templates for other prions to misfold, triggering an exponential reaction that prompts the rapid degeneration seen in patients. Accumulating inside neurons, they cause them to undergo apoptosis by utilising the help of a certain 14-3-3 family of proteins. Prions form plaques (medically known as amyloids) which appear to be toxic to the brain. We’ve also recently discovered another prion-related debilitating disease: Fatal Insomnia.

Why should we support prion research?

Although biologists are extensively curious creatures, that’s not the only reason we should give them money. For the time being, little can be done to slow or stop the progress of prion diseases. Currently, prion diseases are extremely rare to non-incident, but increasingly mounting evidence suggests that prion research has strong ties to other more common neurodegenerative diseases like Alzheimer’s or ALS. Alas, prions have set us backward, but they may possess the key to flinging us forward.

A final warning to zombies: the next time you decide to indulge in the decadence of cerebrospinal cuisine, beware the prion.

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