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Exploring the Darker Side of Everything

Prions: The Misfolding Proteins That Create Incurable Diseases

Pathogens, organisms that causes disease. Viruses, Bacteria, Fungi and Parasites are the four that most people have heard of. Their job is to infect a host, reproduce or replicate and be transmitted to a new host. They want to pass on their DNA. We’ve got loads of ways to kill them alcohol, bleach, radiation, heat. The list goes on. So while they can be scary and fatal we know their motives and when they’re out in the open we know we can win.

So what about Prions? They aren’t alive, they’ve no DNA or nucleic acid, no reason to want to infect and kill their hosts, but they do. And we can’t kill them. Not with heat, not with bleach. We can’t even destroy them with radiation! Can they kill us? Absolutely, their mortality rate is 100%. If prions get into your body you’re either going to die of prion disease or be hit by a bus before it has the chance. Either way, you won’t survive.

What are Prions?

stanley prusiner
Stanley Prusiner. By SISSA is licensed under BY-NC-ND

Prions are an infectious, self-propagating protein that has the potential to cause rapid-onset dementia, tremors, loss of bodily control and death within months. Records of the disease show it to have been in animals and humans for centuries, however, the cause was always unknown. Our understanding of infection was that it had to be caused by a traditional pathogen. Proteinsy weren’t even on the radar. It wasn’t until 1982 that the word prion was even invented. American neurologist, Stanley Prusiner coined the term. He simply took some letters from the words protein infection and came up with prion.

How are Prions made?

Our cells are constantly producing proteins because we need them for almost everything. Our muscles, enzymes, hormones and antibodies are all made of proteins. We’re held together by proteins like collagen and the chemical reactions in our cells are driven by them. They’re even responsible for carrying oxygen around our bodies as haemoglobin are, you guessed it, proteins.

Considering so much of us is made of proteins you’d think they’d last a long time but many degrade within a couple of days. Our cells are frantically working to produce more so we don’t die or collapse into a gruesome puddle of human. Organelles called ribosomes read our DNA and assemble chains of amino acids to match. These chains then fold themselves into complex shapes to become functioning proteins.

One of these necessary proteins is PrPC. It’s found on the membranes of cells in both healthy humans and animals. Its function isn’t entirely understood but it may play a role in long term memory, stem cell renewal and the innate immune system.

Now, proteins are folding themselves incorrectly all the time. Their shapes are incredibly complex and we’re producing so many that mistakes are bound to be made. Normally these proteins would just float about, being generally useless at their jobs and breakdown within a few hours or days. However, if the PrP becomes misfolded in just the wrong way it becomes PrPSc or a prion. These are a problem because they float about looking for PrP that did fold correctly, corrupting them and turning them into prions too. The growth rate is exponential.

Symptoms of Prion Disease

It can take a very long time for enough prions to build up in your system before symptoms start. Sometimes even 40 to 50 years after the first prion appears. 5 different variants appear in humans, Creutzfeldt-Jakob Disease (CJD), Variant Creutzfeldt-Jakob Disease (vCJD), Gerstmann-Straussler-Scheinker Syndrome, Fatal Familial Insomnia and Kuru. Generally, they include rapidly developing dementia, confusion, muscle spasms, difficulty walking, impaired vision, slurred speech and finally death.

As animals also have the PrP protein they can develop prions too. Bovine Spongiform Encephalopathy (BSE), Chronic Wasting Disease (CWD), Scrapie, Transmissible mink encephalopathy, Feline spongiform encephalopathy and Ungulate spongiform encephalopathy are all caused by these misfolded proteins.

Mad Cow Disease

Perhaps the most famous prion outbreak is known as Mad Cow Disease. It kills cattle by destroying the brain and spinal cord. Horrifically, microscopic holes are made in the brain tissue causing it to take on a spongy texture. Hence its proper name, Bovine Spongiform Encephalopathy. Infected cows will tremble, stumble and might start behaving particularly nervous, aggressive or enter a frenzy like state – becoming mad.

The artistamp commemorates the scourge of Mad Cow disease when it was destroying the livestock in UK beginning in 1986.
The artistamp commemorates the scourge of Mad Cow disease when it was destroying the livestock in UK beginning in 1986. By
Michaelfthompson, is licensed under CC-BY-SA

In the 1980s the UK suffered a mad cow epizootic, an epidemic spreading through an animal population. Cases peaked in 1993 and by the time it was over 184,500 cases had been confirmed in more than 35,000 herds. Now, prion disease can’t be transmitted through conventional methods like coughing or sneezing. In order to catch it, you need to consume the brain. So how did it spread through the cattle population so extensively? Did we have herds of zombie cattle roaming the fields mooing for brains? No, as usual, it was our fault. We’d been grinding up waste meat, spinal cord and bone products and feeding them to calves. Fortunately, a practice that’s now banned.

The chain of events that followed the first discovery in 1986 is both tragic and frustrating. In the early 1990s, the British government insisted that BSE couldn’t jump to humans or any other animal for that matter. However, house cats and zoo antelope were the first to prove this theory wrong by dying after consuming contaminated food. It wasn’t until the mid-1990s that the government chose to ban feeding cattle meat and bone meal to animals.

What made this epizootic so famous? It made the jump into humans. Again, by consumption of brain and spinal cord matter. Mostly, this wasn’t due to people frying up brain on a Tuesday evening but rather contamination in the beef production industry. Prions can’t be destroyed with heat so if there’s any in your food you won’t be able to do anything about it.

In 1995 the first human death occurred, Stephen Churchill aged 19. He’d been having symptoms since 1994, slowly becoming confused, losing his memory and coordination. He was diagnosed with depression and doctors seemed reluctant to call it what it was. v-CJD a variant of Creutzfeldt-Jacob Disease caused by eating BSE contaminated food. Doing so would mean proving the government wrong and could’ve trigger the collapse of the British Beef Industry. 2 more deaths followed him that year.

It wasn’t until 1996 that the British Health Secretary finally admitted beef was causing vCJD and 4.5 million cattle were killed. Distressingly, British farmers began committing suicide at a rate of 3 per week. Cases started declining after bans, tests and rules surrounding animal feed were put into place. In total 232 people contracted the disease. All of them died.

To avoid this happening again all brain and spinal cord materials are required to be completely removed from any cattle showing neurological symptoms. So they won’t enter the food supply chain. I mean, I’d be more comfortable with a guarantee that none of my burgers contained spinal cord but at least they’re trying.

Kuru Disease

While Mad Cow Disease might be the most famous human outbreak of a prion disease, it wasn’t the first. Nor was it the most deadly. Between 1957 and 2004, 2700 people in the Fore tribe of Papua New Guinea died of a disease named Kuru. It mostly affected women and children and was named for the Fore tribe’s word for trembling – Kuru. This is because patients would experience uncontrollable tremors and shakes. They’d also call it ‘laughing death’ as victims would frequently burst into fits of manic laughter. Within a year they’d lose control of their bodies becoming unable to walk, stand or feed themselves. There was no cure and no recovery. Only death.

Fore child in advanced kuru stage, cannot sit or stand without help. By Liberski PP , is licensed under
CC-BY

The tribe believed the cause to be sorcery, witchcraft or ghosts. Medical scientists suspected genetics or something environmental. They were all wrong.

In the 1950s American scientist Carleton Gajdusek began studying Kuru but it wasn’t until he was joined in the field by biologist, Micheal Alpers that the mystery would finally be solved. They believed the disease was transmissible and wanted to test their theory by injecting chimps with affected brain samples. Unfortunately, the local field officer blocked their research. He said the Fore tribe were fed up and he wouldn’t consent to any bodies being taken for autopsy.

This slowed Gajdusek but Alpers wasn’t discouraged. He befriended the tribe and when a person seemed close to death he’d move into the village and wait by their side. The waiting was long as the deaths were slow, with victims sinking deep into paralysis before passing away. At their death he’d conduct the autopsy in the village. He’d remove the brain with family members present and send it to inject into the chimps, Daisey and Georgette.

True to his character Alpers stayed close to the chimps, visiting them twice a week. After 2 years symptoms began. They started struggling with their coordination. They couldn’t pick up their apples and began eating them from the ground with their mouths. Within a week they were staggering and falling and Alpers and Gajdusek became sure their theory was correct.

7 months later the chimps died. Georgette’s brain tissue was examined, confirming Kuru. This led to the groundbreaking discovery in 1966 that proteins could be infectious agents, despite lacking any genetic material of their own. They can be pathogens, the first identified in over a century. Why they do it is still not understood. They’re not alive, they’ve no nucleic acid and they’ve no reason to create infections because they don’t need to in order to replicate.

However there were some mysteries possible for Alpers to solve. How had Kuru spread through the Fore tribe and why did it only affect women and children?

Alpers combined forces with Robert and Shirley Glasse (later Lindenbaum) who’d been looking for a link between Kuru and the tribe’s diet and traditions. They’d discovered that the Fore tribe believed a person has five souls and on death, they travel to the land of the ancestors. To get there the body must be eaten. Without intervention, this would be by maggots or worms. Not a nice thought or particularly quick. They believed the fastest and most respectful way for their family members to pass on was to be consumed by those who loved them. The brain would be removed, mixed with ferns and cooked in a bamboo tube. It was the women who took part in the tradition as they were the only ones deemed capable of containing the dangerous spirit of the dead body. Children were affected by the disease too as their mothers would pass them small pieces to eat as snacks.

Now that Alpers and Gajdusek had proven Kuru could be passed on to the chimps through brain matter, all the pieces of the puzzle came together. The outbreak had begun with one villager. When they were consumed the disease was passed on to the next victim. When they died, they were eaten and so it continued, for decades.

Sporadic Prion Disease

Now you may be thinking ‘these outbreaks sound horrifying but I’m probably safe, as long as I don’t eat any brains.’ Unfortunately, acquired cases of prion disease account for only 1% of patients. The vast majority, 85%, are sporadic, occurring as a freak accident in normal protein production. This means that even whilst watching this video, one of your cells could be folding a PrPC protein in just the wrong way, turning it into a brain-eating pathogen.

The good news is that it takes an incredibly long time for enough prions to build up in your body to cause symptoms. The bad news is that once they appeared you’d be diagnosed with Creutzfeldt–Jakob disease (CJD), a degenerative brain disorder that’s fatal and incurable. It was first discovered in the 1920s by German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob. Each had patients exhibiting signs of behavioural changes, abnormal vision, involuntary movements and rapid onset dementia. Generally, sporadic CJD affects people later in life, as it progresses so slowly at first. The typical age of onset is between 60 and 70 years old. About 1-2 people per million are diagnosed every year and 70% die within the next 12 months. Nobody has been cured.

Genetic Prion Disease

So if you’ve been doing the maths you’re probably wondering what accounts for the final 14% of CJD cases. They’re genetic, which means a mutated gene causes the misfolded protein and can be passed down through families. One of the most famous cases was documented by science writer D.T. Max in the book ‘The Family Who Couldn’t Sleep’. He traced several generations of an Italian family all the way back to the 1760s. They all had the same affliction, crippling and fatal insomnia. At some point in their 50s, symptoms would begin. They’d start sweating, their pupils would be pinprick small and they’d become unable to sleep. The insomnia was inescapable and they’d eventually die of exhaustion.

Decades passed for the family. They’d wait for the symptoms to begin and dread the excruciating death. It was made more painful by the fact they’d be awake to experience every second of it. In the 1980’s one family member, Silvano, began to experience the telltale warning signs and decided to take action. The disease had killed his father and 2 sisters and he wanted to get to the bottom of it. So he submitted himself for testing and extensive EEGs were taken of his brain. They showed abnormal brainwaves but no one knew what they meant. After his death, more family members came down with the disease and followed Silvano’s lead, submitting themselves for EEGs. These took place in the 1990s, after the BSE outbreak. They showed incredible similarities to the brainwaves of CJD patients and the link to prions was confirmed. Advances in technology had also made it possible to find the gene responsible and the mutation causing the fatal familial insomnia was identified. However, there’s still no cure.

Weaponising Prions

Now, unfortunately the headline ‘100% mortality rate’ will always attract the attention of individuals looking to kill a lot of people. So it shouldn’t surprise you that many countries are worried about the threat of a prion based attack.

One reason for the concern is that weaponising prions is actually fairly simple. The disease can be passed on through inhalation of aerosolized brain particles. So, with enough infected animals, it would be possible to conduct large scale attacks.

More worryingly, if they don’t fancy breeding herds of mad cows, aggressors can simply manufacture prions in a lab. Yes, of course humans would identify an unstoppable, fatal and infectious agent and think ‘Hey – we should make more of that.’ In fairness, the process was invented with nothing but good intentions for study and finding a cure. But it does raise the threat level significantly. Even more so when you learn that we weren’t happy just creating regular kill you in 50-years prions. Oh no, we had to make them worse. It’s hard to study something with such a long incubation period and so we augmented it to kill us faster. Again, if we get a cure for CJD sooner because of this, then fantastic. But if someone weaponises it first… not so thrilling.

However, faster is not necessarily fast enough to make a very effective bioweapon. So it’s unlikely warheads filled with brains will be launched anytime soon. So don’t worry, it’s far more likely contaminated meat would be introduced into the food chain to cause panic, disruption and force us to buy treatments and alternative meat products from the attacker instead. One of many reasons to hope that the authorities keep checking our food is safe and brain free.

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