Within 27 months of her symptoms appearing, she was dead. But Parkinson’s Disease was not what had killed her.
Scientists were curious about what had. Instead of freezing her brain, they immersed it in the chemical preservative formaldehyde – which cross-links the amino acids in proteins, “fixing” them — for three long days. They sliced it thinly and placed the pieces in paraffin. After examining the tissue under the microscope and forming an opinion, they filed the slides away, and they sat for several years at room temperature.
A second set of scientists acquired the slides and extracted some of the preserved, dried tissue. They diluted it and injected the solution into mice. To their surprise, four of eight mice so injected developed signs of the woman’s disease, despite a brutal processing regimen that should have been sufficient to kill just about any pathogen.
A prion is an illness-inducing misfolded protein. Depending on how it is misfolded, the prion may also be infectious, and they often are.
Oddly enough, all known prion diseases but one are caused by changes to a single mammalian protein, the somewhat confusingly-named “prion protein”. This protein, in its healthy, properly-folded state, is, if not trivial, relatively unimportant. Its complete loss is certainly not catastrophic.
Yet in a highly unfortunate accident of nature, this protein stirs up an extraordinary amount of trouble when broken. When mutated or misfolded in one of 34 known ways, it becomes a prion proper. When a prion bumps into a normal prion protein, the prion protein’s shape metamorphoses to the diseased form. Like a zombie, now it, too, can create more prions.
This, at least, is the prion hypothesis as promulgated by biologist Stanley Prusiner, who won the Nobel Prize in Medicine in 1997 for the idea. The ensuing chain reaction drives a relentless conversion of normal prion proteins into prions. In many prion diseases, the shape of the prion also drives them to polymerize into fibers called amyloid (erroneously and confusingly named after starches in the 19th century because early tests had trouble distinguishing them, but having nothing to do with starches in reality).
Amyloid fibers accumulate outside cells, where they may punch holes in brain tissue that cause a swiss-cheese-like situation (which certainly happens with or without their help). Or they may be toxic in some other way that generates the neural degeneration and brain atrophy seen in prion diseases. In the case of variant Creutzfeldt-Jakob disease (seen at the top of this post), the fibrils of the amyloid plaques radiate from a central point, giving them the appearance of tribbles.
Prion protein, for reasons again unknown, has a remarkably similar structure among mammals, which provides prions it a passport to interspecies mischief. Famous prion diseases include mad cow disease (a.k.a. bovine spongiform encephalopathy, contracted when cattle were given feed laced with sheep that had died of the prion disease scrapie; note that cattle are vegetarians); kuru (infamously contracted by people who ritually consuming the brains of dead relatives in Papua New Guinea), and variant Creutzfeldt-Jakob Disease (acquired by people who ate Mad-Cow-infected beef).
Prion diseases are universally dreaded because they are uniformly lethal. Once symptoms appear, they cause a relatively swift full-system shut down that may include, in addition to the symptoms the Dutch woman experienced, uncontrolled drooling, uncoordinated movement, and convulsions. It is not a nice way to go, and you will go.
The Stainless Steel Vector
Avoiding this awful, if improbable, fate is something you unfortunately have little control over.
Prion diseases are most commonly acquired by inheriting a faulty prion protein gene from a parent, consuming prion-contaminated food, or receiving prion-contaminated donor tissues or organs.
But there is a final disturbing transmission possibility, one that stems from prions’ mind-boggling powers of endurance.
Those powers are considerable. According to one account, prions resist digestion by protein-cleaving enzymes, may remain infectious for years when fixed by drying or chemicals, can survive 200°C heat for 1-2 hours, and become glued to stainless steel within minutes. Oh, and they’re also resistant to ionizing radiation.
Why are prions so hard to kill (if kill is even the right word for an evil protein meme)?
No one knows for sure. One expert hypothesized that because our decontamination methods have always targeted DNA and RNA – molecules possessed by all actual living creatures — they are by design not as effective on proteins.
The structure of prions themselves may also lend them supernatural survival powers. Just 3% of a prion protein is composed of beta-sheets, a common fold. But 43% of a prion is so folded. Such a substantial percentage makes the protein highly resistant to degradation, the reasoning goes. The herding of prions into chain-linked amyloid fiber may also protect them from assault.
Whatever the cause, prions are, to put it mildly, good survivors. And that may be why neurosurgical equipment can remain infectious even after it undergoes standard sterilization.
At least 2 cases of prion disease were contracted by people whose implanted depth electrodes had been previously used on a patient with Creutzfeldt-Jakob but were “inadequately” cleaned with benzene and disinfected with 70% alcohol and formaldehyde and sat unused for 2 years prior to implantation. And at least nine other cases of spontaneous Creutzfeldt-Jakob seem likely to have been contracted from inadequately sterilized medical equipment.
What is actually required to remove prions from medical equipment could best be described as destructive at best and draconian at worst and usually involves large quantities of sodium hydroxide or bleach (which is very hard on stainless steel), heat, and pressure, but even these measures are not 100% certain to get the job done. The World Health Organization recommends disposing of any suspected contaminated equipment entirely.
Standard sterilization routines have improved since most of the suspected surgical transmission cases occurred. And it should be heartily emphasized that the number of strongly suspected or confirmed cases of surgical prion transmission is tiny.
But because the incubation period of prion diseases can be decades, patients with prion diseases don’t always know they are ill when operated on, and hospitals still don’t routinely use the extreme sterilization protocols recommended for prions, risk remains. Many people have been so exposed over the years, a worrying occurrence Scientific American editor Phil Yam wrote about just a few years ago.
Are Prions More Common Than We Realize?
The enduring infectious power of prions is unsettling all on its own, but some scientists are beginning to suspect something far scarier.
Aggregates of prions form amyloids. But amyloids also form from proteins called amyloid-beta, tau, and alpha-synuclein. You may recognize these names. The accumulation of these proteins in amyloids — as plaques, tangles, and Lewy bodies — are signature indications, and perhaps causes, of Alzheimer’s and Parkinson’s diseases. These amyloids, like prions, stick to surgical instruments “like glue” and survive standard sterilization procedures. They, too, are distressingly hard to “kill”.
The only thing that keeps such amyloids from being considered prions is infectivity. But recently, at least one team of scientists found circumstantial, controversial — and stomach-churning — evidence that amyloids from patients with these diseases may be infective. What if Alzheimer’s could be transmitted on surgical equipment? Prion diseases are rare. Alzheimer’s and Parkinson’s are not.
Given the horrifying implications, and in spite of the expense and effort, I think it’s time for surgeons to start taking this possibility very seriously. If there’s one thing prions have shown me, it’s that you should never underestimate the capabilities of the most badass protein polymers on the planet.
Race, Brent, Katie Williams, Andrew G. Hughson, Casper Jansen, Piero Parchi, Annemieke JM Rozemuller, and Bruce Chesebro. “Familial human prion diseases associated with prion protein mutations Y226X and G131V are transmissible to transgenic mice expressing human prion protein.” Acta neuropathologica communications 6, no. 1 (2018): 13.