by Bill Schutt
The authors of the Southwood report also painted a rosy picture for anyone concerned about the spread of BSE, predicting that it would begin to decline in the early 1990s and die out spontaneously sometime after 1996. No further effort was required. Beef was safe. Long Live the Queen!
I met Dr. Laura Manuelidis on a beautiful summer day in New York City’s Chelsea district. When she isn’t writing and publishing critically acclaimed poetry, Manuelidis heads up the Neuropathology section at Yale. She has become the foremost spokesperson for the relatively few scientists who believe that prions are not the self-replicating, seemingly immortal, proteinaceous pathogens we’ve been led to believe. In 2007, she and her coworkers identified a 25-nanometer viruslike particle found in both sheep scrapie and CJD.
No one has ever seen a prion protein (PrP), but according to Manuelidis the reason has nothing to do with size.
“They probably don’t exist,” she told me.
Manuelidis has been researching neurodegenerative diseases for more than 30 years, and she and her colleagues have performed a wide range of studies on transmissible spongiform encephalopathies (TSEs) like Creutzfeldt-Jakob disease. Their results support a very different, though far from new, conclusion—that viruses are the cause of these neurodegenerative diseases, which also include kuru and bovine spongiform encephalopathy (BSE). Since the name “prion” implies infectivity (the ability of a pathogen to establish infection), in Manuelidis’s book, clumps (or plaques) of misfolded proteins exist, but since they aren’t infective, prions do not exist. According to Manuelidis, then, what is being called a prion requires a new name.
She explained that proteinaceous plaques aren’t confined to neurological disorders like kuru, but are also seen in peripherally located viral diseases. “Conventional viruses also induce protein aggregates and amyloid fibers that are prionlike. The plaques are an end-stage product that doesn’t occur early in these infections.” I later learned that the abnormal protein masses were also characteristic of diseases like rheumatoid arthritis and diabetes—and in none of these instances were the clumps or the proteins that made them up transmissible.
“So what you’re saying is that the misfolded proteins aren’t the cause of the spongiform encephalopathy, they’re an effect—a late-stage result of a viral assault. Correct?”
“Yes,” she replied.
But if these plaques aren’t pathogens and they’re not infective, what exactly are they?
According to Manuelidis, they’re “a runaway defense mechanism against the infecting agent,” which she believes is viral in origin.
“When these misfolded proteins do show up, infectivity drops through the floor,” she told me. In other words, once the body’s defenses kick into gear (which ultimately leads to the production of amyloid plaques), the pathogen is less able to infect another host. The spread of the virus is curtailed.
On May 16, 1990, John Gummer, the head of the UK’s Ministry of Agriculture, infamously responded to the public concerns over potentially contaminated beef in the UK by feeding a hamburger to his four-year-old daughter on the BBC television show Newsnight.
In 1993, two British dairy farmers died of CJD, a disease that was supposed to strike one out of every 1 million people. The government response was that it was just a bizarre coincidence. In May of the same year, 15-year-old British schoolgirl Victoria Rimmer began having trouble keeping her balance and within weeks she was falling constantly. Admitted to the hospital, Rimmer underwent a battery of tests—all of which came back negative. Finally a brain biopsy was obtained and the doctor who examined the results was stunned. Her brain was riddled with holes and amyloid plaques identical to those seen in the brains of kuru victims. With hesitancy, the physician informed Victoria’s grandmother that the girl had spongiform encephalopathy—mad cow disease. What took place next was even more incredible. An investigator from the government’s CJD-surveillance unit in Edinburgh visited Mrs. Rimmer, warning her not to say anything about her granddaughter’s condition. “Think about the economy,” he told her, “think about the Common Market.”
Victoria Rimmer died in November 1997. After an inquest into her death, coroner John Hughes concluded that she died of natural causes.
In 1994, a 16-year-old schoolgirl and an 18-year-old boy were diagnosed with CJD, which had hardly ever been reported in people less than 30 years of age. By the following year, seven people were already dead or dying.
On March 8, 1996, the hammer fell on the government’s “British Beef is Safe to Eat” stance in the form of a memo written by Dr. Eileen Rubery, a policy maker and longtime government adviser. Rubery confirmed what others had feared for 11 years—the emergence of a new form of spongiform encephalopathy, this one transmitted to humans via the consumption of contaminated beef. She also used the dreaded “e” word: epidemic. The new disease was initially referred to as sporadic CJD or atypical CJD, but scientists eventually settled on Variant Creutzfeldt-Jakob disease (vCJD).
By October 2013, the number of definite and probable deaths from vCJD in the United Kingdom stood at 177. Some researchers see the epidemic as over, pointing to the fact that after peaking in 2000, when 28 people in the UK died of vCJD, deaths from the disease have fallen off dramatically (i.e., three deaths in 2009, three in 2010, and one in 2013). Others believe that these 177 deaths are only the tip of the iceberg. They rationalize that, because thousands of Fore died as adults, sometimes 50 years after being exposed to kuru via ritual cannibalism, many Europeans (and others) who had consumed contaminated beef in the 1970s and 1980s would not have been stricken yet, and might not start dying en masse until decades after exposure.
In a 2013 study published online by the British Medical Journal, researchers tested 32,000 “anonymous appendix samples from people of all ages who had their appendix removed between 2000 and 2012.” Sixteen of the samples, which came from 41 hospitals across England, tested positive for the abnormal prion protein. This translates into one carrier for every 2,000 people in the United Kingdom, a scary number that gets even scarier if you project that out to 493 people per 1 million inhabitants. There are approximately 63.5 million people in the United Kingdom.
On a related but more upbeat note, scientists like Simon Mead and John Collinge, both of whom are experts in the field of kuru research, think there’s another reason why everyone exposed to prion-contaminated meat may not come down with a lethal neurodegenerative disease. As evidence they point to a common human gene (the prion protein gene, or PRNP) with a worldwide distribution. The researchers and their colleagues discovered a mutated form of this gene (i.e., a variant) in descendants of the Fore who survived the famous kuru outbreak. Initially, they hypothesized that this variant might have provided protection from kuru to the individuals who possessed it. These kuru-resistant survivors would have passed down their genes (and their resistance) to their descendants. In 2015, Collinge and his research team published a follow-up study in Nature in which they presented experimental evidence that when the genetic variant of PRNP was transferred to mice, it provided complete resistance to both kuru and classical CJD.
In a best-case scenario, thanks to what may have been their ancient ancestors’ brush with cannibalism (and kuru), at least some of the individuals consuming prion-contaminated meat in the 1980s were already resistant to the disease.52 If this is true, then the gloom-and-gloomers may be waiting for an epidemic that never arrives. From a therapeutic viewpoint, if these genetic variants can somehow be transmitted to humans, we may one day be able to confer resistance to the pathogens that cause spongiform encephalopathies—whether they turn out to be prions or viruses.
On the other hand, if Laura Manuelidis is correct and spongiform encephalopathies are the results of viruses, it would be wise to remember one of their key characteristics: Viruses mutate.
Back in Chelsea, Manuelidis and I were seated in the back of a 9th Avenue bar. As she explained why viruses and not prions were the real culprits in the transmissible spongiform en
cephalopathy story, we sipped a pair of melon-based something-or-others. In retrospect, given the fact that my understanding of biochemistry was already more than a bit wobbly, a weak drink was probably a good thing.
“What do you make of the fact that researchers in the 1960s never saw an immune response during their experiments with kuru extracts?”
“There is an immune response,” she replied. “They just didn’t see it because it was transient or diminished. Like with HIV, there are many mechanisms that can make something not apparent as an immune response.”
Manuelidis explained that with diseases like kuru, CJD, and BSE, “what we found is that there are innate immune responses, very early in the disease.”
I shifted easily into Insistent Mode. “All right, but why couldn’t prions be the TSE pathogens?”
“Because that stuff [anything composed of protein] gets digested in the gastrointestinal tract, while viruses can go through gastric and intestinal juices unscathed. Viruses are built to be protected from the body’s defense mechanisms—and proteins are not.”
“But what about the reports, by Prusiner and others, indicating that prions couldn’t be destroyed by digestive enzymes like proteases?”
Manuelidis shook her head. She was wearing a look that suggested the question was one she’d heard plenty of times before. “Bill, everyone knows that PrP [prion protein] is relatively resistant to limited exposure to PK [a protein-dissolving enzyme found in our digestive tracts], but it breaks down if given a longer time to digest. In fact, it disappears.”
I was reminded of earlier studies in which lab chimps did not become infected with kuru after being fed infected material through a gastric tube. “So you’re saying that these seemingly immortal proteins can be broken down by our own digestive juices?”
“They’re not immortal,” Manuelidis replied. “And yes, all detectable forms of PrP are digested in the gastrointestinal tract, yet the invasive infectious particle [that causes TSEs like kuru] is not destroyed.”
“The same way that many viruses aren’t destroyed in our GI tract?”
“Right.”
If this was in fact true, then how were the prions, which researchers like Prusiner claimed to be the cause of kuru, getting past a gastrointestinal tract that had evolved to digest dietary proteins? At the very least, if prions did exist, then their spread through the Fore via cannibalism no longer made sense—since their digestive tracts would have broken down the proteins during the normal process of digestion. But if the infective agent causing kuru had been a virus, then transmission through the practice of ritual cannibalism made even more sense, since viruses weren’t broken down by our digestive systems.
Although the majority of the scientific community had clearly accepted prions as the pathogens behind a range of neurological diseases, there are still some strong voices besides Manuelidis’s opposing this view. In a new afterword of his 1998 book, Deadly Feasts, Richard Rhodes admitted to being intrigued by the very real possibility that Dr. Manuelidis could be right.
“I raise the virus issue,” he wrote, “partly because I now believe I gave it less than a fair hearing in the body of this book and partly because the arguments I’ve heard in its favor since I wrote, especially from Laura Manuelidis, seem to me compelling.”
Clearly there remains much for science to explore regarding transmissible spongiform encephalopathies. One can only hope that the funding agencies that poured tens of millions of dollars into prion-related research will not see this story as a fait accompli or that researchers who challenge the very existence of self-replicating, infectious proteins won’t have their voices silenced by skittish granting agencies or peer reviewers, perhaps too set in the conviction that prions are the cause of transmissible spongiform encephalopathies from kuru to mad cow disease and beyond.
* * *
52 According to Noel Gill, lead investigator of the “Appendix” study, further research is now underway to determine whether prion proteins also occurred in samples from the 1970s and earlier—before the appearance of BSE in the UK. Such a finding could reduce the significance of the 2013 study, since it would suggest that prion proteins in a population do not necessarily translate to a major outbreak of spongiform encephalopathy.
Epilogue: One Step Beyond
Hunger hath no conscience.
— Author unknown
Cannibalism makes perfect evolutionary sense. If a population of spiders has an abundance of males from which a female can choose, then cannibalizing a few of them may serve to increase Charlotte’s overall fitness by increasing the odds that she can raise a new batch of spiderlings. On the other hand (and in spiders there are eight of these to choose from), in a population where males aren’t plentiful or where the sexes cross paths infrequently, cannibalizing males would likely have a negative impact on a female’s overall fitness by decreasing her mating opportunities. As a zoologist, I find this kind of dichotomy pleasing, since it’s logical and appears to be more or less predictable in occurrence. In nature, as far as cannibalism is concerned, I’ve found no gray areas, no guilt, and no deception. There is only a fascinating variety of innocent—though often gory—responses to an almost equally variable set of environmental conditions: too many kids, not enough space, too many males, not enough food. The real complexity and the uncertainty didn’t kick in until I shimmied out farther onto our own branch of the evolutionary tree. It was here that I found cannibalism painted in equal shades of red and gray.
Sigmund Freud believed that in humans, atavistic urges like cannibalism and incest are hidden below a veneer of culturally imposed taboos, and that the suppression of such forbidden behaviors signaled the birth of modern human society. This is a compelling explanation, but it’s one that likely requires some serious tweaking.
Compared to other groups such as insects and fishes, cannibalism occurs less frequently in mammals and even less frequently in our closest relatives, the primates—where most examples appear to be either stress-related or due to a lack of alternative forms of nutrition. Though we humans do share some of our genetic makeup with fish, reptiles, and birds, we’ve evolved along a path where cultural or societal rules influence our behavior to an extent unseen in nature. Freud believed that these rules and the associated taboos prevent us from harkening back to our guilt-free and often violent animal past. Similarly, my studies have led me to conclude that the rules we’ve imposed in the West regarding cannibalism serve as constraints to behavior that might otherwise be deemed acceptable if we were looking at protein-starved Mormon crickets instead of indigenous Brazilians consuming their unburied dead.
There is a considerable body of evidence that cultures that were never exposed to these taboos (like Homo antecessor) or encountered them only relatively recently (the Chinese and the Fore of New Guinea) had no such problems undertaking a range of cannibalism-related behaviors as they developed their own sets of rules and rituals. Much to our Western dismay, some of these cultural mores extolled the virtues of cannibalism as an honor bestowed upon a deceased relative or a slain foe, or as a respectful way to treat a gravely ill parent. But even in societies where cannibalism might once have been a perfectly acceptable practice, given the pervasive influence of Western culture across the world, it’s unlikely that ritual cannibalism currently exists, even on a small scale.
It’s also likely that Freud would have called upon long-hidden impulses to explain our titillation with all things violent, gruesome, and forbidden. But although it’s unclear to me the extent to which atavistic urges are involved, there is no doubt that we are, and seemingly have always been, fascinated by cannibalism. We need look no further than the popularity of novels like Cormac McCarthy’s The Road (with its depiction of post-apocalyptic cannibalism), or even our obsession with vampires and zombies. A long list of popular films might begin with The Night of the Living Dead and its cinematic progeny, and according to Variety, 17.29 million viewers helped turn The Walking Dead’s season five premiere into
the most watched cable TV show of all time.
Our language is filled with cannibal references: a woman who uses men for sex is a man-eater, while in the 1920s and 1930s a cannibal was “an older homosexual tramp who traveled with a young boy.” To “eat someone” is a popular term for performing oral sex.
As for the media, consider the recent tabloid obsession with Gilberto Valle, New York City’s so-called “Cannibal Cop” who was accused of conspiring to kidnap, cook, and devour his wife and another woman. “He is guilty of nothing more than having very unconventional thoughts,” said Paul Gardephe, the judge who eventually overturned Valle’s conviction. But besides an interesting take on “thought crimes,” Valle’s story also provided a glimpse into the darker corners of the Internet, where there are apparently thousands of people whose everyday fantasies revolve around cannibalizing coworkers, loved ones, or even you, Dear Reader.
Most cannibalism-related crimes, though, are thought to stem from psychological aberrations. According to forensic pathologist George Palermo, cannibal killers “are people who have a tremendous desire to destroy—a tremendous amount of hostility that they need to release. They have something stored up inside them in order to reach the point of where they want to destroy the human body and eat human flesh, and they feel a need to release that violence.” Of course, such incidents are immediately condemned, although once again they often lead to fame for the cannibal and millions of dollars in revenue for those who care to recreate their stories in books or on film.
If one goes by the examples in the media (“Woman Dies After Cannibal Eats Her Face”; “Nude Face-eating Cannibal? Must Be Miami”), it would certainly seem that there are more cannibal killers out there than ever before. Even if the same percentage of cannibal killers exists now as has in the past (even the recent past), the population explosion across the planet would make it likely that there are simply more of them now. Then there’s the fact that overpopulation and overcrowding are key catalysts for cannibalistic behavior in nature. Of course, some would consider it a stretch to extrapolate human behavior from the examples of spiders, fish, or hamsters. But for a zoologist, those comparisons are far less problematic.
