Rogue Proteins

Five or six years ago, when I reported more frequently about prion diseases than I now do, a Canadian wildlife scientist told me about a looming threat involving chronic wasting disease in deer.

Scientists studying CWD, the deer equivalent of mad cow, were worried the disease would spread north, making its way into caribou herds. The potential for decimation of caribou populations was obvious; so too was the potential devastation such a development might wreak on First Nations people who rely on caribou meat. Not only would an important source of protein be threatened, but if CWD, like bovine spongiform encephalopathy before it, could make the species jump to infect people, then the way the animals are butchered and consumed could put the hunters and those who eat their kills on the path to developing a human form of this prion disease. Britain’s mad cow crisis could be replayed with tragic results across the North.

The idea was terrifying but speculative. And fortunately, years later it still is. Scientists are still concerned about the possibility, one of several explored in Jay Ingram’s new book on prion diseases, Fatal Flaws: How a Misfolded Protein Baffled Scientists and Changed the Way We Look at the Brain. But one of the most vexing things about these diseases is their incubation periods—the time it takes from the prion exposure to the development of the symptoms that signal disease. People who contract influenza typically get sick within a day or two of having flu viruses latch onto the cells of their upper respiratory tract. People who consumed prion-containing meat or who are exposed to these puzzling disease agents through other means may take decades to start showing the symptoms of a cruel degenerative disease that is always fatal. Even in animals, evidence of disease can take years to manifest.

It has been more than a half a century since scientists started to home in on prions, misfolded proteins that challenge the very thinking about what can cause disease. Healthy forms of these proteins—which are widespread in the brain and which undoubtedly serve some as yet poorly defined purpose—become corrupted by the misfolded versions, in a process Ingram nicely likens to ice-nine, a fictional water-freezing polymorph dreamt up by the fertile imagination of none other than Kurt Vonnegut for his novel Cat’s Cradle.

Prions cause scrapie (the sheep disease that was suspected to have been the cause of BSE in cattle) and kuru (a prion disease linked to ritual cannibalism previously practised among the Fore tribe on the island of New Guinea) and a range of related diseases that afflict a number of species including humans, ruminants, felines and mink. These diseases fit under the classification umbrella known as transmissible spongiform encephalopathies. Spongiform refers to the characteristic holes seen in the brains of victims of these diseases; encephalopathy means disease of the brain.

Ingram’s book recounts how science was baffled by the earliest versions of these diseases to be spotted, and the controversy that erupted when a brash American scientist named Stanley Prusiner announced their unconventional source and gave it a name, prions.

Frustratingly, the book spends very little time on the initial work that led others—including Prusiner, who won a Nobel Prize for his prion work—to conclude the diseases were caused by rogue proteins. In fact, there is no explanation of how British scientist David Wilson, credited in the book as the first person to examine the agent closely, came to do so. Ingram notes Wilson’s work was largely unpublished, a significant limitation all these years later. But it would have been nice to have had a sense of how Wilson even knew what he was looking at.

While much has been learned about prions and the diseases they cause since the 1940s and ’50s, hugely important questions about these diseases remain unanswered, plaguing scientists and public health authorities.

Ingram explores many of the most pressing questions, including whether diseases that have not been thought to be caused by prions—conditions such as Alzheimer’s disease, Parkinson’s, amyotrophic lateral sclerosis or Lou Gehrig’s disease, and chronic traumatic encephalopathy—may actually be triggered by misfolding prion proteins. The jury is still out.

He also raises the alarming, although again speculative, spectre that the apparently waning human outbreak of mad cow disease—more accurately called variant Creutzfeldt-Jakob disease—may actually represent only the first in a series of waves of human cases that will result from the fact that meat from BSE-infected cows found its way into the food chain, primarily in Britain and France in the 1980s and early ’90s. On New Guinea, cases of kuru are still developing among Fore tribespeople who participated in cannibalism decades ago. (The practice was stopped in the late 1950s and no cases of the disease have been seen in those born after the funeral ritual of eating deceased family members was ended.) Given the experience with kuru, the average incubation period for BSE prions in humans might be 30 to 40 years, Ingram reckons. If he is correct, the 176 cases of variant CJD reported in Britain (as of May 7) may be the tip of the iceberg.

It could be that there are hundreds, if not thousands, of people in England who seem perfectly healthy but are incubating prions that might one day kill them. It’s also possible that, because of their genes, their personal incubation periods will turn out to be extraordinarily long, long enough that they will die of something else before they die of human mad cow disease. It’s even possible that their genes have protected them from infection altogether.

Ingram notes that over the years scientific estimates of how many human cases of variant CJD will result from the mad cow outbreak range from ten (already wrong) to several million. Better estimates may emanate from a study currently underway; British researchers are examining 100,000 appendixes and tonsils removed in surgery, looking for prions. A smaller study, done earlier, found three samples containing variant CJD prions in 11,109 appendixes and 1,565 tonsils.

The questions Ingram raises are interesting, but those who like questions that come with answers will need to curb their expectations. These diseases are in no hurry to reveal their secrets. For instance, the only way to know the upper range of the incubation period for kuru is to wait until the last tribesperson who participated in ritual cannibalism has died. It will be years before the world knows whether there will be future waves of human cases of variant CJD. Likewise, if there is a link between sporadic CJD—the human form of the disease that is thought to occur by chance at a rate of about one case per million people per year—and the consumption of BSE-contaminated meat, it likely will not become clear any time soon.

Still, at a time when prion diseases have not been hitting the news as often as they did in the past, it is valuable to be reminded that just because BSE discoveries in cows are less frequent than they once were—although the United States reported finding an infected dairy cow in late April, the first since 2006—and human deaths caused by variant CJD have trickled to fewer than a handful a year, the story of prion diseases is still being written.