Brain attacks: How the culprit was named as rogue proteins

Review Medicine


The Family That Couldn't Sleep: A Medical Mystery

D.T. Max

Random House / 336 pages / $25.95

Ah, the unsung wonder of proteins. Many of us scarcely think of them (except, perhaps, when contemplating low-carb diets). Yet, inside our bodies, proteins scaffold organs, catalyze reactions and signal countless other nano-processes on which our lives and health depend. They also form with beauty and grace. Spun like silk from intracellular factories called ribosomes, they sheet and twist and fold into unique 3-D shapes, which, in turn, govern their function. To people who study proteins for a living, their elegant choreography inspires almost reverential awe.

Maybe that's why rogue proteins attacking the brain - like stealth foes bent on a fiendish plot - seem so far-fetched. We all know about flesh-eating bacteria and evil viruses, but proteins are so pristine. Plus, they're dead, right?

D.T. Max answers this conundrum in The Family That Couldn't Sleep, a highly readable book that doubles as a lay primer on "prions" (the term stands for "proteinaceous infectious particles") and also proves that proteins can truly deprave and harm. The story of an Italian family with a genetic prion disease targeting the thalamus launches the work.

In literary flashback, Max first presents a dying Venetian doctor circa 1765 whose final months are wracked with sleeplessness and paralysis. Then we learn of subsequent generations' premature deaths attributed to dementia, pellagra, schizophrenia, brain tumor and "familial encephalitis." Later chapters interweave decades of prion research with further tales of fatal insomnia, cannibalism, self-mutilating sheep and mad cows.

But at the end of the day, there is no sentient victor. As Max reminds us from the outset, prions "are just proteins. ... They have no DNA to pass on. They are not in competition with us, trying to increase their numbers, like viruses and bacteria are - they are just molecules, attracting and repelling and folding and mis-folding according to chemical forces."

In 1997, the biologic principle that was revealed by prion disease earned a Nobel Prize for UC San Francisco researcher Stanley Prusiner. As Max relates, a keen grasp of chemistry and medicine allowed the ambitious scientist to picture deformed proteins detonating a deadly chain reaction: an exponential increase of proteins propagating like bewitched crystals and ultimately forming dense fibrillary masses in brain and other tissues. Prusiner then proved his theory by recreating in experimental animals the same spongy or plaque-laden brain seen in naturally prion-afflicted hosts. He also coined the media-friendly "prion" label.

Prusiner was not the first prion honoree in Stockholm, however. In 1976, Carleton Gajdusek won the Nobel Prize for seminal studies of kuru - an epidemic neurological blight among the Fore people of Papua New Guinea. Back then, the pediatrician-turned-field-researcher blamed the fatal, trembling disease on something he called a "slow virus." Only later was kuru's agent shown to lack the nucleic acids that encode viral life. According to Max, Gajdusek still refuses to use the term "prion" in everyday speech - for reasons more personal than scientific, it seems.

As for the Fore, a once-isolated tribe now memorialized in medical texts, their prion tragedy began around the turn of the 20th century when they adopted a new mortuary practice. After mourning their relatives, they ritually consumed them - muscle, brain, spinal cord and all. Years to decades later, women and young children who partook of nervous tissues were most likely to develop the relentless, shaking scourge.

Even 40 years after disavowing cannibalism, several Fore have developed late-onset kuru from the remnants of those early funeral feasts. You could call them lucky, having escaped their fate for so long. But of course their reprieve was not simply a fluke. Recent data suggest that long-term survivors are blessed with protective genetic factors, while victims who succumb more quickly have subtle genetic vulnerabilities.

That raises an interesting question regarding the latest outbreak of bovine spongiform encephalopathy (aka mad cow disease) in humans. Despite BSE's cumulative toll of nearly 2 million cows in Britain, so far fewer than 200 people have been affected, a fact suggesting stout firewalls in the majority of those exposed. (Max estimates that 640 million doses of prion-contaminated beef were consumed by the British during the height of the mad cow crisis in the 1980s and 1990s.) On the other hand, if favorable genetics merely lengthen the incubation of BSE, unhappy surprises may be ahead.

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