Detective Story: Brains Turn to Sponge And Scientists Find Some Bizarre Clues --- Research on Deadly Disease May Bear On Alzheimer's And Theories of Life Itself --- An Outbreak in Pennsylvania ---- By David Stipp Staff Reporter of The Wall Street Journal
Thus began another chapter in one of medicine's most bizarre mysteries, a tale of sick sheep and mad cows, cannibals and Pennsylvanians, ancient life forms and a cat named Max. The plot revolves around a family of brain diseases, probably variations of a single disorder, called spongiform encephalopathy. It is infectious, invariably fatal and as insidious as termites, sometimes eating away brain cells for years without detection before a critical mass is spongified. Then, over a few months, motor control buckles and cognition crumbles. Victims then die quickly, usually within a year. Now, after decades of detective work, medical sleuths appear to be closing in on the molecular culprits behind the disease. Their dogged pursuit won't nail a public-health enemy No. 1 -- the disease is rare -- but it may pay off in a big way because the findings could shed light on more common killers, including Alzheimer's disease. The work also promises basic science breakthroughs. Spongiform research already has raised questions about a cornerstone of biology and spawned a Nobel Prize. The uncanny nature of the disorder sometimes grips scientists with a kind of obsessive fascination, notes NIH researcher D. Carleton Gajdusek. He should know, having chased spongiform leads around the globe for 33 years and won a Nobel Prize in the process. Recently the fascination has taken on a more anxious cast as the disease has struck humans and animals with suspicious regularity in several places, underscoring a longstanding question: Do people get the disease from animals? The question has burned with special intensity since scrapie, the form of the disease in sheep, jumped to British cattle a few years ago after they were fed ground-up parts of infected sheep. About 20,000 British cattle have been destroyed since 1986 in hopes of eradicating the spongiform "mad cow" disease, which makes the animals jittery before they keel over. A few weeks ago, the first confirmed case of mad cow disease outside Britain turned up in Switzerland. U.S. meat producers have reason to be anxious about this because the incidence of scrapie has been rising in American sheep since the mid-1980s, says Richard Marsh, a University of Wisconsin scrapie expert. Scientists agree, however, that the disease in animals probably poses little danger to people. Scrapie has existed for centuries and "the world is bathed" in its infectious agent, says Dr. Gajdusek. Yet sheep have never been strongly implicated in cases of the human form of the disease, Creutzfeldt-Jakob disease, or CJD. At least not until the Poltar journalist and two other people died of CJD at about the same time in a rural, sheep-herding part of eastern Czechoslovakia. When Dr. Mitrova, a researcher at a Bratislava medical institute, heard of the unusual cluster of cases, she decided to investigate. From the first, one clue stood out like a bloodstain: "Almost all of the people are involved in raising and taking care of sheep," she says. The local cuisine includes a soup of sheep meat stewed in sheep milk. The area's equivalent of chicken soup for colds is sheep brain fried in onions. One CJD victim even slept with a pet sheep until age 13. Now such coincidences seem like a serial killer's pattern. Against all odds, CJD has struck again and again in the same region, called Slovakia -- 69 times since 1975, mainly grouped in two areas. The outbreak has become something of an epidemic around the Orava area, where 26 cases have occurred since 1987, a rate hundreds of times higher than normal for CJD. Residents of the affected areas "are very afraid," says Dr. Mitrova. She has found evidence of scrapie in the area's sheep. Now villagers there call CJD "our sheep disease." That's a leap of folklore, though, and the sheep link may well turn out to be false, cautions Dr. Mitrova. Indeed, CJD is a nefarious trickster; the first reported case of the disease, which entered medical texts in the 1920s, really wasn't CJD after all, scientists now believe. And it usually strikes so rarely and randomly -- killing about one in a million people world-wide each year -- that scientists didn't even begin to suspect it was infectious until 1957. That year, the NIH's Dr. Gajdusek, then a young scientist casting about for big questions, planned a trip to Papua New Guinea to visit a friend. He never arrived. En route, he heard that a primitive New Guinea tribe, the Fore, were dying in droves from an unknown brain disorder they called kuru, "the shivering disease," because it started with tremors. Fascinated, he dropped everything, plunged into the backwoods with a local doctor and took charge of investigating the affair, to the great annoyance of Australian authorities then overseeing the area. "Gajdusek . . . has an intelligence quotient up in the 180s and the emotional immaturity of a 15-year-old," one of his mentors warned the Australians in a letter, and "won't let danger, physical difficulty, or other people's feelings interfere in the least with what he wants to do." In short, he was perfect for the job. Soon kuru victims' brains started issuing from the heart of darkness to distant medical centers, compliments of Dr. Gajdusek. He swapped axes and salt for autopsy rights, dissecting one victim with a carving knife by lantern-light in a native hut during a howling storm, according to his letters home. He and the local doctor, Vincent Zigas, tried everything from tranquilizers to hormones on kuru patients. Nothing helped. The cause remained elusive. Two years later, William Hadlow, a U.S. veterinarian, saw a picture of one of the kuru brains in a medical journal and was struck by its spongy appearance. He had seen that look before in scrapie, the sheep disease, and put in a call to the NIH. Another link fell into place when Igor Klatzo, an NIH scientist, noticed kuru brains resembled ones from CJD victims. Based on the clues, Dr. Gajdusek, back at NIH, led studies in the 1960s showing kuru, CJD and scrapie to be essentially the same infectious disease, studies that won the 1976 Nobel Prize for medicine. The discoveries confirmed a long-suspected connection: The kuru outbreak sprang from a Fore mourning ritual, in which relatives ate their deceased kin's lightly cooked, and often kuru-infected, brains. But the infectious agent continued to baffle scientists. It somehow could hide in the brain for decades without causing the usual signs of infection, such as fever. Brain tissue of infected animals could transmit the disease when injected into different animals' brains, yet microscopes revealed no signs of infectious microbes. And why did the agent sporadically appear in people with no known exposure? It seemed like "biological spontaneous combustion," says NIH researcher Paul Brown. In the early 1980s, scientists discovered that CJD, like Alzheimer's disease, often gums up the brain with a kind of junk, or "amyloid," protein. Further studies showed the junk mainly contains a botched form of a naturally occurring brain protein, sometimes called a prion. Many scientists now believe it's the culprit. But their theory entails a biologically weird premise: that the altered protein replicates itself without the aid of genetic material, the basis of all known reproduction.
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