By Debbie Gilbert
DECEMBER 15, 1997: When Dr. Stanley Prusiner accepted the Nobel Prize for Physiology or Medicine in Stockholm, Sweden, on December 10th, Memphis neurologist Dr. Darel Butler was determined to be there.
We knew he'd win, says Butler. When I left San Francisco, I told him that when he gets his Nobel Prize, I want to have my picture taken with him and the award.
Butler took a sabbatical from medical school in the mid-1980s to work in Prusiner's lab at the University of California-San Francisco. His primary task there was to set up a cell-culture system so that more experiments could be done in vitro instead of on live animals.
But animals were crucial to the work, because Prusiner and his colleagues were studying brains specifically, brains so diseased they were riddled with holes like a sponge. Such spongiform encephalopathies, as these illnesses are called, invariably cause incoordination, dementia, and death. The most notorious of these is bovine spongiform encephalopathy (BSE), popularly known as "mad-cow disease."
In humans, there's an equivalent called Creutzfeldt-Jakob disease (CJD), which strikes about one in a million people, usually over age 60. But in March 1996, health officials announced the appearance of a new-variant CJD that seemed to be linked to eating beef from BSE-infected cows. More than 20 young people in Britain have died from this new form, leading to restrictions on the sale and consumption of beef in England.
Scientists know that the disease can jump from one species to another, because the cows originally got it from sheep that were infected with scrapie, another spongiform disease. By adding ground-up sheep carcasses to cattle feed, English farmers had inadvertantly passed on the infectious agent.
But what was that agent? Scientists assumed a virus was responsible, yet none could be found. In 1974, Prusiner had begun a series of experiments on scrapie-infected brains, and through a process of elimination he concluded that the disease was not caused by a virus or any other known organism. He hypothesized something completely new: a pathogen made only of protein, somehow able to reproduce itself without DNA or RNA. Prusiner called it a "prion" (pronounced PREE-on).
Naturally, the scientific world scoffed at the idea. To believe in prions - which are apparently much smaller than viruses and cannot be seen through an electron microscope - was like believing in fairies. Prusiner's peers contended that there had to be a virus and that he had simply missed it due to sloppy lab technique. But Prusiner clung tenaciously to his theory and eventually prevailed, winning the prestigious Albert Lasker and Paul Ehrlich scientific awards before copping the Nobel.
"He can be opinionated, and he'll tell people if he thinks they're wrong," says Butler. "For years he was called a quack, a kook. But he's turned out to be right."
Not everyone is convinced, however. Critics, notably science writer Gary Taubes, have claimed that Prusiner's studies were not adequately peer-reviewed or replicated by other researchers, and that there are still major unresolved questions about the prion theory. And some scientists have complained that because prions are now all the rage, they can't get grant money for their less-trendy virus-based research. "If it turns out that viruses do cause the diseases," Taubes wrote in the October 10th edition of Slate, "Prusiner will have won the prize for something spectacularly wrong."
And just last week in The New Yorker, Richard Rhodes warned that the prion theory could end up in the scientific dumpster, like cold fusion did a decade ago.
Butler, though, isn't worried about his mentor being discredited. "There was the same kind of controversy when DNA was discovered," he points out.
Instead, Butler is looking for ways to apply prion research to his own work. "I'm interested in molecular biology and how things happen on the most basic level," he says.
A native Memphian, Butler graduated from Fairley High School in 1979. Encouraged by his mother, a nurse, to consider becoming a doctor, he studied pre-med at Harvard, then attended medical school at UCSF, where he decided to make neurology his specialty.
"I'm very interested in how organisms learn," he explains, "and the closest clinical thing you can get to that is to study forgetting. That's why I specialized in dementia."
Butler joined the Wesley Neurology Clinic in May 1996 and has recently set up Memphis' first comprehensive clinic for Alzheimer's patients. He's assembling a team of health-care providers who will address patients' physical, mental, emotional, and social needs, and he also plans to conduct clinical research, mainly testing new drugs. He stresses the importance of conducting autopsies, because Alzheimer's can only be definitively diagnosed after death, when the characteristic changes in brain tissue can be observed. By seeing which patients had less deterioration in their brain cells, doctors can determine which medications were more effective.
Both Alzheimer's and CJD form plaques - patches of abnormal tissue - in the brain, but Alzheimer's is not considered one of the prion diseases. However, says Butler, "If you define prions in more general terms as shape-changing proteins, there are similarities in pathology. The major focus of research now is how proteins change shape [from a benign form to an illness-causing one], both in prion diseases and Alzheimer's."
Some doctors might find it depressing to study Alzheimer's, since there's no known cause or cure, and patients inexorably lose their mental functions. But Butler sees cause for optimism. "I'm very excited about gene research [being done on Alzheimer's]," he says. There are also two new drugs, Aricept and Cognex, that relieve symptoms in at least some patients, and studies have shown that ginkgo biloba, an herbal supplement, and Vitamin E, an antioxidant, may be helpful. "I personally think the process of oxidation - the damage that can happen to nerve cells over long periods of time - is going to be important," says Butler. There doesn't seem to be an Alzheimer's breakthrough on the horizon, but the nature of experimentation is that discoveries - like penicillin - tend to be stumbled upon. "Science, unfortunately, is not predictable," Butler says. "There's no way to know when a cure will come."
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