A leading researcher into wasting diseases such as mad cow says scientists may have long been looking at the wrong culprit

HAMILTON – Bruce Chesebro is waiting for his monkeys to get chronic wasting disease.

A few months ago, Chesebro and other researchers at Rocky Mountain Laboratories here injected a slurry of infected deer brain tissue into the brains of small black-eyed macaque and squirrel monkeys. Other monkeys drank a fruit drink mixed with the tainted brains. Today, the monkeys sit in a room sealed off from most human contact while scientists like Chesebro wonder if one of the world’s most mysterious vectors is eating little holes within their primate brains.

He and his colleagues are part of one of the nation’s oldest and most respected research programs into the bizarre family of brain-wasting diseases called transmissible spongiform encephalopathies, or TSEs.

Researchers at the National Institutes of Health’s Rocky Mountain Labs have been quietly shedding light on TSEs since 1961, helping to explain the suite of always deadly ailments that includes chronic wasting in deer and elk, mad cow disease in cattle and a similar malady in humans called Creutzfeldt-Jakob disease.

Their work has taken on a new urgency since mad cow disease was found in the United States and everyone from consumers to Congress is demanding to know more about these killers – and how likely people are to catch them.

But what Chesebro has to say may be unsettling: He thinks mainstream science may have been running down the wrong road for decades on TSE research. While conventional wisdom holds that TSEs are caused by an infectious protein, Chesebro thinks it is just as likely – maybe even more so – that these diseases are really caused by some hearty “ubiquitous virus” science has yet to identify. A virus present in everyone’s body.

It’s a suggestion that challenges the very foundations of most TSE research. And, if true, it means science knows even less about a family of diseases experts like Chesebro admit are still largely a mystery.

“We’ve never seen a spontaneously infectious protein,” Chesebro said. “No one has ever generated it in the lab.”

“At its basic element, it’s really pretty simple,” said Suzette Priola, another Rocky Mountain Labs researcher. “A normal protein goes bad.”

All TSEs are marked by a phenomenon Priola describes as “weird”: normal proteins somehow become disfigured, accumulate in the brain and destroy it.

When science first started paying attention to TSEs in the 1950s, there was only one: scrapie, and people didn’t know much about it except it struck sheep in England. That’s where Bill Hadlow comes in. Hadlow, a retired Rocky Mountain Labs scientist, was the first person to draw a link between scrapie, a hitherto innocuous brain-wasting sheep disease, and kuru, a neurological disorder that was killing hundreds of cannibals in New Guinea in the 1950s.

Thin and gray-haired, Hadlow keeps an impeccable house a block from the Hamilton lab where he worked for more than 40 years. He started researching scrapie in 1958 at a veterinary lab in Compton, England. That was decades before the words “transmissible spongiform encephalopathies” were on anyone’s lips and almost 40 years before any person had ever contracted brain disease from eating contaminated meat. But scrapie was nothing new, even then, he said. It had been around in English sheep and goats since at least the 1700s, although it was not known to spread to people, and sick animals were routinely sold to slaughterhouses.

“It was a strange disease,” Hadlow said. “There was great uncertainty about its actual cause.”

It was in England that Hadlow happened upon a presentation on the wasted brains of New Guinea tribal women and children. The presenter – American pediatrician and future Nobel prize winner Carleton Gajdusek – couldn’t possibly know, Hadlow said, that the disease vexing epidemiologists in the South Pacific caused the same kind of brain wasting as an English barnyard mystery.

But Hadlow instantly saw the connection and in 1959 sent a letter to the editor of the British medical journal Lancet, suggesting that scrapie and kuru might be cousins in a new family of disease.

“That’s given rise to this whole thing,” he said.

Hadlow returned to Rocky Mountain Labs in 1961 and a few months later, scientists there inoculated mice with scrapie, beginning a research program into TSEs that continues to this day.

Since then, Hadlow and other scientists have found other naturally occurring brain-wasting diseases in house cats, mink, deer, elk and, most notably, cows and people. They have shown that these diseases can be spread to many other animals. They have found the diseases are also typified by clutters of certain kinds of disfigured, naturally occurring proteins which seem to do the most damage in the brain, but are present in other parts of infected animals, too.

What’s more, they found the body – human and animal – makes lots and lots of this protein for reasons that are not entirely clear. It is a protein that when not twisted with infection causes no problems and must have some biological function.

Today, mainstream science believes that these twisted proteins, called prions, are not just a symptoms of all TSEs; they actually cause the infections.

When Stanley Prusiner, a Nobel laureate, first published that idea it was so nontraditional, many dismissed it. And for seemingly good reason: Proteins are chemicals. Chemicals are not infectious. To say that a disfigured protein can teach other proteins to disfigure themselves is like saying that a green rock tossed in a box of blue rocks can make the blue rocks change color.

But the prion theory did explain many elements of the disease and today is so dominant, scientists like Chesebro and Hadlow find themselves on the sidelines by pointing out that TSEs could just as easily be caused by something else.

Chesebro thinks an unknown but widespread virus might be behind TSEs, with the host’s own genetics playing a strong supporting role. While everyone may have this virus, only a small percentage of people have the genetic susceptibility to get sick from it.

He has reasons to question the prion theory.

Some of the evidence initially supporting it has been questioned in recent years. When Prusiner first published the idea, one of things that seemed to support it was the fact that whatever caused TSEs could not be killed using any of the known methods that easily kill other viruses, like extreme heat. But today, Chesebro said, researchers at Montana State University in Bozeman have shown that some viruses live quite nicely in the sizzling hot pools of Yellowstone National Park – an environment that would kill any “normal” virus.

“The idea of what it takes to kill a virus is different than it used to be,” he said.

Plus, Priola said, the prion hypothesis cannot explain why there are different strains of some TSE diseases.

“That’s the most compelling point,” she said.

A protein has no genetic material; it’s not alive like a virus. It is a substance, like water is a substance. Just like water is always water, she said, a protein is always a protein. How can one protein cause different shades of the same disease? A virus, on the other hand, can have different genetic variations. That means there are different strains of one virus that can cause the same disease, like different strains of the flu.

Scientists can also make normal proteins change into twisted proteins in the lab – but so far they haven’t been able to show that those proteins can cause infections, Chesebro said.

Chesebro said he’s not advocating his theory over any other. But he said that all possible explanations of these diseases should be aggressively researched.

While many details of TSEs are still unknown – a situation Hadlow laments – symptoms of the disease are something science does know quite a bit about. In people, the symptoms are devastating: depression, dementia, hallucinations, staggered walking, uncontrollable body movements, a vegetative state, death.

Many TSEs are associated with eating the rendered remains of other sick animals. Cattle catch mad cow disease from eating bone meal processed from dead cows. Gajdusek and others eventually figured out that the cannibals dying from kuru in New Guinea got the disease from eating infected corpses. When cannibalism ceased, so, too, did kuru.

But TSEs haven’t given up all their secrets: scientists still don’t know how sheep get scrapie or how deer and elk get chronic wasting disease.

More recently, Priola discovered that certain compounds can arrest the progression of TSE diseases if taken early enough. It’s bittersweet knowledge, though, she said. TSEs generally don’t produce any symptoms until they have practically killed their host and, by then, nothing can stop it.

One thing everyone agrees on, Chesebro said, is that you don’t have to know everything about a disease to know how to prevent it.

Cattle should not eat other cattle, he said. Deer and elk should not be artificially confined because confined animals get chronic wasting more easily.

And the research should go on – hence, the monkeys.

In order to see if chronic wasting disease can spread to humans, researchers injected the disease into the brains of monkeys. TSEs generally take a long time to produce symptoms, so Chesebro and his colleagues have a long time to wait and chip away at the riddle of TSEs.

“Rocky Mountain Labs is pretty well supported to do basic research,” he said. “A lot of basic research is needed to answer these basic questions.”

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