November 3, 2002 Milwaukee Journal Sentinel by Mark Johnson and John Fauber Markjohnson@Journalsentinel.Com
Later this month in an austere, concrete building in Ames, Iowa,
scientists expect to begin a macabre experiment involving the two
animals that most define Wisconsin's culture and economy:
white-tailed deer and dairy cattle.
Researchers will inject brain tissue from deer infected with chronic wasting disease into the brains of healthy cattle to see whether the cows develop a similar illness.
With Wisconsin's 1.6 million deer and 1.3 million cattle living so close to one another, scientists want to know whether what threatens one, also threatens the other.
Can chronic wasting disease, which crossed the Mississippi River this year to infect Wisconsin's white-tailed deer, also cross the species barrier to infect cattle?
In a sense, the experiment in Iowa represents the hand of man trying to undo the hand of man. For nearly 250 years, sheep appeared to be the only species of animal afflicted with a type of fatal brain disease now called a transmissible spongiform encephalopathy. All of that changed in the last 60 years.
In short order, mink, deer and cattle developed similar brain diseases, and the outbreaks appeared to have human fingerprints on them. Researchers believe that changes in the way animals were fed, housed and recycled may have opened a door to the deadly new diseases.
One of the first warnings was sounded in Wisconsin, a state that has become an epicenter for this family of animal brain illnesses. Only the cattle disease, "mad cow," has yet to be found here, or anywhere in the United States.
Although Richard Marsh might dispute that if he were still alive.
It was Marsh, an affable, intensely curious scientist from the University of Wisconsin-Madison, who sounded a warning about questionable animal feeding practices more than a decade ago and kept sounding it until his death in 1997, even as critics dismissed him as an alarmist.
What worried Marsh was the feeding of rendered cattle and other ruminant animal products back to cattle, a practice widely blamed for the outbreak of mad cow disease in Great Britain.
"We caused these animals that are vegetarians to cannibalize themselves with these feeds," Roger C. Viadero, the former inspector general of the U.S. Department of Agriculture, said in a recent interview. "To a large extent, man is responsible."
Humans have suffered the consequences as well. About 130 people have died so far from variant Creutzfeldt-Jakob disease, believed to be the result of mad cow jumping to humans who ate infected beef. And the mad cow experience raised the specter that other diseases in the same family -- such as chronic wasting disease -- might infect people, with harrowing results.
Today, some scientists suggest that man may yet have an opportunity to repair the damage.
They believe genetic testing could reveal animals that are resistant to diseases such as mad cow and chronic wasting. Once identified, resistant animals could be bred in captivity and then used to repopulate herds after susceptible animals have been killed off. Veterinarians already have found a breed of sheep that appears resistant to the brain disease scrapie.
Theoretically, the same could be done for deer, said Gary Voelker, a research scientist with Infigen, a DeForest biotechnology firm and one the country's leading animal cloning companies.
But finding white-tailed deer that are resistant to chronic wasting disease may not be so easy. Preliminary research by Judd Aiken, a UW professor in the department of animal health and biomedical sciences, suggests that a majority of white-tailed deer in Wisconsin may be susceptible to the disease.
If whitetails with natural resistance can't be found, there may be an even more meddlesome option: genetically engineering resistant deer. Such a feat would entail adding a gene to the DNA of deer.
Once accomplished, "You would just turn them into the wild and say 'breed away guys,' because every one of their offspring would be resistant," said Bob Wagner, a molecular biologist and president of Gene Check, a Fort Collins, Colo., biotech company.
Even in the biotech frenzy of the 21st century, such a feat would be a considerable challenge. But it would have seemed like science fiction to Marsh when he first began to understand man's role in these deadly diseases.
Mink outbreak Scientist suspects cattle is source
The mink on Ed Brecke's farm were behaving strangely.
They left droppings, not in one place as usual, but all over the cages. They arched their tails over their backs like squirrels.
Within weeks, the normally agile mink were staggering about the cages, their legs plunging through gaps in the wire mesh. Some circled rapidly; others lay trance-like, noses buried in a corner.
Then, one by one, they died. Thousands of them.
Reports of the dying animals brought Marsh to an unlikely setting for scientific discovery, a mink ranch in a village called Stetsonville, about 40 miles west of Wausau.
It was April 1985, the very month a veterinarian in England was discovering a frightening, new disease in cattle, similar to the one infecting the Wisconsin mink.
Mad cow disease.
Marsh, the son of an Oregon mink rancher, was already one of the nation's experts on the family of fatal brain diseases that afflicted mink, sheep, deer and now cattle. For a renowned researcher he seemed deceptively simple, with his taste for polyester pants and fondness for doughnuts.
"He always came across -- he had this act down to perfection -- sort of like the bumbling, old veterinarian who didn't know a whole lot of things," said Debbie McKenzie, a senior scientist at UW-Madison who worked with Marsh for more than a decade.
But in the arcane field of transmissible spongiform encephalopathies, Marsh held a special place.
"He was god in those circles," McKenzie said. "People would defer to his opinion."
In Stetsonville, Marsh knew right away that he was dealing with transmissible mink encephalopathy.
The disease was no stranger to Wisconsin, a state that led the nation in mink production in the 1960s. In fact, the first place in the world to see an outbreak of the mink illness was a farm in Brown County in 1947. Virtually all of the adult mink on the Brown County farm got the disease. They became uncoordinated and drowsy, then died.
Other outbreaks hit Wisconsin ranches in 1961 and 1963. Finally in 1965, a Wisconsin veterinarian, G.R. Hartsough, and a UW-Madison researcher, Dieter Burger, wrote the first paper identifying a new disease in mink "that reveals many traits in common with scrapie of sheep."
The disease intrigued Marsh. In the late 1960s, he studied infected mink brain from the 1963 outbreak, noting that the infectious agent resisted attack by chemicals and ultraviolet radiation, and seemed to have no genetic material.
"The biochemical properties of the agent are quite unusual for a virus," Marsh wrote in a 1968 paper. "The only other agent which has been shown to havesimilar properties is that of scrapie."
Marsh had no way of knowing that more than a decade later a new theory would shock the scientific world by suggesting that the mysterious agent was not a virus, but a rogue protein.
Medford veterinarian Oscar Hildebrandt, who specialized in mink and knew the Stetsonville rancher, also was intrigued by the disease.
Hildebrandt said the disease was a terrible financial blow to the young rancher, who ultimately lost 60% of his 7,300 adult mink. Hildebrandt had read about the disease, but the visit to Stetsonvile was the only time he ever saw it in a living animal.
"The mink that were pointed out to me had intense itching all over their bodies, mainly the hindquarters," he said. "They were rubbing themselves on the wire of the cages, rubbing themselves so their fur was coming off. Because of this intense irritation, they weren't eating. They were skinny."
What Hildebrandt saw brought to mind scrapie. He wondered whether the rancher had fed sheep remains to his mink.
But Marsh's investigation led him in another direction. Marsh returned to the ranch several times, questioning the rancher closely about what he fed his mink.
The rancher, Marsh wrote, had never fed sheep to his mink. Nor did he use supplements of meat and bone meal.
Most of the meat he fed the mink had come from fallen and sick dairy cattle.
This led Marsh to the startling conclusion that would shape his career and launch a scientific debate: Cattle had passed a killer to the mink.
The possibility that the mink disease came from cows had been raised by Hartsough and Burger 20 years earlier when they wrote that "tissues of bovine or perhaps ovine (sheep) origin are possible sources" for the illness. But Marsh had eliminated sheep as the source of the Stetsonville outbreak.
His critics -- and there were plenty, especially in the feed and rendering industries -- would claim there were crucial errors in his work.
The stakes were high, perhaps nowhere higher than in his own state of Wisconsin, with its large herd of dairy cattle.
If Marsh was right, the cows harbored their own brain-destroying illness caused by an extraordinary infectious agent, an agent that had jumped the species barrier from cattle to mink.
If Marsh was right, mad cow disease, or something like it, had reached the U.S.
Scrapie was first A minor disease in a minor species
The earliest record of these brain-destroying illnesses dates back to 1732, when sheep scrapie was first described in Great Britain.
Scrapie got its name from the way in which infected sheep -- or goats -- often rubbed against objects and scraped off wool or hair. As the disease progressed, sheep sometimes became uncoordinated in their hind limbs, struggling to stand and swaying unsteadily when they did. They lost weight and displayed other odd behaviors, including high-stepping and lip smacking.
In the early 1900s the disease was thought to be a virus, but the virus could not be isolated. Later, some experts believed scrapie was genetic. That theory too has been rejected, though genes do appear to play a role, making some sheep more susceptible than others.
The most common explanation for how the disease spreads is through contact with the placenta in birthing areas.
For years, even after scrapie first reached the U.S., North American interest in the disease was limited.
"For a long time scrapie was considered a minor disease, and in the U.S., a minor disease in a minor species," said Linda Detwiler, a U.S. Department of Agriculture veterinarian who began studying the disease in Ohio in the 1980s. In the hierarchy of American agriculture, sheep lagged far behind cattle.
But to Ed Dittbrenner, scrapie was no minor disease, and sheep no minor species.
In the summer of 1980, five years before Marsh went to Stetsonville, a state veterinarian showed up on Dittbrenner's sheep farm in Cumberland.
Dittbrenner had been raising sheep since he was 4 years old, but this was the first year he had gone into the business full time. He had 380 head of Suffolk sheep, some purchased from Illinois and North Dakota.
There was a problem, the state veterinarian said. Dittbrenner had sold two sheep to a livestock broker who then sold the sheep to another farmer. The sheep had come down with scrapie, raising the likelihood that they had carried the disease when they were on Dittbrenner's farm.
The veterinarian told Dittbrenner he could not sell or move any of his sheep. His 200-acre farm was quarantined.
A month later came worse news: State agriculture officials had decided that all of his sheep would have to be killed, even though they appeared to be generally healthy. All of the sheep belonging to the livestock broker and the other farmer would also be destroyed. And so would the sheep Dittbrenner had sold to a dozen children to raise as a project for 4-H.
The slaughter couldn't take place until federal reimbursement for the farmers was available.
"I was going to have to feed them and care for them and know that the end result was that they were going to be killed," Dittbrenner said. "This was the only thing I had, these sheep. I had raised sheep all of my life."
In August of that year, a trailer pulled into his farm. He watched as a veterinarian killed each animal with a pistol shot to the head.
Then the farmer loaded his dead sheep onto a trailer and hauled them to the top of a hill on his property, where a pit, 8 feet wide and 40 feet long, had been dug. There, his entire herd was buried.
Fear of scrapie ran so strong that when Dittbrenner went looking for new sheep to buy, a farmer in Hayward refused to allow him on the property.
"They were afraid we would spread it," said Dittbrenner, who has since returned to raising sheep.
Today Dittbrenner buys only sheep that have been tested and found to have a gene that appears to be resistant to scrapie. Still, there are no guarantees. Detwiler said scientists don't know if the gene is truly resistant to scrapie or just gives animals a longer incubation period before they get sick.
In the years since Dittbrenner's flock was destroyed, however, scientists have made progress in understanding what causes scrapie, and indeed the whole family of related diseases. In a landmark 1982 article in the journal Science, a California researcher, Stanley Prusiner, wrote that scrapie was caused by a mutant protein called a prion. This abnormally shaped protein caused disease, he said, simply by inducing another protein in the brain to mimic its deformed shape.
Although Prusiner would win many converts to his theory, including the committee that awarded him the Nobel Prize, other scientists continue to voice doubts.
And no one yet has figured out how to eliminate the disease in the U.S.
"I had a couple of wishes before I retire, and now I've pushed them back to before I die," Detwiler said. "One is to see what the agent (in scrapie) really is. The other is to see scrapie eradicated from the U.S."
English lessons Mad cow concerns lead to feed ban
In the late 1980s and early 1990s, Marsh's work in Stetsonville began to have wide repercussions, igniting a debate over how to protect the U.S. from a disease that had grown into a full-blown crisis in Great Britain.
The prevailing theory is that mad cow disease came from sheep scrapie. The British had used the scrapie-infected carcasses of sheep to make the meat and bone meal fed to dairy cattle. The meat and bone meal also included the remains of so-called downer cattle, cows too ill to walk.
In addition, the British had changed the rendering process used to make the meat and bone meal, phasing out the use of flammable solvents to get rid of animal fat and imitating American firms that used lower temperatures.
The combination of more fat protecting the infectious agent and less heat attacking it may have allowed the scrapie agent to survive in feed and then jump to the cows that consumed it.
An alternate theory holds that the disease emerged after a genetic mutation that occurred in a small number of cows, which then were used to make cattle feed.
Whatever the disease's origin, it spread through meat and bone meal, a man-made product used to boost protein in animals. And by the late 1980s, man was paying a price.
In 1989, the number of British cows testing positive for mad cow tripled to more than 7,000 annually. The following year, the number doubled to more than 14,000. The disease ultimately infected nearly 180,000 cattle in Great Britain and spread to other countries in Europe and South America, as well as Israel and Japan.
In a gruesome effort to eradicate the disease, British authorities slaughtered nearly 4.5 million cattle that had no symptoms.
The mounting crisis in Britain lent a sense of urgency to what Marsh had found in Stetsonville.
If U.S. cows already had a similar illness, as he believed, then using them to make meat and bone meal for other cows risked unleashing a sizable outbreak in this country.
The same troubling conclusion had occurred to an acquaintance of Marsh, William Wustenberg, a Minnesota animal health consultant who had grown up on a mink ranch.
In 1990, the two men published an article, not in a medical journal, but in a publication that would reach farmers, Hoard's Dairyman.
"The question facing American dairy farmers and feed companies is one of economic benefit versus risk," they wrote, "Are the benefits of feeding meat and bone meal enough to justify the risk of (mad cow)? . . . Evidence provided by the (mink) outbreak in Stetsonville, Wis. indicates there may be a risk in feeding meat and bone meal of cattle origin."
The paper unleashed a furious debate.
The warning, if heeded, would dramatically change business for U.S. renderers, who process about 50 billion pounds of animal parts annually -- enough to fill nearly two continuous trains stretching from Miami to Seattle.
Fred Bisplinghoff, a veterinarian and consultant to the $3 billion-a-year rendering industry, had serious doubts about Marsh's work. Bisplinghoff said he conducted his own study of the Stetsonville outbreak, questioning the mink rancher and getting him to admit that he had fed his mink organs and other material from various animals -- not just downer cows -- that had been rejected by feed companies.
"We contacted the owner, and the owner denied the story (he had told Marsh)," Bisplinghoff said.
Officials in the rendering industry tried to get Marsh to change his conclusion. When he refused, they went to the dean of Marsh's college in an attempt to get the professor to recant.
He never did. In fact, Marsh continued to sound the alarm.
"Dick Marsh was an excellent scientist who loved publicity and who came to the wrong conclusion," Bisplinghoff said. "I could never understand why he persisted. He stuck to his story all the way."
He would win one important convert. A year before winning the Nobel Prize, Prusiner was quoted as agreeing with Marsh that mad cow disease must be in the U.S.
Finally, in January 1997, more than six years after the Hoard's Dairyman article, the Food and Drug Administration proposed a ban on the feeding of rendered ruminant protein to cattle. Wustenberg phoned his congratulations to Marsh.
"You got it done."
Marsh was typically restrained.
"He was kind of quietly satisfied that it had been done," Wustenberg recalled, adding that there was also the feeling "like 'Jesus, it's about time. We've been at this for a long time.' "
Two months later, on March 23, Marsh died of cancer, at his home in Middleton. He was 58.
The ban was approved and took effect later that year, though the FDA stressed that mad cow had not been found in the U.S.
Even after his death, Marsh's work in Stetsonville would raise vital questions for Wisconsin when yet another prion disease entered the state: chronic wasting disease.
Deer succumb After years of obscurity, disease on the move
In the late 1960s, researchers in Fort Collins, Colo., were raising mule deer in wildlife pens for nutritional studies. At some point, sheep also were raised in the pens, allowing researchers to compare the two species.
It's not clear whether the sheep arrived before or after deer began falling ill. Nor is there any record that any of the sheep had scrapie. But their presence would raise the same question that haunted mad cow researchers: Had sheep passed a prion disease to another species?
For a disease to jump the biological barrier between species is no simple matter. Different species have different structures for the normal protein in their brains. Scientists believe those differences make it difficult for prions from one animal to infect an animal of a different species.
Sometimes, though, there is enough similarity that a prion can cause a normal protein to misfold, triggering a cascade of misfolding that kills off brain cells.
Researchers in Colorado noticed that in the early stages of chronic wasting disease, deer got a dull, vacant look in their eyes and appeared standoffish. Later they urinated much more than normal and their bodies wasted away -- the characteristic that gave the disease its name.
At first, the animal's weight loss didn't suggest a brain disease, but rather something like exposure to toxins. Roughly a decade would pass before a scientist made the connection between chronic wasting disease and scrapie.
Late one night in 1977, a graduate student in Colorado State University's Department of Pathology peered through a microscope, seeking clues to the mysterious deer disease.
Elizabeth Williams, daughter of a professor of dairy science, had wanted to be a veterinarian since childhood. She was determined now to examine every way in which the deer that were dying differed from normal deer.
She sectioned the brain of a dead mule deer and put a slide under the microscope. What she saw was striking. Clear holes in the otherwise pink tissue. Williams had written a term paper on a sheep disease that looked like this, so the image set off a flash of recognition.
I think this is scrapie.
It wasn't scrapie exactly, but Williams had the right idea. Deer now had their own transmissible spongiform encephalopathy. As researchers learned more, they grew to suspect that chronic wasting disease spread from deer to deer either by direct contact or through saliva, urine or feces.
For years, the disease remained as obscure as scrapie had been, confined to portions of Colorado and Wyoming, and of interest to just a few scientists. Not until the mid-1990s did chronic wasting show up outside those two states.
But then it began to move, propelled, some believe, by the growing trade in farmed deer and elk.
In 1996, the disease was found on an elk farm in Saskatchewan. In 1997, an elk farm in South Dakota. In 1998, an elk farm in Nebraska, then a farm in Oklahoma. Then, in subsequent years, Montana. Kansas. Alberta.
In 2002, the first cases showed up in New Mexico, Minnesota and most significantly, Wisconsin, the first state east of the Mississippi River. On Friday, Illinois confirmed that chronic wasting had been found there, in a doe shot near the Wisconsin border.
Deer and elk farmers quickly learned the same lesson driven home to Ed Dittbrenner by scrapie and to Ed Brecke by the mink disease: The infectious agent brought economic devastation.
Wisconsin's once-thriving deer and elk trade shut down.
All of a sudden Corey Bauldry couldn't sell the red deer on his Sturgeon Bay game farm, and he needed to badly. His delivery business had been struggling.
The 95 deer on Bauldry's farm -- apparently quite healthy -- could once have commanded between $70,000 and $80,000 total. Now he couldn't sell them at all.
In past years, the 33-year-old Bauldry enjoyed watching the fawns being born. This year, he was running low on money to feed his animals. In September, all 22 fawns were shot and buried. The remaining deer will be shot and butchered soon, which is why Bauldry won't be hunting.
"I'm not going this year, because I'm going to have a freezer full of my own deer," he said.
Jumping species Prions may adapt, become more virulent
Apoor hunt and hardships for deer farmers may be just the short-term effects of chronic wasting disease. The state's wildlife could face long-term problems if the disease spreads to other animals or gets in the soil.
Here again Marsh's work in Stetsonville seemed to anticipate the long-range threat from these diseases. When he studied the mink 17 years ago, Marsh wondered not only where their disease had come from, but also where it might go.
Marsh and other UW-Madison researchers began injecting tissue from diseased mink brains into a variety of other animals. It turned out the disease could be transmitted "with relative ease" into sheep, goats, hamsters, squirrel monkeys, raccoons and skunks, according to a 1996 paper by Marsh and two other researchers.
In addition, when infected mink brain tissue was injected into two Holstein steers, both animals developed a fatal brain disease within 19 months after exposure. Marsh did not label the ailment mad cow disease, calling it only a fatal spongiform encephalopathy.
The species barrier, though formidable, was not impenetrable.
Moreover, recent research suggests that prion diseases adapt over time, becoming more virulent and shortening incubation periods.
Last year, scientists at the National Institutes of Health described a series of experiments in which they injected mice with a strain of a hamster prion disease. Although the mice never got sick, it turned out that the prions persisted in the mice for years at undetectable levels.
When researchers injected brain tissue from the mice back into healthy hamsters, all of the hamsters got sick. In addition, when brain tissue from the first group of mice was injected into more groups of mice, the disease grew more virulent and began making the mice sick.
It was as though the prions learned how to deal with a new species, said Richard Race, an NIH researcher.
"It replicated faster in additional rounds of mice and even became more lethal to them," he said.
The NIH researchers warned that prion disease may be more common than originally thought. And they said the research raised public health concerns about the practice of giving other farm animals -- not just cows -- feed made from the byproducts of other animals.
Those experiments and others now raise questions about whether chronic wasting disease can jump, not just to dairy cattle, but to wild animals such as raccoons, skunks, possums and feral cats.
Long-term concerns 'It's naive to think we can get rid of it'
Complicating matters further, the prions that cause chronic wasting may persist in the environment for years.
As the centerpiece of its effort to eradicate the disease from Wisconsin deer, the state Department of Natural Resources plans to have an estimated 25,000 deer killed in a zone southwest of Madison where the disease was first detected. But even that may not be enough, given the ability of prions to remain infectious for years in the ground.
"You can go into Sauk County and kill every deer there and when the deer come back, they are going to be infected," said Robert Petersen, a Wisconsin native and prion expert at the National Prion Disease Pathology Surveillance Center in Cleveland. "It's naive to think we can get rid of it."
In a 1991 experiment, NIH scientists mixed brain material from scrapie-infected hamsters with soil, packed it in perforated petri dishes, placed those in soil-filled clay pots and buried the pots in the ground.
When the pots were dug up three years later, the prions were still strong enough to infect other animals.
The researchers suggested halting the practice of plowing under the carcasses of animals that have died of scrapie or mad cow disease or using those carcasses in fertilizer.
In Iceland, where there have been scrapie outbreaks, pastures grazed by scrapie-infected sheep were left vacant for several years. When new sheep were brought in from flocks believed to be scrapie-free, the disease reappeared, according to a 1992 U.S. Department of Agriculture review paper.
The deer pens in Fort Collins experienced a similar phenomenon -- a new generation of sick elk -- despite efforts to purge the soil of deadly prions.
Part of the concern is that animals may consume contaminated soil. Cattle, for instance, can consume more than two pounds of soil a day while grazing.
Another possibility: Prions in the soil could be absorbed by plants and worms that animals might consume.
"I think that's a legitimate concern," said Joel Pedersen, an assistant professor of soil biochemistry and environmental toxicology at UW-Madison.
Pedersen is hoping to get a federal grant to study how scrapie and chronic wasting disease prions react with various soil components.
"Clearly, the more deer that get infected and die out there, the more of a problem there will be," Aiken said.
The next step Final results of experiments may take several years
By the end of this month, researchers at the USDA hope to begin what might be described as the ultimate Wisconsin chronic wasting disease experiment: injecting brain tissue from diseased white-tailed deer into dairy cattle.
So far, chronic wasting disease has not been found to naturally infect cows -- in a five-year experiment by Williams, now at the University of Wyoming, cows have lived near infected deer, and none of the cows have gotten sick.
But other experiments involving mule deer and beef cattle suggest cattle may be susceptible.
In one, tissue from the diseased brains of mule deer was injected into the brains of a type of Angus beef cow.
Of the 13 that were inoculated nearly five years ago, four have developed a prion disease.
But the concern for Wisconsin is white-tailed deer, not mule deer.
Test tube studies show that prions from white-tailed deer can induce changes in the normal brain protein of several other animals, including elk, mule deer, and to a lesser extent, sheep and cattle.
In Ames, scientists are taking the next step.
Twenty Jersey calves will be brought into pens, where a ventilation system will filter out bacteria and a special drainage system will allow fluids and animal waste to be collected and steam-heated to at least weaken any prions.
The young cattle brought there will spend their lives standing on a concrete floor in a pen with concrete walls and steel bars.
"We aren't allowed to put them outside," said Janice Miller, a USDA veterinarian who will be in charge of the experiment.
Each calf will be injected with a concoction that includes 10% diseased brain tissue from Wisconsin white-tailed deer and 90% saline. Each animal will receive about one-tenth of a gram of brain tissue.
Next year, USDA researchers plan similar experiments with white-tailed deer and pigs and sheep.
It may take several years before the final results of the dairy cattle experiment are known.
Based on previous research, Miller said, she believes it will be very difficult for chronic wasting disease to naturally jump to dairy cattle.
But, she added: "There is no way you can say 'no risk.' The way the research is piling up, I think you can say 'low.' In two years or three years or four years or five years we'll have some results.
"I've learned not to make predictions because I always get surprised."