Bent Out Of Shape, Part 4: The Next Mad Cow Disease?

Apr 25, 2019

Michael Osterholm is worried. He directs the Center for Infectious Disease Research and Policy at the University of Minnesota. He's also serving a one-year stint as a "Science Envoy for Health Security" with the State Department. And he told Minnesota lawmakers that when it comes to chronic wasting disease, we are playing with fire.

"You are going to hear from people that this is not going to be a problem other than a game farm issue. You're going to hear from people that it's not going to transmit to people and I hope they're right, but I wouldn't bet on it," he said. "And if we lose this one and haven’t done all we can do, we will pay a price."

If that wasn't warning enough he added: "Just remember what happened in England."

Decades ago, Osterholm got involved in a newly emerging disease — bovine spongiform encephalopathy, later dubbed "mad cow disease."

"I was included in a group that actually provided an initial assessment to the British government on the potential for the BSE prion to be transmitted on to humans," he said.

At that point, scientists hadn't documented a prion disease in animals that could infect people, but they did have a few pieces of the puzzle. For one, work in Papua New Guinea had showed that people could transmit prion diseases to each other if they practiced cannibalism, especially of the brain-eating variety. They also knew that BSE was spreading quickly between cattle. Osterholm says he and others worried that the more it spread, the more chances the disease might have to change into something that could sicken people.

"A lot of people thought that it was an overreaction," says Osterholm. "Then, of course, in 1996, ten years later, we recognized that in fact transmission had occurred."

Variant Creutzfeldt-Jakob disease, as the illness is called in people, has infected about 230 people worldwide.

Osterholm feels like he's having a deja vu moment, except instead of mad cow, it's chronic wasting disease that's now spreading in animals, with the potential to cross a species barrier and infect humans.

Daniel Schmidt says Osterholm needs to lower the fear flag.

"To say that without any concrete proof — I think that's irrational," said Schmidt, editor-in-chief of Deer & Deer Hunting.

"If CWD is a threat, it is more to the lifestyle of the hunting public in America," said Schmidt. "Because if you scare people enough in America they're going to stop doing something."

Schmidt and his family live in Wisconsin. He says they eat wild venison almost every day and don't give chronic wasting disease a second thought.

If you need something to worry about, he says, how about climate change, or pesticides in your strawberries?

"This is not a zombie apocalypse and the hamster wheel of fear-mongering is nothing short of sensationalism, in my opinion," Schmidt said.

So, who's right? Could chronic wasting disease present a public health crisis? Or are we, as Schmidt put it, merely hamsters spinning the wheel of fear?

A section of brain from a cow infected with bovine spongiform encephalopathy. The brown staining indicates the presence of the agent causing the disease.
Credit Dr. Peter Hooper / CSIRO / CC BY 3.0

The answer to that question largely rests on the shoulders of Stefanie Czub. She's a professor of veterinary medicine with the University of Calgary and she also runs the Canadian Food Inspection Agency lab that tests for mad cow disease. Everyone's waiting for results from her decade-long study of chronic wasting disease in macaque monkeys. It’s actually about to end, in March 2020.

"Which is too bad, because such an experiment will never, ever be repeated," said Czub.

She says the experiment has cost Canadian taxpayers about $8.5 million, paid for primarily by Canadian taxpayers through the Alberta Prion Research Institute. Now, funds are running out. So is support for research on primates.

"At this point, what we would like to stress — my collaborators and I — is that we have some evidence that it might infect non-human primates," said Czub. "However, the project is not completed yet."

Czub and her collaborators took 18 macaque monkeys and exposed them to chronic wasting disease prions. Some had the prions inserted straight into their brains. Some ate infected venison. Others got exposed via blood transfusion. And some were given little cuts, which were then wrapped in infected deer brain, which was meant to model how a hunter might be exposed to infectious material after getting cut during field dressing. There were also three control animals, which received tissue from healthy deer and elk.

Here's what the group has found. So far, four out of the 18 monkeys developed what Czub calls "subtle and transient" symptoms that "could be indicative of a prion disease." Two of them had received CWD straight into their brains. Two had eaten infected meat.

They lost weight and became anxious.

"Anxiety is a very common clinical expression in animal prion diseases," said Czub. "It is one of the main symptoms in bovine spongiform encephalopathy, and that is the reason why some people decided to call it 'mad cow disease.' The animals are not mad, they are scared to death."

She says in monkeys, that involves crouching in the farthest corner of the cage. They would also shiver and have difficulties picking up pieces of food. One monkey lost a third of its body weight in six months.

After the four symptomatic animals were euthanized, Czub and her colleagues ran a bunch of tests, which Czub says "suggested the presence of CWD" and concluded that they did, indeed, have chronic wasting disease. But there are a number of things that make this complicated. First off, three of the four sick monkeys also happened to have diabetes.

"And it's really important to mention that because diabetes — uncontrolled diabetes — really does induce wasting, so we need we need to be super careful in the interpretation of wasting," said Czub.

It's also really important to say that Czub has presented her preliminary results at conferences, but they've never gone through the true scientific wringer: peer-reviewed publication. That's a really important step, because where one researcher might see an unusual level of anxiety, another might just see an animal in captivity. Even results from more technical evaluations, like analyzing slices of the brain for neuron death, could potentially be interpreted in different ways.

Macaque monkeys (left) are biologically closer to humans than squirrel monkeys (right).
Credit Kathryn F and Dave Pape / CC BY 2.0

"We'd like to see them published so we can get a better idea of how strong the data really is to support transmission," said Brent Race, a staff scientist at Rocky Mountain Laboratories in Montana, which is part of the NIH's National Institute of Allergy and Infectious Diseases. He and his colleagues ran an experiment similar to Czub's.

"Our studies in macaques have been published three different times now," said Race. "We watched our macaque monkeys for over 13 years in some cases and we were unable to find any evidence of transmission of chronic wasting disease."

Their study on "humanized" mice spliced with a human gene also showed no strong proof of transmission. Race and his colleagues tried to make it as easy as possible for the infection to take hold: They used mice that not only had human prion protein, but a lot of it, they injected CWD straight into the animals’ brains, and they also used a very sensitive test to check for signs of disease transmission. Eighty-four out of 88 mice came back negative. The remaining four came back with fuzzy results, which Race is now investigating further.

Race's study on squirrel monkeys, on the other hand, concluded that those animals were highly susceptible to chronic wasting disease. Thirteen squirrel monkeys were exposed to the disease directly in their brains. All of them developed symptoms including severe weight loss, tremors, drooling and weakness after an average of about four years. The researchers fed another group of 12 squirrel monkeys with infected meat and found that 11 of them developed CWD an average of about six years after exposure. Importantly, the researchers wrote in the journal Emerging Infectious Diseases, macaque monkeys are biologically much closer to humans than squirrel monkeys.

"Aside from a few benchtop assays and the unpublished macaque study from Canada, news has been very encouraging," said Race.

A systematic review of 23 studies including Race’s concluded that, "Five epidemiological studies, two studies on macaques and seven studies on humanized transgenic mice provided no evidence to support the possibility of transmission of CWD prions to humans."

However, the review added that the results from the squirrel monkeys — along with a number of test tube studies — muddy the waters. "Therefore, future discovery of CWD transmission to humans cannot be entirely ruled out," the review stated.

Christina Sigursdon, a professor of pathology at UC San Diego and UC Davis, did a study that hunting enthusiasts have pointed to as a reason not to worry about chronic wasting disease.

It showed that a certain part of human prion proteins makes them incompatible with chronic wasting disease prions and so healthy human prions shouldn’t be capable of getting misfolded, kind of like how a zipper just won't zip if the teeth are different sizes.

"So, it suggested that this region was a barrier — at least, a partial barrier — for blocking infection," said Sigurdson.

But only a partial barrier — and even then, only a partial barrier against the particular versions of chronic wasting disease from Colorado that Sigurdson used.

"We need more research to find out how many strains there are, how different are these different strains and would there potentially be some strains in the U.S. that could be infectious for people," she said.

Distribution of chronic wasting disease in North America, updated April 2019.
Credit Bryan Richards / USGS National Wildlife Health Center

The Centers for Disease Control and Prevention haven't found any evidence of chronic wasting disease in people, despite researchers actively looking for them. Epidemiologists in states like Colorado and Wyoming are also watching for an elevated rate of prion disease in hunters, who would be most at risk from eating venison.

Hunters like researcher Brent Race.

"I'm an avid hunter myself and my entire family eats it," Race said. "Actually, we raise cattle and we sell all of our cattle and eat deer and elk instead."

But Race wouldn't go so far as to eat meat that hasn't been tested for chronic wasting disease. In fact, that's a feeling shared by pretty much every person in this story: If you're hunting in an area with chronic wasting disease, get the animal tested before it ever hits the plate, and don't eat meat that tests positive.

"Otherwise," said Michael Osterholm, "I wish you well and hope you enjoy your venison."

This story is part two "Bent Out Of Shape," a four-part special report about chronic wasting disease.

Part One: A Mysterious Animal Epidemic
Part Two: An Animal Epidemic Goes Global
Part Three: A Complicated Turn Of Events

This series was produced by the Mountain West News Bureau, a collaboration between Wyoming Public Media, Boise State Public Radio in Idaho, KUER in Salt Lake City and KRCC and KUNC in Colorado, and published in collaboration with High Country News.