GREAT FALLS — An illness that strikes family members in their 50s, affecting their behavior and keeping them from sleeping. A disease that strikes sheep and goats, causing them to scrape their bodies against anything they can get near, in an attempt to scratch an itch that exists only in their brains.
Mysterious illnesses baffled doctors and scientists for years, until the early 1980s when their cause was finally discovered. The discovery — that these and other diseases are caused not by genetic mutations or outside pathogens like viruses or bacteria, but by naturally occurring but damaged proteins within the body — turned the scientific community on its head.
They are called prions — misfolded proteins that are infectious and cause fatal neurodegenerative diseases in animals and humans.
And while they are unusual and glamorous, in a biological way, research into prion disease is happening everywhere, including Montana, and livestock and wildlife experts are keeping close eyes on populations to keep them healthy.
Rocky Mountain Laboratories in Hamilton is a biomedical research facility equipped for scientists to study some of the most dangerous, infectious diseases on the planet.
In August, the New England Journal of Medicine published a paper that represents a significant step forward in prion disease research. One of the authors of the paper, which details a new test for Creutzfeldt-Jakob disease, is Byron Caughey of RML.
Caughey has been working for 30 years on prion disease, and he admits his fascination with the tiny, nearly indestructible rogue proteins is partly practical, partly because of simple fascination.
“We need to figure out how to cope with them,” Caughey said. “That’s the bottom line, really, besides the scientific fascination with working with a strange new class of infectious agents that is neither a virus nor a bacterium nor a protozoan. So (there is) fundamental interest in prions as well as the practical concerns of helping people and animals that get these diseases.”
Creutzfeldt-Jakob disease, or CJD, occurs in about one per one million people, meaning about 300 Americans are diagnosed with it each year.
The disease causes loss of muscular coordination, personality changes, depression and insomnia, among other symptoms.
The traditional test for CJD lacked sensitivity and practicality, so the team Caughey worked with developed a test that detects the biomarker of CJD using nasal swabs. The test is more accurate and less invasive than other methods.
It’s a victory for Caughey and the rest of his team because being able to identify the disease quickly may help with treatment, even if it doesn’t exist yet.
“One of the problems when people show up in the clinic with early neurological signs is to get a definitive diagnosis, so these tests might really help in that regard, and if therapies are available, to get them started as soon as possible,” Caughey said.
Caughey has worked on another prion disease, chronic wasting disease, that affects deer, elk and moose.
While CWD has been detected in states and provinces surrounding Montana, to date the only CWD-positive animals detected in the state were part of a game farm near Philipsburg in 1999. Those animals were destroyed, according to the Montana Fish, Wildlife and Parks website.
But FWP conducts a surveillance program that involves testing the carcasses of sick or symptomatic animals. Beginning this year, live animals in northern Montana will be collared and tested using a rectal biopsy, said Dr. Jennifer Ramsey, a wildlife veterinarian with FWP. This is the first time live animals can be tested.
The new surveillance program, which will provide data about how deer move and interact among herds, may provide information about the spread of CWD.
Two other prion diseases that affect animals, scrapie in sheep and goats and bovine spongiform encephalopathy in cattle, are monitored by the United States Department of Agriculture. BSE, commonly known as mad cow disease, is rarely seen in the United States, with the last reported case in 2012. Scrapie crops up occasionally, with the last reported case in Montana in April 2011.
Scrapie cases have decreased thanks to aggressive surveillance, testing and certification of scrapie-free herds, according to the USDA-Animal and Plant Health Inspection Services.
McLaughlin Research Institute has become a biomedical outpost of the Montana prairie. Its scientists have built reputations studying neurodegenerative brain diseases like Alzheimer’s, Parkinson’s and multiple sclerosis.
Institute director George Carlson focuses his research on Alzheimer’s disease, the brain-ravaging, progressive illness that eventually robs its sufferers of their memory and ability to communicate.
Finding a way to test for and effectively treat Alzheimer’s, costly both in terms of monetary value and emotional toll on patients and families, is at the top of the priority list for many.
Carlson believes Alzheimer’s is a prion disease.
Carlson’s career of prion research began in 1983, a year after the publication of a paper by Dr. Stanley Prusiner and his team. Prusiner’s paper argued that some diseases were caused not by a slow virus, but by protein that occurred naturally within all people’s bodies.
“It was essentially heresy,” Carlson said of Prusiner’s theory.
Carlson was invited into Prusiner’s research group, and he joined on.
But in those early days, many in the scientific community were skeptical of or completely rejected Prusiner’s theory. Up until then, infectious diseases were thought to be caused by outside agents — a virus, bacterium or fungus.
The idea that the infectious agent was coming from within the body flew in the face of accepted scientific gospel.
“You go to meetings and people would accuse us of fraud,” Carlson recalled.
For his discovery of prions, Prusiner earned the Nobel Prize in Physiology or Medicine in 1997.
Three decades later, Carlson is still fascinated by the prion, but he’s turned his attention to neurodegenerative diseases, particularly Alzheimer’s.
Like Carlson, Dr. Deborah Cabin applies what science has learned about the prion to her research on Parkinson’s disease and a protein called alpha-synuclein, which misfolds in patients who have that disease.
Likewise, the proteins amyloid-beta-peptide and tau misfold in Alzheimer’s disease, causing the plaques and tangles in the brain that are the disease’s hallmark.
Everyone has alpha-beta-peptide, which makes it such a challenge for scientists to understand where the trouble comes in.
Alpha-synuclein, Cabin’s protein, also is naturally occurring. In Parkinson’s patients, it seems to occur in higher numbers. So, it would make sense to remove the alpha-synuclein or prevent the body from producing it, to cure or prevent the Parkinson’s disease, right?
But Cabin has tried that, and it isn’t so simple. Mice that lack alpha-synuclein end up living shorter lives than control mice, indicating the protein may play a role in the aging process. But that’s only a hypothesis at this point, and another wrench in the prion mystery.
But Cabin, like many researchers, is motivated by the unknown, by the questions she still needs to answer.
“If we knew the outcome of a test, there’s no reason to do it,” she said.
A test she once ran on mutagenic mice, one that took years and thousands of mice to complete, did not give her satisfactory results because, she says, she did not choose the right assays for the test.
“I still want to find out. This is the sort of thing I lie in bed at night and think about,” she said.
With their rarity, it may be easy to lose sight of the fact that prion diseases affect real people.
One hereditary prion disease, fatal familial insomnia, unexpectedly became part of the lives of Sonia Vallabh and Eric Minikel in 2011.
Vallabh’s mother was born with a spontaneous genetic mutation that guaranteed she would get FFI. After her mother’s death, Vallabh was tested and discovered that she, too, will contract FFI someday, perhaps when she is in her 50s.
Three years later, the married couple has devoted their lives to raising money and finding a cure for prion disease.
They have also left their original careers — Vallabh was trained as a lawyer and Minikel had a city planning and software engineering background — to pursue PhDs in biological and biomedical studies at Harvard University.
Vallabh and Minikel are also working with McLaughlin Research Institute in Great Falls. MRI director Carlson is doing experiments with a new drug candidate on a colony of mice with FFI.
“Obviously, treating the mice is a first step, and that doesn’t mean you can treat the people, but in prion disease, we couldn’t even treat the mice for decades,” Minikel said.
The two have started a nonprofit called the Prion Alliance (www.prionalliance.org) to raise awareness of prion diseases and money for research. Minikel also maintains a blog, www.cureffi.org.
Even with the specter of contracting FFI, an illness that causes personality changes and prevents patients from sleeping, Vallabh remains upbeat.
“I’m so grateful we decided to get the (genetic) test results,” said Vallabh, 30. “Once we knew, we knew, and it could start becoming another thing that we knew about our life.”
As research has progressed, the term “prion” is almost taking on a new meaning, a class of proteins, Cabin said.
“Mechanistically, they’re similar but with misfolding of different proteins,” Carlson said.
Caughey believes the nasal brushings test he and his research partners devised may be adaptable for early tests for not only Alzheimer’s and Parkinson’s but also Huntington’s disease and amyotrophic lateral sclerosis, or ALS.
“(These diseases) all involve accumulation of abnormal clusters of different proteins and it’s possible, we hope it’s possible, that we could get earlier, more definitive diagnoses of these diseases as well as by developing related types of amplification tests,” he said.
With research into this class of diseases ongoing, scientists continue to make advances and learn more about how prions work and cause disease. And while the pace may at times seem painstakingly slow, breakthroughs may be around the corner.
“Sometimes it’s like plodding, but then with this diagnostics test, for instance, we’ve made very rapid and exciting (progress),” Caughey said. “Who knows, maybe tomorrow we’ll make a big discovery in the direction of therapeutics.”
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