In 1967, mule deer in a research facility near Fort Collins, Colorado, in the United
States apparently began to react badly to their captivity. At least, that was the guess of
researchers working on the natural history and nutrition of the deer, which became listless
and showed signs of depressed mood, hanging their heads and lowering their ears. They lost
appetite and weight. Then they died—of emaciation, pneumonia, and other complications—or
were euthanized. The scientists dubbed it chronic wasting disease (CWD), and for years they
thought it might be caused by stress, nutritional deficiencies, or poisoning. A decade
later, CWD was identified as one of the neurodegenerative diseases called spongiform
encephalopathies, the most notorious example of which is bovine spongiform encephalopathy
(BSE), more commonly known as mad cow disease. Nowadays, CWD is epidemic in the United
States. Although no proof has yet emerged that it's transmissible to humans, scientific
authorities haven't ruled out the possibility of a public health threat. The media have
concentrated on this concern, and politicians have responded with escalated funding over
the past two years for fundamental research into the many questions surrounding this
mysterious disease.
Quite apart from how little is yet known about CWD, media interest is reason enough to
step up investigation of it, says Mo Salman, a veterinary epidemiologist at Colorado State
University in Fort Collins. He's been scientifically involved with BSE, since it was first
discovered among cattle in the United Kingdom in 1986. He recalls predicting that lay
interest in BSE would wane after five years. Instead, the disease was found in the
mid-1990s to be capable of killing humans who ate tainted beef. “I was wrong, and it really
changed my way of thinking, to differentiate between scientific evidence and the public
perception,” Salman admits. “Because CWD is similar to BSE, the public perception is that
we need to address this disease, to see if it has any link to human health.”
CWD is the only spongiform encephalopathy known to naturally infect both
free-ranging and captive animals, a situation that greatly complicates efforts to
monitor, control, or eradicate it.
Increasing Attention
In 2001, the United States' Department of Agriculture (USDA) declared an emergency after
CWD was first diagnosed in deer east of the Mississippi River, indicating a potential
nationwide problem. This year, the USDA is developing a herd certification program to help
prevent the movement of infected animals in the game farming industry. This will bolster
monitoring already underway in virtually every state, including postmortem examinations of
game killed by hunters and by sharpshooters in mass culling operations.
By June 2003, brain tissue from more than 111,000 animals had been sampled in North
America, and 629 were found to have tested positive for CWD. That's a small epidemic
compared to the thousands of BSE cases detected in cattle in the United Kingdom, but CWD is
thought to be slow-spreading and perhaps lurking undiscovered elsewhere. So far, the United
States and Canada are the only countries in which it has been identified, apart from a few
imported cases in the Republic of Korea, but surveillance has not been thorough in North
America and is virtually nonexistent in the rest of the world.
Considered 100% fatal once clinical signs develop, CWD has struck three species of the
cervid family—mule deer, white-tailed deer, and Rocky Mountain elk—which roam wild and are
raised on farms for meat and hunting. It's the only spongiform encephalopathy known to
naturally infect both free-ranging and captive animals, a situation that greatly
complicates efforts to monitor, control, or eradicate it.
The economic costs are hard to quantify, but a 2001 survey by the United States
Department of Commerce's Bureau of Census shows that big-game hunters nationwide spend more
than US$10 billion annually for trips and equipment. By far, their main target is deer.
Wildlife watching of large land mammals, principally deer, drew 12.2 million participants
in 2001. The North American Deer Farmers Association represents owners of 75,000 cervid
livestock raised for their meat and for velvet antler, a health-food supplement made from
antlers. These animals are valued at more than US$111 million.
Over the past two years, the federal government's emphasis on CWD has been “quite high”
compared to other wildlife diseases, says USDA staff veterinarian Dan Goeldner. “In no
small part, that's because the disease has cropped up in new places, and those are states
that have political clout.” It has now been found in ten more states beyond what became
known as the endemic region of Colorado and neighboring Wyoming (Figure 1). Last year, the
USDA received US$14.8 million to monitor and manage the disease, and Goeldner says the
department expects to get about US$16 million this year.
The Prion Diseases
Those figures don't include scientific research funded by other organizations, such as
the US$42.5 million received by the United States' Department of Defense in 2002 to start
up a National Prion Research Program. The prion is the protein-like agent that causes
transmissible spongiform encephalopathies (TSEs). Its normal function is uncertain, but
when it misfolds into an abnormal or “infectious” form, it causes the microscopic holes and
globs of toxic, misshapen protein found in the brains of TSE victims. Unlike viruses,
prions don't contain nucleic acids—only protein. Without DNA or RNA to issue biochemical
commands, abnormal prions shouldn't be able to convert normal prions to the infectious
state, but that's exactly what they do (Box 1).
Prion diseases occur in many species. In domestic sheep and goats, prion diseases occur
as scrapie, which has a virtually worldwide distribution. North America and Europe have
also reported rare cases of TSE in ranched mink. Humans get kuru, Creutzfeldt-Jacob disease
(CJD), and Gerstmann-Sträussler-Scheinker syndrome—all rare—and BSE itself manifests in
people as a variant form of CJD. Since the United Kingdom outbreak, BSE has been discovered
in more than 20 countries, most recently in North America. As public fear rose of possible
CWD transmission to humans who eat infected venison, the United States' Centers for Disease
Control and Prevention (CDC) released a report last year of its investigation into several
deaths among venison eaters who might have had a TSE. The report concluded that none of the
deaths could be attributed to venison, but it nevertheless cautioned that animals showing
evidence of CWD should be excluded from the human and animal feed chains (Box 2).
CWD is the least understood of all the prion diseases. Its origins are unknown and may
well never be discovered. The question is largely academic, unless one hypothesis is proven
true, that it derives from scrapie. In that case, the knowledge might help in efforts to
control the two diseases through herd and flock management.
Researchers are working to determine the minimum incubation time of CWD before clinical
signs appear, now roughly estimated at 15 months in deer and 12—34 months in elk. They're
trying to discover whether CWD strains exist that can affect the length of the disease
process and different regions of the brain or that can infect different species, including
humans. They are also investigating the period during which the prion is passed on, as well
as its modes of transmission. They want to know whether disease reservoirs exist in the
bodily fluids of hosts, in the environment, or both. They're racing to develop a diagnostic
test that can be performed on live animals, enabling identification of the disease before
clinical signs appear, which would eliminate the need to kill thousands of apparently
healthy animals in areas where CWD is detected. But among the first things they need to
clarify are CWD's distribution across North America and its prevalence.
“…the disease has cropped up in new places, and those are states that
have political clout.”
An Initial Step: Improved Surveillance
“Before you can start to control CWD, you need to understand where it is and how much of
it you have,” says veterinary pathologist Beth Williams of the University of Wyoming in
Laramie. “So I think you really need surveillance.” Research on its pathogenesis and
transmission will help to develop better diagnostic tools, which will improve surveillance,
adds Williams, who first identified the disease as a TSE more than a quarter-century
ago.
Colorado State's Salman argues that current surveillance is primarily a series of
reactions to reported cases, rather than a systematic strategy designed to determine where
and at what prevalence the disease exists and where it's absent. The estimated prevalence
is about 1% in elk and 2.5% in deer. But Salman says, “We don't have a good idea of areas
in which we are saying we haven't found the disease because these areas are not yet, in my
estimation, negative for the disease. Scrapie is a wonderful example of systematic
surveillance but, to be fair to the decision-makers and technical people involved with CWD,
surveillance on wildlife species is very difficult.”
The USDA's Goeldner declares, “We have the goal and the hope to eradicate the disease
from the farm population.” But Colorado Department of Wildlife veterinarian and CWD expert
Mike Miller warns, “Given existing tools, it seems unlikely that CWD can be eradicated from
free-ranging populations once established.”
The gold standard of diagnosis is based on examination of the brain for spongiform
lesions and abnormal prion aggregation. Suspect animals are decapitated and their bodies
incinerated. “This is an approach that nobody wants, including the people who have to
implement it,” says wildlife ecologist Michael Samuel, principal investigator in the United
States Geological Survey–Wisconsin Cooperative Wildlife Research Unit at the University of
Wisconsin in Madison.
Nevertheless, when three white-tailed deer shot by hunters in the south-central part of
that state during the fall of 2001 were diagnosed with CWD, the state government took swift
action. By the spring of 2003, almost 40,000 deer had been sacrificed and sampled for the
disease, both within and without a 411 square-mile (1065 square-kilometer) region dubbed
the eradication zone. There the goal was to remove as many deer as possible, whereas the
plan in contiguous outlying areas was to reduce density to about ten deer per square mile.
CWD is thought to spread more efficiently in high-density populations, and normal densities
in Wisconsin are 50–100 deer per square mile, about five times that of Colorado and
Wyoming. The main objectives of the Wisconsin culling were to discover where the disease
existed and its prevalence in affected areas. In the eradication zone, it was 6%–7%,
although in the outlying region it was only 1%–2%. Samples elsewhere in the state tested
negative.
In Search of a Live Assay
A key to combating the spread of CWD is to put into widespread use a preclinical
diagnostic test on live animals. Miller and colleagues recently developed and validated the
first such assay, based on a biopsy of lymphoid tissue, where the infectious agent is known
to incubate. They showed that tonsillar biopsies taken from live animals can confirm
disease at least 20 months prior to death and up to 14 months before the onset of clinical
signs. Although the method is a useful screening tool, it requires much time and training.
Each deer must be anaesthetized and blindfolded, placed in a restraint, its mouth held open
with a gag, the tonsil visualized with a laryngoscope, and the biopsy taken with endoscopic
forceps. Lymphoid tissue sampling was first used as a preclinical test in sheep scrapie.
“Many attempts have been made to develop and evaluate tests for live animals, but it is
fraught with difficulties,” declares TSE specialist Danny Matthews of the United Kingdom
Government's Veterinary Laboratories Agency in Weybridge. He says that a live test for BSE
in cattle is likely to be evaluated shortly by the European Food Safety Authority, but
warns of a major problem: test samples are collected early in the incubation, whereas brain
pathology only arises two to three years later. This creates long delays in determining
whether a positive preclinical test result is, in fact, accurate: “How can one do an
appropriate evaluation?”
Matthews notes that blood appears to be a useful medium for testing scrapie in sheep,
but current technology cannot deliver a tool applicable across a range of different scrapie
genotypes. “Like sheep, elk and mule deer do have a peripheral pathogenesis, which suggests
that the blood test route may have some potential, especially if the genotype variability
is more restricted than in sheep.”
Transmission Mysteries
Scrapie can be vertically transmitted from mother to offspring, either in the womb or
from the transfer of infected germ plasm. It also can be transmitted horizontally, from any
one animal to another. CWD, the only other known contagious TSE, is thought to be
transmitted solely by as-yet-undetermined direct or indirect horizontal contact. It
probably is not transmitted through infected feed, as is the case for BSE.
A number of scientists are currently on the trail of suspected CWD disease reservoirs.
Saliva is a leading candidate, because clinical signs of CWD include excessive thirst,
drinking, and drooling. Work with lab animals suggests that the infectious agent might be
produced in salivary glands and, if so, it could be transmitted through social
interactions. Feces is also a possible reservoir because animals nose in the ground for
feed, and urine is yet another candidate, because it is involved in the scenting activities
of cervids.
Soil could be an environmental reservoir, because cervids ingest dirt to supplement
their diets with minerals. Bucks also lick soil on which does have urinated to ascertain
their mating status. University of Wisconsin soil science professor Joel Pedersen has
discovered that abnormally folded prions stick to the surface of some soil types, such as
clay, resisting environmental and chemical damage. “Captive elk contracted CWD when
introduced into paddocks occupied by infected elk more than 12 months earlier, despite
fairly extensive efforts to disinfect the enclosures,” Pedersen notes. He has begun a
five-year project to characterize interactions between infectious prions and soil particles
and determine the extent to which infectivity is retained.
No matter how CWD is transmitted between cervids, the likelihood of human susceptibility
seems low. Laboratory evidence has demonstrated a molecular barrier against such
cross-species infection, based on the failure of abnormal cervid prions to efficiently
convert normal human prions to the infectious state. Likewise, abnormal cervid prions don't
easily convert normal cattle prions, suggesting that cattle won't get CWD and pass it on to
humans who eat tainted beef. While cattle can contract CWD if inoculated with the
infectious agent, long-term studies placing cattle in close proximity to diseased cervids
have resulted in no cases of natural transmission. Williams summarizes what all this
suggests: “Never say never, but based on the [molecular] work, the CDC's findings, and the
epidemiology, we certainly don't have evidence that humans have gotten CWD.”
