November 10, 2003
Volume 81, Number 45
CENEAR 81 45 pp. 50-51
THE INSIDIOUS MARCH OF PRION DISEASES
THE PATHOLOGICAL PROTEIN: Mad Cow, Chronic Wasting, and Other Deadly Prion
Diseases, by Philip Yam, Copernicus Books, 2003, 284 pages, $27.50 (ISBN
REVIEWED BY STEPHEN F. DEALLER
To some degree, we treat our agricultural animals as if they are just
there to make food and money. So when bovine spongiform encephalopathy
(BSE) first appeared in 1986 in the U.K., many of the worries focused on
the country's agricultural industry, while the disease was simply pushed
to one side. Much of the literature on the subject tells the story of how
we gradually realized that maybe humans were at risk, and that perhaps we
should worry a bit more.
THE PATHOLOGICAL PROTEIN: Mad Cow, Chronic Wasting, and Other Deadly Prion
DiseasesIn his well-written and easy-to-understand book "The Pathological
Protein: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases,"
Philip Yam paints a different picture. The disease actually hit the minds
of the population like a freight train when they realized they were not
only in danger, but that they had already taken much of the risk and
teenagers were starting to die.
Yam, an editor for Scientific American, begins this compelling book with
the tale of Stephen Churchill, a 19-year-old boy from Southwest England
who in 1996 appeared to contract Creutzfeldt-Jakob disease (CJD), a malady
normally seen only in elderly people. The disease begins insidiously, with
symptoms such as depression and loss of balance. Over several months,
Stephen lost his ability to think, see, and move. He finally slipped into
a coma and died. Stephen's youth and his disease's resemblance to BSE set
off alarm bells around the world, signaling the fear that a lot more
disease could be on the way.
The most astounding thing about Churchill's case was that, despite its
being a single incident of a previously unknown disease, we could start
anticipating the epidemic that might be on its way. The reason--which Yam
picks up and explains well--is that the human form of BSE, dubbed variant
Creutzfeldt-Jakob disease (vCJD), is just one of a whole range of
transmissible spongiform encephalopathies (TSEs). The libraries of data
available on the other conditions allowed us to see that they all shared
specific factors, such as dementia and long incubation periods. Yam goes
back to those other illnesses and shows how the scientific literature has
evolved over the previous 95 years to arrive at our current understanding:
These diseases are caused by proteins known as prions.
The erstwhile famous prion disease kuru suffered by a cannibalistic tribe
of New Guinea was actually relatively unknown before World War II.
Numerous scientists back then were intrigued by the sudden appearance of
this fatal illness, which disproportionately struck young women of the
tribe. The researchers discovered that people who died from diseases were
eaten as a mark of respect by other members of the tribe, and many years
later those tribe members themselves developed the symptoms.
Epidemiologist Carleton Gajdusek, who received the Nobel Prize in
Physiology or Medicine in 1976 for his findings, first demonstrated how
kuru could be transmitted by injecting monkeys with infected brain tissue.
In the early 1960s, scientists noted that, side by side, microscopic
slides of brains of patients with kuru looked remarkably similar to brains
of sheep dying of scrapie, another form of BSE. Though scrapie was then
thought to be uninfectious, the disease's transmissibility, like that of
kuru, was demonstrated through experiments in which samples of brain
tissue infected with kuru, scrapie, and CJD were injected into animals.
CJD is a rare human disease that appears sporadically around the world.
Yam explains how the endemic nature of scrapie, the sporadic cases of CJD,
and the infectious nature of kuru were brought together in the minds of
the researchers, who demonstrated how the diseases were all closely
related, but yet not the same.
Small groups in Europe and the U.S. knew prior to the 1980s that TSEs were
potentially one of the most important groups of diseases yet to be
examined, but few could find the funding for research. Small international
groups moved in to understand the diseases' pathology, and learned the
disease could be both genetically transmitted and also spread from one
animal or species to another.
IMAGE IN ORIGINAL
PROTEIN TWIST Structural differences are notable between a prion protein
cellular model (left) resolved by NMR by Kurt Wuethrich of the Swiss
Federal Institute of Technology, Zurich, and coworkers [Proc. Natl. Acad.
Sci. USA, 97, 145 (2000)] and a theoretical structural model of prion
protein scrapie--the "pathological protein"--developed by Cedric Govaerts,
Holger Wille, Prusiner, and Fred Cohen at the University of California,
San Francisco. IMAGES COURTESY OF CEDRIC GOVAERTS, UCSF
In the early 1980s, neurology and biochemistry professor Stanley B.
Prusiner's group at the University of California, San Francisco, first
demonstrated how changes in the conformation of a single normal protein
found in animals could give rise to such a devastating illness. If a
species didn't produce the normal protein, which he called PrPc (prion
protein cellular), it could not be infected with the "pathological
protein," or PrPSc (prion protein scrapie).
This finding was potentially the key to understanding how to diagnose the
disease by looking for prions in the brain. It also gave scientists a
starting point for investigating treatments. Though Prusiner's work was
initially dismissed as heretical, most of the scientific community
eventually came around, and Prusiner won the Nobel Prize in Physiology or
Medicine in 1997.
While Prusiner was making his findings, clouds were starting to gather
over Britain. Scrapie infected a few sheep on farms, but apparently not
many, and CJD appeared out of the blue in rare cases. In many countries
around the world, the bovine tissue with which we did not want to feed
ourselves was fed back to other animals, including cattle. Although it was
not known at the beginning, each cow that died of BSE in fact transferred
the illness to 50 more. By the time British officials recognized what was
happening, more than 95% of the herds in the U.K. had become infected, and
citizens there had eaten on average 50 meals each made of the tissues of
Yam's interviews with scientists involved early on in the crisis make
clear that they were very worried, but that they initially assumed that
BSE was scrapie in cattle and therefore might not be a risk to humans. It
was only when "Mad Max," the first cat to develop a TSE, appeared in 1990
that the scientific community recognized the illness as a BSE and that
humans had been put at risk. Within a few months, the European Union
banned the export of most beef and cattle feed from Britain.
Even before then, the U.S. had decided that, when dealing with a fatal
untreatable disease such as BSE, the risk simply was not worth the meat.
Since 1987, the U.S. has banned the import of British beef. The government
also rounded up all cattle from the U.K. living in the U.S. and took them
to the Department of Agriculture's Plum Island Animal Disease Center in
New York to be investigated.
It was only when "Mad Max," the first cat to develop a TSE, appeared in
1990 that the scientific community recognized the illness as a BSE and
that humans had been put at risk.
Yam next introduces chronic wasting disease (CWD), the TSE of deer and
elk. He points out that the original case of the disease at the zoo in
Fort Collins, Colo., in 1967, was treated as an interesting but
unimportant blip. However, "between 1970 and 1981, 90% of the deer that
stayed at the zoo more than two years died from the disease or had to be
euthanized after the onset of symptoms." It was clear that the disease was
not transmitted in the food and that it seemed to pass from one animal to
another, even between deer that had been in pens next door to each other.
The nature of CWD transmission is still unknown, and it continues to be an
CWD has now been shown to be present throughout the northern part of the
Rocky Mountains and is continuing to spread. The U.S. has realized that
its hope of simply locking out BSE coming from Europe yet continuing the
unsafe practice of feeding bovine material to other animals is
unrealistic, if only because CWD might cross over into cattle. And since
the mid-1990s, the USDA has been testing for CWD in hunted deer and deer
The announcement of Stephen Churchill's disease and the realization that
more cases were on the way created a political horror story at the time.
But scientists could still take the data from the other TSEs and predict
the number of cases of vCJD to be expected, as well as decide which human
body parts should be looked on as infectious.
Finally listening to the scientists, the British government banned the use
of bovine eyes in school experiments and stopped the use of blood from
U.K. donors for the manufacture of pharmaceuticals. Officials crossed
their fingers, hoping that vCJD had not already infected a wide number of
people, who could then infect others via needles, blood products, surgery,
and dentistry. The media-fueled fear spread around the world faster than
the disease itself. But, as Yam shows, to some degree this was actually
helpful, stimulating a flurry of research.
The ability to grow prions in cell cultures gave researchers the
opportunity to test many chemicals for antiprion activity. They tested
hundreds of such compounds, and discovered that some well-known drugs,
including the antimalarial quinacrine, stopped normal prions from
converting to the pathological variety in cell cultures.
In 2001, a regimen of quinacrine and the antischizophrenic drug
chlorpromazine, developed in Prusiner's lab, was tested in a 21-year-old
British woman named Rachel Forbes. She appeared to make some recovery, but
hopes were dashed when she died a few months later, likely from drug side
effects. But her case has spurred researchers to continue looking for both
diagnostic and therapeutic methods to treat TSEs.
So, despite the deaths of teenagers, the incompetence of officials, the
short-term money-grabbing nature of agriculture, the worldwide spread of
disease, and the horror writers in the media, in the end we may find a
cure not only for TSEs, but also for other diseases that have been killing
people for many years.
But there has been a cost. Many researchers had to fight for years with
the British government, trying to persuade them to deal with BSE before
strong proof of human risk was available. They have often felt like the
messengers shot by officials for bearing bad news.
Anyone who reads Yam's excellent book will understand how data on TSEs
were in fact readily accessible during the past 20 years. And readers
should wonder how our governments could have made such mistakes when
brilliant experts in many countries warned them of the danger.
Stephen F. Dealler is consultant medical microbiologist in the Royal
Lancaster Infirmary at the University of Lancaster, in England, and
secretary of the Spongiform Encephalopathy Research Campaign.
THE INSIDIOUS MARCH OF PRION DISEASES
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