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November 10, 2003
Volume 81, Number 45
CENEAR 81 45 pp. 50-51
ISSN 0009-2347


THE PATHOLOGICAL PROTEIN: Mad Cow, Chronic Wasting, and Other Deadly Prion Diseases, by Philip Yam, Copernicus Books, 2003, 284 pages, $27.50 (ISBN 0-387-95508-9)


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 Diseases
In 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.


PROTEIN TWIST Structural differences are notable between a prion protein cellular model (left) resolved by NMR by Kurt Wüthrich 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 infected cattle.

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 expanding problem.

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 found dead.

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.


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