Data establishes link between 'mad cow' disease, human brain disorder

December 19, 1999

Researchers are reporting what they say is the most compelling evidence, to date, that the infectious proteins called prions that cause bovine spongiform encephalopathy (BSE), or "mad cow" disease, have infected humans, causing fatal brain degeneration.

Recent studies have suggested that the outbreak of mad cow disease in the late 1980s in Great Britain was responsible for the emergence of a new variant of Creutzfeldt-Jakob disease, a fatal brain-degenerative disease in humans also caused by prions. However, the link has been inconclusive. The current study establishes that the particular strain of prions, responsible for mad cow disease, is, in fact, the same strain that causes new variant Creutzfeldt-Jakob disease.

The finding, reported in the December 20 issue of Proceedings of National Academy of Sciences, is particularly unsettling because it undermines the comforting presumption that a "species barrier" dramatically lessened the likelihood that people exposed to "mad cow" disease through meats, cosmetics, and medicinal supplies would be infected. The species barrier refers to the relative lack of susceptibility of one species to prions derived from another species.

While Great Britain took the necessary measures in the late 1980s to limit spread of the disease, the disease is believed to incubate for at least 10 years, making it impossible to predict, the researchers said, how many people have been infected.1

More than 175,000 cattle, primarily dairy cows have died of BSE during the past decade. More than 50 teenagers and young adults have died of new-variant Creutzfeldt-Jakob disease (nvCJD) since 1995. Nine new deaths from CJD were reported in the last quarter of 1998.

While the origins of BSE remain obscure, one possibility is that the cattle developed the disease by being fed meat and bone meal contaminated with prions from the sheep with the disease, scrapie.

No cattle in the United States were contaminated with "mad cow" disease, and no cases of new-variant CJD, have been reported in this country, according to public health officials at the U.S. Centers for Disease Control. To protect public health, the U.S. Food and Drug Administration banned the use of most mammalian protein in the production of animal feeds for cows, sheep and goats in 1997.

The study was conducted by researchers in the UC San Francisco Institute for Neurodegenerative Diseases, using brain tissue from human cases supplied by researchers at the National CJD Survelliance Unit, Western General Hospital, Edinburgh, Scotland. The Director of the UC San Francisco Institute, Stanley B. Prusiner, MD, UCSF professor of neurology, biochemistry and biophysics, won the Nobel Prize in Physiology or Medicine in 1997 for discovering that the neurodegenerative diseases known as spongiform encephalopathies were caused by prions.2

Prusiner and Stephen A. DeArmond, MD, PhD, UCSF professor of pathology and chief of the Division of Neuropathology, were the senior authors of the study.

The current finding builds on recent epidemiological studies, along with studies of the prion protein and transmissions to inbred mice and primates, that suggest a link between the cow and human forms of prion disease.

The researchers conducted their study by first creating a line of transgenic mice genetically engineered to contain genes for the bovine prion protein. (Prion proteins are not, in themselves, lethal. They exist in all mammals and birds that have been examined, including humans, and become destructive only when their shape is altered, a change that occurs either through infection by an already infectious protein or through a genetic mutation.) The line of mice was known as Tg(BOPrP).

The researchers then inoculated the mice with prions from diseased cows. And approximately 250 days after being inoculated, all of the transgenic mice developed the neurologic disease.

Next, another group of mice was inoculated with prions from the diseased mice, and this group became sick after a virtually identical period of time, confirming that the transgenic mice transmit mad cow disease prions with no detectable change of strain or species-specific properties attributable to the mice, themselves.

Finally, and most important, transgenic mice inoculated with prions from human cases of new variant Creutzfeldt-Jakob disease produced the same incubation period and pattern of brain damage as had inoculation with prions from diseased cows.

To test their findings, the researchers inoculated transgenic mice with prions from sheep with scrapie, another prion disease causing neurological damage, and determined that these prions have dramatically different biological properties.

"BSE and new variant CJD produce the identical disease pattern of disease in Tg(BOPrP) mice, and those characteristics were those different than that found with inocula from other CJD cases or scrapie from sheep. These findings argue unequivocally that BSE and new variant CJD are the same strain of prion," said senior author DeArmond.

"The fact that the human new-variant CJD prions so precisely duplicate the properties of native bovine BSE prions in their behavior on transmission to the transgenic mice creates a compelling argument for a persuasive link between BSE and nvCJD," said Michael R. Scott, PhD, UCSF associate adjunct professor in the Institute for Neurodegenerative Diseases and the lead author of the study.

Given the enormity of the affected cattle population in Great Britain, a means of assessing risk to the human population is paramount, and more sensitive methods for detection of prions are urgently needed, the researchers said. The newly developed mouse model, Tg (BoPrP), should provide a sensitive test for detecting BSE prions, they said.

Co-authors of the paper were Hoang-Oanh B. Nguyen, BS, UCSF staff research associate, and Patrick Tremblay, PhD, UCSF assistant adjunct professor, both of the UCSF Institute for Neurodegenerative Diseases, Departments of Neurology; and Robert Will, MD, and James Ironside, MD, of National CJD Survelliance Unit, Western General Hospital, Edinburgh, Scotland.

The work was funded by the National Institutes of Health and the G. Harold and Leila Y. Mathers Foundation.
1 To protect public health, the U.S. Food and Drug Administration banned the use of most mammalian protein in the production of animal feeds for cows, sheep and goats in 1997. And companies that produce drugs from animal tissues are required to conduct a purification process intended to destroy prions. These moves followed the 1989 regulation in Great Britain banning the use of offal in cattle feed.

But the FDA ban excludes processed products produced from blood, collagen and gelatin for human consumption. And the UCSF scientists are concerned that these materials might harbor prions under some unusual circumstances. Moreover, they are worried that the technique being used to screen cattle products is not sensitive enough.

Prior to development of transgenic mice harboring bovine prion protein genes, the only sure-proof way to determine if a live cow has bovine spongiform encephalopathy (BSE) is to wait out its lengthy incubation period--a minimum of four years. To circumvent this delay, scientists inject cattle tissue into "wild-type," or normal, mice to see if they develop the disease. But non-transgenic, normal mice have severe limitations: the animals take nearly a year to develop signs of the disease, they develop it only sporadically, and acquire it only when exposed to high levels of prions. 2 Prusiner won the Nobel Prize in Physiology or Medicine in 1997 for discovering that the neurodegenerative diseases known as spongiform encephalopathies, which include "mad cow disease," are caused by an infectious form of a protein that exists in all mammals and birds examined, including humans.

He proposed that the protein becomes infectious and destructive only when its shape is altered, and that this change occurs either through infection by an already infectious protein or through a genetic mutation. The protein is believed to be the principal, if not sole, component of an infectious particle that Prusiner named "prion" (PREE-on), for proteinaceous infectious particle. The normal protein is referred to as PrPc.

University of California - San Francisco

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