Mad Cows and Prions

Mad cow disease, a deadly infection that creates holes in the brain, has figured prominently in the news in recent years. There is widespread fear that humans may become infected by consuming tainted beef and considerable speculation as to the cause of the disease. This year’s Nobel Prize was given to a researcher who proposes a controversial answer.

For decades scientists have been fascinated by a peculiar group of fatal brain infections. These diseases have the unusual property that it takes years after the infection before the disease appears. Then, with devastating effect, the brains of infected individuals develop numerous small cavities as neurons die, producing a marked spongy appearance. Brain function rapidly fails, and death follows. Called transmissible spongiform encephalopathies (TSEs), these diseases include scrapie in sheep, “mad cow” disease in cattle, and kuru and Creutzfeldt-Jakob disease in humans.

TSEs can be transmitted between individuals of a species by injecting infected brain tissue into a recipient animal’s brain. TSEs can also spread via tissue transplants and, apparently, food. Kuru was common in the Fore people of Papua New Guinea when they practiced ritual cannibalism, literally eating the brains of infected individuals. Mad cow disease spread widely among the cattle herds of England in the 1990s because cows were fed bone meal prepared from cattle carcasses to increase the protein content of their diet. Like the Fore, the British cattle were literally eating the tissue of cattle that had died of the disease.

In the 1960s, British researchers T. Alper and J. Griffith noted that infectious TSE preparations remained infectious even after exposed to radiation that would destroy any DNA or RNA. Because protein, are resistant to these levels of radiation, this result led them to suggest that the TSE infectious agent was a protein. Perhaps, they speculated, the protein usually preferred one folding pattern, but could sometimes misfold, and then catalyze other proteins to do the same, the misfolding spreading like a chain reaction. This heretical suggestion was not accepted by the scientific community, as it violates a key tenant of molecular biology: only DNA or RNA acts as hereditary material, transmitting information from one generation to the next. That is why, these scientists argued, all infectious diseases are caused by other organisms, viruses, or naked genes. The idea that some perverted protein could transmit a disease seemed silly.

In the early 1970s, American physician Stanley Prusiner, moved by the death of a patient from Creutzfeldt-Jakob disease, began to study TSEs. Prusiner became fascinated with Alper and Griffith’s hypothesis. Try as he might, Prusiner could find no evidence of nucleic acids or viruses in the infectious TSE preparations he studied, and concluded, as Alper and Griffith had, that the infectious agent was a protein, which in a 1982 paper he named a prion, for “proteinaceous infectious particle.”

Prusiner went on to isolate a distinctive prion protein, and for two decades continued to amass evidence that prions play a key role in triggering TSEs. The scientific community resisted Prusiner’s renegade conclusions, but eventually experiments done in Prusiner’s and other laboratories became too convincing to ignore. For example, when Prusiner injected prions of a different abnormal conformations into several different hosts, these hosts developed prions with the same abnormal conformations as the parent prions. In another important experiment, Swiss researcher Charles Weissmann showed that mice genetically engineered to lack Prusiner’s prion protein are immune to TSE infection. However, if brain tissue with the prion protein is grafted into the mice, the grafted tissue—but not the rest of the brain—can then be infected with TSE. In 1997, Prusiner was awarded the Nobel Prize in physiology or medicine for his work on prions.

Despite Prusiner’s Nobel Prize, not all scientists are convinced that he is right. So far no one has been able to inject a prion protein synthesized in a test tube (and thus sure to be free of any contaminating virus or nucleic acid) into a healthy animal and make it sick with TSE. Until this experiment has been done successfully, or enough becomes known about the process to understand why it cannot be, these scientists argue that the prion theory is not firmly established.
While there is ongoing debate about how TSEs are transmitted, there is no doubt that they pose a significant public health threat. Increasing numbers of scientists are becoming worried that prions may be transmitting such diseases to unsuspecting humans right now, as you read these words. Specifically, they worry that prion-caused bovine spongiform encephalopathy (BSE), commonly known as mad-cow disease, may infect humans and produce a similar fatal disorder called Creutzfeldt-Jakob disease (CJD).

In March 1996, an outbreak of mad-cow disease in Britain, with many thousands of cattle apparently affected, created widespread concern. BSE, a degeneration of the cow brain caused by prions, appears to have entered the British cattle herds from sheep! Sheep are subject to a prion disease called scrapie, and the disease is thought to have passed from sheep to cows through protein supplemented feed pellets containing ground-up sheep brains. The passage of prions from one species to another has British scientists worried: the death of four dairy farmers in Britain from CJD in the last four years suggests that prions may be able to pass from cows to people!

The case for a connection between eating British beef and CJD is strongly supported by the finding this winter that tissue from the brains of the dead farmers and from BSE cows induces the same brain lesions in mice, while classic CJD produces quite different lesions—clearly the form of CJD that killed them was caused by the same agent that caused BSE. Thus, there appears to be legitimate cause for caution. Because the incubation period for CJD can vary from 15 to 45 years, the number of people infected by eating BSE-contaminated meat in Great Britain may not become apparent for some time.

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