The sheep disease that changed human biology

By ALLISON CHEN | November 30, 2017

Throughout the 18th century, wool dominated England’s commerce, with the wool trade involving, directly or indirectly, almost one-fourth of the population. It fed the nation’s mills and coffers, and anything that threatened the sheep that produced it was clearly a cause for concern.

One such danger was a fatal disease that would come to be known as scrapie. It caused behavioral changes in the animals it affected, including tremors, loss of coordination and a compulsive tendency to rub against objects as though dealing with an itch, hence the name.

The first English cases of scrapie appeared in 1732, and the disease was brought to the attention of the government by 1755, although it likely had a longer history in northern and central continental Europe.

Over the next 200 years, European scientists researching the disease managed to infect healthy sheep and goats with scrapie, concluding that it was transmissible. They took note of its years-long incubation period and discovered that whatever caused scrapie was unaffected by formaldehyde. Still, the infectious agent remained unknown.

Though the elusive nature of scrapie’s etiology had already led some researchers, including veterinary neurologist Anthony Palmer, to predict the cause of the disease, it remained something that had to do with farm animals.

It became relevant to humans in 1959, when veterinary pathologist William Hadlow published a letter in The Lancet noting the clinical and pathological similarities between scrapie and a disease found in New Guinea’s eastern highlands, kuru.

Emerging at the beginning of the 20th century, kuru predominantly affected New Guinea’s Fore people, and by the late 1950s, it was killing around two percent of the Fore population per year and up to five or 10 percent in heavily affected communities.

Over the course of months, those afflicted, mainly women and children, would gradually exhibit a progression of neurological symptoms, losing control of their limbs, their emotions, then the ability to speak, swallow or sit up.

Carleton Gajdusek and Vincent Zigas, the scientists who first described the illness in Western medical literature in 1957, initially suspected an infectious agent. But this theory stalled when an agent could not be found in samples sent to labs in Australia and America and when Gajdusek and Zigas could find no evidence of an immune response in kuru patients.

Hadlow’s observation, and his suggestion that experiments should be conducted to test whether kuru could be transmitted from humans to laboratory primates, opened new possibilities.

Gajdusek took up the veterinary pathologist’s suggestion and between 1963 and 1966, successfully infected chimpanzees with the disease. He also transmitted the disease between chimpanzees and began trying to transmit other human nervous system diseases to chimps, successfully doing so with Creutzfeldt-Jakob disease (CJD) in 1968.

Scrapie, kuru and CJD became part of a group of progressive, neurodegenerative diseases labeled “transmissible spongiform encephalopathies” (TSEs). The cause remained undetermined, and it was tentatively attributed to a “slow virus.”

By the late 1960s, it was becoming more apparent that a virus was not going to cut one as the sole explanation. Experiments with scrapie showed that its agent was sub-viral in size and unusually resistant to conditions that would kill other pathogens.

A 1965 paper by Iain Pattison supplied a list of treatments it had survived, everything from boiling for hours to chloroform to phenol to DNAse and RNAse.

Radiobiologist Tikvah Alper also demonstrated that the agent remained infectious after exposure to radiation of a wavelength specifically targeted at nucleic acids, suggesting that the agent did not contain them.

Then, in 1982, Stanley Prusiner sparked a furor with his paper hypothesizing that proteins, which he dubbed “prions,” for proteinaceous infectious particles, were the infectious agent responsible for scrapie.

This proposal of an agent, a misfolded protein, that replicates without genetic material by transforming normal proteins, was “heretical” at first. It has since gained widespread acceptance, especially after prions were artificially created in vitro.

Though exact mechanisms and the role of genetics in someone’s potential for developing some prion diseases are still being explored, prions have already reshaped views on infectious agents and are involved in research surrounding other neurodegenerative diseases, including Alzheimer’s and Parkinson’s. Scrapie’s influential past is likely only to grow.

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