What is Creutzfeldt-Jakob disease and how was it discovered?

In 1920, at a congress of German neurologists, the pathologist Alfons Maria Jakob presented the case of a patient, a 52-year-old woman and housewife, whose first symptoms were incoordination of voluntary movements (ataxia), intense tendon reflexes and rigid posture. Later, her movements became spasmodic and she became unable to walk. Not long after, before she died of pneumonia, she presented symptoms of confusion, disorientation and severe dementia. Two other patients of Jakob, aged 34 and 42, developed similar symptoms, and autopsies of all three showed extensive neurodegeneration in the cerebral cortex and the deep ganglia of the brain (basal ganglia).

Hans-Gerhard Creutzfeldt, a fellow German doctor, had previously described a similar case, both with respect to the symptoms and in the histopathology of the autopsies, but for Jakob, these cases were not as clear as his own, which he believed were part of a new and rare form of presenile dementia — a condition we know today as Creutzfeldt-Jakob disease. Now, as reported by EL PAÍS, an investigation has just been opened to clarify the causes of the death of a biochemist who studied Creutzfeldt-Jakob disease in a laboratory at the University of Barcelona and who died in 2022, at the age of 45, after showing symptoms compatible with the disease he was researching. Thousands of unauthorized samples, some of them potentially infectious, were found in his laboratory. The investigation could ultimately confirm the scientist’s contagion and the lethal nature of the disease, for which there is still no known cure.

Its origin was discovered far from Germany, in places such as Iceland and Papua New Guinea. It was first discovered by the Institute of Experimental Pathology in Reykjavík, where the physician Björn Sigurdsson was investigating the causes of an epidemic in sheep in the north of the country, which started with stumbling and shaking of the head and led to paralysis of the legs and the whole body. The name of that epidemic, “rida,” derives from the Icelandic word for ataxia or tremors. Sigurdsson believed that it had come from sheep that had been brought there from Germany in 1933, and since in his analyses he did not detect parasites or bacteria that could justify the disease, he attributed it to the contagion of a possible slow-acting virus, with more than a year of incubation. The suspicion gained ground when it was demonstrated that the infectious agent and rida could be transmitted by inoculating healthy goats with brain extracts from sick goats.

Today, rida is considered a form of scrapie, a disease that affects goats and sheep causing them to lose their balance and rub and scratch themselves on trees, rocks and fences, resulting in bald patches of wool on their bodies. Autopsy of diseased animals shows extensive neuronal degeneration, especially in the brain stem. The infectious agent, presumably the slowly progressive virus proposed by Sigurdsson, is transmitted and spread by feces left by sick animals on grass eaten by healthy ones. The disease is dormant for years until the first symptoms appear.

Surprisingly, something similar to scrapie was also observed in the first half of the 20th century in the inhabitants of the Fore people of Okapa in Papua New Guinea. Its members still practiced cannibalism and many died of a rare disease called kuru, a name that also means “to tremble.” As in Icelandic sheep, the disease in the natives began with balance problems and slight tremors of the head and limbs, progressing in months to an inability to speak, walk or control movements, as well as dementia and progressive emotional changes. Patients died with 18 months and sometimes as quickly as half a year.

Autopsy of the patients showed degeneration of the brain, particularly of the basal ganglia, and considerable atrophy of the cerebellum. The disease closely resembled, both in symptoms and neuropathology, that of the Icelandic sheep, a similarity that was confirmed when non-human primates were inoculated with brain extracts from human kuru victims. After an incubation period of six months to four years, the non-human primates also showed the same symptoms as the Papua New Guinea natives, who contracted kuru by eating the human flesh of their deceased in mourning rituals, but attributed the disease to witchcraft. As expected, the elimination of cannibalism put an end to the disease.

It was around this time that the Hungarian-born American physician Daniel Carleton Gajdusek, who visited the site of the epidemic, was quick to observe the similarity between the symptoms and pathology of kuru and those of Creutzfeldt-Jakob disease, also showing that it could be transmitted to non-human primates by inoculating their brains with extracts from human biopsies carrying the infectious agent. These diseases, generically called “spongiform encephalopathies,” were thought to be caused by an infectious agent of the slow virus type proposed by Sigurdsson. However, despite the efforts of Gajdusek and other researchers, this possible virus was nowhere to be found.

It was then, in 1982, that Stanley B. Prusiner, an expert in virology and neuropathology at the University of California, San Francisco, succeeded in obtaining purified brain extracts that transmitted Creutzfeldt-Jakob disease and contained a protein-like substance that he called “prion” (infectious protein particle). The hypothesis that a protein could be the agent of an infectious disease caused much skepticism, but that did not discourage Prusiner who, two years later, in 1984, surprised the scientific community again by showing that the gene encoding such a protein is found in the genome of many mammals, including man. It was incredible that the prion, the alleged agent of very serious neurodegenerative lesions, was normally synthesized in our own organism.

For his discovery of prions, Stanley B. Prusiner received the 1997 Nobel Prize in Physiology and Medicine, and for his research on kuru, Daniel Carleton Gajdusek was also awarded the Nobel Prize in Physiology and Medicine in 1976. Unfortunately, the latter’s scientific record was tarnished when, a few years later, he was sentenced to 19 months in prison for child molestation after pleading guilty. He later went into exile in Europe, where he died.

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