I recently came across a fascinating article by D.T. Max, in the magazine Proto, published by the Massachusetts General Hospital, and I thought I should share it with you.

In November of 1765, a physician from a respected Venetian family died in the Campo Santi Apostoli, near the Jewish ghetto. The cause of death, according to a contemporary parish account, was “an organic defect of the heart’s sack,” though this was probably just guesswork. But priests ordinarily wrote detailed descriptions only of diseases that caught their eye, and this report is one of the longest in that year. In addition to suffering from the symptoms that were recorded (breathing difficulties, eventual paralysis), it is likely that the doctor had been extraordinarily anxious, like a horse at full gallop, sweaty and prone to shaking. And that he had been exhausted, falling in and out of a light, dream-wracked sleep. Many of the doctor’s descendants, down to the present decade, have shown similar symptoms in the course of dying from a disease we now call fatal familial insomnia, or FFI, suggesting that the doctor may have been the earliest recorded case.

FFI is an autosomal dominant mutation, which means that a child of a parent with the disease has a 50% chance of getting it, too. This Italian family is one of a handful in the world afflicted with FFI. The family members have a carefully charted family tree: They can trace their disease back maybe to the Venetian doctor and with certainty to a relative of his, an aristocrat named Giuseppe who lived in the Veneto in the mid-nineteenth century. From him, the disease goes down to Vincenzo in the 1880s, Giovanni in the 1910s, Pietro in the 1940s, and Assunta, Pierina, and Silvano in the last three decades of the twentieth century.

Although obscure, FFI is an important disease, a key constituent of a cluster called prion diseases.

The first known prion disease was scrapie, initially chronicled in sheep in eighteenth-century England. With scrapie, the affected sheep, suffering from an itch caused by neurological alterations, rubs its back against objects until it rips its wool off. The disease is always fatal.

In the early 1950s, Australian officials had discovered that members of the Fore tribe, in New Guinea’s remote Eastern Highlands, were being stricken with a mysterious ailment. The Fore thought that sufferers of the disease, whose chief symptom was uncontrollable laughter, were under a spell, and they called the sorcery that afflicted these shivering victims kuru (“shaking”).

Carleton Gajdusek, who had trained at Harvard Medical School and the California Institute of Technology, took a more scientific approach, investigating everything the Fore ate, drank, and touched. He suspected the smoke in their huts and the copper in their water. He sent patients to Port Moresby, New Guinea, and brain tissue to a top laboratory in Melbourne, Australia and to the National Institutes of Health (NIH) in Bethesda, Md. for pathology studies.

Melbourne saw nothing wrong with the tissue Gajdusek had sent, but the NIH was more thorough. What they saw was eye-opening: “very spectacular neuronophagia…very intense gliosis…striking changes affecting Purkinje cells…and bizarre deformities of Purkinje-cell dendrites,” in the words of pathologist Igor Klatzo, who studied them. In other words, what Klatzo described was an extreme destruction of neurons and their replacement with something akin to scar formation. Klatzo also noted that the disease reminded him of one “described by Jakob and Creutzfeldt” (now called Jakob Creutzfeldt disease, or CJD) in the 1920s that struck a handful of elderly people, leaving holes in their brains.

Gajdusek never did discover how the Fore were getting kuru.

In the early 1960s, the anthropologist Shirley Glasse and her husband Robert would trace it to mortuary cannibalism—mothers and children would ritually eat the brains of recently deceased family members. But by that time, Gajdusek had left the Fore region for the NIH to continue working on the disease.

Gajdusek thought the disease was hereditary, but he was not sure. Then in 1959, he got some important new information. An American veterinary pathologist working in England named William Hadlow happened to see an exhibit on kuru at the Wellcome Medical Museum in London that included photographs of the victims’ brains. He felt as if he were seeing the same scrapie slides he had in his lab and wrote a note to the Lancet, the British medical journal, about the coincidence. He also sent a copy of his letter to Gajdusek.

Gajdusek was intrigued by Klatzo’s comparison of kuru to CJD, so he began inoculating healthy chimps with tissue from sufferers of CJD as well. Ultimately, these chimps also grew sick. When the animals died, pathologists examined their brains and saw that the sponginess and the holes resembled those of both kuru and scrapie victims. Gajdusek received the Nobel Prize for his work.

 

Prion diseases

Thanks to the pioneering work of Stanley Prusiner of UCSF (for which he received the Nobel Prize in 1998), we now know what causes these dreadful diseases. The agent of infection is neither a virus nor a bacterium. Rather, prions are ordinary cellular proteins. Unlike most proteins, each of which takes only one 3-D shape, prions appear to be able to form two: One normally folded shape and a misfolded one that causes disease (for example, mad cow disease, scrapie in sheep, CJD, kuru, and fatal familial insomnia or FFI). Misfolded prion proteins cause neighboring prions to misfold, spreading the “infection” and promoting a lethal chain of events.

Sounds quite straightforward, but it wasn’t. Stan Prusiner had to endure the skepticism, and many times the outright derision of the scientific community. After all, how can you have an infection without an infectious agent? Or even more unbelievably, “infection” by a normal cell protein? It took an incredible amount of courage to proceed with this research under constant withering criticism.

 

Is there a cure?

Researchers at NYU injected mice with a vaccine against scrapie, the sheep prion disease. After the mice were exposed to the disease, 30% of the vaccinated mice remained symptom-free for 500 days, whereas all unvaccinated mice were dead within 300 days. From here to a clinically approved vaccine is still a long road, but there is hope.

 

Science never ceases to surprise

If you think that the story ends with the discovery of the agents that cause FFI, CJD, and mad cow disease—here is a surprise. Scientists at the University of Leeds found that normal prions might protect against Alzheimer’s disease. In mice and lab-grown cells, a high level of normal prions had an inhibitory effect on the production of a protein called beta-amyloid, which builds sticky plaques in the brain that characterizes Alzheimer’s disease.

This may be an entry point to the synthesis of a drug that would mimic healthy prions, thus prevent the progression of this dread disease.

Could you guess that the story of Kuru disease, or the sheep’s scrapie, or mad cow disease would lead us to Alzheimer’s? You never know where scientific research is going to lead, but the journey is always exciting.

Dov Michaeli, MD, PhD
Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.