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I was at my laboratory bench one morning in 1980 when a colleague walked in and declared that he had identified the cause of scrapie, a mysterious and fatal infection that leaves tiny holes in the brains of sheep and goats. the disease for some years and was stirring up controversy with his outlandish claim that the scrapie agent lacked genes or indeed any genetic material. It was, he said, an infectious protein 鈥� something never heard of before.

His issue that morning was what to call this unique protein. He had two candidates: 鈥減iaf鈥� and 鈥減rion鈥�. I have forgotten what piaf stood for, but I remember pointing out that the name was already taken by a popular French singer. Fine, he said, in any case he preferred prion, a contraction of protein and infection. I agreed. What I didn鈥檛 say was that in my native French tongue prions means 鈥渓et us pray鈥� 鈥� and that if he persisted with his idea of infectious proteins, he would need prayers.

Prusiner held strong in the face of adversity and, in 1997, won a Nobel prize for his discovery. By then, prions had been linked to Creutzfeldt-Jakob disease (CJD) in humans and to bovine spongiform encephalopathy or 鈥渕ad cow disease鈥�. There were also suggestions that they were involved in common neurodegenerative diseases including Alzheimer鈥檚. What nobody predicted was the existence of 鈥済ood鈥� prions. We now know that prions emerged early in the evolution of life and play essential biological roles, from giving yeasts the ability to rapidly adapt to allowing you to form long-term memories.

The story of prions didn鈥檛 start with Prusiner. Back in the 1950s, two medics, Carleton Gajdusek and Vincent Zigas, were in the remote highlands of New Guinea puzzling over the cause of kuru, a strange neurological disease that was spreading among local populations. They managed to perform autopsies on people who had died of kuru and, between 1957 and 1959, they published articles describing the disease and their discovery that the brains of those with it showed a . These papers caught the attention of a veterinarian called William Hadlow who, in a letter to The Lancet, pointed out the similarities between kuru and scrapie. Scrapie was known to be infectious, but with an extremely long incubation period. To test the link, Hadlow suggested inoculating animals with extracts from the brains of people with kuru. Sure enough, when Gajdusek did the experiment on chimpanzees, the apes .

That still left the question of how kuru was transmitted outside the lab. The prime suspect was a peculiar mortuary rite of the New Guinean highlanders 鈥� the only people known to contract kuru 鈥� that entailed eating the flesh and brains of the dead. This transmission route was confirmed by the fact that no case has been observed in people born after the cessation of ritual cannibalism.

Strange contagion

We now know that other transmissible spongiform encephalopathies spread in a similar way. Sheep get infected with scrapie by eating grass contaminated by saliva and other secretions, and by eating the placentas of lambs. Bovine spongiform encephalopathy spreads when cattle eat feed containing meat and bonemeal from other infected animals. CJD doesn鈥檛 spread by physical contact with a carrier, either. It arises spontaneously in around one in every million people per year, and has in the past been transmitted accidentally through contaminated surgical material or injections of growth hormone extracted from human cadavers.

That a protein could be infectious was heretical when Prusiner coined the name prion. Other infectious diseases are caused by microbes and viruses, all of which have genes that allow them to replicate and spread. Doing this without replication of DNA or RNA was considered impossible. Fortunately, we now think we know what makes prions infectious.

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The chain of amino acids that makes up any protein must fold in a precise way to give the protein its shape and function. Prions belong to a group called intrinsically disordered proteins, which cannot do this unless they are bound to a specific partner. Until then, they fold and unfold into many thousands of unstable intermediate forms, lasting just milliseconds each. Uniquely, prion proteins have an alternative way to fold into a stable form: one unstable intermediate binds to another in the same configuration. This is called self-templating and is what creates a prion. The probability of this happening is extremely low, but when it does, the combination of two identical subunits is very stable. The resulting prion then binds and stabilises more prions with the same shape, eventually forming a thread-like fibril, which is visible using an electron microscope (see 鈥�How can a protein be infectious?鈥�).

Cells are equipped with a quality-control system that steps in when protein folding goes astray. Under normal circumstances, misfolded proteins are either unfolded and correctly refolded or simply degraded 鈥� and this is what usually happens when prions form. However, the control system sometimes amplifies the problem by fragmenting the fibrils to create smaller seeds from which more can grow. This, it is thought, is how prions spread from cell to cell like an infectious agent.

How prions cause diseases isn鈥檛 yet known. They may be toxic for infected cells. Another possibility is that turning more and more of a particular protein into its prion form might deprive the cell of a crucial component. What has become increasingly apparent, however, is that prions aren鈥檛 only responsible for transmissible spongiform encephalopathies. Research has focused on the brain 鈥� and it may be more susceptible to prion diseases because brain cells don鈥檛 regenerate well, or at all. But prion diseases have also been found outside the brain. .

Prions appear to contribute to a range of neurodegenerative diseases, too. These conditions, which include Alzheimer鈥檚, Parkinson鈥檚 and amyotrophic lateral sclerosis, are characterised by specific brain lesions made of aggregated proteins. It is now generally accepted that these proteins are prions, which spread within the brain like an infection. Some neurodegenerative diseases are associated with more than one prion and some prions contribute to more than one disease through their ability to fold into alternative forms (see 鈥�Prions in neurodegenerative diseases鈥�). They spread within a brain through the nerve fibres. Exactly how is unknown, but the realisation that prions contribute to these diseases offers hope that we can find drugs to slow down, or even halt, their progression.

Another intriguing discovery is that . Proteins with the capacity to fold into two functionally distinct configurations, one of which is self-perpetuating, have been found in all branches of life, and even occur in viruses. The fact that these have survived and proliferated raises the question of whether, as well as causing diseases, prions might confer evolutionary advantages. In recent years, experiments have suggested they do 鈥� in yeasts, at least.

The other face of prions

A key challenge for life is to adapt to changing environments. Adaptation can occur genetically as a result of random mutations followed by natural selection of those fitter genes. But this is a slow process, even for fast-dividing organisms such as yeast. Moreover, if the environment reverts to its original state, the mutation must be reversed. . Studies reveal that changes in a yeast鈥檚 environment, such as the presence of different nutrients, induce a prion protein to switch into an alternative form that helps the yeast exploit the new food source. What鈥檚 more, this adaptation is , non-genetic type of inheritance.

Experiments showing that prions can give organisms an evolutionary advantage have, so far, only been done with yeasts. However, good prions 鈥� ones that perform useful roles within an organism 鈥� have been found in a variety of animals. This line of research began back in the 1970s, when started exploring the molecular mechanism of memory. Their studies of a simple organism, a sea slug, cemented the idea that creating a long-term memory involves the enlargement of synapses, the points of contact through which a nerve impulse is transmitted between neurons. This requires protein synthesis. The research hinted that prions make this possible.

The puzzle was this: a neuron may have thousands of synapses, so how does it know which one has been stimulated by a nerve impulse and therefore needs to be enlarged? Kandel and his colleague Kausik Si thought that a protein called CPEB might be involved. It is present at synapses and was known to activate the production of other proteins, which could be used to remodel the synapse. Kandel and Si also noticed that CPEB is an intrinsically disordered protein. Might it be a prion, they wondered? To test this idea, they teamed up with Susan Lindquist at the Massachusetts Institute of Technology and for one in a yeast prion. It made no difference to the yeast. In other words, the CPEB acted as a prion.

This led Si and Kandel to propose that a long-term memory is formed when repeated stimulation of a synapse causes CPEB to fold into a prion. As a result of self-templating, the CPEB prion grows into a fibril, which is too large to move into the neuron. In this form, CPEB activates the production of other proteins that permanently alter the structure of the synapse. It took a long time to get evidence to back up this model, but in 2020 , and his collaborators . Meanwhile, a team led by Kandel showed that mice bred so that their CPEB was inactive had .

So it seems that prions play a central role in learning in organisms from sea slugs to fruit flies to mammals. And CPEB isn鈥檛 the only known good prion protein. Others identified so far include proteins essential for the mammalian immune system to respond to viral infections by ensuring a .

The hunt is now on for more good prions. We are also starting to understand what distinguishes them from bad ones. The two share fundamental properties such as self-templating, but, unlike bad prions, the good ones studied so far don鈥檛 spread. Another difference is that the folding of good prions is induced by an external stimulus 鈥� chemical stimulation of the synapse in brains, for example, or environmental chemicals in the case of yeasts. This induction is precise and efficient, its mechanism having been refined during millions of years of evolution. The folding of proteins into bad prions, by contrast, is random and rare. That is one reason why neurodegenerative diseases tend to be diseases of old age: the longer you live, the greater the chance of a bad prion forming a fibril and seeding.

We are only beginning to appreciate the importance of prions in biology. On rare occasions, things go wrong and they cause diseases. But the list of good prions is steadily getting longer. Could Zigas and Gajdusek have predicted these developments when they were in New Guinea wondering about the role of cannibalism in the kuru epidemic? Certainly not. The prion story teaches us, once again, the power of pure curiosity to change our understanding of the world.

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How can a protein be infectious?

A so-called intrinsically disordered protein must bind to a partner to form a stable structure. Very rarely, this partner is an identical copy of the same protein and a prion is formed, which grows into a fibril as more identical copies bind to it.

When a cell鈥檚 quality-control system tries to correct this mistake, prion fibrils can fragment into seeds. These are small enough to pass into other cells, where they can grow into new fibrils. This is thought to be why prions are infectious.