A sinister, deadly brain protein could reveal the origins of all life

In 1944, Erwin Schrödinger published a book called What Is Life?. The physicist, famous for his alive-and-dead cat, clearly relished a brainteaser. Today, there is still no good definition. Life is generally agreed to require a minimum of two things: metabolism and reproduction. But the question of how chemistry morphed into biology billions of years ago is very much open to debate.

Now, a surprising contender has emerged as the catalyst for sparking the first life – and it is one we typically associate with deadly diseases.

Advances in molecular genetics have revealed that all living things on Earth are descended from a single organism dubbed the last universal common ancestor, or LUCA, which emerged around 4 billion years ago. We also know that our planet is approximately 4.5 billion years old. During those first half a billion years, simple, then more complicated, organic molecules were spontaneously synthesised and assembled in larger complexes, eventually evolving into the primitive, single-celled LUCA. How did that happen?

Biologists have long debated which key molecule of life came first. RNA – a cousin of DNA – has been a front-runner because some RNA may be able to copy itself. However, these molecules seem too unstable to develop into life. Another possibility is proteins. Here, the problem is that they can’t reproduce. Now, some researchers are suggesting a solution to these roadblocks – and it comes from an unexpected quarter.

What are prions?

Prions are weird proteins, originally fingered as agents of infectious neurodegenerative diseases such as kuru and scrapie. That’s how, as a virologist, I became interested in them. But it has become apparent that prions aren’t, in fact, a malevolent rarity, but are found in many organisms, playing a host of crucial roles, from the immune system to memory formation. Could they also be the missing piece in the puzzle of life’s origins?

Life requires metabolism – the ability to import useful molecules from the environment and jettison waste products. This allows organisms to produce energy to grow, persist and respond to their environment. But enduring isn’t enough: life must also reproduce. As François Jacob poetically puts it in his book The Logic of Life: “Everything in a living being is centred on reproduction. A bacterium, an amoeba, a fern – what destiny can they dream of other than forming two bacteria, two amoebae or several more ferns?”

In the beginning, reproduction simply meant molecules that could copy themselves or that could be copied by interacting with other molecules. This gave them a chance to persist despite the inevitable degradation that happens over time. There would be no life if metabolising, replicating molecules hadn’t appeared. How this happened is a central question for scientists working on abiogenesis – the emergence of life from inanimate chemicals.

When life emerged

One of the first people to explore this question was Stanley Miller. As a PhD student in the 1950s, he joined the laboratory of chemist and Nobel laureate Harold Urey at the University of Chicago. Miller then convinced a reluctant Urey to let him test his hypothesis that life started in ponds rich in salts, when the atmosphere contained hydrogen, ammonia and methane, with electricity from lightning providing the required energy. To do this, Miller built an apparatus that recreated these conditions. After several days of continuous electrical discharges, he found that several amino acids, identical to those that constitute the building blocks of proteins today, had formed. This result was published in Science and became a classic in biology known as the Miller-Urey experiment, despite Urey having declined authorship of the paper to give Miller full credit.

Since then, a range of environments have been suggested as the place where life began. The shallow pond hypothesis is still favoured by some. They argue that the regular alternation between ultraviolet-rich light and darkness and between high and low temperatures caused by Earth’s rotation on its axis created the cycles of synthesis followed by quenching of chemical reactions needed to stabilise the production of complex organic molecules.

However, most experts now believe that life got started at hydrothermal vents in the oceans or in hot springs where the temperature, pressure and chemical composition would promote the formation of these molecules. In the oceanic scenario, it is assumed that the rapid drop in temperature between the vent and the surrounding cold water provided the necessary quenching. Although Miller’s experiment suggested life began with proteins, now the leading idea is that RNA came first.

The RNA world hypothesis

This RNA world hypothesis goes back to the 1960s, when it was pioneered by several influential scientists, including Francis Crick, co-discoverer of the structure of DNA. One reason why it has been so enduring is that it addresses the issues of both metabolism and reproduction. RNA is a linear molecule comprised of building blocks called nucleotides made of two types of bases – purines and pyrimidines – and a sugar called ribose.

These organic components formed spontaneously and were subsequently linked together to make RNA, according to the RNA world hypothesis. Linear RNA molecules can fold into three-dimensional shapes that give some of them – called ribozymes –the abilities of enzymes. That is crucial because enzymes catalyse essential biochemical reactions that can only proceed with them: there would be no metabolism without enzymes. In present-day organisms, some enzymes are still ribozymes, although most are now proteins.

Another argument in favour of the RNA world is that RNA, like DNA, can encode genetic information – the basis for Darwinian evolution. The order of the nucleotides in a strand of RNA forms a code that is copied when the molecule is duplicated. Like DNA replication, this requires enzymes called polymerases. Today, these are all proteins, but, since there would have been no proteins in an RNA world, the hypothesis requires that, back then, some ribozymes would have functioned as RNA polymerases.

Several scientists have attempted to recreate such ribozymes. For instance, in 2023, Annalena Salditt at Ludwig Maximilian University of Munich in Germany and her colleagues created ribozymes that could copy short RNA molecules, including the ribozyme itself, making more ribozymes. Others have even devised elegant experiments in which primitive ribozymes could mutate and evolve, acquiring new enzymatic activities.

The RNA world hypothesis has some flaws, however. A major one is that RNA molecules are very unstable in water, which means they would have quickly degraded in the sort of environment where life originated. To survive, they would have needed to be protected by proteins, but, by definition, there would have been no proteins in an RNA world. To get around this, several researchers have suggested that protection may have been provided by the tight folding of RNA molecules, along with them binding to physical supports such as clays or similar natural substances. Others, however, believe that the problem of RNA instability, as well as the difficulty of spontaneous synthesis of nucleotides compared with the easy synthesis of amino acids, undermines the RNA world hypothesis, and that proteins formed first instead.

Earth’s prebiotic soup

Miller’s experiment in the 1950s demonstrated that amino acids form spontaneously under conditions that mimic Earth’s primitive prebiotic soup. Since then, experiments have repeatedly confirmed the spontaneous formation of amino acids, including under the conditions found in hydrothermal vents at the bottom of the ocean and in hot springs. Amino acids are also commonly found on meteorites – they are components of the universe. Furthermore, in laboratory experiments that reproduce prebiotic conditions, amino acids link together to form chains like those in present-day proteins.

The same cannot be said of RNA. Building an RNA world from scratch requires the spontaneous formation of purine and pyrimidine bases and ribose, their assembly into nucleotides and finally the linking of nucleotides to each other. However, such a chain of reactions has never been achieved in the laboratory under the conditions that prevailed during Earth’s first half a billion years. All this makes the creation of a protein world far simpler to explain than the creation of an RNA one.

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The idea that a protein could be infectious was a bombshell
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There’s another advantage to the protein-first idea. Almost all the enzymes we know are proteins, meaning that metabolism would have been possible from the start. However, there is one major problem: today, RNA is required to carry the information to make proteins, and ribozymes are needed to link amino acids together, so it is unclear how a protein-only life form could have reproduced. This stumbling block explains why the RNA world hypothesis has dominated. Now, however, there is a possible solution – and this is where prions come in.

Prion was the name given by my colleague Stanley Prusiner to the agent of neurodegenerative diseases including scrapie in sheep and goats, bovine spongiform encephalopathy – or “mad cow disease” – in cattle and Creutzfeldt-Jakob disease in humans. They are infectious and can be transmitted by inoculation with contaminated material, just as viral diseases can. However, in the 1980s, Prusiner discovered that the agent of these diseases, the prion, is made of a single protein. There is no DNA or RNA, as there is in viruses.

The idea that a protein could be infectious was a bombshell. More recently, “prion-like” proteins – which are different from Prusiner’s original prions and don’t spread between individuals – have been found in people with common neurodegenerative conditions, including Parkinson’s and Alzheimer’s disease.

But the story doesn’t end there. In my book, The Power of Prions, I describe how scientists have discovered that prion-like proteins are, in fact, common in organisms from bacteria all the way to mammals, suggesting they were retained during evolution because they had important functions. Indeed, some of these functions have been identified. Prion-like proteins are used by yeasts to adapt to changes in their food environment, for example. In animals, including mammals, neurons employ a prion-like protein to establish long-term memory. Others are used by immune cells in their fight against viruses. In other words, we need to rethink these proteins. The prions and the prion-like proteins responsible for disease appear to be exceptions in a family of useful proteins that has been associated with life for a very long time.

The thing that sets these proteins apart from other proteins is the way they fold. It is also what makes them central to the protein world hypothesis of the origin of life.

Proteins are chains formed from combinations of 20 amino acids, each with a different chemical structure, linked to its neighbour by a chemical bond called a peptide bond. The order of amino acids in the chain and its overall length vary widely, resulting in the enormous range of proteins found in nature. To play a biological role, including being an enzyme, a protein chain must fold into a very precise shape.

Prions are a type of intrinsically disordered protein, which don’t fold spontaneously into stable shapes. They constantly fold and unfold into many thousands of unstable shapes, lasting just milliseconds each. To fold properly, they need to interact with a partner that is usually a different protein. For prion proteins, though, the partner is another copy of the same prion protein that happens to be in the same unstable shape. The two bind together and form a stable pair that persists. It also recruits more copies of the unstable protein in this same shape and stabilises them. This process, called self-templating, creates a stack of identically folded prions or prion-like proteins that looks a bit like a pile of soup dishes. Eventually, it will form into long fibrils, which can be seen with an electron microscope. When a fibril fragments, it creates “seeds” that will initiate the formation of more fibrils. The protein is making copies of itself – it is reproducing.

Intriguingly, experiments reveal that these fibrils are extremely resistant to harsh environments, including those found in hydrothermal vents and hot springs. They have also been created in the lab by researchers attempting to make protein chains from spontaneously generated amino acids. In 2010, for example, Jacqui Carnall at the University of Cambridge and her colleagues created proteins that took the form of fibrils and also behaved as prion-like proteins, producing seeds and replicating. Later, several groups showed that spontaneously formed protein fibrils can have a large range of enzymatic activities.

These results prompted some researchers to propose that a protein world may have appeared very early on Earth, and before the RNA world. The sequences of amino acids and the sizes of these proteins must have been extremely diverse since they resulted from the random assembly of the amino acids that formed spontaneously in this environment. By chance, the sequence of some allowed them to form highly resistant fibrils with prion-like properties. Being prion-like, they would also have been able to replicate, enriching the milieu with more copies of themselves. Some of them behaved as enzymes with various activities, possibly including acting as the catalysts needed to build RNA. Over many millions of years, a collection of proteins with diverse enzymatic activities may have built up, setting the stage for the formation of LUCA.

How did the last common universal ancestor form?

But that still leaves one big mystery. By the time LUCA appeared, it was equipped with an efficient mechanism to make proteins and reproduce. It had RNA and a way to translate the genetic information encoded in RNA into proteins. This complex operation is performed by a micro-machine called a ribosome, made of both proteins and RNA. All descendants of LUCA, from bacteria to humans, use ribosomes. In all of them, the enzyme that joins amino acids to make proteins is a ribozyme, made of RNA. What’s more, this ribozyme is nearly identical in all present-day organisms, suggesting that it has been conserved because of some unique property. And it is special: protein enzymes tend to be very specific for their substrates, but this ribozyme can work with all 20 different amino acids, regardless of their structure and position in the chain.

The ribosome results from a remarkable collaboration between protein and RNA. We don’t know when this collaboration began. However, an ingenious solution has been suggested, one that is finally taking us beyond the old debate about whether life began as protein or RNA.

The new idea posits that there was collaboration from the start. A number of researchers have suggested that several RNA worlds and prion-like protein worlds emerged spontaneously on the young Earth. Only a few of these survived the harsh environment for any length of time. Nevertheless, on some occasions, a protein world and an RNA world overlapped, giving RNA molecules a chance to be stabilised through interaction with proteins.

Among various RNA-protein assemblies, one formed a primitive ribosome, kick-starting an efficient mechanism of protein synthesis. These merged RNA-protein worlds also produced structures enclosed in membranes by combining with other spontaneously formed organic molecules, including lipids. Meanwhile, DNA appeared, providing a repository of protein sequences in the form of genes and helping these proto-cells to multiply. One was especially successful at dividing and evolving and became LUCA.

The formation of LUCA from a soup of chemicals was an extremely unlikely event, with a probability estimated at less than 1 in a billion. Other forms of life may have emerged, but they disappeared due to a lack of stability. LUCA was probably the lucky winner of a competition for survival run under strong evolutionary selection pressure. However, it is possible that alternative life forms may still be present – perhaps as microorganisms hidden in rocks – and that abiogenesis on other planets produced types of life different from ours.

In any event, these new developments in our understanding of the emergence of life place prion-like proteins – originally discovered as agents of disease – at the centre of a marvellous chain of events that first produced LUCA and then, after more than 4 billion years of evolution, led to us.

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