What leaps out at me is our core ignorance. Rather like inspecting a modern processor inside your cell phone and successfully identifying copper.
We have now detected possibly thousands of obvious automata in the biology, icluding viruses and look for something BAD. Is it possible tha tthey are all GOOD?
It make sense that a living cell makes full use of automata to extend capabilities. Again our ignorance is breathtaking and we do not even know how to label GOOD.
A whole new world of tiny beings challenges fundamental ideas of life
The surprising discovery of entities smaller than viruses raises profound questions about what life is and how it got started
12 February 2025
https://www.newscientist.com/article/mg26535300-700-a-whole-new-world-of-tiny-beings-challenges-fundamental-ideas-of-life/
Theodor Diener had a problem. It was 1967, and he and a colleague had successfully isolated the infectious agent causing potato spindle tuber disease, which devastates crops. But it wasn’t like anything they recognised. Although they called it a virus, it didn’t behave like one.
It took Diener four years to demonstrate that the mysterious entity was something even simpler than a virus: a single “naked” molecule that could infect the cells of potato plants and thereby reproduce. He suggested calling it a viroid. It was the smallest replicating agent ever identified. At a stroke, Diener had expanded our understanding of life in the microscopic world.
You might think that such a dramatic discovery would go, er, viral. Yet hardly anyone noticed. Apart from a few other plant pathologists, the scientific world largely forgot about viroids for half a century. So obscure were they that, in 2020, when Benjamin Lee at the National Center for Biotechnology Information in Bethesda, Maryland, was advised to try looking into viroids, he had never even heard of them.
Since then, thanks to Lee and others, there has been an explosion of discoveries. We now know of thousands of viroids and viroid-like entities, with exotic names like obelisks, ribozyviruses and satellites. They appear to be everywhere, in a huge range of organisms and microorganisms. We have no idea what most of them are doing, including whether they are benign or dangerous. But these simplest-possible replicators raise fundamental questions about what it means to be alive. They may even date back to the origins of life.
Part of the story of biology over the centuries has been the quest to find smaller and smaller life forms. It began in the 1670s when Antonie van Leeuwenhoek, a master of microscopes and lenses, observed tiny “animalcules” living in rainwater. Biologists eventually realised that these were single-celled organisms, which include bacteria and yeast. The most minuscule are just a few micrometres across, but they are incredibly intricate, containing hundreds of different kinds of molecules – including the DNA that carries their genes.
It would be more than two centuries before botanist Dmitri Ivanovsky discovered something even tinier. In an attempt to find out what was causing another disease in potato plants, he managed to catch the culprit using an incredibly fine filter. In 1898, microbiologist Martinus Beijerinck gave this kind of infectious agent a name: virus. Viruses consist of a piece of genetic material – either DNA or a similar molecule called RNA – encased in a shell, or capsid, made of protein. They are often a tenth of a micrometre across and some are even smaller. On their own, they can’t multiply. But if they infect a living cell, they can take over its internal machinery and use it to make thousands of new viruses. The cells are destroyed in the process, explaining why viruses can cause serious illness.
Smaller and smaller life forms
Viruses pushed the limit of how small a living thing can be. But, seven decades later, with Diener’s discovery of viroids, the envelope began to expand (see Denizens of the invisible realm). Viroids consist of a strand of RNA without even a capsid. Like viruses, they replicate by entering a host cell and subverting its systems. But the precise mechanism is different because the RNA of a viroid is circular. The viroid takes over an enzyme that the host uses to make its own RNA, which then “walks” around the circular RNA, copying it as it goes to create a long, ticker-tape-like strand of RNA with many repetitions of the viroid sequence. This is cut into pieces, each one holding a single copy of the viroid’s RNA, and these then form loops. Electron microscopes sometimes show viroids as rod-shaped, indicating that the loop of RNA is further twisted and folded.
The way viroids work is unique and their tiny size unprecedented. But for decades, nobody paid them much notice. Even within biology, they were a niche subject. Viroid research proceeded at a glacial pace for 50 years, says Zasha Weinberg at Leipzig University in Germany. He suspects that the lack of interest was partly because viroids seemed only to infect plants. However, in 2021, Weinberg and his colleagues published a study that changed everything.
The irony is that they weren’t even looking for viroids. They were compiling information about ribozymes – RNA molecules that can also act as enzymes to speed up biochemical reactions – and were particularly interested in a group called hairpin ribozymes. Named after the shape the RNA strand is folded into, hairpin ribozymes were discovered in the late 1980s, yet until 2021 only four types were known. When the researchers trawled through a huge volume of genetic sequence data, both DNA and RNA, collected from different species over the years, they found 941 new ones – expanding the diversity more than 200-fold. On closer examination, these ribozymes were all found within circular RNA sequences, just like viroids. But there was something distinct about them: their genetic sequences varied wildly in length, from 381 to 5170 nucleotides, whereas previously known viroids spanned just a few hundred nucleotides.
“5000 is crazy,” says Weinberg. “There’s something really different going on here.” What’s more, these “viroid-like entities” weren’t confined to plants. Weinberg’s team had found them in several fungi, narrow-headed ants, a marine sponge and a bristle worm.
Are viroids and their ilk alive? Should we view them as biological or chemical?
More discoveries followed over the next two years. When a new system designed to examine enormous volumes of genetic sequence data uncovered more than 100,000 new RNA viruses, it also found other strange entities called satellites. Although known about since 1960, satellites remain enigmatic. Superficially, they resemble viruses: a bit of genetic material is surrounded by a protein shell. But a satellite can only infect a cell if it pairs up with a specific virus.
Meanwhile, Lee and his colleagues had been actively searching genetic sequence data for evidence of new viroids. In 2023, they reported finding more than 11,000 viroid-like circular RNAs. Some of them appear to be classic viroids while others are probably satellites. The set also includes some “ribozyviruses” – these have circular RNA and replicate like a viroid, but also have a gene that codes for a protein shell, blurring the line between viroids and viruses.
In the same year, a team that included Beatriz Navarro at the Institute for Sustainable Plant Protection in Bari, Italy, and Lee reported new entities called ambiviruses, which they described as “hybrids of RNA viruses and viroid-like elements”. Unlike classic viroids, they have a gene coding for the enzyme that copies their own RNA. Nevertheless, they are still reliant on a host to replicate – the team found them in fungi.
Last year, researchers discovered perhaps the oddest things so far. A team led by Andrew Fire at Stanford University in California identified entities in the human gut microbiome that, like viroids, are circular RNAs, but folded into a rod-like shape – earning them the name obelisks. Also unlike classic viroids, their genomes code for proteins, dubbed oblins, that bear no resemblance to any known protein, and whose function is a complete mystery. The researchers found 29,959 distinct types of obelisks.
Bacteria in our mouths can contain viroid-like obelisks (not visible)
Despite the sudden discovery of all these viroid-like entities, we have almost no information about whether most of them harm their hosts. Some viroids are known to naturally infect plants, resulting in crop losses. And in 2022, a team led by Wenxing Xu at Huazhong Agricultural University in Wuhan, China, reported viroid-like RNAs infecting a fungus, which, ironically, is itself a pathogen of plants. The researchers called them mycoviroids. Obelisks also seem to enter cells: Fire’s team found some in bacteria called Streptococcus sanguinis, which live in our mouths. But, to date, very few actual experiments have been done with viroid-like entities – partly because interest in them is so recent and restrictions caused by the covid-19 pandemic have limited the time available for such work. “You can’t rule out that there could be viroids that would infect humans,” says Weinberg. But neither is there any evidence that they do.
What this series of discoveries makes very clear, however, is that there are life-like entities that are even tinier than viruses – and they are everywhere. We don’t know how many there are, not least because the available search tools work by looking for familiar genetic sequences, so they won’t pick up entities with more peculiar kinds of RNA. “I think we’re only scratching the surface,” says Lee.
Are viroids really alive?
The flurry of findings has also created a lot of confusion. How can we subdivide all these different little things? Existing categories such as viroid and satellite don’t capture the full variety. To add to the complexity, what starts as a viroid doesn’t necessarily stay that way. “It’s very likely that there can be transitions between categories of viroid-like entities,” says Lee. For instance, a viroid could gain the gene for a protein, becoming a satellite or virus, then later revert back. The RNA sequences concerned are so short that they can readily be swapped around or evolve at random in a large population of viroids.
It is even unclear how we should think about the members of this sub-viral world. Are they alive or not? Should we view them as biological or are they just complicated chemistry? After all, many biologists baulk at the idea that viruses are living. “I personally believe that the definition of life should be dramatically expanded to include viruses and viroids, but that’s by no means a consensus view,” says Lee. “They’re clearly biological replicators subject to evolution by natural selection and that’s what matters for biologists.”
The deeper issue is that nobody has yet managed to come up with a definition of life that a majority of biologists can get behind. “It maybe depends on the context of what scientific question you are asking,” says Weinberg. But these strange little entities might help. There has been a growing move to treat life as a spectrum rather than a yes-no phenomenon. In which case, viroids and their ilk are at the base of things – they are more alive than rocks, but not as alive as bacteria or elephants.
Another obvious question is where all these viroids and viroid-like entities come from. There are two main possibilities. The first is that they form spontaneously inside living cells. Because viroids are short sequences of RNA, and all cells produce huge volumes of RNA all the time, it isn’t inconceivable that viroid-like entities could form by sheer chance, says Weinberg. Lee and his colleague Eugene Koonin have argued that this is the most likely explanation, pointing to sequences in plant genomes called retrozymes that resemble viroids. “A replicator might basically grow legs and walk away,” says Lee.
If this is true, many viroid species may have quite recent origins – even if the general phenomenon is ancient. However, Lee and Koonin wrote their paper before all the recent discoveries. “A lot of that was predicated on the fact that viroids were only found in plants,” says Lee. We now know that isn’t true. Instead, it seems viroids and viroid-like entities are universal. This suggests a second possibility, that they may be truly ancient, dating back to the dawn of life. “They have all the characteristics to be the first entities that replicate,” says Navarro. They are small, making them easier to replicate without too many mistakes. Furthermore, “they are stable, because they are compact”, she says.
Quite how life began on Earth is a profound mystery, despite decades of research into the question. One much-discussed hypothesis is that its origins lie in a so-called RNA world. This idea was prompted by the discovery of the first ribozymes in the early 1980s: the finding that RNA could act as an enzyme as well as storing genetic information made the molecule a good contender for the simplest form of life. Navarro and her colleagues believe viroids may be relics of that time. “Our hypothesis is that they are fossils of the precellular RNA world,” she says.
Living fossils from the dawn of life
However, the idea remains unproven, and Lee says it has some major issues. Perhaps the biggest is that nobody has ever found a ribozyme in nature that can increase the size of RNA molecules – which would have been essential for a primordial viroid to self-replicate. Nevertheless, this has been achieved in the lab. Gerald Joyce at the Salk Institute in La Jolla, California, has used artificial evolution to modify ribozymes. In 2016, he and his colleague David Horning created one that could copy short RNA sequences. And in March last year, they evolved one that was able to copy an RNA sequence that included a ribozyme. “Those are demonstrably pretty easy to evolve,” says Weinberg.
But if a ribozyme like this was essential at the dawn of life, asks Lee, why isn’t it still around? He accepts that it could simply have died out, but also notes that life is both diverse and thrifty, so it is odd that we haven’t found something like this clinging on anywhere.
For now, the question of whether viroid-like entities are living fossils from the dawn of life remains wide open. But, in a pleasing instance of circularity, this is exactly what Diener, the discoverer of viroids, suggested back in 1989.
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