Did Viruses Create the Nucleus? The Answer May Be Near.

An unorthodox symbiotic theory about the origin of eukaryotes’ defining characteristic may soon be put to the test.
Electron micrograph showing a viral factory and new viral particles inside a cell.

Inside a cell, a “viral factory” (large circular compartment left of center) is surrounded by the new virus particles (smaller polyhedral objects) that it has manufactured. Some viruses direct the formation of these compartments to isolate their DNA from the host.

Quanta Magazine; original micrograph: Masaharu Takemura

Different as the cells from animals, plants, fungi and protozoa can be, they all share one prominent feature: a nucleus. They have other organelles, too, like the energy-producing mitochondria, but the presence of a nucleus — a well-defined porous pouch full of genetic material — is what inspired the biologist Édouard Chatton in 1925 to coin the term eukaryotes, which referred to living things with a “true kernel.” All the rest he labeled prokaryotes, for life “before kernel.” This dichotomy between nucleated and nonnucleated life became fundamental to biology.

No one knows exactly how the nucleus evolved and created that division. Growing evidence has persuaded some researchers, however, that the nucleus might have arisen through a symbiotic partnership much like the one believed to have produced mitochondria. A crucial difference, though, is that the partner responsible for the nucleus might not have been a cell at all, but a virus.

“What we [eukaryotes] are is a classic case of what they call emergent complexity,” explained Philip Bell, the head of research for the yeast biotechnology company MicroBioGen. Bell proposed a viral origin for the eukaryotic nucleus back in 2001 and refreshed the theory in September. “It’s three organisms that came together to make a new community, which eventually integrated to such an extent that it became, effectively, a new life-form.”

He and other researchers take their confidence from findings such as the demonstration that giant viruses build “viral factories” inside prokaryotic cells — compartments that, much like the nucleus, uncouple the processes of transcription (reading genes) and translation (constructing proteins). “I think it’s now the strongest model,” he said.

Most researchers who study the origins of eukaryotes might not agree with him; some still describe it as an idea on the fringe. But proponents of a viral origin point out that several recent discoveries line up conveniently with a viral model — and they believe that conclusive evidence in their favor is finally within reach.

A Viral Gift or Grift

Scientists generally think eukaryotes first came on the scene between 2.5 billion and 1.5 billion years ago, when evidence suggests that a bacterium took up residence inside a different kind of prokaryote, an archaeon, and became its mitochondrion. But a deeper mystery surrounds the emergence of the nucleus; no one even knows whether that ancient archaeon was already a kind of proto-eukaryote with a nucleus, or whether the nucleus came later.

Any origin story for the eukaryotic nucleus needs to explain several of its features. There’s the nature of the structure, for starters: its nested inner and outer membranes, and the pores that connect its interior to the rest of the cell. There’s also the curious way it compartmentalizes the expression of genes within itself but leaves the construction of proteins outside. And a truly persuasive origin story must also explain why the nucleus exists at all — what evolutionary pressures pushed those ancient cells to wall up their genomes.

For most of the past century and more, conjectures about the origin of the nucleus failed to answer at least one of those questions. But around the turn of the 21st century, two researchers independently came up with the idea that viruses were responsible for the nucleus.

In Japan, Masaharu Takemura (then a research associate at Nagoya University) was studying the biochemistry of DNA polymerases — enzymes that cells use to copy DNA — when he became interested in their evolution. “I performed a phylogenetic analysis of DNA polymerases including eukaryotic, bacterial, archaeal and viral ones,” Takemura, now a molecular biologist and virologist at Tokyo University of Science, recalled in an email. His analysis revealed that one group of viruses (the poxviruses) had DNA polymerases that were surprisingly similar to one of the major classes of polymerases from eukaryotes. He hypothesized that the eukaryotic enzyme originated as a contribution from some ancient poxvirus.

Fluorescent image that shows the DNA from a medusavirus clustered but separate from the host cell DNA inside an amoeba’s nucleus.

Fluorescent microscopy of an amoeba infected with a medusavirus. The viral DNA (pink) clusters within the nucleus, separate from the amoeba’s DNA (blue).

Masaharu Takemura

Takemura also knew that poxviruses create and replicate inside compartments within the cells they infect. This combination of facts led him to theorize that the eukaryotic cell nucleus was derived from one of these ancestral poxvirus compartments — a proposal he published in the Journal of Molecular Evolution in May 2001.

Meanwhile, in Australia, Bell had come to a similar conclusion for different reasons. As a graduate student in the early 1990s, he had taken an interest in theories about the origin of the nucleus, especially the idea that, like mitochondria, it might have started as an endosymbiont. “Five minutes of looking and I go, ‘Jeez, if it’s an endosymbiont, it’s not a bacterial one,’” he recalled. There were just too many differences between bacterial and eukaryotic genomes, he felt, like the fact that eukaryotes have linear chromosomes while bacteria tend to have circular ones.

But when he looked at viral genomes, he came across striking similarities between the genome structure of poxviruses and eukaryotes. “It took me nine years to publish the first version of the model,” he noted. Then it took 18 months of back-and-forth to get the paper published in the Journal of Molecular Evolution … four issues after Takemura’s paper.

Now, nearly 20 years later, both Takemura and Bell have independently updated their hypotheses. Takemura’s revision was published online in Frontiers in Microbiology on September 3, Bell’s in Virus Research on September 20. “He’s done it to me again,” Bell said, laughing.

Both scientists cited recent discoveries involving an extraordinary group of “giant viruses” as one of the main reasons for the updates. These viruses were totally unknown when Takemura and Bell published their initial hypotheses. Their genomes, which have more than 1 million base pairs, rival those of small, free-living bacteria in size, and they carry viral versions of genes for proteins involved in essential processes in cells. (There’s some evidence that the eukaryotic versions of several of these proteins came from these viruses.)

But most importantly, these giant viruses replicate inside complex, self-constructed compartments in a host cell’s cytoplasm, which is why these viruses, like poxviruses, are classified as nucleocytoplasmic large DNA viruses (NCLDVs). For these giant viruses, the compartments they make are “viral factories which are as big as a eukaryotic nucleus,” said Patrick Forterre, an evolutionary biologist at the Pasteur Institute in Paris. Tellingly, the viral factories made by NCLDVs that infect eukaryotes also have inner and outer membranes like the nucleus. Giant viruses are what Forterre, Takemura and Bell say are responsible for the origin of the nucleus.

There are two possible ways the nucleus could have come from giant viruses, according to Forterre. “Either the viral factories became the nucleus, or proto-eukaryotic cells … learned from the virus in order to make themselves a kind of viral factory to protect the chromosomes,” he said.

Takemura thinks the latter is more likely: that a virus was more of an unintentional contributor to eukaryotic cells, as both the stimulus for an archaeon’s construction of a genetic barrier and the source of some of the genes needed to construct it.

According to his hypothesis, long ago, a giant virus constructed a viral factory, enclosing its own genome but also that of its archaeon host. But unlike most infected cells, this host managed to steal the virus’s barrier-building trick and constructed its own compartment — one that defended its genome against the virus. Over time, this semipermanent barrier evolved into the nucleus as we know it.

Bell prefers the version in which a viral factory directly became the nucleus, as the process more closely mirrors the known behavior of viruses that infect prokaryotes today. “They’re more like Invasion of the Body Snatchers,” he said.

He believes an ancient giant virus infected an archaeon and set up a viral factory but didn’t kill its host cell. Instead, the structure managed to stick around. “And then the virus, which is a gene thief, stole the genes from the archaea and completely destroyed its genome,” he explained. That’s a common theme with viruses, especially giant ones — they take genes from their hosts, which makes them less dependent on their hosts. That might even help explain why so many mitochondrial genes have moved to the nucleus: “Over the years it has been stealing the genes from the mitochondria and starting to control it as well.”

So in a way, “the virus just wears the archaeon’s cell as a cloak,” Bell said. And if that model is right, he pointed out, “you could say at the heart of every human cell is a virus.”

Contested Origins

Since those early publications from Takemura and Bell, several discoveries have lined up well with the idea of a viral origin for the nucleus. Whole branches of the giant virus family tree have been discovered, for instance, broadening our understanding of their evolution and, in particular, the essential genes they’ve swapped with their hosts — ones they have stolen or, in some cases, perhaps given to cells.

In addition, in 2017 researchers discovered a virus that constructed a viral factory inside a bacterial host. Up until then, viral factories appeared to be exclusive to the viruses that infect eukaryotes, so finding one in a prokaryote bolstered the idea that something similar could have happened long ago to initiate the formation of a nucleus.

In the case of that virus, “this nucleus-like structure is not membrane-based,” Takemura said, which makes it distinct from many viral factories and eukaryotic nuclei. Still, he feels that this instance of a virus constructing a protective “compartment” around its genome inside prokaryotic cells “strongly suggests that in [the] ancestral eukaryotic cell … the same kind of compartmentalization by virus [could have] occurred.”

Just this year, researchers spotted pores in the double-membrane-bound viral factories of coronaviruses, which are eerily reminiscent of the pores found in cell nuclei. “If this result holds up, and assuming that the pore-forming protein was not derived from a eukaryotic genome, then it does blunt one argument against the virus model,” wrote David A. Baum, an evolutionary biologist at the University of Wisconsin, Madison, in an email.

Still, Baum doesn’t buy the idea that viruses had anything to do with the origin of the nucleus. To him, the idea only complicates matters. “What problem in eukaryogenesis requires viruses as its solution?” he wrote.

Baum, along with his cousin, Buzz Baum, a cell biologist at University College London, has proposed a different hypothesis: that the nucleus is actually a remnant of the ancestral archaeon’s outer membrane. Essentially, they think an ancestral archaeon began reaching into the world around it and associating with bacteria through these exploratory blebs of membrane. Over time, the blebs grew and grew, until they fused together again — generating a new outer membrane and inner membrane folds that gave rise to other intracellular compartments. “The closest living known relatives of eukaryotes have extensive extracellular protrusions” that interact with prokaryotes, David Baum noted, “very surprisingly similar to the model we proposed.”

As for the evidence that viruses gave eukaryotes some of their most essential nuclear proteins, his chief concern is that it’s very hard to be sure about directionality. “Viruses are the ultimate kleptomaniacs,” he said, so they’re constantly taking genes from their hosts. “I think we’ve got to be very careful to ask whether we find similarities between viruses and eukaryotes. We don’t know whether they gave it to the eukaryotes, or the eukaryotes gave it to them.”

Purificación López-García, a microbial ecologist at Paris-Saclay University and a research director at the French National Center for Scientific Research, is similarly unconvinced that eukaryotes rely on what were originally viral proteins. “There is no evidence at all that there is any homologous relationship between viruses and cell and eukaryotic nuclei,” she said.

Yet López-García doesn’t agree with the Baums’ blebbing model, either. She and her colleagues don’t think that eukaryotes started with an archaeon engulfing bacteria that would become mitochondria. Instead, in their view, the archaeon was already living inside a bigger bacterium, the result of an earlier endosymbiotic event. “So in our model, the nucleus would derive from this archaeon, and the cytoplasm would derive from a bacterium,” and this duo took in the mitochondria-to-be, she explained.

But Takemura says these other hypotheses are flawed, because at best they “only explain the phenomenon that the nucleus emerged” — they lack the evolutionary rationale for why the genome was boxed up, and why the protein-making parts were excluded. That’s a sticking point for Bell, too: He doesn’t see how any of the other hypotheses explain the separation of transcription and translation.

The viral origin just makes the most sense and has the strongest evidence, Forterre said. “I don’t think they are really serious,” he said of the opposing theories. “I would say that viruses play a major role in this story.”

Awaiting Discovery

It will take a lot more evidence to convince scientists like the Baums and López-García to come around to Forterre’s point of view. But two decades’ worth of advances in technology may finally be bringing that evidence within reach.

Just this year, researchers from Japan announced that after more than a decade of trying, they had finally isolated and cultured Lokiarchaeota — archaea of the type believed to have been part of the original eukaryotic partnership. That could open the door to discovering viruses that infect these distant relatives of ours and visualizing exactly what those infections actually look like.

“If you were to find a new class of viruses infecting the Lokiarchaeota, that got inside the cells and set up camp there and opened pores to facilitate rapid flow of transcripts into the cytoplasm — that would be [more] compelling” evidence that viruses gave rise to the nucleus, David Baum said.

Bell noted that a trove of giant viruses was recently sequenced from the very same deep-sea sediments where Lokiarchaeota were discovered. He hopes someone will test whether any of these viruses can infect archaea and, if so, whether they build viral factories similar to those made by the NCLDVs that infect eukaryotes. Demonstrating that, he said, would be “game over.”

Takemura, too, is hopeful such a virus exists. “The discovery of archaeal viruses which construct nucleus-like and membrane-based structures in archaeal cells will be the strongest evidence of the viral origin for the nucleus,” he said.

Until that kind of extraordinary evidence is in hand, viral eukaryogenesis will likely remain controversial. But even if it doesn’t end up winning the battle for acceptance, every test of the theory reveals bits and pieces of our evolutionary past — and because of that, we’re getting closer and closer to learning the truth about where we came from.

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