Animals, plants, fungi, and protozoans all have different cells, but they all have one striking feature in common: the nucleus.
Although they have other organelles, such as mitochondria, which produce energy, the nucleus, a clearly identifiable pouch containing genetic material, inspired the biologist Edouard Chatton in 1925 to cointhe term “eukaryotes” to refer to organisms with a “true core.”
He called the rest “prokaryotes,” meaning “pre-nucleated.”
This dichotomy between nucleated and non-nucleated organisms later became the basis of biology.
No one knows exactly how the nucleus evolved into a critical region within the cell.
However, growing evidence has led researchers to suggest that the nucleus may have originated in a symbiotic relationship, just as mitochondria do.
But the key difference is that a virus, rather than a single cell, may be responsible for the nucleus.
“The question of what we are, or what eukaryotes are, may be a classic case of what is called emergent complexity,” explains Philip Bell, director of research at Microbiogen, a yeast biotech company.
Bell proposed the theory of viral origin of eukaryotic cell nuclei as early as 2001 and updated the theory in September 2020.
“Three organisms come together to form a new community, and they fuse so well that they actually form a new form of life.”
He and other researchers have reinforced this reasoning by showing, for example, that giant viruses set up “viral factories” inside prokaryotic cells — compartments much like a nucleus that separate the transcription (reading genes) and translation (building proteins) processes.
“I think this is the most compelling model out there,” he said.
Most people who study the origins of eukaryotes would probably disagree with him;
Some still describe it as a fringe idea.
But proponents of the viral origin theory point to recent discoveries that support the model as well, and they believe conclusive evidence in favor of the hypothesis is already at hand.
A gift or a scam?
Scientists generally agree that eukaryotes first appeared between 2.5 billion and 1.5 billion years ago.
There is evidence that a bacterium colonised another prokaryote, the archaea, and became its mitochondria.
But the nucleus is an even bigger mystery: No one even knows whether the primitive archaea was already a nucleated proto-eukaryotic cell, or whether the nucleus came much later.
Any theory of the origin of the nucleus in eukaryotes must account for several of its characteristics.
The first is its structural properties: the outer membrane of the nucleus and the inner membrane, which contains a network of fibres, and the nuclear pore, which connects its interior to the rest of the cell.
Then there is the strange way it keeps gene expression inside, leaving the building of proteins outside.
A truly convincing origin theory would also have to explain why the nucleus exists at all — what evolutionary pressures prompted these ancient cells to encase their genomes?
For most of the past century or more, conjectures about the origin of the cell nucleus did not answer any of these questions.
But in the early 2000s, two researchers independently came up with the idea that the nucleus came from viruses.
Masaharu Takemura, then a research assistant at Nagoya University, became interested in how they evolved while studying the biochemical nature of DNA polymerases, the enzymes cells use to copy DNA.
“I conducted an evolutionary phylogenetic analysis of DNA polymerases in eukaryotes, bacteria, archaea and viruses,” Takemura, now a molecular biologist and virologist at the Tokyo University of Science, recalled in an email.
His analysis showed that the DNA polymerase of one group of viruses (poxviruses) was strikingly similar to one of the major polymerases in eukaryotes.
He speculated that the eukaryotic enzyme might have originated from an ancient poxvirus.
Microscopically, an amoeba infected with a jellyfish virus fluoresces.
Viral DNA (pink) is isolated from amoeba DNA (blue).
(Source: Masayharu Takemura) Takemura already knew that poxviruses create a compartment in the cells they infect, where they make and replicate the virus.
These facts combined led him to theorize that the nuclei of eukaryotic cells were produced in these primitive poxvirus compartments.
In May 2001, he published his theory in the Journal of Molecular Evolution.
In Australia, meanwhile, Bell came to a similar conclusion for different reasons.
In the early 1990s, as a graduate student, he became interested in theories about the origin of the nucleus, particularly the idea that the nucleus, like mitochondria, might have evolved from endosymbionts.
“Five minutes into it, I said, ‘My God, if it’s an endosymbiont, it’s not a bacterial endosymbiont,'” he recalled.
He thinks there are too many differences between the bacterial and eukaryotic genomes — eukaryotes have linear chromosomes, for example, while bacteria tend to have round ones.
But when he looked at viral genomes, he found striking similarities between the genomic structures of poxviruses and eukaryotes.
“It took me nine years to publish the first version of the model,” he points out.
Then it took him 18 months, back and forth, before he published his paper…… in the Journal of Molecular Evolution
But the Bivu paper was published four issues late.
Now, nearly 20 years later, both Takemura and Bell have independently updated their hypotheses.
Takemura’s modified version will be published online September 3, 2020, in Frontiers in Microbiology, and Bell’s will be published September 20, 2020, in Virus Research.
“He stole a march on me again,” Bale said with a laugh.
Both scientists cited the recent discovery of an unusual “giant virus” as one of the main reasons for revising their papers.
When Takemura and Bell published their initial hypothesis, these viruses had not yet been discovered.
Their genomes, with more than a million base pairs, rival those of small bacteria that grow on their own in size, and they carry genes that encode proteins involved in basic cellular processes.
(There is some evidence that the proteins in eukaryotic cells came from these viruses.)
But most importantly, these giant viruses replicate in complex, self-built compartments in the cytoplasm of the host cell, which is why these viruses, like poxviruses, are classified as nucleoplasmic giant DNA viruses (NCLDVs).
Patrick Forterre, an evolutionary biologist at the Institut Pasteur in Paris, argues that for these giant viruses, the chambers they make are “viral factories the size of eukaryotic nuclei.”
Even more surprising, the viral factories produced by NCLDVs that infect eukaryotic cells also have an inner and outer membrane like the nucleus.
Fortrey, Takemura, and Bell all believe that the giant virus was the origin of the nucleus.
According to Fortrey, there are two possible ways a giant virus could have evolved into a nucleus.
“Either the virus factory becomes the nucleus, or the prokaryotic cell……
Take a page from viruses and turn yourself into virus factories to protect your chromosomes, “he said.
Takemura thinks the latter is more likely: the virus was more likely to have inadvertently contributed to the creation of the nucleus, both by stimulating the archaea to build a barrier to protect its genetic material and by providing the source of some of the genes needed to build the barrier.
One possible origin of cells: Viruses build “virus factories” in protozoan cells and start stealing genes from their hosts.
And the host learns the “virus factory” model and builds a chamber of its own to separate its DNA from the outside world.
Long ago, according to his hypothesis, a giant virus built a virus factory that sealed off its own genome, but also that of its host, the archaea.
But unlike most infected cells, this host has managed to steal the virus’s road-building skills and build its own compartment, which can protect its genome from the virus.
Over time, this semi-permanent barrier evolved into what we know as the nucleus.
Bell prefers the virus factory to go directly to the nucleus, because the process is more similar to the behaviour of viruses known to infect protists.
“They’re more like ‘Invasion of the Body Snatchers,'” he said.
He suggested that the giant virus infected the archaea and set up a virus factory without killing its host cells.
Instead, the structure has endured.
“The virus then acted as a gene thief, stealing the archaea’s genes and completely destroying its genome,” he explained.
This is a common feature of viruses, especially giant viruses — they steal genes from their hosts, which makes them less dependent on them.
The theory might even explain why so many mitochondrial genes are transferred to the nucleus: “The nucleus has also been stealing genes from the mitochondria for years and has begun to control it.”
So in a way, “the virus is just wearing the archaea as a coat,” Dr. Bell said.
If the model is correct, he notes, “you could say that at the core of every human cell is a virus.”
Since Takemura and Bell’s earlier paper, several findings have been consistent with the idea that the nucleus originated in viruses.
For example, scientists have discovered all the branches of the family tree of giant viruses, broadening our understanding of their evolution, particularly the important genes they exchange with their hosts — in some cases, stealing them and giving them back to the cell.
In addition, in 2017, researchers discovered a virus that built a virus factory inside a bacterial host.
Until now, it seemed that only viruses that infected eukaryotes could make virus factories.
So the discovery of viruses in prokaryotes suggests that a similar process may have taken place long ago, leading to the creation of the nucleus.
In the case of the 2017 virus, “this nucleus-like structure is not membrane-based,” Takemura said, making it different from many virus factories and eukaryotic nuclei.
Still, he thinks that the ability of viruses to build protective compartments around their genomes in prokaryotic cells “strongly suggests that in ancient eukaryotic cells……
The virus [probably] makes the same compartment.”
The bacteroidovirus shown here is a giant virus that was discovered only a few years ago.
(Photo: JP Baudoin and Dbrahim Belhaouari, Ihu Mediterranee Infection)
As recently as 2020, researchers found pores in a coronavirus-made bilayer virus factory that were oddly reminiscent of nuclear pores in the nucleus.
David A. Baum, an evolutionary biologist at the University of Wisconsin-Madison, wrote in an email: “If this result holds up, and assumes that the pore-forming proteins do not come from eukaryotic genomes, then it does serve as A basis for tackling anti-virus models.”
Baum, however, does not believe that viruses were involved in the origin of the nucleus.
For him, the idea only makes things more complicated.
He wrote: “What is the difficulty in the production of the nucleus that a virus needs to solve?”
Together with his cousin Buzz Baum, a cell biologist at University College London, Baum has come up with a different hypothesis: that the nucleus is actually what remains of the outer membrane of an early archaea.
Essentially, they think an early archaea began to contact the world around it and make contact with bacteria through these exploratory membrane vesicles.
Over time, these vesicles grow until they fuse together again — creating new outer membranes and intimal folds, and giving rise to other intracellular compartments.
“The organisms closest known eukaryotic relatives have extensive extracellular projections” that interact with prokaryotes, Davey notes, “and are strikingly similar to the model we proposed.”
As for the evidence that viruses give eukaryotes some of their most important nuclear proteins, he is most concerned about the difficulty of determining the direction of the process.
“Viruses are the greediest thieves,” he says, so they constantly pick up genes from their hosts.
“I think we have to be very careful to determine whether we have found any similarities between viruses and eukaryotes.
We don’t know yet whether they gave it to the eukaryotes or the eukaryotes gave it to them.”
Purificacion Lopez-Garcia, a microbial ecologist at the University of Paris-Thackeray and research director at the National Center for Scientific Research in France, is similarly unconvinced that eukaryotes rely on virus-derived proteins.
“There is absolutely no evidence of any homology between the virus and the cell and nucleus,” she said.
Lopez-Garcia, however, also disagrees with the bubble model proposed by Baum’s Cousins.
She and her colleagues argued that eukaryotes did not originate from the ancient bacteria that devoured the bacteria that later became mitochondria.
Instead, they thought the archaea had been living inside a larger bacterium because of an earlier symbiotic event.
“So in our model, the nucleus comes from this archaea, and the cytoplasm comes from the bacteria.”
This dual model, she explains, contains unformed mitochondria.
But those hypotheses are flawed, Takemura said, because at best they can only “explain the emergence of the nucleus,” and they lack evolutionary logic to explain why genomes are framed and protein-making components are excluded.
This is also a position that Bell maintains: he does not believe that any other hypothesis can explain the separation of transcription and translation processes.
The origin of the virus is the most plausible and has the strongest evidence, says Fortrey.
“I don’t think their theory is necessarily rigorous,” he said of those who argue against it. “Viruses play a big role in it.”
Wait for new discoveries
More evidence is needed to convince scientists like the Baum Cousins and Lopez-Garcia to accept Forterey’s view.
But two decades of technological progress may finally make such evidence within reach.
Just in 2020, researchers from Japan announced that, after more than a decade of effort, they had finally isolated and cultivated the Lokiarchaeota, a group of archaea that is thought to have a symbiotic relationship with primitive eukaryotes.
This could lead us to further discoveries about the virus that infects our distant relatives, and the process of infection.
“If you find a new class of virus infecting Archaea rooki, gets inside the cell and sets up camp there, and makes holes to facilitate the rapid flow of transcriptional information into the cytoplasm — that would be much more compelling evidence,” says Davey, it would prove that the nucleus came from a virus.
Bell noted that researchers recently sequenced a large number of giant viruses in deep-sea sediments where the archaea loci were found.
He wants someone to test whether any of these viruses can infect archaea, and if so, whether they can build viral factories similar to those made by nucleoplasmic megdna viruses.
Proving that, he said, would “end the game.”
Takemura also hopes the virus does exist.
“Finding an archaea virus that can build a membrane-like structure in a paleontological cell would be the strongest evidence that the nucleus originated in a virus,” he said.
Until such remarkable evidence is available, the theory that the nucleus originated from viruses is likely to remain controversial.
But even if it doesn’t end up being accepted, every test of the theory reveals little by little about our evolutionary past — and because of that, we’re getting closer to the truth of where I came from.