One of the enduring mysteries of biology today is the origin of the nucleus. The most controversial hypothesis addressing that mystery says that a giant virus invaded a cell and became the nucleus. Especially today thanks to COVID-19, we think of viruses as ravaging invaders, like the Vikings who raided England. But could a virus be the origin of the nucleus, the heart of each and every one of our cells?
1. Nucleus or no nucleus?
The defining feature of cells is whether they have a nucleus or not. We call simpler single-celled organisms lacking a nucleus, prokaryotes. Prokaryotes fall into two very broad classes of organisms, the bacteria, and the distantly related but similar-looking archaea. The more complex cells with a nucleus we call eukaryotes. Eukaryotes encompass an incredible diversity of organisms from single-celled yeast to humans.
The nucleus contains most of the genetic material that defines the eukaryotic organism. Many of the genes in the nuclear DNA encode the instructions to build proteins, the workhorse of the cell. The first step in the central dogma of biology — the transfer of genetic information from DNA to RNA, called transcription — occurs in the nucleus. To complete the protein synthesis process, RNA must travel out of the nucleus.
The second step of the central dogma — the transfer of information from RNA to build proteins, called translation — happens in the cytoplasm. Cytoplasm is all the cellular material outside the nucleus, but within the skin of the cell called the cell membrane.
The nucleus has a number of fascinating features. For example, the nucleus has a double membrane, the inner and outer nuclear membrane, each of which is composed of a lipid bilayer similar to the cell membrane.
Another important feature is the nuclear pores which make the nucleus look somewhat like a whiffle ball. But the pores are not passive holes allowing materials to drift in and out. Each pore has a complex machine built of many different proteins which together act as active transporters and gatekeepers to and from the nucleus.
The most important material that the nuclear pores manage are the messenger RNAs (mRNAs) which carry the protein-building code from the nucleus to the cytoplasm where proteins are made.
These and other features of the nucleus challenged biologist to understand its origins.
2. Origin story
Eukaryotes have many features which separate us from, and add complexity to, the basic features of a prokaryote. Simply looking into a microscope, we see that eukaryotic cells are ten times the diameter or 1,000 times the volume of a prokaryotic cell. The volume is consumed firstly by the nucleus, but also by a zoo of other organelles (specialized structures within a cell). Eukaryotes have energy-producing organelles called mitochondria. There are protein-processing organelles called the endoplasmic reticulum and Golgi bodies. There are metabolic organelles called vesicles. Plants have light-energy-harvesting organelles called plastids. There are motorized organelles called flagella. Like I said. A zoo.
We have learned, by fits and starts, much about how complex eukaryotes originated and evolved from the more ancient and simple prokaryotes. Perhaps the biggest leap came from the work of Lynn Margulis, who showed that eukaryotes gained much of their complexity by an ancestral prokaryote capturing and becoming symbiotic with other prokaryotes who donated their specialized functions to the developing host cell. She termed this process endosymbiosis. Mitochondria, for example, came from an aerobic (oxygen using) bacterium which became engulfed within an anaerobic (oxygen-hating) cell so that it could survive in an increasingly oxygenated world.
But where did the nucleus come from?
Did it evolve organically, over millions of years of incremental changes driven by natural selection? Or was it a relatively sudden acquisition, such as by endosymbiosis, by swallowing a new ability whole?
3. Giant viruses
This is where a couple intrepid biologists looked to giant viruses as a way to answer this long-standing question of nuclear origins. They claimed that viruses, and specifically giant viruses, may be the origin of our nucleus and many of its unique features.
Giant viruses are in themselves a biological conundrum.
Viruses are normally tiny undead things which carry a stripped-down genome insufficient to support life. Viruses, therefore, depend on host cells to provide the vast majority of the genetic as well as functional machinery to support viral reproduction and release into the environment.
Most eukaryotic cells are on the order of tens of micrometers in size (there are one thousand micrometers in a millimeter).
Most bacteria are about one tenth the size of typical eukaryotic cells, so approximately one micrometer in size.
Viruses are yet another one tenth the size of bacteria, so approximately 0.1 micrometer, or 100 nanometers in size (one thousand nanometers in a micrometer).
This is a fun interactive web page illustrating scales of biological organisms from cells down:
Cell Size and Scale
The smallest objects that the unaided human eye can see are about 0.1 mm long. That means that under the right…
Giant viruses are about half the size of bacteria or five times larger than typical viruses — about 500 nanometers in size.
Importantly, that large size means giant viruses carry many more genes than typical viruses do.
So, while a typical virus might have a hundred genes contained within an average 40 Kb genome, a giant virus might have a thousand genes, compared to bacteria with about 2,000 genes.
4. What is special about giant viruses besides size?
Takemura came to his 2001 conclusion through examining the molecular machine called a DNA polymerase which is like a copy-machine for genetic material. DNA polymerase is essential for replication and repair of the genome, and therefore for the health, growth and propagation of cells. Eukaryotes have alpha, delta, and epsilon-polymerases, and their origins provided Takemura with a clue.
Delta-polymerases derived from archaea, one of the prokaryotes distantly related to bacteria. A couple poxviruses have polymerases similar to alpha-DNA polymerase. Poxviruses were also known to proliferate outside of the host’s nucleus, suggesting that these viruses could infect prokaryotes (in other words, the ancestor of eukaryotes).
Takemura updated his hypothesis in 2020. He noted that large mimiviruses build a partially or wholly membrane-bound compartment where viral DNA replication occurs. Ribosomes are excluded from the compartment, called a viral factory, just as they are from a nucleus.
Takemura wove an interestingly complex story of how the nucleus developed. The host cell did not directly steal the viral factory. Instead, the host cell stole some of the viral machinery to build its own compartment as a means to defend itself from viral infections. He comes to this bit of complexity from noting the multiple lateral transfers of genes between viruses and their hosts, and that this specifically happened between the giant medusavirus and its amoeba host.
Bell noted in 2001 that the eukaryotic nucleus is more similar to giant DNA viruses than to its prokaryotic ancestors. For example, giant DNA viruses and eukaryotes have membrane-bound genetic material where prokaryotes do not. Giant DNA viruses and eukaryotes have linear DNA with short tandem repeats at the ends, while prokaryotes have circular DNA with no ends. Giant DNA viruses and eukaryotes both transport mRNA with chemically modified ends (called capped mRNA) into the cytoplasm, features lacking in prokaryotes.
Bell updated his hypothesis in 2020 by focusing on the recently discovered process by which giant viruses replicate in their bacterial hosts by building virus factories. The virus factory is like a nucleus within a bacterium — the virus builds a protein wall to separate the linear viral DNA from the bacteria’s circular DNA. Viral DNA replication and transcription and happens inside the nucleus-like viral factory. Viral RNA is transported out of the factory into the host’s cytoplasm. Viral translation and assembly also occur outside the virus factory in the cytoplasm.
Bell noted other processes shared between giant viruses and eukaryotes. One was the capping of mRNA. In eukaryotes, mRNA is capped (modified) with a 7-methyl-guanylate (abbreviated as m7G). This chemical modification of mRNA signals that it is ready for processing (splicing), nuclear export via the nuclear pore machinery, and finally translation within the cytoplasm into the final protein product.
Bell showed that the archaeal ancestor of eukaryotes lacked these features and machineries of mRNA processing. However, certain viruses like the giant mimiviruses possess the machinery for capping mRNA.
An important piece of evidence is the detailed protein sequences of the m7G machinery. Protein sequence suggests that eukaryotic nuclei and mimiviruses shared a common ancestor for their m7G enzymes long before the origin of eukaryotes.
In other words, an ancient virus could have been the original nucleus, or what Bell terms the “First Eukaryotic Nuclear Ancestor” or FENA.