This episode is brought to you by the Music  for Scientists album, now available on all   streaming services. {♫Intro♫}.

For more than a billion years, the only life on Earth were single-celled organisms  without much of an internal structure. We call them prokaryotes, and  they include bacteria and archaea.

Then, about two billion years ago,  something groundbreaking happened:  . Some of these organisms developed an internal   compartment where they started storing  their genetic material — the nucleus. Having a compartment like this  may not sound like a big deal,   but this more organized structure paved  the way for life to become multicellular, and for it to diversify into plants, animals,   fungi, and algae — a whole new  group we call the eukaryotes.

Now, almost every cell in our bodies has  a nucleus that protects our genetic code   and commands the activities that keep us alive. So, given all that, you’d think we’d have a   solid idea of how the nucleus  evolved and why. But we don’t.

Scientists do have several ideas, though.   And exploring them can give us clues as to  how complex creatures like us came to be. The basic textbook explanation of how the  nucleus evolved is called invagination. In this hypothesis, a prokaryote’s outer  membrane folded inward to form a cavity.

That’s actually why it’s called  invagination — because it’s similar   to the word “vagina,” which  essentially means a cavity. Regardless, over time,   lots of invaginations created little  wrinkles and pockets inside the cell. Then, those infolds pinched themselves off,   forming self-contained bubbles — one of which  happened to surround the cell’s genetic material.

And voilà: the nucleus. This hypothesis offers a simple and  elegant model of nucleus formation.   Plus, it explains a few things about  why the nucleus looks like it does. For instance, it explains why the nucleus  is surrounded by a double membrane instead   of just a single one — because when the outer  membrane folded in on itself, it doubled up.

But despite what textbooks say, there are a few  reasons this explanation doesn’t hold water. The big one is that we can’t  explain why it would happen. Like,   what would make a cell just  start folding in like this?

It doesn’t make sense that it would happen just  to create a pocket to protect genetic material,   because invagination involves lots of folds  creating several different structures. To answer this, some researchers have  proposed that the infolds evolved for feeding   and acted like mouths. Then, nucleus  formation was just a side effect.

But that’s a pretty important side effect for   something that’s stuck around  for billions of generations. Also, invagination by itself just isn’t  great at explaining other features of cells,   like the evolution of some of  their organelles, or mini-organs. One of these is the mitochondria,  which are the energy centers of cells.

The classic invagination hypothesis  says mitochondria evolved from material   that was already in the cell. But...  mitochondria have their own, separate DNA. Really, it seems like they were once another  organism that somehow got inside the cell.

So, eventually, scientists came  up with other hypotheses to better   explain the evolution of both  the nucleus and mitochondria. The most famous of these is  endosymbiosis. It’s a really   popular idea, and over the years scientists  have proposed at least 20 versions of it.

The basic idea of all of them is  that at some point in history,   one prokaryote swallowed another  one, but didn’t digest it. Scientists aren’t sure which  prokaryotes were involved,   but most of them think an  archaeon swallowed a bacterium. Then, the bacterium just kind of  hung around, and the two provided   mutual benefits to each other — like offering  protection and sharing energy and nutrients.

In the end, this friendship lasted so long that,   eventually, the bacteria  evolved into mitochondria. And either before or after that, the  nucleus formed through invagination. So, this model is a little more complex, and  it does solve some things.

But it also has its   own problems. Like, there’s a sort of chicken  and egg thing with the mitochondria themselves. It takes a lot of energy  for one organism to swallow   another.

And the way organisms typically  get lots of energy is from mitochondria. So how did the archaea get the energy  to eat that bacterium in the first   place? It’s a question we can’t answer.

Also, this hypothesis retains a lot of the  original problems with pure invagination,   too — like why it would happen. So in 2014, scientists proposed another hypothesis   about how the nucleus got here that  dodges these problems altogether. It’s called the “inside-out” model.

And  it takes a pretty different approach. In this idea, the starting  point was an archaeal cell   that had bacteria living on its outer surface. To feed on these bacteria, the archaeon oozed  blobby protrusions from its outer membrane,   which very serious scientists have named blebs.

The blebs trapped the bacteria between them.   Then, the archaeon took some of the bacteria’s  energy and used it to grow and swell its blebs,   so that it would have even more surface  area to trap and feed on more bacteria. And eventually, the blebs completely engulfed the  bacteria and incorporated them into the cells. In the end, the bacteria went  on to evolve into mitochondria.

The archaeon itself turned into the nucleus. And the blebs became so large that they  evolved into a few things — including   the cell’s outer membrane, but also  the outer membrane of the nucleus. Overall, the inside-out hypothesis  has several things going for it.

Like, it explains why nuclei  have a double membrane. But also,   it jibes with things archaea actually do. Because they really do form blebs!

Like, in 2020, researchers described an  archaeal cell that has a nucleus-like   cell body with bleb-like protrusions. And they may use these protrusions to exchange  material with organisms living on the cell. So, there is precedence for this sort of thing.

Also? This cell is an Asgard archaea,  which scientists think are the closest   living relatives of the archaea  that became the first eukaryotes. And beyond all that, this hypothesis also  explains why and how the nucleus evolved: It   was basically a side effect of an archaeon trying  to interact with bacteria living on its surface.

That said... there’s still one piece missing. If the nucleus were originally a standalone  archaeon, it would have had the ability to   take the information from its DNA, and  use that information to make proteins. So theoretically, there should  be machinery for protein assembly   inside the nucleus.

And there isn’t. In eukaryotes, DNA is copied into another  molecule, called RNA. And then, RNA leaves   the nucleus and goes to make proteins elsewhere  in the cell, with the help of another organelle.

So, how did that happen? Well, some scientists have proposed a fourth  hypothesis that’s pretty controversial,   but also pretty fascinating: giant viruses. Scientists discovered these in 2003.

And  they’re roughly the size of bacteria,   which is huge compared to normal. Like,  many viruses are half that size or less. These giants enter cells and then build  compartments called viral factories,   which the viruses use to replicate themselves.

And there are a couple interesting  things about these factories. First, the process of copying  DNA takes place inside them,   while the construction of  the proteins happens outside. Which sounds a lot like what happens inside  and outside the nucleus in eukaryotes.

Second, giant viral factories happen  to be roughly the size of a nucleus. So, there are two ways these  viruses could have played a   role in the evolution of these key structures. In one version of the hypothesis, a giant virus  infected an archaeon and built a viral factory.

The virus stole genes from the archaeon  and stashed them in the factory. And then,   over time, it evolved into the nucleus. This is great, in that it explains why a nucleus  would form as a mechanism of protecting

DNA:  . The virus needed somewhere safe  to set up shop and replicate. And if it’s true, it means that inside  every one of your cells are the remnants   of a giant virus! Which is a little disturbing!

The other version of this hypothesis starts the   same way: A giant virus infected an  archaeon and built a viral factory. But in this scenario, the viral factory  surrounded both the virus’s genetic material   and the archaeon’s. Then, the archaeon learned from the virus how  to make a factory-like compartment of its own   to protect its precious genetic material.

Overall, this idea that an ancient virus  infected a prokaryote is plausible,   because we do see that happening today. Like, in 2017, researchers found a virus   that infects bacteria and builds  viral factories inside of them. And in 2020, scientists discovered that another   virus forms viral factories  that have double membranes.

The downside is,   neither of the giant virus hypotheses  explain how these things could have happened. For example, there’s no explanation  of the evolutionary process that   would have turned a viral factory into a nucleus. Also, scientists haven’t yet found a giant virus   that builds viral factories  inside archaea specifically.

So in the end, despite it being this fundamental  thing about us and complex life on Earth… we still   don’t know where the nucleus came from, and the  only way to sort it out is to do more research. Fortunately, scientists are constantly discovering  new archaea, bacteria, and giant viruses,   in places as diverse as the bottom  of the ocean and inside your mouth. And the more we find out  about these ancient organisms,   the closer we’ll get to understanding  how nuclei formed, and how we came to be.

If you enjoy thinking about big  questions and mysteries like this,   you might also be interested in  the Music for Scientists album. It was inspired by the beauty of science,   as it pushes the boundaries of our  understanding and our view of the   world. And it’s a tribute to those who’ve  dedicated themselves to science-driven work.

If you want to check it out, click the  link in the description to start streaming.   All the songs are great, but we  recommend starting with “The Current.”  ♫Outro♫}.