Why humans have bigger brains than other apes

How do our human brains differ from gorilla and chimp brains?
30 March 2021

Interview with 

Madeline Lancaster, MRC LMB Cambridge


The human brain.


If you’re listening to this, chances are you have a remarkably large brain. That’s not just because you’re a Naked Scientists fan, but because you’re a human: by the time you’re born, your brain contains 3 times as many nerve cells as the brains of our close primate relatives. Now scientists from the MRC Laboratory of Molecular Biology in Cambridge think they know why: a gene called Zeb2, which affects how cells move, kicks in later in human brains, giving us extra time to make extra brain matter. The work is the “brain child” of Madeline Lancaster and she told Katie Haylor about it...

Madeline - We've used what are called brain organoids. These are in vitro models of the developing brain that we generate from embryonic stem cells. And we've generated these from human stem cells as well as ape cells, and then compared them and looked at their size over time, and been able to discover why they're increasing in size in humans, compared with non-human apes.

Katie - Okay. So you looked at these organoids growing over time. What happened then? What did you see?

Madeline - Well, first of all, we of course wanted to look at size, because that's what we know is very different about our brains. Our brains are around three times larger. We just generated these organoids, and compared them and found that the human organoids were indeed about two times larger than the chimpanzee and gorilla organoids that we generated.

Katie - So what's changing then what's different in their development. Do you, kind of get to a point when you're observing these in the lab and something changes between the two?

Madeline - Yeah, exactly. So once we saw this difference in size of the organoids, we could actually go in and see what the cells were doing inside. And what we found is that the neural stem cells, so these are precursor cells that will give rise later in time, they'll generate the neurons of the brain. So all the nerve cells of the brain. But what we found is that before they even started making all those nerve cells, the human cells had a different shape than the cells of the chimpanzee and the gorilla. And this shape was indicating that the cells were maturing more slowly, and because they were maturing more slowly, they were actually able to proliferate faster. So that means they were making more and more of themselves more quickly. So they ended up with an increased number of these mother cells, if you will, that once those cells start making nerve cells, you have more of them. So you're able to then generate more of these nerve cells.

Katie - Is it a bit like the sort of tortoise and the hare situation? You know, he's taking longer to develop the brain, but you're going to get something, well, I guess we would say, maybe a bit better out of it, but maybe that's a bit human-centric

Madeline - It's probably a bit human-centric, but I like that analogy. Definitely. You take a little bit longer with these steps so that you can set up a bigger starting pool of cells. And once you have this bigger pool of cells, then everything that happens after that is going to be increased.

Katie - Did you look at why this is happening? What's going on genetically?

Madeline - So then we compared their genetic signature. So what genes are actually on in these organoids from these different species, and what we found is that when there's this delay happening in the human, there's also a delay in a particular gene and it's called Zeb2. And this is a gene that in other contexts, for example in cancer, has been shown to trigger a change in shape, which is in some ways similar to the change in shape that we're seeing. And so that was really kind of a red flag, that really suggests that Zeb2 might be responsible for this change that we're seeing and for the delay that we see in humans.

Katie - And can you confirm that by altering Zeb2 and seeing what happens?

Madeline - Yeah, exactly. So the real test then is to play around with Zeb2 expression basically. So we could turn it on earlier in the human, mimicking the kind of expression that we see in apes. And when we do that, then we see these cells change their shape earlier than they normally would, just like in the other apes. And we can also do the opposite where we can perturb the signaling that Zeb2 is doing within those cells and basically delay its effects in the ape's organoids. And then we can see that those cells start to look more like human cells.

Katie - This is really cool, but I'm wondering how much can this tell you about why human brains are different from other apes? Because we're talking about organoids, they're not full brains.

Madeline - Yeah, absolutely. No, I think that's a really important point. I mean, of course these are a model. They're a very useful model because we can't do, nor would we want to do experiments, you know, on developing ape brain. And it's very difficult to do any kind of experiments on developing human brain tissue. So this is really kind of the best option we have, but we can compare the human organoids to actual human foetal tissue. And we find that early in development actually organoids are quite a good model for the developing brain. And so there's no reason to believe that that wouldn't be true for apes as well. And so it's a fairly safe assumption that these findings would probably apply to what's happening in the early brain. But of course, this is really only the very early events. And later on, the organoids do start to diverge from the actual brain quite a bit.


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