‘The most striking difference about the human brain is just how big it is’

24.6.2022 | Madeline Lancaster is known as the inventor of brain organoids, also called ‘mini brains’. We caught up with her for a conversation about how we can study psychiatric conditions in a tiny clump of cells, and what exactly it is about the human brain that sets it apart from that of our closest relatives.
Madeline Lancaster
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Madeline Lancaster
You consider yourself a developmental neurobiologist. Did you always know that was the field you wanted to pursue?

I was always pretty taken with the brain. But actually, when I took developmental biology in undergrad, I thought it was really boring. I didn’t get into it until later, when I started working in a lab as a PhD student. The lab focused on a group of neurological disorders which are really developmental disorders. Looking at these patients and the phenotypes that they had, it was all coming about because of developmental abnormalities. It finally clicked for me why developmental biology was so important.

You’re most famous for your pioneering work on brain organoids, these self-organising 3D neuron structures often called ‘mini brains’. Did that grow organically from your interest in developmental neurological disorders?

It definitely came about naturally. I started thinking about what was going wrong in these patients with neurodevelopmental disorders, which then sparked an interest in what normally happens during development.

And then of course, the evolutionary side got me really excited. Thinking about what’s really unique about our human brains during development, because when you look at all of these relatively common conditions that human beings suffer from, like depression and autism spectrum disorders – these are affecting uniquely human qualities.

For example, it’s very difficult to model something like schizophrenia in a mouse. Being able to speak and then hearing voices speaking to you, a mouse isn’t going to be able to experience that.

So how do you go about modelling something like schizophrenia in an organoid? Of course, they also can’t hear voices.

When you start to think about what is special about the human brain, you see that already during development, our brains are developing differently. And so we can look at cell biology and tissue morphology: how cells come together and make decisions about what cell types to make.

We can actually take cells from a patient, so for example a blood sample, a skin biopsy or even a plucked hair. You get live cells, culture them in a dish and then you can reprogram them. You can trick them and take them back to the really early embryonic stem cell stage, and then we can use those to generate brain organoids.

Of course, you can’t look at social abilities in a brain organoid made from an autistic person, but what you can do is look at things like what neurons are present. Are there differences in the types of neurons being made?

Do we know that an organoid made like that reflects the brain of the person it came from?

It depends on what exactly you’re studying. Brain organoids are small. So if you are studying, say, a person with epilepsy, you can do an EEG and see that during an epileptic seizure, these long distance abnormal activities spread across the brain. Obviously, a tiny little organoid is not going to have that long range.

But what you could model are things on a more local level. For example, in the brain of a person with epilepsy, there might be a place where the seizure starts. So you could look at the organoid and ask, is there an imbalance of a particular type of neuron, like excitatory versus inhibitory neurons?

Also, organoids are very good models for the developing brain. For example, one of the first things we did was make an organoid from the skin sample of a patient with microcephaly, where the brain is smaller. And the organoids are smaller. You can see that, already during the early stages of development, there’s a difference in size.

That’s so interesting. You mentioned the evolutionary side of things earlier and finding out what makes human brains human. Do you compare with non-humans?

That’s exactly what we do. Just like we can make organoids from a patient, we can make organoids from an animal. For example, we can use leftover blood samples from Zoo animals, from standard veterinary checkups. So we’ve been comparing human organoids to those of chimpanzees and gorillas, and we find some really interesting differences that point to why our brains are so large.

The most striking difference about the human brain is just how big it is. Our brains are about three times larger than a chimpanzee’s or a gorilla’s, and yet when you look at body size, we’re actually smaller than them. Three times maybe doesn’t sound that impressive, but when you look at the neuron number, you’re talking about 60 billion more neurons.

If you look at absolute neuron number, a chimpanzee brain is actually closer to a mouse’s than it is to a human’s. It’s like a supercomputer compared to a Gameboy.

Do we know why our brains are so much larger?

It is a real core interest in my lab. What we’ve been finding is that really early in development, there’s a difference in the founder stem cells that are going to give rise to the entire neuron population, particularly the cerebral cortex, which is the part that is really important for our higher cognitive capabilities.

We find that in the human organoids, those progenitors have a chance to proliferate and make more of themselves for longer, compared to the chimpanzee or gorilla organoids. So what happens is that you get this increase in the number of founder cells, and once they start making neurons, you just end up with many more neurons in humans.

At the same time, one thing we’re realizing is just how similar the human, chimpanzee and gorilla brains are. We are really, really closely related. It’s a quantitative difference, not a qualitative difference. There’s no special brain region that only humans have. Even the language parts of our brains, gorillas and chimpanzees have those too, and they use them to communicate with each other.

It’s remarkable how size matters so much. Many would probably assume that there was something additional at play.

Well, we know that for primates in general, our neurons have more elaborate connections. If you look at the same type of neuron in a mouse, the human neuron has way more branches. But what we don’t know much about is that difference between humans and our closest relatives.

In the long term, I’m also very interested in what sort of mechanisms different animals use to get big brains. We often focus on ourselves, but there are lots of really smart animals out there, like elephants. Can we look at elephant organoids and understand whether their brain enlargement is coming about through the same mechanisms as ours, or is it something completely different?

What an interesting thought to end on. Dr. Lancaster, thank you very much for your time.
  (© Emilie Steinmark / AcademiaNet /

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