What's so special

about the
human brain?
Torrents of data from cell atlases, brain
organoids and other methods are finally
delivering answers to an age-old question.
Illustrations by Phil Wheeler
By Kerri Smith
Infographics by Nik Spencer

PAUSE VIDEO
T
here must be something about the human brain that’s
different from the brains of other animals — something that
enables humans to plan, imagine the future, solve crossword
puzzles, tell sarcastic jokes and do the many other things that
together make our species unique. And something that explains why
humans get devastating conditions that other animals don’t — such as
bipolar disorder and schizophrenia.
So, what is that
something?
In the past few years, new methods for studying the human brain —
and those of other species — have started to reveal key differences in
greater detail than ever before.

Researchers can now snoop on what happens inside millions of brain

cells by cataloguing the genes, RNA and proteins they produce. And
by studying brain tissue, scientists are learning key lessons about how
the organ develops and functions.

One is that the differences between human brain cells and those of
other species are often subtle. Another is that the human brain
develops slowly compared with other animals. But how these features
give rise to our cognitive skills is still a mystery — although
researchers have plenty of promising leads.
Size matters
If there is one thing that stands out about the human brain compared
with those of other primates — and even those of some extinct human
relatives — it is its size.
There is also a big difference between the number of neurons in the
human brain compared with those of other animals. The human brain
has about 1,000 times more neurons than the mouse brain, for
instance, and 13.5 times more than the macaque1..

But brain size and neuron number aren’t everything; some animals
whose brains look and develop differently to mammals — such as
ravens and other members of the crow family — can learn or
remember impressively. “Brain size alone can’t explain human
cognition,” says Chet Sherwood, an anthropologist and
neuroscientist at The George Washington University in Washington
DC.
Sources: Brain outlines: C. C. Sherwood & M. Schumacher (2018); A. M. M. Sousa et al.
(2017). Brain weights: G. Tartarelli & M. Bisconti (2006). Brain EQ: G. Roth & U. Dicke
(2005). Chimpanzee and human: C. C. Sherwood & M. Schumacher (2018). Neuron numbers:
Ref. 1; S. Herculano-Houzel (2014); S. Olkowicz et al. (2016).
Special recipe
Looking at brain cells closely has shown some interesting patterns.
Over the past five years, techniques that enable scientists to
catalogue the genes expressed in a single cell have been revealing the
many different types of cell that make up a brain — at a level of detail
much higher than anything achieved before.

Last year, a team based at the Allen Institute for Brain Science in
Seattle, Washington, reported the most-comprehensive atlases yet of
cell types in both the mouse and human brain. As part of an
international effort called the BRAIN Initiative Cell Census Network
(BICCN), researchers catalogued the whole mouse brain, finding
5,300 cell types2; the human atlas is unfinished but so far includes
more than 3,300 types from 100 locations3; researchers expect to find
many more.

Some regions do have distinct cell types — for instance, the human
visual cortex contained several types of neuron that were exclusive to
that area4. But in general, human-specific cell types are rare.

The overall impression, when comparing the cell types of the human
brain with other species, is one of similarity. “I was expecting bigger
differences,” says Ed Lein, a neuroscientist at the Allen Institute, who
is involved in efforts to catalogue cells in human, mouse and other
brains. “The basic cellular architecture is remarkably conserved until
you get down to the finer details”, he says.

Most human brain regions differ from primates and mice in the
relative proportions of cell types that appear5, and in the ways those
cells express their genes: it's not the ingredients that are different, but
the recipe.

Take these two comparable regions of the human and mouse cortex,
which both process auditory information. The mouse area contains a
higher proportion of excitatory neurons, which propagate signals,
relative to inhibitory neurons, which dampen activity. The human
region had a much greater proportion of non-neuronal cells, such as
astrocytes, oligodendrocytes and microglia. These cells support
neurons and also help to prune and refine their connections during
development. The ratio of these cells to neurons was five times that of
mice.
Source: Ref. 5
The upshot of the differences still isn’t clear, but the atlases provide a
way to study these cells and the genes they express, to better
understand their function.
Source: Ref. 6
Making connections
No neuron is an island, and the networks they form could be a huge
part of what gives various brains their different functions and
specialisms.
Source: Ref. 7; M. Sievers et al. (2024)
The finding was “super surprising”, says study leader Moritz
Helmstaedter at the Max Planck Institute for Brain Research in
Frankfurt, Germany. He thinks that this expanded network of
interneurons might help to solve one major problem in the human
brain: neurons operate quickly but thoughts and actions take
seconds. Larger networks of interneurons could prolong neuronal
activity, allowing the brain to generate more complex thoughts and
keep things ‘in mind’ for longer.

The team is now looking at larger segments of the human cortex.

The results of Helmstaedter's connectome study are supported by

genetic work. When comparing gene expression across species, many
differences turn out to be related to how the connections between
neurons — called synapses — connect with and signal to each other.

In a study8 led by researchers at the Allen Institute, a few hundred

genes showed expression patterns unique to humans. Often, these
specializations were related to circuit function — they were involved
in synapse-building or signalling. And they were often seen in non-
neuronal cells, such as astrocytes and microglia.
Slow to develop
Some scientists think that there is one key pedal that has been
pressed in the human brain that can explain many of the differences
between us and other species. The brake.

“Whatever you look at, it’s happening more slowly in humans,” says
neuroscientist Madeline Lancaster, who studies human brain
development at the MRC Laboratory of Molecular Biology in
Cambridge, UK.
Source: Ref. 6
This sluggish pace could help humans to grow more neurons, and
foster more diversity and complexity. It also gives the brain more time
to be shaped by its environment. Research suggests that, in humans,
neural progenitors, the cells that give rise to neurons, spend longer in
a limbo state before assuming their final identities9. Human
progenitors also have more potential — they can become more than
one broad type of neuron, whereas in rodents one type of progenitor
tends to develop into just one type of neuron10.
Source: Ref. 6
Although some changes to genes and cells undoubtedly make us who
we are, it's too early to leap to any conclusions, says Alex Pollen, a
geneticist who studies human brain evolution at the University of
California San Francisco. Some changes could just be side effects of
other adaptations — for example, an increase in certain types of
neuron so that brain regions could still communicate when the brain
expanded.

There are downsides, too, to our special abilities. Sherwood says that
humans undergo more drastic changes than other primates, such as a
shrinkage of the cortex, owing to ageing — in part because we live so
much longer. But even the oldest great ape brains don’t seem to
change as much as human brains do with age, he says. And some
conditions that seem specific to humans could be the price we pay for
complexity, says Lancaster. “Even a small defect could have more
dramatic consequences,” she says.

There’s plenty more to discover about how our brains make us so

talkative, sociable and intelligent. Scientists are interested in how
gene variants act on neurons and the brain; how neural activity during
development influences growth; and how parts of the brain other
than the cortex might have changed to endow humans with our
unique skills.

The confluence of technologies has energized researchers to look

afresh at a classic question, says Lancaster. “I feel lucky to be doing
science at this moment.”
 References
1. Herculano-Houzel, S. Front. Hum. Neurosci. 3, 31 (2009).

2. Yao, Z. et al. Nature 624, 317–332 (2023).

3. Siletti, K. et al. Science 382, eadd7046 (2023).

4. Jorstad, N. L. et al. Science 382, eadf6812 (2023).

5. Fang, R. et al. Science 377, 56–62 (2022).

6. Lindhout, F. W. et al. Nature 630, 596–608 (2024).

7. Loomba, S. et al. Science 377, eabo0924 (2022).

8. Jorstad, N. L. et al. Science 382, eade9516 (2023).

9. Otani, T. et al. Cell Stem Cell 18, 467–480 (2016).

10. Delgado, R. N. et al. Nature 601, 397–403 (2022).

11. Schmidt, E. R. E. et al. Nature 599, 640–644 (2021).

12. Fiddes, I. T. et al. Cell 173, 1356–1369 (2018).

13. Suzuki, I. K. et al. Cell 173, 1370–1384 (2018).

Author: Kerri Smith

Illustration: Phil Wheeler

Infographics: Nik Spencer

Design: Wes Fernandes

Subeditor: Joanna Beckett

Editor: Richard Monastersky

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