We humans are proud of our big brains, which are responsible for our ability to plan ahead, communicate, and create. Inside our skulls, we pack, on average, 86 billion neurons—up to three times more than those of our primate cousins. For years, researchers have tried to figure out how we manage to develop so many brain cells. Now, they’ve come a step closer: A new study shows a single amino acid change in a metabolic gene helps our brains develop more neurons than other mammals—and more than our extinct cousins, the Neanderthals.
The finding “is really a breakthrough,” says Brigitte Malgrange, a developmental neurobiologist at the University of Liège who was not involved in the study. “A single amino acid change is really, really important and gives rise to incredible consequences regarding the brain.”
What makes our brain human has been the interest of neurobiologist Wieland Huttner at the Max Planck Institute of Molecular Cell Biology and Genetics for years. In 2016, his team found that a mutation in the ARHGAP11B gene, found in humans, Neanderthals, and Denisovans but not other primates, caused more production of cells that develop into neurons. Although our brains are roughly the same size as those of Neanderthals, our brain shapes differ and we created complex technologies they never developed. So, Huttner and his team set out to find genetic differences between Neanderthals and modern humans, especially in cells that give rise to neurons of the neocortex. This region behind the forehead is the largest and most recently evolved part of our brain, where major cognitive processes happen.
The team focused on TKTL1, a gene that in modern humans has a single amino acid change—from lysine to arginine—from the version in Neanderthals and other mammals. By analyzing previously published data, researchers found that TKTL1 was mainly expressed in progenitor cells called basal radial glia, which give rise to most of the cortical neurons during development.
The researchers introduced both the human and archaic versions of the gene into mice, which typically don’t express either form during development. Mouse brains with the human version produced more basal radial glia, which in turn developed into more cortical neurons, than did mice with the archaic version.
The team also wondered whether TKTL1 influenced the deep folding of the human brain, a geometry that allows us to squeeze extra neurons inside our skulls. Mice lack those folds completely, but ferrets, despite carrying the archaic version of TKTL1, have some folds. When the researchers introduced the human version of the gene into ferrets, the animals produced more cortical neurons and had larger brain folds, the researchers report today in Science. “I was not expecting to see an increase in [folds],” says first author Anneline Pinson, a postdoc at Max Planck. “It makes sense because we have more neurons, but to look at it was quite striking and surprising.”
Next, the researchers used CRISPR technology to knock out TKTL1 in fetal human neocortex cells; tissue lacking the gene produced fewer basal radial glia. Finally, the team compared the effect of both versions of the gene in brain organoids made of human embryonic cells floating in petri dishes. The human version again led to more progenitor cells and eventually more neurons compared with the archaic gene. Although additional genes may be involved, the finding “makes the point that this one gene is an essential player,” in shaping our big brains, Huttner says.
The team also probed how TKTL1 exerts its effects, with experiments in human tissue and in mice. TKTL1 encodes an enzyme that helps cells produce fatty acids, which are important in cell division. The researchers suspect the extra fatty acids produced by the human version allow progenitor cells to grow and divide more, resulting in more neurons.
The paper, with its multiple experiments, “is a tour de force,” says Alysson Muotri, a neuroscientist at the University of California, San Diego, School of Medicine. However, he wished the team had also explored changes in electrical activity in the modified brain organoids. He and his team showed last year that NOVA1, another gene with a unique version in modern humans, altered the appearance, growth, and electrical activity of such organoids. If the TKTL1 findings hold up, he says, “We are building up a list of genes that probably affect neural development and were positively selected in a human population.”
For Christoph Zollikofer, a paleoanthropologist at the University of Zürich, the new paper presents a “completely new … smoking gun” that shows how our brains differ from those of Neanderthals. But he cautions that the data can’t settle debates about Neanderthal mental capabilities. Brain size and neuron numbers don’t always translate into higher intelligence; for him, better cognition is all about the connections between neurons.
Pinson and Huttner acknowledge the point. Still, Huttner says, “Having more neurons is probably not bad.”