Humans take pride in having large brains because they enable us to communicate, plan ahead, and create. We have 86 billion neurons on average in our skulls, which is up to three times as many as our monkey relatives. Researchers have been attempting to understand how we are able to grow such a large number of brain cells for years. They’ve now made progress: According to a recent study, human brains produce more neurons than those of other mammals and even those of our extinct cousins, the Neanderthals, when a single amino acid in a metabolic gene is changed.
Brigitte Malgrange, a developmental neurobiologist at the University of Liège who was not involved in the study, calls the discovery “truly a breakthrough.” “A single amino acid substitution has amazing effects on the brain and is very, really essential.”
Wieland Huttner, a neurobiologist at the Max Planck Institute of Molecular Cell Biology and Genetics, has long been interested in what makes our brains human. His team discovered in 2016 that a mutation in the ARHGAP11B gene, which is present in humans, Neanderthals, and Denisovans but not in other primates, increased the number of cells that give rise to neurons.
While the size of our brains is similar to that of a Neanderthal, the structure of our brains is different, and we developed sophisticated technology that they were unable to. In order to identify these genetic differences, Huttner and his team focused on cells that give rise to neurons in the neocortex, particularly in Neanderthals and contemporary humans. The largest and most recently evolved area of our brain, located below the forehead, is where important cognitive functions take place.
The scientists concentrated on TKTL1, a gene whose version in Neanderthals and other mammals contains a single amino acid shift from lysine to arginine in contemporary humans. Researchers discovered that TKTL1 was mostly expressed in progenitor cells known as basal radial glia, which give rise to the majority of cortical neurons during development.
The gene was inserted into mice, which normally do not express either type during development, in both its human and ancient forms. Comparatively to mice with the archaic version, mouse brains with the human version produced more basal radial glia, which then gave rise to more cortical neurons.
The team also questioned if TKTL1 affected the human brain’s deep folding, a geometry that enables humans to cram more neurons inside our skulls. Ferrets contain some folds despite having an ancient form of TKTL1, but mice are completely devoid of those folds. According to a study published in Science today, ferrets with the human form of the gene created more cortical neurons and had larger brain folds. According to the first author and postdoc at Max Planck, Anneline Pinson, “I was not expecting to see an increase in [folds].” Although it makes sense given that we have more neurons, the observation was quite startling and unexpected.
The TKTL1 gene was then deleted using CRISPR technology in foetal human neocortex cells, which resulted in a decrease in basal radial glia production. Finally, using brain organoids created from human embryonic stem cells and floating in petri plates, the scientists compared the impact of both variants of the gene. In comparison to the ancient gene, the human version produced more progenitor cells and subsequently more neurons. The discovery “makes the point that this one gene is a crucial role” in forming our large brains, according to Huttner, even though other genes may also be involved.
The team conducted studies in mouse and human tissue to better understand how TKTL1 exerts its effects. Fatty acids are necessary for cell division and are produced by cells with the aid of an enzyme that is encoded by TKTL1. The extra fatty acids produced by the human version may enable progenitor cells to grow and divide more, leading to an increase in the number of neurons, according to the researchers.
According to Alysson Muotri, a neurologist at the University of California, San Diego School of Medicine, the study, with its numerous experiments, “is a tour de force.” He did regret that the scientists hadn’t also looked into variations in electrical activity in the altered brain organoids. He and his team demonstrated last year how the look, development, and electrical activity of these organoids were affected by NOVA1, another gene having a distinct form in contemporary people. He states that “We are building up a list of genes that probably affect cerebral development and were positively selected in a human population” if the TKTL1 findings are valid.
The new study, according to Christoph Zollikofer, a paleoanthropologist at the University of Zürich, “totally fresh… smoking gun” that demonstrates how human brains differ from Neanderthals’. He does, however, issue a warning that the evidence cannot end the controversy on Neanderthal mental prowess. Higher intelligence is not always correlated with larger brains or more neurons; for him, stronger connections between neurons are the key to improved cognition.
Pinson and Huttner agree with this statement. Huttner asserts that “having more neurons is probably not bad,” despite this.