Neanderthal-type "mini-brains" created in the laboratory with the CRISPR tool

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Rest assured, no one has (yet) created lab brains with consciousness. But, yes, researchers have been able for years to create mini-brains, called brain organoids, serving as models of neuronal behavior in the context of various research, including the study of certain brain pathologies. Recently, scientists have created brain organoids containing a genetic variant harbored by two extinct human relatives, Neanderthals and Denisovans.

To begin with, you should know that the tissues here developed from human stem cells are far from being true representations of the brain of Neanderthals or Denisova. However, they have distinct differences from classical human organoids, especially in terms of size, shape and texture. The findings, published in the journal Science on February 11, could help researchers around the world understand the genetic pathways that allowed the human brain to evolve like this.

It's an extraordinary document with extraordinary claims ," says Gray Camp, a developmental biologist at the University of Basel in Switzerland, whose lab reported last year that it had cultivated brain organoids containing a gene common to Neanderthals. and humans. This latest work takes research further by examining the variants of genes that humans have lost during evolution. But Camp remains skeptical of the implications of the findings, and says this work brings up other questions that will need to be explored in turn.

Humans are more closely related to Neanderthals and Denisovans than to any living primate, and some 40% of the Neanderthal genome is still found distributed in the current population. But researchers have limited means to study the brains of these ancient species: soft tissue is not well preserved, and most studies rely solely on inspecting the size and shape of fossilized skulls. But it's important to know how the genes of species differ from those of humans, because it helps researchers understand what makes the human species unique, especially its brain.

When attached to a lab plate, neurons in brain organoids (yellow) divide among other cells called astrocytes (blue). © Muotri Lab / University of California

The researchers, led by Alysson Muotri, a neuroscientist at the University of California at San Diego, used the CRISPR-Cas9 genome editing technique to introduce the "Neanderthal" and "Denisovan" version of a gene called NOVA1 into human pluripotent stem cells (which can develop into any type of cell). They cultured them to form organoids, clumps of brain tissue-like tissue up to 5 millimeters in diameter, next to normal human brain organoids for comparison.

NOVA1, the key gene for synapse formation

It immediately appeared that the organoids expressing the archaic variant of NOVA1 were different. “ As soon as we saw the shape of the organoids, we knew we were on the right track, ” says Muotri. Organoids in the human brain are generally smooth and spherical, whereas organoids produced with the old gene had rough and complex surfaces, and were smaller. This is probably due to the differences in the way cells grow and multiply, according to the authors.

To determine which archaic gene to express in organoids, the researchers compared a library of human genome sequences with the nearly complete genomes of two Neanderthals and one Denisovan. They identified 61 genes for which the human version is systematically different from that of ancient species. Among these, NOVA1 is involved in the formation of brain synapses, or nerve junctions, and is associated with neurological disorders when its activity is impaired

Brain organoids containing an archaic gene variant (right) were smaller and more coarsely textured than human organoids (left). © CA Trujillo et al./Science

The human NOVA1 gene differs from the archaic variant - which is still present in other living primates - by a single base which the researchers integrated into stem cells using CRISPR-Cas9. This difference exchanges a single amino acid of the NOVA1 protein produced by archaic organoids. “ The fact that all humans, or almost all humans, now have this version and not the old one, means that it has given us a huge advantage at certain points in evolution. So the question we ask ourselves now is what are these advantages, ”says Muotri.

The differences between the resulting organoids continued at the molecular level. The team found 277 genes that have different activity between the old gene and human organoids; some of these genes are known to affect neural development and connectivity. As a result, archaic organoids contained different levels of synapse proteins, and their neurons were activated in a less orderly fashion than those in control tissues. It is also proven that they have matured faster.

A small genetic step, but a big evolutionary step

The most significant finding is that if you reverse [the gene] to an ancestral state, you observe an effect in the organoid, ” says Wolfgang Enard, evolutionary geneticist at Ludwig Maximilian University in Munich, Germany. Maximilian is amazed that such a small genetic difference causes such obvious changes, but he doubts that just the particular aspect of organoids tells us a lot about the brain of Neanderthals.

He also cautions that these organoids from ancient genes are unlikely to fully represent the true brain tissue of Neanderthals. On the contrary, the observed characteristics could be the result of the modification of an important protein present in humans due to the cumulative effects of many mutations stacked on top of each other over time. “ It's like the (board game of skill) Jenga. […] You remove this amino acid and the brain no longer works  ”

A "plan" to extend human life through artificial intelligence

Nonetheless, the edited organoid approach could be useful for studying brain evolution in primates, says Suzana Herculano-Houzel, evolutionary neuroscientist at Vanderbilt University in Nashville, Tennessee. Muotri's team now plans to develop organoids edited to contain other reversible genes that could offer insights into the human brain. If researchers can understand the evolutionary path that led humans to their current state, they could improve our understanding of diseases specific to the human brain.

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