Scientists, including one of Indian origin, have created brain "organoids" of chimpanzees - our closest living relatives - in laboratory to help explain the evolutionary origins of the distinctly human brain. At some point during human evolution, a handful of genetic changes triggered a dramatic three-fold expansion of the brain's neocortex, the wrinkly outermost layer of brain tissue responsible for everything from language to self-awareness to abstract thought, according to the study published in the journal Cell. Identifying what drove this evolutionary shift is fundamental to understanding what makes us human, but has been particularly challenging for scientists because of ethical prohibitions against studying the developing brains of the chimpanzees in the lab. "By birth, the human cortex is already twice as large as in the chimpanzee, so we need to go back much earlier into embryonic development to understand the events that drive this incredible growth," said Arnold Kriegstein, a professor at University of California, San Francisco in the US. Now, researchers, including Aparna Bhaduri, a postdoctoral researcher in the Kriegstein lab, have gotten around this impasse by creating chimpanzee brain "organoids" - small clusters of brain cells grown from stem cells in a laboratory dish that mimic the development and organisation of full-size brains. They generated 56 organoids from stem cells derived from the skin of eight chimpanzees and 10 humans, marking the first time researchers have been able to produce and study chimpanzee brain organoids en masse. "Our ability to take skin cells from an adult chimpanzee, turn them into iPSCs, and then study their development in laboratory dishes is astounding," said Kriegstein. Induced pluripotent stem cells or iPSCs are adult cells, usually skin cells, reprogrammed into stem cells that can become any tissue in the body. "It's a 'science fiction' experiment that couldn't have happened 10 years ago," he said. "These chimpanzee organoids give us an otherwise inaccessible window to six million years of our evolution. They let us ask new questions about what makes us human," said Alex Pollen, an assistant professor at UC San Francisco. Bhaduri deconstructed human and chimpanzee organoids at different stages of development, allowing her to directly compare the specific cell types and genetic programmes that orchestrate the growth of the chimp and human brain. By looking for differences in gene activity between human organoids and chimp organoids, Bhaduri identified several hundred genetic changes unique to the human lineage that could help explain the evolutionary origins of the distinctly human brain. For instance, Bhaduri discovered that neural precursor cells called outer radial glia (oRG) showed heightened activity of a key growth signalling network known as the mTOR pathway in human organoids. "It was particularly exciting to discover a molecular pathway in these cells that appears to have been specifically targeted during evolution and may help explain their specialised role in generating the advanced human cortex," Bhaduri said. Problems with mTOR signalling have also been linked to autism and other uniquely human neurodevelopmental disorders, suggesting new questions about whether pathways involved in the relatively recent evolution of our unusually large brains play some special role in these disorders.