Humans live in a world of ideas—born in the brain, shared through language, accumulated in culture across generations, and made reality. Professor Alysson Muotri, UC San Diego Departments of Pediatrics and Cellular and Molecular Medicine, examines how human brain evolution reflects the interplay between genetic innovation and environmental pressures, focusing on Neuro-oncological ventral antigen 1 (NOVA1), an evolutionarily conserved splicing regulator essential for neural development with a protein-coding substitution unique to modern humans compared with Neanderthals and Denisovans. By reintroducing the archaic NOVA1 allele into human induced pluripotent stem cells and studying cortical organoids, the work finds accelerated maturation, increased surface complexity, altered synaptic marker expression, and changes in electrophysiological properties. Muotri also analyzes long-term lead exposure using fossilized teeth from multiple hominid species spanning over two million years, revealing pervasive exposure across extinct and extant hominids. Lead exposure selectively disrupted FOXP2 expression in cortical and thalamic organoids carrying the archaic NOVA1 variant, and findings were independently validated in NOVA1 humanized mouse models with altered vocalization. Together, these results suggest gene–environment interactions may have influenced neural circuit development, social behavior, and complex language capacity. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Science] [Show ID: 41297]