The Idea Organ

A fundamental question in biology is: how did humans acquire their unique characteristics? What allows us to stand upright, while our primate ancestors walked on all fours? What brain alterations drove our increased intelligence and allowed us to perceive our own mortality? One of the mechanisms that has been hypothesized to be involved is changes in gene expression elicited by nucleotide alterations in non-coding regions of the human genome. In my talk, I will focus on a class of DNA sequences hypothesized to have this role. These human accelerated regions (HARs) are segments of DNA that exhibit 3 characteristics that—together—make them prime candidates for specifying human-specific traits by altering patterns of gene expression. First, HARs have rapidly changed in sequence specifically in the human lineage. Second, HARs are highly conserved in sequence, indicating they that must have been selected for the ability to confer one or more function in higher organisms. Third, the vast majority of HARs are in the non-coding portion of animal genomes, indicating that most are likely to have a regulatory function.

While HARs are hypothesized to confer human-specific traits, this has yet to be demonstrated. In my talk, I will describe a HAR—called “HAR123”—that has properties consistent with such a role in the nervous system. We elected to focus on HAR123 because it is in the intron of a gene essential for a RNA turnover pathway—nonsense-mediated RNA decay (NMD)—that has roles in the nervous system and whose disruption causes neural disease. Through both in vitro and in vivo studies, we discovered that HAR123 is a conserved transcriptional enhancer that influences nervous system development and function. HAR123 promotes human neural progenitor cell (NPC) formation, influences the ratio of neurons and glial cells produced from NPCs, and functions in cognitive flexibility in vivo. We identified targets of HAR123 and found that one of these targets, HIC1, acts downstream of HAR123 to promote NPC generation. Finally, we found that the human and chimpanzee orthologs of HAR123 subtly differ in their molecular and cellular effects, consistent with the possibility that HAR123 has evolved since the human-chimpanzee split to confer nervous system traits specific to humans.

Humans excel at transmitting ideas, skills, and knowledge across generations, and at building on those competencies in a cumulative manner. The transmission of our cumulative culture is assumed to depend on both language and mental perspective-taking, or theory of mind. If humans have specialized abilities in these domains, we must have neurobiological specializations to support them. Our research has used comparative primate neuroimaging to attempt to identify such specializations. The arcuate fasciculus is a white matter fiber tract that links Wernicke’s and Broca’s language areas. It is known to be involved in multiple, high level linguistic functions such as lexical semantics, complex syntax, and speech fluency. Using diffusion weighted imaging and tractography, we have demonstrated human specializations in the size and trajectory of the arcuate fasciculus that may partially explain human linguistic abilities. Theory of Mind depends on a set of cortical regions that belong to a neural network known as the default mode network that is functionally connected, highly active at rest, and deactivated by attention-demanding cognitive tasks. We and others have used functional neuroimaging to show that chimpanzees and other primates appear to have a default mode network that is similar to that of humans. However, the non-human primate default mode network seems to have weaker connectivity between certain key nodes, suggesting that these connections could play a role in human theory of mind specializations.

Human brain expansion is often discussed in terms of the genetic and molecular innovations that drove uniquely human cognitive abilities. Yet evolution is fundamentally a process of tradeoffs. Disproportionate expansion of forebrain structures increases the demands placed on long-range connectivity, metabolism, and cellular maintenance, imposing costs that scale with brain size. These constraints may be especially acute for small populations of midbrain dopaminergic neurons, which must sustain extraordinarily large axonal arbors to coordinate activity across striatum and cortex.

In this talk, I will discuss how we are using stem-cell-derived brain organoids to investigate the development of human-specific connectivity differences in dopaminergic neurons and to test whether these cells deploy compensatory mechanisms to cope with the metabolic and structural demands of large brains. We differentiated pluripotent stem cells from humans, chimpanzees, orangutans, and macaques together into interspecies ventral midbrain organoids capable of long-range axonal growth, spontaneous activity, and dopamine release and further exposed these organoids to bioenergetic stress. This “phylogeny-in-a-dish” approach revealed human-specific changes in gene expression linked to mitochondrial transport and oxidative stress buffering, as well as candidate regulatory mechanisms underlying their evolution, consistent with evolved neuroprotective effects in the human lineage.

Together, these findings support a model in which human brain evolution involves not only mechanisms driving greater computational capacity, but also the emergence of cellular adaptations that mitigate the costs of large, highly connected brains.

The evolution of the human brain reflects the interplay between genetic innovation and environmental pressures. Neuro-oncological ventral antigen 1 (NOVA1) is an evolutionarily conserved splicing regulator essential for neural development and harbors a protein-coding substitution unique to modern humans compared with Neanderthals and Denisovans. To investigate the functional consequences of this human-specific change, we reintroduced the archaic NOVA1 allele into human induced pluripotent stem cells and examined neural development using cortical organoids. Organoids expressing the archaic variant exhibited accelerated maturation, increased surface complexity, altered synaptic marker expression, and changes in electrophysiological properties, indicating that the extinct human NOVA1 allele contributes to accelerated and distinct cortical development. To explore potential evolutionary pressures underlying the selection of the modern allele, we assessed long-term environmental exposure to lead using fossilized teeth from multiple hominid species spanning over two million years. Our analysis reveals pervasive lead exposure across extinct and extant hominids, challenging the notion that lead toxicity is exclusively a modern phenomenon. Notably, lead exposure selectively disrupted FOXP2 expression in cortical and thalamic organoids carrying the archaic NOVA1 variant, implicating a gene critical for speech and language development. These findings were independently validated in NOVA1 humanized mouse models with altered vocalization. Together, these fossil, cellular, and molecular findings suggest that gene–environment interactions involving NOVA1 and environmental neurotoxins may have influenced neural circuit development, social behavior, and complex language capacity, potentially conferring a selective advantage to modern humans during evolution.