The Human Brain Is Two Separate Organs, Stanford Researchers Say. The Front and the Back Grow From Two Different Progenitor Cells That Never Mix, With Their DNA Packaged Differently From the Start, a Split That Goes Back 550 Million Years to Acorn Worms and Jellyfish.

For as long as anyone has drawn diagrams of embryonic development, the brain has been shown growing from a single sheet of cells that folds, bulges and subdivides into the regions of the adult organ. A Stanford Medicine-led team reports in Nature Neuroscience that the diagram is wrong at its root. The front of the brain and the back of the brain arise from two different progenitor cell populations that are separate from the earliest moments of development and never overlap, which means the human brain is, in a real developmental sense, two organs fused together. "We've shown for the first time that the front of the brain arises from a totally different progenitor cell than the back of the brain," said Kyle Loh, associate professor of developmental biology and the study's senior author.

The two lineages are marked by two genes. Progenitor cells that express Otx2 go on to form the forebrain and midbrain, the seat of language, consciousness and abstract reasoning. Cells that express Gbx2 form the hindbrain, the brain stem that regulates breathing, heartbeat, appetite and the muscles of the face and throat. Working in mouse embryos during gastrulation, the stage when the body's basic layers are laid down, the team found the two populations mutually exclusive from the start. When they examined the cells' chromatin, the packaging that determines which genes are accessible and which are bundled away, they found the DNA arranged differently in each type, locking each progenitor into its fate before any recognizable brain structure exists.

That lock explains a long-standing failure in the lab. Researchers have been able to coax human pluripotent stem cells into forebrain neurons for years, but authentic hindbrain neurons have proved stubbornly out of reach. "Previous attempts to make hindbrain neurons likely tried to coax forebrain progenitors into hindbrain cells, which our study shows is not possible," said Rayyan Jokhai, a graduate student and co-first author with Carolyn Dundes. Once the team started from the correct Gbx2 lineage, they guided human stem cells into functional hindbrain motor neurons for the first time.

The split is old. The same two-origin pattern appears in chickens and zebrafish, and in acorn worms, which branched off more than 550 million years ago. Jellyfish, whose ancestors diverged 600 to 700 million years ago, possess two entirely separate nervous systems. The authors read that as evidence that the vertebrate brain was assembled by evolution from two ancient nervous systems that were joined rather than one that grew more elaborate, with the seam still visible in every human embryo.

The practical payoff is a new set of cells to study. Hindbrain motor neurons are the cells that die in amyotrophic lateral sclerosis and in spinal muscular atrophy, the leading genetic cause of death in infants, and until now there was no reliable way to grow human versions in a dish. The hindbrain also houses the hunger circuits that weight-loss drugs act on. Being able to build the back of the brain from its own progenitors, the researchers say, is the starting point for modeling those diseases and testing treatments on the right cells. The work, which included collaborators at Caltech and UC San Francisco, was supported by the NIH, the NSF, the California Institute for Regenerative Medicine and the Spinal Muscular Atrophy Foundation, among others.