Researchers at Stanford University have created mice with half-human brains by transplanting lab-grown human brain cells into newborn rodents engineered to lack a cerebral cortex and hippocampus, a development aimed at studying neurological and psychiatric disorders like schizophrenia, epilepsy, and cerebral palsy, according to a study published in Nature by Sergiu Pașca, a professor of psychiatry who led the work.

## Making Space for Human Cells in Rodent Brains To overcome the size limitations faced in previous animal models where human neurons were transplanted into rat brains, researchers genetically engineered mice to stunt the growth of the cerebral cortex and hippocampus. According to Sergiu Pașca, the newborn mice received several injections, each containing about 100,000 human brain cells derived from reprogrammed skin cells, placed directly into the missing tissue cavities. The rodents lacked about 14m mouse brain cells and ended up with about 4m human ones, which accounted for approximately half the brain by volume. Three months after the surgery, the human tissue successfully integrated with the mouse blood supply and filled the cavity. Some human neurons formed active connections with mouse brain cells and the spinal cord. Tests on these xenocortical mice showed the animals were not cognitively enhanced by the transplants, though their shaky gait and cognitive problems showed slight improvements, according to the findings. ## Bridging the Gap in Brain Medicine The approach addresses a major bottleneck in neurology and psychiatry. According to Sergiu Pașca, researchers have lagged behind every other branch of medicine in finding therapeutic solutions because the human brain is both highly complex and largely inaccessible for direct investigation. By growing human tissue from patients with brain disorders inside living animals, scientists can observe how these conditions take hold and test potential drug treatments. To demonstrate this utility, researchers exposed some of the xenocortical mice to five hours of low oxygen. According to the study, this test revealed the distinct vulnerability of human nerve cells to oxygen deprivation—a factor that can cause cerebral palsy during pregnancy and birth. Furthermore, the human tissue inside the mice contained rare von Economo neurons, cells previously only observed in postmortem examinations and known to be among the first to die in frontotemporal dementia. Sergiu Pașca now plans to study this rare form of dementia using the xenocortical mouse model. ## Ethical Oversight and Scientific Perspectives The development of neural organoids has raised significant ethical questions regarding animal welfare and whether clumps of tissue could ever become conscious or feel pain. According to Sergiu Pașca, the Stanford project received extensive ethical oversight from the start. Emily Jackson, a professor of law at the London School of Economics and chair of a recent report on neural organoids for the Nuffield Council on Bioethics, noted that animal welfare remains a critical concern, stating that it will be necessary to closely monitor these animals to evaluate the impact on them. Other researchers have noted both the promise and the limitations of the model. Dr. H. Isaac Chen, an associate professor of neurosurgery at the University of Pennsylvania Perelman School of Medicine who was not involved in the study, described the work as an advance that creates interesting options for modeling human neurodevelopment and related disorders from a cellular and molecular perspective. Meanwhile, Prof. Madeline Lancaster, group leader at the MRC Laboratory of Molecular Biology in Cambridge, suggested the approach is best suited for questions requiring a whole animal, though she noted it is less clear how it informs natural human brain development due to its artificial nature. While many organoid researchers continue to work with in vitro dishes to reduce animal use in research, Lancaster added that in vivo work can help inform improvements for mature in vitro models.