Scientists at Stanford have grown human brain tissue inside mice, and in some of the animals, this tissue now accounts for half the brain by volume.
The point of the experiment published in Nature is to study disorders such as schizophrenia, epilepsy, cerebral palsy, intellectual disability, and rare dementias that have proven almost impossible to investigate directly. In each case, researchers can take skin cells from a patient, reprogram them into brain tissue, implant that tissue in a living animal, and watch how the disorder takes hold.
“These animal models offer a unique opportunity to study how disease-associated alterations in human brain circuitry manifest in an intact nervous system,” said Sergiu Pașca, a professor of psychiatry and behavioral sciences at Stanford Medicine who led the study, in a Stanford Medicine statement.
The ultimate aim, Pașca noted, is to test interventions that can prevent or correct these conditions, a longstanding hurdle in neurology, where live human brain tissue has historically been inaccessible.
The experimental path
An earlier version of the experiment put human neurons into rat brains. The cells were wired in successfully, but there was not much room for them to expand. So the team engineered mice that develop without a cerebral cortex or hippocampus, leaving a cavity the size of roughly 14 million mouse cells.
The mice ended up surviving whilst other brain regions took over the missing functions. Essentially, they looked normal but walked cautiously and forgot things.
As newborns, the mice received several injections of about 100,000 human cells each, grown from donated skin cells. Three months later, the tissue had connected to the animals’ blood supply and filled the cavity with about four million human neurons, some of them even forming links with mouse brain cells and spinal cord.
The tissue was not organized the way a human brain is, however, and it stayed immature, roughly equivalent to a human fetal brain at mid-gestation. The mice showed no cognitive enhancement, though their gait and memory problems eased slightly.
To show what the model can do, the team deprived some animals of oxygen for five hours (they were kept at 5% O₂), reminiscent of the conditions that cause cerebral palsy during pregnancy and birth. The human neurons within the mice turned out to be strikingly vulnerable.
The researchers also found von Economo neurons in the transplanted tissue, cells previously observed only in postmortem brains and among the first to die in frontotemporal dementia, a condition Pașca now plans to study in these mice.
Ethical concerns
The ethical questions remain unsettled. Organoid research has long raised concerns about whether lab-grown brain tissue could become conscious or feel pain and about the welfare of animals carrying it.
Pașca says the project has had ethical oversight throughout. The paper’s ethics statement says all experiments involving human cells “were predicated on ethical guidelines and safeguards and were adherent to all relevant guidelines and regulations, including the International Society for Stem Cell Research (ISSCR),” and that human donors consented to the use of their cells for transplantation into animals.
Still, bioethicists, including those associated with the UK’s Nuffield Council on Bioethics, caution that close monitoring and ethical oversight must continue to assess the welfare of animals carrying human brain tissue.
The research also highlights a divide within neuroscience. While in vivo models solve the challenge of providing blood vessels and biological signals to human cells, critics in developmental biology point out that growing human tissue inside an engineered rodent cavity is artificial and may not accurately reflect natural human brain formation. Many researchers argue the field should prioritize purely laboratory dish models to reduce animal experimentation and avoid ethical friction.
Sources: Nature, Stanford Medicine, Nuffield Council, The Guardian