Human brain tissue grown in mice for first time

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Scientists have genetically engineered mice brains to enable human cerebral tissue to take root in them, in a breakthrough that promises to boost efforts to develop treatments for diseases and developmental disorders.

The rodents grafted with human brain tissue showed different behaviours from their unmodified peers, such as walking differently when subjected to oxygen shortages, the researchers said.

The transplant technique opens the way to observing human fetal-stage neuron activity with a detail impossible to achieve in either living people or lab-grown brain tissue cultures. The ability to recreate and sustain at least some processes of the developing human brain in another organism has long been a central target of researchers in the field.

“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, research leader and professor at Stanford University in California.

“Neuroscientists will be able to learn much more about the causes and mechanisms of neurodevelopmental and pregnancy-incurred disorders and to test possible interventions to correct or prevent them.”

Pașca’s team engineered and bred the mice so that almost all of their cerebral cortex — the brain’s outermost layer — was absent, according to a paper published in Nature on Wednesday. That gave the grafted human brain tissue room to grow and form connections with its rodent host’s brain and spinal cord. The human tissue was grown from stem cells that were originally derived from skin and are capable of differentiating into most body cell types.

The researchers exposed the engineered so-called xenocortical mice to a low-oxygen environment for five hours, mimicking a cause of cerebral palsy in humans when it occurs during pregnancy or around birth. The oxygen-starved rodents found it harder to maintain their balance and gait, while their unengineered peers were almost unaffected.

The xenocortical organisms could aid better understanding of the causes of other conditions including schizophrenia, epilepsy and profound autism, Pasca said.

The new technique had undergone extensive ethical scrutiny, both internally at Stanford and from external experts, he said. He pointed to questions over whether it would be ethical not to carry out this kind of research given the large numbers of people worldwide who suffer from incurable neurological disorders.

The research was a “technical leap” with the “immediate prize” of “watching human cortical neurons develop, molecularly and electrically, in a far more realistic setting than a dish”, said Oscar Marín, professor of neuroscience at King’s College London.

“That allows benchmarking their maturation against genuine human fetal tissue, and recording the activity of large populations of human neurons in an awake animal,” Marín said. “It is also a good platform for testing whether a drug or gene therapy changes how human neurons behave.”

Marín and other experts highlighted constraints on the xenocortical technique. These included that the grafted tissue did not reflect the full complexity of the human brain and that the connections being studied were human to mouse rather than human to human.

“Although this hybrid model addresses some limitations of both human tissue in a Petri dish and non-human animal models, it also creates its own technical limitations,” said Cedric Bardy, Matthew Flinders Professor at Australia’s Flinders University. “For example, artificially removing critical parts of the mouse brain . . . is a drastic approach that is highly disruptive and may introduce factors that complicate therapeutic translation.”

The research offered “huge potential to deepen our understanding of neurological development and treat disease” but consideration of associated ethical questions must keep pace, said Danielle Hamm, director of the UK-based Nuffield Council on Bioethics. Hamm pointed to a “lack of co-ordinated best practice and ethical guidance” across the field of human neural organoids — brain tissue cultures that mimic the organ’s structure and function.