Hybrid human-mouse brain created in landmark lab experiment

A landmark experiment led by Stanford University researchers expands the scope of what we can learn from lab-grown neural models, dramatically improving the integration of a human cortical organoid with another animal's nervous system.

The team transplanted cortical tissues developed from human stem cells into mice with a partially formed brain, successfully blending the organoid and nervous system together into a functioning unit.

While experts recognize the immense scientific potential of the findings, some warn that the ability to create hybrid mouse-human cortical brain cells could bring us closer than ever to a concerning ethical boundary.

Our ability to turn stem cells into functional 3D models of human organs is revolutionizing how we study disease and development. Not only do these models – called organoids – present researchers with a convenient way to test presumptions on how tissues grow and change, but they also allow scientists a way to test drugs with improved efficiency and accuracy.

For all of their practical applications in the laboratory, a solitary organoid floating in a nutrient broth on a lab bench isn’t a complete human. It’s not even close; whether it represents a part of our central nervous system, a liver, or a piece of skin, the amalgamation of tissues only represents a tiny sample of the mechanisms present in a bona fide living organ.

This creates an obstacle for survival time and for understanding how target tissues govern and react to changes elsewhere in the body.

Transplanting tailor-designed organoids into living animals, such as a mouse or rat, provides something of a solution, though this comes with a bit of a space problem. Human cortical organoids squeezed into the brains of growing rats risk being stunted by a system that matures faster than it can develop key characteristics, for example.

By genetically creating "apallial" mice that lack the tissues required to form a hippocampus or the outer layers of their brain, researchers created a model with enough real estate for a human cortical organoid to not only grow freely, but to wire itself into the growing mouse in a typical fashion.

“In this study, the human graft in fact grew until it accounted for about 92 per cent of the cortical tissue present in mice,” explains Bryce Vissel, Director of the Centre for Neuroscience and Regenerative Medicine at St Vincent's Hospital, Sydney.

“It connected with the mouse brain and spinal cord and became active while the animals were awake. This opens a new route to treatments tailored to an individual patient and, perhaps eventually, to repairing a brain that is diseased.”

Though Vissel wasn’t involved in the research, he is concerned about the potential ethical consequences of blending the complex part of a human brain with the nervous system of another animal, and whether it crosses a line in not just creating a hybrid nervous system, but a novel means of thinking.

“The decisive ethical experiment will be to activate or silence the human graft and determine whether this changes perception, learning, or behavior. If it does, the human tissue will have become causally involved in the animal’s capacities,” he says.

The tissue itself wasn’t a mere appendage to the mouse – further testing using fluorescent labelling and measures of its electrical activity demonstrated that the organoid and its host brain communicated. Behavioral testing on the mice showed that the transplant affected their limb movements, suggesting it was actively influencing their motor activity.

Monash University computational neuroscientist Adeel Razi also provides an outsider’s perspective on the potential for future risks and benefits.

“The ethical concerns will increase with the increased maturity and scale of these grafting methods, and with the extent of the functional integration of human tissue in a non-human host,” says Razi.

“To me here, the most interesting question is not whether the mouse brain has been 'humanised', but what happens to human brain computation when human brain cells develop and learn within a mouse world.”

The researchers affirm that their experiment met current ethical guidelines and safeguards, while also cautioning that making mouse brains any more human-like would “require early and proactive engagement to establish ethical guidance”.

High ethical stakes aside, the incredible potential for advancing stem cell research could open doors to regrowing brain tissue, personalizing therapies, and diagnosing neurological conditions long before symptoms emerge.

“This is a very elegant and ambitious study with profound implications for understanding human brain development and disease,” says Razi.

This research was published in Nature.

Source: Scimex