Scientifically Speaking: The mouse with human brain tissue

The mouse looks ordinary as it explores its enclosure. Inside its skull, however, human nerve cells have grown into a large mass of tissue. Their fibers extend into the mouse’s brain and down its spinal cord. Three months after transplantation, the human tissue makes up about 92% of the mouse’s cortical tissue by volume. The cortex is the outer region of the brain that helps process information.Rat nerve cells develop faster than human nerve cells. (Representative file photo)Scientists engineered these mice by making room for human cells in a developing mouse brain. The cells grew and formed connections with the animal’s nervous system. The mice could move around. On one memory test, those that had human brain tissue did better than mice with the same missing brain regions but no transplant.The study, led by Stanford neuroscientist Sergiu Pașca and published in Nature on September 16, offers a way to investigate human brain development and injury through experiments that would be unethical in people. Scientists were able to study how living human brain tissue is injured while also watching how an animal’s behavior changed. This approach could eventually be used to test treatments.Also Read: Scientifically Speaking: AI changing biology but it won’t cure all diseasesSmall changes in how the brain develops can affect how we think, feel, and behave, and can sometimes lead to neurological disorders. But studying that development cell by cell inside a living human brain is extraordinarily difficult. It’s almost as if we need to grow brain tissue from cells to understand it. Which is exactly what some scientists thought of doing.A skin cell normally stays a skin cell. But in 2006, Shinya Yamanaka’s team showed that mature mouse cells could be reprogrammed into stem cells, which can develop into different kinds of cells. The team did the same with human cells in 2007. This made it possible to start with a person’s skin cells and, with the right chemical signals, produce nerve cells.In 2013, Madeline Lancaster and her colleagues grew these kinds of stem cells into small, three-dimensional clusters of tissue with features of a developing human brain. These brain organoids gave scientists a way to watch aspects of human brain development in the lab. Organoids grown from a patient’s cells could also help reveal how a genetic disorder disrupts that development.These organoids are often called “minibrains,” although they lack much of what makes a brain work. Their nerve cells can fire electrical signals, but they do not have the full organization or connections of a human brain inside a body. In a dish, they also lack a working blood supply, which limits how well they grow and mature. In short, they’re not really brains.In 2022, I wrote in this column about how Pașca’s group had transplanted human brain organoids into newborn rats. Inside the animals, the human nerve cells matured, connected to the rats’ nervous systems, and responded when the rats’ whiskers were touched. Human brain tissue was receiving signals from a rat’s body.But the human tissue had to grow alongside an existing rat brain. Rat nerve cells develop faster than human nerve cells, so they had already claimed much of the space and established connections before the human cells could catch up.Also Read: Scientifically Speaking: Do early winners become winning adults?This time, the researchers made room first. They genetically engineered mice so that many cells that would normally form the cortex and hippocampus died during development. These regions of the brain are involved in perception and memory. The scientists then transplanted human cortical organoids into the available space shortly after the mice were born. With less competition from mouse cells, the human tissue expanded and produced several types of nerve cells.One surprise was how much the mice could do without the transplant. Even with roughly half their normal brain volume missing, they could survive with specialized care and move around. Their remaining brain circuits supported many basic behaviors.Some memory problems became apparent during testing. In a Y-shaped maze, for example, mice usually prefer to explore an arm they have not just visited. To do this consistently, they need to remember where they have recently been. Mice missing the brain regions did not perform better than by chance. Those given human grafts, like the control mice, did better.The result suggests that the human tissue may be helping with the task, but other experiments are needed to establish which behaviors depend on the transplanted human nerve cells.The researchers also exposed the mice to low oxygen. The human grafts showed signs of injury, and the animals carrying them changed how they walked. They spent more time with three or four paws supporting their weight. The comparison groups did not show the same changes.Make no mistake. These animals remain mice. The human tissue was still immature and lacked the layered structure and full range of cells found in a mature cortex. Nothing in the study shows that the mice had the capacity for human-like thought or consciousness.Also Read: Scientifically Speaking: The animal that can survive five years without eatingBut as scientists improve these models, the tissue could mature further and form more connections. They will need to assess how those changes affect the animal.We also have to consider the ethics of inserting human brain tissue into animals more closely related to us. Pașca told MIT Technology Review that repeating this experiment in a primate would cross a clear red line for him. A more closely related animal, such as a monkey, might integrate human nerve cells in ways a mouse cannot, raising harder questions about its mental abilities and welfare.Anirban Mahapatra is a microbiologist, author, and science leader. His work spans microbes, medicine, AI, and the institutions that shape science. His most recent book is When the Drugs Don’t Work. The views expressed are personal