In recent years, there has been a lot of excitement about the potential for studying human diseases in what are called “organoids.” These small patches of tissue, formed using stem cells, appear to produce many of the same cell types and at least some of the structures normally formed in actual organs, and thus can provide a better model for diseases that rely on the sometimes complex interactions among multiple specialized cell types that are a feature of the human body.
But even the most sophisticated organoids lack a lot of the features of a real human body. This is especially true for brain organoids, which don’t form any of the connections with specialized brain structures needed to behave “normally.” On Wednesday, a research group at Stanford University described a possible way to study brain organoids in a somewhat more natural context: They genetically wiped out a large portion of the mouse brain and replaced it with human brain organoid cells.
The replacements
Organoids, because they adopt a three-dimensional tissue structure and consist of various specialized cells, provide a much better model for an intact tissue than simply having a bunch of disassociated cells lying flat on a culture dish. But they still have a lot of limitations—they’re not hooked up to a circulatory system that allows the liver to process chemicals the organoid produces and don’t have immune cells moving through them, to give just a couple of examples.
This is especially limiting for studies of the brain, where any specialized structures are surrounded by structures that may exchange information with them, and often have long-range connections. An organoid is better than nothing, but it may not be a lot better if you’re interested in a disease that impacts communication among multiple brain regions.
One alternative has been to implant human neural stem cells into the brains of another species, where they’ll generally integrate into the nervous system and actively signal to their neighbors. But, given that those human cells are surrounded by the normally functioning neurons of their hosts, it’s not clear how much you can learn from this.
The obvious solution there is to get rid of the host cells and try to have the human cells take over their functions. But that option runs into all sorts of problems, largely related to the fact that the organism you’re implanting them into (generally a mouse) actually needs its brain cells. Human neurons mature much more slowly than those of mice and may not form the connections that are needed quickly enough for an animal that only requires 21 days of gestation. In the absence of normal mouse tissue, nothing would provide the human cells with the signals that help organize them into functional units.
The Stanford team decided to test a compromise and delete a portion of the mouse’s brain and put human brain organoids in its place. But they took a bold step and chose the cortex as the portion they would delete. The cortex handles many of the complex features of the nervous system, such as decision-making and memory, and its disruption would be expected to have dramatic consequences. Still, the researchers found a gene that is active in almost all cortical cells and used it to drive the deletion of a key gene that’s needed to separate chromosomes during cell division.
Amazingly, despite killing off most of the cells that should go on to form the mature cortex and cutting the brain’s volume in half, it was possible for the mice to survive this. The researchers had to eliminate most of the other pups to ensure the cortex-free mice got enough nursing. They left them with their mothers to nurse longer and then provided them with very high-calorie food. But these steps allowed nearly full survival of mice without much in the way of a cortex. (The mice were also immunocompromised to avoid an immune reaction to human cells, but this is less of an issue in a sterile mouse care facility.)
With that in place, the researchers then started implanting human cortex organoids into the area where the mouse’s cortex was no longer developing.
Partial recovery
A bit over 85 percent of the animals that were implanted with a human organoid successfully incorporated the graft tissues. Those went on to contribute 92 percent of the cells found in the cortex of these animals. So, it wasn’t a complete replacement, but the human cells largely took over the space normally occupied by the cortex. Once there, they formed all the major types of neurons that are known to be present in the cortex. So, all that is good.
The human cells also formed some long-distance connections, as evidenced by the fact that processes from human cells were detected as far away as the spinal cord. And the neurons did engage in synchronized activity spikes, suggesting a degree of coordination.
The less good is a general lack of structure. There is some indication of local organization, in that specific cell types that form within distinct layers of a normal cortex tended to be near each other in the cortex of these animals. But there was no sign of those distinct layers being formed, suggesting that larger-scale organization is lacking.
What does this mean for the mice? Overall, it appears that having a disorganized human replacement cortex was better than having no cortex at all, but not as good as having a normally structured one.
The researchers set them loose in an area with video monitoring and then used a machine-learning classifier to group similar behavior patterns. Normal mice and the mice that had their cortex eliminated showed distinct patterns of behavior. The mice with a humanized cortex formed a third cluster, distinct from the other two. Similar things were true with body weight: mice that lacked a cortex were much lighter than normal mice, but the ones with the humanized cortex were intermediate between the two.
Tested for memory in a simple maze, the mice without a cortex performed at a level consistent with random chance. Mice with the humanized cortex did better than chance, but not as well as normal mice. But on a test of the ability to form associative memories, the mice with a humanized cortex did no better than the mice with no cortex at all. On tests of fine motor coordination, the mice with the human implants were again somewhere between the normal and cortex-free mice.
What’s needed
The research team hasn’t described the sort of careful study of anatomy and development needed to draw any conclusions about what structures may be formed by the human cells once they’re within the mice, much less tried to quantify any variation among individuals that might give us some hints of what sort of capacity these animals might be expected to have. As a result, it’s impossible to associate the mild improvements that come from having the human cells present with any specific function they’re providing.
As a result, this isn’t yet the sort of model system that can help us understand the sorts of complex neural diseases that we might ultimately be interested in using this for. They do show that the human cells respond differently to brief periods of hypoxia, consistent with what we see in normal human cells. But that’s quite a bit different from showing that this is a great model for something like ALS.
There remains a chance that it ultimately won’t be—that the sorts of disorganized connections that do get formed in these brains will never make them a good model for human neural processing. But without further characterization of what the cells are doing in these humanized cortexes, it’s going to be difficult to know.
Nature, 2026. DOI: 10.1038/s41586-026-11032-2 (About DOIs).
