In a first, researchers integrate and grow human cells in newborn rat brains

After leaving them to grow for 140 days, they discovered that the organoids developed, integrated partially into neuronal circuits, and displayed functioning in rodent brains.

The organoids did, in fact, develop to eventually make up about one-sixth of the rats' brains, claimed the researchers, which is about the size of a pea. In context, consider that the rat-grown human nerve cells are approximately six times larger than those generated outside the body (i.e., in a test tube).

Researchers use blue light to control rats' behavior - they would 'lick' for a water reward

And that's not all. When applying blue light to the enlarged neurons during a reward-training task, the researchers discovered that activation of human neurons caused the rats to lick for a water reward. This proved that the rat tissue and human tissue integrated at the circuit level and controlled animal behavior.

"What is important and novel [is that] transplanted organoids receive sensory-related inputs, and their optogenetic activation (activated by light) could drive rat behavior during reward-seeking," reveals Dr. Agnieszka Rybak-Wolf, head of the Organoids Technology Platform, Max Delbrück Center for Molecular Medicine (MDC) in Berlin (not part of the study).

Additionally, the investigators deflected the rats' whiskers on the opposite side of the organoid, which triggered a group of neurons in the organoid to light up. This demonstrated that the transplanted neurons could respond to sensory stimulation.

'A step closer to non-invasively seeing inside the human mind": exposing neuronal defects of Timothy syndrome cells

The researchers anticipate that growing human brain organoids in another species will bring them a step closer to non-invasively seeing inside the human mind- at least 'non-invasively' to humans.

For example, during the study, the researchers implanted organoids from the stem cells of people with Timothy syndrome. This rare genetic disease causes autism spectrum disorders and heart defects. The organoids successfully highlighted neuronal defects, demonstrating that the new method could be promising in the search for neurodevelopmental disorder treatments.

Still, "more work will need to be done to be sure this system is a robust model for brain development and neurodevelopmental disorders," said Professor Tara Spires-Jones at the Centre for Discovery Brain Sciences, the University of Edinburgh in a document accompanying the study.

Could an organoid have consciousness and moral status?

Integrating human-derived cells into a rat that grows to the size of a pea is one thing- would going beyond that raise profound ethical questions?

"Crucial questions surround whether an organoid can have consciousness and moral status," said J Gray Camp and Barbara Treutline, who are organoid experts not part of the study.

According to the research team, there were no behavioral differences between the rats with and without human brain grafts. Furthermore, human brain tissue, which takes years to reach maturity, can only develop so much, given the short lifespan of rats.

'Transplantation into primates is not something we would do or encourage doing'

Injecting human brain organoids into primates is a logical next step since they have brains that can hold more human brain tissue than rats and live a lot longer. This would allow the brain cells to develop.

Still, Pasca shuts this idea down, "Transplantation into primates is not something we would do or encourage doing." While primate brains are more similar to human brains, this would be very controversial.

What we already know about brain organoids

Brain organoids, which are created from human stem cells, are frequently mislabeled as "mini-brains"- much to the annoyance of the scientists who work with them.

When growing outside the body, organoids lack the interconnectedness found in living creatures, making them a less-than-ideal model for human development and disease. Their ability to simulate brain disorders that are genetically complicated and behaviorally defined is limited.

With its approach to developing rats, the new study advances the understanding of organoids where previous research focusing on adult rat brains has failed- i.e., cells did not mature successfully.

Therefore, future investigation of the new method may allow us to identify disease traits in patient-derived cells that were previously inaccessible.

Abstract:

Self-organizing neural organoids represent a promising in vitro platform with which to model human development and disease1–5. However, organoids lack the connectivity that exists in vivo, which limits maturation and makes integration with other circuits that control behaviour impossible. Here we show that human stem cell-derived cortical organoids transplanted into the somatosensory cortex of newborn athymic rats develop mature cell types that integrate into sensory and motivation-related circuits. MRI reveals post-transplantation organoid growth across multiple stem cell lines and animals, whereas single-nucleus profiling shows progression of corticogenesis and the emergence of activity-dependent transcriptional programs. Indeed, transplanted cortical neurons display more complex morphological, synaptic and intrinsic membrane properties than their in vitro counterparts, which enables the discovery of defects in neurons derived from individuals with Timothy syndrome. Anatomical and functional tracings show that transplanted organoids receive thalamocortical and corticocortical inputs, and in vivo recordings of neural activity demonstrate that these inputs can produce sensory responses in human cells. Finally, cortical organoids extend axons throughout the rat brain, and their optogenetic activation can drive reward-seeking behaviour. Thus, transplanted human cortical neurons mature and engage host circuits that control behaviour. We anticipate that this approach will be useful for detecting circuit-level phenotypes in patient-derived cells that cannot otherwise be uncovered.