Reacción a "Human brain organoids form neuronal networks in mice"

This work builds upon their earlier study whereby they transplanted human cortical organoid tissue into the developing rat cerebral cortex demonstrating that the cells from the organoid integrated into the host brain.

“The advance here is they now use a genetic strategy to generate mice that have a depleted cerebral cortex, then transplant the human cortical organoid tissue into the brains of these mice. This remains technically challenging in terms of reducing variability when injecting the cortical organoid cells (4 injections per mouse), but they use fairly standard neurosurgical techniques that will be familiar to most rodent neurophysiologists/neuroanatomists.

‘Acortical’ mice are not a new concept, generated mice that lack a large proportion of the cerebral cortex. This remains an active area of research, e.g. Zheng et al used such mice to show they can still perform complex behavioural tasks, which makes for an interesting discussion on the roles of the cortex - the cortex only functions because it is integrated with the rest of the brain.

“I remain cautious about such studies, as these are high risk models that depend on the successful transplantation of viable cells that developed within the organoids. It is still not fully clear to me the methods for preparing the organoids for transplantation, but I think the cells from the organoids are not organised into ‘circuits’ when they are injected in to the mice, rather they are free in solution, hence it is tricky to understand how they become integrated in the host.

Note that the organoids themselves do not represent the complexities of the human brain, despite the expression of familiar molecular markers and structural characteristics of brain cells. The advantage of organoids comes from the genetic background of the donor, and the possibility to manipulate certain genes to see how mutations can affect particular cellular pathways. But they are not ‘brains in a dish’, as the connectivity is highly artificial (and typically simplified with minimal cell types). The authors themselves state as well the mismatch between the relatively rapid development of the mouse versus the much longer developmental trajectory of human cells. 

They used a clever strategy to virally label cells in the organoids prior to transplantation, followed by adapting an existing technology of rabies tracing from the organoid graft. Otherwise, most of the techniques alone are quite standard, including behavioural tests, electrophysiology, histology.

The most informative and still gold standard way to investigate the human brain network organisation and activity is using acute ex vivo slice recordings - tissue is removed during neurosurgery then the living tissue can be kept alive (with all its local circuits intact) for at least 12 hours for physiological and anatomical studies. The other complementary technique is in vivo recordings in patients (e.g. epilepsy patients awaiting surgery).