Disease models in 3D: A human brain in mice skulls?
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Organoids and 3D culture have long been regarded as a promising tool for modeling human disease in the lab and even as the next big thing in personalized medicine. Organoids are tiny collections of tissue, which can organize into 3D structures that are able to mimic fully formed organs. In today’s world of personalized and precision medicine, organoids and 3D cultures blossomed into methodologies which hold unprecedented significance as well as promise in treatment of cancers and several other debilitating diseases. Modeling brain disorders, for example, have been long considered as an important milestone in proper characterization and elucidation of neurological ailments such as Alzheimer’s and Parkinson’s diseases and microencephalies. Back in 2013 (Lancaster et al, Nature 2013) the first lab grown brain organoids were established and recently two independent studies from different research groups have shown how human brain cells can indeed make a spectacular species’ leap and be cultured amidst rat/mice brain matter (Basuodan et al, J. Anat, 2018, Mansour et al, Nat. Biotechnol., 2018).
The exquisite complexity of the human brain has impeded progress in understanding neurological disorders. The development of cerebral organoids (a human pluripotent stem cell-derived 3D organoid culture system) is poised to give insight into several quandaries in neurobiological diseases. Amazingly a 2013 study had shown that within brain organoids the cerebral cortex is able form as an interdependent region of the brain and can organize and form cortical neuron subtypes as well as show features reminiscent of human cortical development. What the recent studies from the Clowry and Gage labs have shown takes this technical advance takes us a step further (and maybe a tad further into the realm of next-gen research and even, some might say, 1970s science fiction). Clowry and the team derived human neural stem cells from induced pluripotent stem cells and introduced them into a 3D matrix of artificial extracellular material and grafted the material into the sensorimotor cortex of 14-day-old rat pups. What was surprising was that when differentiated in vivo, by 1 month these neural stem cells organized themselves into cerebral organoids indicating features of human neurons and expressing human cerebral markers. By 10 weeks however, the organoids did fail to continue differentiation and the matrix broke down. The Gage lab went one step further to, in fact, graft brain organoids into an adult mouse brain. The results were somewhat more promising as the grafts showed neural differentiation as well axonal growth into regions of the host brain as well as blood vessels and functional neuronal networks.
Studies such as these not only attempt to answer questions regarding human disease but can also attempt to model the human brain during various developmental programs in different regions of the human brain. When coupled with the Human Brain Project, understanding cortical regions one at a time can accelerate mapping of the human brain. These “mini-brains” have already shown promise in understanding how serious pathogens such as Zika virus infiltrate the human brain (Qian et al, Development, 2017). Some obvious ethical queries do arise from these experiments suggestive of transference, or existence of human consciousness – in case someone might think of utilizing brain organoids to define a structurally and functionally various parts of the limbic system, amygdala or the hippocampus. Does this not remind you of the H.G Wells novel - “The Island of Dr. Moreau”? Will the mice have a trapped human consciousness? Only further research will tell.
Science fiction aside, real world data from these studies suggest that cerebral organoids hold immense potential for understanding brain disorders as well as embryonic brain development and this area is set to gain immense ground in the years to come. A development which is soon become a novelty in this area is the generation of brain organoids on-chip tending to longer term visualization as well as real-time imaging of these structures. Microfabrication with brain on-chip has been a forte of Dr. Orly Reiner at Weizmann Institute of Science and her research group continues to investigate how human brain wrinkling (literal brain folding) occurs. This in turn helps to identify causal effects in microencephalies as well as diseases such as epilepsy and autism. The future is definitely looking bright for utilization of this emergent technology in brain research and development.