New research reveals why the brain like organs of human beings lack the complex circuits unique to the normal human brain

As a three-dimensional sphere of brain like tissue usually produced by human stem cells in the laboratory, brain like organs are touted as having the potential for scientists to study the formation of brain circuits under controlled laboratory conditions There is a lot of talk about brain like organs, which some scientists think will make it possible to rapidly develop treatments for devastating brain diseases, while others warn that brain like organs may soon acquire some form of consciousness In a new study, however, researchers from the University of California, San Francisco and other research institutions have come up with a more restrained view: the widely used brain like organ model cannot replicate the basic characteristics of brain development and tissue structure, let alone simulate the complex circuits required for complex brain diseases or normal cognition The relevant research results were published in the nature Journal on February 6, 2020, and the title of the paper is "cell stress in coral organizations implements molecular subtype specification" The corresponding author is Arnold kriegstein, Ph.D., Professor of neuroscience, University of California, San Francisco The first authors of this paper are Dr aparna Bhaduri and Dr Madeline Andrews, postdoctoral researchers, kriegstein laboratory, University of California, San Francisco Picture from nature, 2020, DOI: 10.1038/s41586-020-1962-0 "Some people call brain like organs' brains in a dish, 'but our data shows that this is a huge exaggeration," kriegstein said We found that brain like organs did not produce the unique cell subtype or regional circuit structure unique to normal human brain circuits Because most human brain diseases are highly specific to specific cell types and circuits in the brain, it poses a serious challenge to the efforts of using brain like organs to accurately simulate these complex diseases " This new study is based on the ongoing work of kriegstein laboratory, which is to draw the gene expression program to coordinate brain development on the basis of normal human brain tissue samples Kriegstein laboratory aims to build a genetic map of human brain development as a valuable resource to compare normal brain development with errors in brain development diseases such as autism But when the researchers compared data from the developing brain to kriegstein's brain like organ model, they quickly found that the well-organized development process observed in normal brain tissue was significantly disrupted in kriegstein's brain like organs The researchers measured gene expression in more than 235000 cells extracted from 37 different brain like organs (produced using three different laboratory processes and four different initial stem cell lines), and compared these gene expression patterns with about 189000 brains in a series of brain regions from the normally developing human brain at different development time points Compare the situation observed in the cells This analysis suggests that brain organ like cells do not normally differentiate into unique cell types in the brain, but rather seem to experience an identity crisis: simultaneously expressing genes commonly found in very different types of cells At first, these brain like organs formed the cell "rose like structure" similar to some characteristics of the developing brain, but they soon melted into a mixture of cells "We were able to identify the main cell types, but we lacked the normal diversity of cell subtypes that play a key role in the normal function of the neural circuit," kriegstein said To ensure that these results extend to other common methods of preparing brain like organs used outside kriegstein's laboratory, the researchers compared the single-cell gene expression data (more than 276000 cells in total) of eight different methods of preparing brain like organs published in the scientific literature with their normal gene expression profiles constructed in the developing brain In each case, these published organoids showed the same results as kriegstein's lab observed in their own brain organoid models: they lacked the ability to properly produce unique cell types "The ability of the brain to connect different types of cells to highly structured, regionally unique circuits is essential not only for normal brain function and cognition, but also for these highly specific circuits to go wrong in different ways in autism, schizophrenia, mental and neurological disorders," Andrew said Bhaduri added, "before we can use brain like organs to study these diseases and find possible cures, we need to make sure they are actually simulating the affected brain circuits." In addition to the disordered development process, brain organ like models express abnormally high levels of cell "stress" genes, thus controlling cell responses to harmful environmental conditions (such as hypoxia) The researchers hypothesized that this increased cellular stress may be caused by methods of culturing brain like organs in the laboratory, and may prevent these organs from producing appropriate neural cell types and regional structures To test this hypothesis, the researchers extracted cells from the brain like organs they produced and implanted them into the brains of mice to eliminate the stress factors caused by culture in laboratory dishes In this more natural environment, the stress level of these brain organ like cells rapidly drops to normal level, and the normal development process begins to play a role again On the contrary, when they acquire the early developing neural tissue and try to culture it with their laboratory brain like organs, the stress genes become more active, and the young neurons in the neural tissue also have the same identity crisis as the laboratory brain like organs These results suggest that neuroscientists' efforts to simulate complex brain tissue in brain like organs will need to rethink how to cultivate brain like organs in the laboratory to try to reduce the level of cell stress "Different research teams have optimized the way brain organs are cultured in many different ways, so the fact that we see these problems in organs from different laboratories shows that improving the way organs are produced is likely to require a lot of improvement," Andrew said It's not easy, but I hope that these results and the unique data set of Bhaduri's genetic programs in the normally developing brain will point the right direction in this area " These researchers emphasize that brain like organs are still useful tools in many studies that do not need to accurately simulate specific brain circuits or their dysfunction, such as Bhaduri and his colleagues in a recently published paper using brain like organs as a method to study the invasive spread of glioblastoma in a laboratory culture dish (cell stem cell, 2020, doi:10.1016/j.stem.2019.11.015）。 "But this new study makes it very clear that in the lab, brain like organs are far from really replicating the developing brain," Bhaduri said Reference: 1 Aparna Bhaduri et al Cell stress in continental organizations implements molecular subtype specification Nature, 2020, DOI: 10.1038/s41586-020-1962-0 2.Not 'brains in a dish': Cerebral organoids flunk comparison to developing nervous system