Cerebrum Winter 2020

As organoid models appear to mimic the rich diversity of cell types found in the human cortex, it gives scientists a rare opportunity to access some aspects of human development. 

Finally, researchers like Blurton- James are utilizing chimeric models of the brain, or experimental models where an animal’s brain has been “humanized” with the addition of human genes or cell types. His own work is looking at how microglia, a special type of neural support cell, are affected in Alzheimer’s disease. “We study microglia and how they contribute to different brain disorders,” Blurton-James explained. “Before, we would isolate microglia in a dish and study them. Yet, when we cultured these cells, we saw that their gene expression changes. In fact, the longer they culture, the [greater the change]. So we put two and two together and realized that we needed to put these stem cells in a brain—in our case, a mouse brain—and what we found is gene expression very similar to what we see in cells we’ve just taken out of the human brain. By using this type of model, we’ve dramatically reduced the differences we saw in microglia in a dish.” The Scientific Limitations – and Ethical Concerns Over the last few years, scientists have used these different models to make discoveries about how different genes contribute to both brain development and disease—discoveries they would have been unable to make without them. Researchers working with these approaches said they are not meant to replace animal models in full, but rather to offer new insights they would be unable to investigate otherwise. As organoid models appear to mimic the rich diversity of cell types found in the human cortex, Arlotta said, it gives scientists a rare opportunity to access some aspects of human development. “It’s exciting, even as primitive and

reductionist as these models are, to look at what is happening in the brain during this time,” she said. “We can answer questions about how different genes are affecting brain development – and with that, we have hope that we can one day understand what may start different brain disorders.” Yet these models do have their limitations. First and foremost, they are limited by size and development. Organoids, to date, max out at the 4-5-millimeter size, even after months of development. And without vital vasculature and other bodily support, the brain cells contained within those models cannot reproduce normal developmental patterns of cell organization and architecture. Arnold Kriegstein, M.D., Ph.D., a researcher at the University of California, San Francisco, agreed with Arlotta that organoids can produce a variety of different cell types, but single cell RNA- sequencing comparisons of organoid cells show that they lack the “cellular and structural complexity” of cells found in a normally developing brain. “Our genetic analysis is showing that the organoid cells lack specificity. It’s almost as if their identity is a bit confused,” said Kriegstein. “Compared to normally developing cells, the organoids are relatively impoverished in terms of diversity...and they don’t mature according to the development programs that you see in normally developing brain tissue. Both cell identity and maturation are important in the study of human disease and these are not faithfully reproduced in current organoid models.” Several laboratories are hard at work to create new paradigms to improve each of these models—techniques that can extend the amount of time ex vivo tissue donations can survive outside the body as well as technologies to improve

the ability of organoid and chimeric models to better mimic normal development. As they do, neuroethicists say it is vital that scientists discuss the potential consequences of such advances. Could scientists inadvertently create a super-mouse, à la The Secrets of NIMH? Could more sophisticated organoids start to learn or perhaps feel pain? While Joshua Gordon, M.D., Ph.D., director of the National Institute of Mental Health, stated that these models remain quite basic today, he agrees that scientists, scientific agencies, policy makers, and other science stakeholders should be talking about the future now. “We don’t take for granted that these models will stay this simple,” he said. “That’s why we’ve had several workshops specifically looking at the question of what we need to think about as organoid preparations and other models get more complex.” He said a few themes have emerged from those discussions, including the need for scientists to appropriately educate and patients who donate tissue and gain their consent about how that tissue will be used, as well as the need to monitor these models to check for more advanced brain activity. Arlotta agreed—but cautioned that it’s important to make sure these discussions are grounded in facts. “We have to constantly consider these issues within the context of the science,” she said. “It doesn’t do us much good to discuss things without relating them to the actual biology of the systems we’re studying. These models offer us a way to study things we have never had access to before. Today, they are so reductionist that I think there is little ethical concern. But as we make advances, it is absolutely necessary that every conversation is strongly rooted in the science or it does us little good in the end.” l


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