BRAINS IN A DISH

By Sayli Sonsurkar

Dr. Steven Sloan (M.D, Ph.D.)., assistant professor in the Department of Genetics at Emory School of Medicine, has long been fascinated by the unknown. To him, science truly revolves around  “thinking of things you don’t know and deliberately trying to answer them.”  Dedicated to this sentiment, his research revolves around trying to understand how the human brain develops, with all of its unique complexity. Brain development has been a fascinating area of study to him, considering “what were just a few thousand cells in a small embryo become so intricate with all the correct instructions and cues.” By focusing on brain development, the Sloan Lab hopes to better understand neurodevelopmental disorders such as autism, schizophrenia, ADHD, and learning disabilities. 

What is most exciting about Dr. Sloan’s research is that the field of research did not really exist as of a few years ago. He explains that “five years ago, it was not possible to answer specific questions about how the human brain develops” due to a lack of precision and accuracy in neural imaging technology. Researchers did not have the necessary techniques to observe early development in a crucial time frame, during which a couple thousand cells become trillions of cells. They could get insight from looking at worms, flies, mice, and even monkeys, but the question of brain development in humans could not be answered. The research of Dr Sloan and others have transformed both the foundations of knowledge and the mechanisms of getting said knowledge in this emerging field. 

Dr. Sloan’s lab has found “ways to use patient-derived stem cells to turn back time, go back to the stage of a couple thousand cells, and watch the process happen in a dish.” The Sloan lab takes reprogrammed stem cells, places them in a dish, and uses them to make 3-D tissue structures, called embryoids, in a dish. These structures recapitulate many aspects of the human brain. This field is still in its infancy, and thus the embryoids have limitations as embryonic brain development involves so many complex signaling pathways that allow for cells to become the right kind of cells in the right time, place, and part of the brain. Dr. Sloan explains that you do not have this kind of control in the lab when you have the cells floating in a dish. 

This experimentation and limitation bring up the question of how a stem cell knows how to become each specific kind of brain cell and how that can be controlled. To target this issue, the Sloan Lab has started collaborating with faculty at both Emory University and Georgia Institute of Technology to bring in engineering as a method of answering this question. Together, they have developed 3-D bioprinting techniques using hydrogels, gelatin-like material in which cells can grow and survive. 3-D bioprinting gives you the flexibility of creating any desired architecture. They are now printing scaffolds, cube-like structures, and placing the organoids inside. This technique allows them to control exactly what is happening in the cube. They can now precisely control the spatial environment in which these stem cells grow to better mimic the environment of an embryo. 

The process by which the Sloan lab is able to take stem cells and create a brain-like structure is fascinating. The process takes three to four weeks to make “baby neurons,” and three to four months later, you begin to have a hefty population of neurons. By four to six months, you begin to see other types of brain cells, such as glial cells. These structures can then be maintained for years. The process is quite analogous to the nine-month gestation of normal human development. 

The advancement of these “brain-in-a-dish” techniques have created a new window to understanding development. They serve as a platform to better understand many aspects of the brain. For example, the Sloan Lab was curious about the process of the maturation of astrocytes, which are a type of glial cell in the brain. Dr. Sloan explains that astrocytes are like the “puppet master of neural circuit function.” With this model, they are able to directly watch these cells develop in the dish and then watch as they get older, comparing the two. They found that the two stages are actually not at all similar, and the cells undergo huge transformation in terms of their gene expression and how they function. 

There are still many questions being asked about brain development, and research still has a long way to go. Current brain-in-a-dish models still have some limitations, and there are still questions as to how blood and other kinds of brain cells can be included in the models. Despite these future challenges, recent developments and innovative techniques from the Sloan Lab are truly fascinating and have greatly transformed the way we approach and understand human conditions. The group also hopes to gain insight on how abnormal development contributes to neurodevelopmental disorders through studying normal brain cellular development and function. By combining state-of-the-art genome engineering, stem cell biology, imaging, and neurobiological approaches, they can hopefully continue to discover new mechanisms and therapeutic targets to improve human health.