Trans-institutional collaboration receives $2 million BRAIN Initiative grant, developing brain organoids to map neurological development

Vivian Gama, assistant professor of cell and developmental biology, and Leon Bellan, associate professor of mechanical engineering and biomedical engineering, have won a $2.3 million, three-year grant from the National Institutes of Health Brain Research through Advancing Innovative Neurotechnologies Initiative. 

The researchers will be developing three-dimensional brain organoids and related tissue—miniaturized and simplified versions produced in vitro—that resemble a human brain at 24 to 25 weeks post-conception. These will provide an unparalleled window into brain development and potentially into currently untreatable neurological disorders. The grant will bring together researchers including Ethan Lippmann, assistant professor of chemical and biomedical engineering, Jose A. Gomez, assistant professor of medicine, and Julie Siegenthaler, associate professor of pediatrics-developmental biology at the University of Colorado.  

Most neurodevelopmental disorders do not have treatments because there has been no way to discern the earliest signals of how the brain grows. “By understanding what makes a brain a brain, we have better access to the human side of disease mechanisms that can be very powerful for basic science,” Gama said. 

Today’s state-of-the-art tactic in organoid development is to fuse two separate brain regions in a second step. Current models lack supportive tissue such as meninges—the layer of cells surrounding the brain that hold signaling molecules that are essential in cortical development. Without the meninges, the organoids cannot truly reflect natural development.  

“What we’re hoping to achieve is the same regional complexity through an approach that is much more similar to the types of signaling occurring during early brain development,” Bellan said. “We are establishing gradients of signaling biomolecules inside hydrogel biomaterials to achieve a greater degree of complexity in brain organoids.” With such cutting-edge tissue engineering techniques, researchers can expose the organoids to environments that more closely resemble natural development.  

The organoids are generated from human induced pluripotent stem cells. These stem cells are derived by reprogramming fibroblasts—cells that produce collagen and connective tissue—that retain genetic information of the patient. Through this technique, Gama explained, the researchers can directly compare data from control sample stem cells and disease sample stem cells. This approach has enormous new potential to model and understand neurodevelopmental disorders.    

In a release, John Ngai, director of the NIH BRAIN Initiative said, “Recent discoveries and new technologies supported by the BRAIN Initiative provide a solid foundation for the next phase of the program, which will focus on large transformative projects and lay the foundation for novel interventions for human brain disorders.  

“We are moving closer to a complete list of all of the components in the brain and learning how those parts work together. That knowledge will enable us to develop better treatments for neurologic and neuropsychiatric diseases.” 

Gama and Bellan say what is most exciting about the BRAIN Initiative grant is the ability to bring together a team with a wide range of expertise to attack a multidimensional problem. The size of the grant also provides the team the rare capacity to test multiple methodologies. “Uniting multiple disciplines is exactly what is needed to address these complex problems, and it highlights the multidisciplinary nature of research conducted at Vanderbilt,” Bellan said.