Brunger leads $1.5 million NSF project to develop advanced brain organoids

Vanderbilt engineers have received a $1.49 million National Science Foundation grant to advance the science of organoids with cells that organize themselves and mimic development of human brain structures.

Organoids are lab-produced groups of cells that serve as research models for human physiology in development and disease, including design and testing of drugs and other therapies. By using both induced pluripotent and embryonic stem cells, researchers can produce miniature organ-like structures that closely reproduce critical aspects of human organ development and cell-cell interactions. Scientists have successfully developed kidney, pancreas, liver, intestine, lung and brain organoids, among others.

Jonathan Brunger

But how the different types of cells in an organoid signal to each other, communicating what, when, where and how to do what they must accomplish remains a complex puzzle. This project aims to establish the molecular logic and design rules required to generate cerebral cortical organoids, said Jonathan Brunger, assistant professor of biomedical engineering.

“The objective is to create a self-contained, self-assembling system that reproducibly yields a defined architecture, size, and cellular composition that mimics the complexity of the human cortex,” said Brunger, who is the principal investigator. “Once we learn how to write and implement the molecular code that governs higher-order structure formation in the brain, we may potentially apply the same principles to other types of tissues, which opens the possibility of engineering tissue replacements for transplantation.”

The project is a collaboration between Brunger; Ethan Lippmann, assistant professor of chemical and biomolecular engineering; and Ken Lau, associate professor of cell and developmental biology.

Ethan Lippmann

“This project is a great example of merging the expertise of our various groups to achieve an outcome above what we could each do on our own,” Lippmann said.

His research group does central nervous system modeling to better understand disease progression and molecular underpinnings that drive pathology. Lau applies computational approaches to investigate how cells and tissues function and organize.

“This is a great project that leverages the technological capabilities right here at Vanderbilt and brings several communities together,” Lau said.

Brunger builds circuits to control cell behavior and engineer the response of cells to their microenvironment. “We want a brain organoid with topography that mimics the human cortex,” he said. “We want to make domains in the proper location and do this in a more controlled and consistent way.”

Creating cell and tissue mimics was the early focus of organoid science. Equally important is understanding and recreating how the cells send and receive signals to organize themselves as human brain cells do on their own.

Ken Lau

Otherwise, a brain organoid can have cells in the wrong place trying to execute the wrong task. The complex mesh may resemble a human brain but not hit the mark, which limits its effectiveness for researchers.

To illustrate, consider a well-known work of art, such as Van Gogh’s Starry Night. Without the right rendition, a derivative of the painting might resemble the original but have random elements that throw it off, such as the moon in the wrong place or a second moon over the horizon, Brunger said.

“There are discrete regions organized within themselves and also relative to one and other,” he said. “We want to try to improve how all of this comes together.”