Pictured above from left to right: Elle Brandt, PhD, and Jubao Duan, PhD
As a young doctoral student in Beijing, Jubao Duan, PhD, loved playing tennis with his mentor’s son. He was a sweet kid — smart and good at math.
That made it all the more painful to watch as schizophrenia slowly took hold of Niu Niu’s mind. He became socially withdrawn, experienced delusions and had difficulty organizing his thoughts and communicating clearly.
“It made me feel so powerless,” said Dr. Duan, now Co-Director of the Center for Psychiatric Genetics and Charles R. Walgreen Research Chair at Endeavor Health. “We still do not know how exactly the disease can occur and how to cure it.”
But Dr. Duan is not powerless — in fact, his pioneering research might lead to new breakthroughs in how we diagnose and treat neurodevelopmental disorders. These disorders, such as schizophrenia and autism, affect some 300 million people worldwide.
Dr. Duan’s research meets this big problem with an equally big idea — and sometimes, big ideas come in small packages.
“Mini brains”
In a research lab in Evanston, post-doctoral fellow Greg Tracy, PhD, holds up a culture tray spotted with little white blobs.
“These are the so called ‘mini brains,’” he says, letting out a small laugh. “These little thinkers will help guide us to a big new world of understanding and psychiatric medicine.”
These ‘mini brains’ are actually tiny mounds of brain cells, complete with neurons and synapses. Dr. Duan’s team uses them as a window — a miniature model of how these disorders develop in the brain. Schizophrenia and others remain a mystery, in part, because they’re so hard to observe.
They’re often diagnosed after symptoms appear, and it’s hard to study genetic causes in living patients. The “mini brains” offer researchers a unique opportunity to watch as schizophrenia develops from the very beginning, which could help us understand its causes what puts certain people at higher risk.
To create these mini brains, the researchers drew blood from patient volunteers at high risk, and then convert them to induced pluripotent stem cells (iPSC). “Pluripotent” means these cells haven’t decided what they want to be yet. They could turn into skin cells, liver cells or, with a small nudge, into brain cells. And thus, the mini brains.
Code breakers
As with many things in medicine, researchers believe neurodevelopmental disorders come down to our genetic code.
“For example, we now know that there are over 280 regions in our genome that are associated with increased risk for schizophrenia,” said Dr. Duan, also a professor at the University of Chicago. “However, which genes and how they can exactly cause the disease remain largely unknown.”
Unraveling that mystery could lead to major breakthroughs in diagnosis and treatment.
Dr. Duan has been working on it for over 20 years, first on gene-hunting through the Genome-wide Association Study (GWAS) and now on understanding what those genes do as part of Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes (SSPsyGene), backed by the National Institutes of Health. SSPsyGene includes four centers using iPSC-derived brain cellular models — Endeavor Health/Rutgers, UCLA, MIT, and Yale — investigating 250 risk genes for neurodevelopmental and neuropsychiatric disorders.
In Duan’s lab, the team aims to model 30-50 distinct gene mutations in each mini brain.
“We’re trying to identify which genes contribute to these brain changes,” said Elle Brandt, PhD, another post-doctoral research fellow in Dr. Duan’s team. “The better we understand the cause, the better we can detect it early and find ways to intervene.”
She added that researchers could use this information to create more precise genetic testing and personalized treatments — not just for schizophrenia, but for a range of brain disorders. She’s also working on developing a “mini-brain” model for studying brain injury/repair and neurodegenerative disorders.
And Dr. Duan hopes that these studies will help patients around the world. That includes his mentor’s family in Beijing, who he visits whenever he gets the chance.
“I am so happy (he) can still call my name every time I see him,” Dr. Duan said. “With this research, I hope we can make a difference for him and many, many others.”
Looking forward
Dr. Duan and his team are also exploring whether induced pluripotent stem cells could help treat some brain disorders.
“You can’t easily access or transplant brain cells,” Dr. Duan said. But blood cells are more accessible, and as in the mini brain models, can be turned into healthy brain cells. This method could reduce immune rejection risks and offer new treatments for conditions like Parkinson’s disease.
The researchers are also investigating gene-editing with induced pluripotent cells to correct inherited defects, and clinical trials are underway for diseases like macular degeneration and Parkinson’s.
“This concept remains experimental, but it holds great promise,” Dr. Duan said.
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