This image of the lab-grown brain is labeled to show identifiable structures: the cerebral hemisphere, the optic stalk, and the cephalic flexure, a bend in the mid-brain region, all characteristic of the human fetal brain (credit: The Ohio State University)
Scientists at The Ohio State University have developed a miniature human brain in a dish with the equivalent brain maturity of a five-week-old fetus.
The brain organoid, engineered from adult human skin cells, is the most complete human brain model yet developed, said Rene Anand, a professor of biological chemistry and pharmacology at Ohio State.
The lab-grown brain, about the size of a pencil eraser, has an identifiable structure and contains 99 percent of the genes present in the human fetal brain. Such a system will enable ethical and more rapid, accurate testing of experimental drugs before the clinical trial stage. It is intended to advance studies of genetic and environmental causes of central nervous system disorders.
“It not only looks like the developing brain, its diverse cell types express nearly all genes like a brain,” Anand said. “The power of this brain model bodes very well for human health because it gives us better and more relevant options to test and develop therapeutics other than [using] rodents.”
Anand reported on his lab-grown brain today (August 18) at the 2015 Military Health System Research Symposium in Ft. Lauderdale, Florida.
The main thing missing in this model is a vascular system. But what is there — a spinal cord, all major regions of the brain, multiple cell types, signaling circuitry and even a retina — has the potential to dramatically accelerate the pace of neuroscience research, said Anand, who is also a professor of neuroscience.
Organoid derivation and development (credit: Rene Anand and Susan McKay)
Created from pluripotent stem cells
“In central nervous system diseases, this will enable studies of either underlying genetic susceptibility or purely environmental influences, or a combination,” he said. According to genomic science, “there are up to 600 genes that give rise to autism, but we are stuck there. Mathematical correlations and statistical methods are insufficient in themselves to identify causation. You need an experimental system — you need a human brain.”
Anand’s method is proprietary and he has filed an invention disclosure with the university. He said he used techniques to differentiate pluripotent stem cells into cells that are designed to become neural tissue, components of the central nervous system or other brain regions..
High-resolution imaging of the organoid identifies functioning neurons and their signal-carrying extensions — axons and dendrites — as well as astrocytes, oligodendrocytes and microglia. The model also activates markers for cells that have the classic excitatory and inhibitory functions in the brain, and that enable chemical signals to travel throughout the structure.
It takes about 15 weeks to build a model system developed to match the 5-week-old fetal human brain. Anand and colleague Susan McKay, a research associate in biological chemistry and pharmacology, let the model continue to grow to the 12-week point, observing expected maturation changes along the way.
“If we let it go to 16 or 20 weeks, that might complete it, filling in that 1 percent of missing genes. We don’t know yet,” he said.
Models of brain disorders and injury with civilian and military uses
He and McKay have already used the platform to create brain organoid models of Alzheimer’s and Parkinson’s diseases and autism in a dish. They hope that with further development and the addition of a pumping blood supply, the model could be used for stroke therapy studies. For military purposes, the system offers a new platform for the study of Gulf War illness, traumatic brain injury, and post-traumatic stress disorder.
Anand hopes his brain model could be incorporated into the Microphysiological Systems program, a platform the Defense Advanced Research Projects Agency is developing by using engineered human tissue to mimic human physiological systems.
Support for the work came from the Marci and Bill Ingram Research Fund for Autism Spectrum Disorders and the Ohio State University Wexner Medical Center Research Fund.
Anand and McKay are co-founders of a Columbus-based start-up company, NeurXstem, to commercialize the brain organoid platform, and have applied for funding from the federal Small Business Technology Transfer program to accelerate its drug discovery applications.