Lotje De Witte, MD, PhD, is one of the few experts on “mini brains,” or cerebral organoids—stem cells grown into small balls of human brain tissue. This video shows a mini brain in her lab, showing the dividing cells in red. Video courtesy of Dilara Ilhan.
Until very recently, there was no way to watch human brain activity in action. Imaging, postmortem brain specimens, and animals, though useful in many respects, can only reveal so much about how a live human brain functions. Enter the “mini brain,” or cerebral organoids: stem cells grown into small balls of human brain tissue.
Aided by a biochemical cocktail of proteins and minerals, they grow and self-assemble in the lab dish, mimicking the development of fetal brains in the womb and forming regions such as the hippocampus and retina. Cerebral organoids were first used in 2013 to model microcephaly, and are now used for studying neurological and psychiatric conditions such as autism and schizophrenia. An important distinction between mini brains and real ones is their lack of vasculature and an immune system—both vital aspects.
Rapid evolution
In March of this year, researchers at the UC Davis Institute for Regenerative Cures found a way to induce vascularization. They encased the mini brains in a nutritious gel containing endothelial cells (the cells that line the insides of blood vessels) so the organoids could grow their own blood vessels. After marinating for three weeks, they were implanted into rodent brains. Over the course of their time in vitro and then for two weeks in the rodents, the endothelial cells grew into functioning blood vessels that expanded into the organoid.
The following month, researchers at the Salk Institute for Biological Studies showed in Nature that organoids implanted in mice connected to the hosts’ circulatory systems. The organoid’s neurons fired in conjunction with the mouse-host’s neurons, suggesting a level of integration that could illuminate long-elusive secrets about many brain conditions.
Dr. De Witte’s breakthrough
Lotje de Witte, MD, PhD, one of the few experts in this field, is interested in the role of microglia cells, the immune cells of the brain. Microglia are involved in both inflammation and construction of the brain (believed to be associated with schizophrenia). Incredibly, she and her team discovered that these cells can innately develop within organoids. This greatly increases the potential of mini brains to illuminate how microglia contribute to human brain development and disease. Dr. De Witte’s team published their groundbreaking findings in Nature Communications in October.
An organoid from Dr. De Witte’s lab, with the microglia shown in green. Image courtesy of Ormel PR et al via Nature Communications.
“We have known for a long time that the immune system is somehow involved in causing neurodevelopmental disorders such as schizophrenia and autism. Now, we finally have a human model to study how microglia contribute to neurodevelopment and neurodevelopmental disorders. This is very exciting because if we find a disease mechanism, these organoids can be used to screen for potential new drugs to help our patients,” said Dr. De Witte.
The ethics of mini brains
Understandably, ethical and philosophical concerns have been raised, most notably in Nature earlier this year. What are the ethics of working with these organoids? Could a mini brain feel pain, or achieve consciousness?
“I’ve read about these issues with great interest,” said Dr. De Witte. “If it’s even possible to create a fully functioning brain or fetus in a dish, it’s far, far in the future. Regardless, it’s certainly critical to think ahead and discuss where the boundaries should be drawn. Our ultimate goal is always to more effectively treat the millions of people worldwide afflicted with neurological and psychiatric conditions, and mini brains are uniquely valuable for research in service of that goal. Optimizing the protocols to use this technology should be encouraged.”
Dr. De Witte is Assistant Professor of Psychiatry at the Icahn School of Medicine at Mount Sinai, where her lab investigates the connection between the immune system and the pathogenesis of psychiatric disorders. She is also affiliated with the MIRECC at the James J. Peters VA Medical Center in the Bronx, where she is establishing a lab to culture organoids. Her PhD is in molecular biology and immunology.