NYSCF — Robertson Investigator Sergiu Pasca Provides a Comprehensive Overview of The Field of Brain Organoids

NYSCF — Robertson Stem Cell Investigator Sergiu Pasca’s lab at Stanford University has been at the forefront of the new field of brain organoids and has been developing such approaches to model human brain development and to understand neuropsychiatric disease. These organoids are little 3D aggregates of lab-grown neural cells that can help researchers examine how the human brain develops. In a recent review article in Nature, Dr. Pasca unpacked the current state of brain organoid research—addressing how they are used, their benefits, and their challenges.

Brain organoids are made by placing human pluripotent stem cells in a 3D structure and then coaxing them to acquire a specific cell fate. Researchers can derive specific regions of the brain and then put them together to create brain assembloids, or miniaturized versions of multiple brain regions to capture cell-cell interaction and develop neural circuits.

Traditional 2D models are informative, and sometimes are a better choice when studying brain development, but 3D models have certain advantages. One advantage is that cross talk between cell types such as astrocytes and neurons is easier to see and study in a 3D setting. In addition, 3D cultures can be maintained for very long periods (over 850 days according to work from the Pasca Lab) and therefore can be used to study maturation in the nervous system. Rodent models can’t capture the years long path of human brain development, but 3D human organoids now give researchers a window into later stages of development of our burgeoning central nervous system.

Dr. Pasca also stresses that organoids don’t just let us examine normal brain development—they can model what happens when it goes wrong in disease. For example, a study conducted in his own lab found that forebrain assembloids generated from patients with Timothy syndrome– a genetic disease associated with autism and epilepsy, showed abnormal migration of GABAergic neurons during the development of the cerebral cortex. His team was then able to treat this issue pharmacologically in the model.

But even with all their advantages, organoids aren’t perfect. Dr. Pasca first explains that organoids carry a problem intrinsic to all models: the fact that they’re models. They only approximate the architecture of neural tissue, appearing much smaller than the regions they represent, and they sometimes show unpredictable cellular architecture. He then describes a few more problems: organoids don’t display white matter (a prominent component of human brains), lack some cells types and don’t have sensory input.

Dr. Pasca suggests that the next steps in creating better organoids should be to put more emphasis on quality control and to identify more effective biomaterials. He believes this will make organoids more reliable as well as better recapitulate the environment in which our brains naturally develop.

For more information, check out the full article in Nature here.

Also check here for a recent poster on brain organoids and assembloids published by Dr. Pasca in Nature Neuroscience.