NYSCF — Robertson Investigator Sergiu Pasca Dives Into The Field of Brain Organoids

NYSCF — Robertson Stem Cell Investigator Sergiu Pasca’s lab at Stanford University uses brain organoids to model neuropsychiatric disease. These organoids are little 3D aggregates of lab-grown brain 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 or bioreactor and then coaxing them to differentiate into neurons. Researchers can even isolate certain sections of the brain to create assembloids, or miniaturized versions of a certain brain region, that better capture some of the more complex circuitry.

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 model long-term development. The human brain takes a long time to mature—some processes don’t stop until we reach our 20s or 30s. Animal models simply can’t capture the unique path of human brain development, but 3D human organoids can remain in culture for months to years, giving researchers a window into the early stages 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. For example, a study conducted in his own lab found that assembloids generated from patients with Timothy syndrome (a disease associated with autism and epilepsy) showed abnormal neuron migration during development. 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 changes in cell architecture. He then describes a few more problems: organoids don’t display white matter (a prominent component of human brains), are missing or severely lacking some important cells types, don’t form in a low-oxygen environment the way the human brain does, and don’t have sensory input. These drawbacks aren’t insignificant and should be taken into account when designing experiments.

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.

Diseases & Conditions:

Neurobiology, Stem Cell Biology

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