Peering Inside the Living Brain to Study Mental Illness

With one in five U.S. adults?living?with some form of mental illness, the need for effective psychiatric treatments and therapies is profound. Discouragingly, the success rate for discovering new drugs for brain disorders is the lowest among all branches of medicine. A key reason is the?lack of methods for studying the living human brain on a molecular level in a non-invasive way. Simply put: We haven’t been able to observe how neurons make connections and build circuits in a healthy human brain, much less how behaviors of these cells differ in individuals with psychiatric diseases, such as schizophrenia or epilepsy.?

Creating models of the living human brain

The work of one of our Stanford Medicine researchers?holds?great promise for helping to fill this need. Professor Sergiu Pasca, MD, and his laboratory have?pioneered?a way to not only grow living neural tissue that replicates specific regions of the human brain, but to fuse these individual models together to mimic the brain’s development and diverse functions.

The scientists start with cells from a person’s skin, and, as Sergiu says, “push them back in time” to a much earlier stage of development known as pluripotent stem cells. Because these kinds of cells can differentiate into almost any cell type, Sergiu can guide them into becoming specialized brain cells. He then coaxes these cells into clumping together to form tiny three-dimensional spheroids called “organoids.” Within these organoids, the cells organize themselves into facsimiles of distinct parts of the nervous system, such as the cerebral cortex or the spinal cord, and develop as these regions normally would over time. When brought together, organoids continue to behave like components of a living nervous system, with the different tissue clumps fusing and cells traveling between them to form more complex circuits called “assembloids.”?

Opening a window into the brain’s interworkings

For Sergiu and other scientists, assembloid models have opened a window into the cellular interworkings of the living brain — including helping them understand what happens when things go wrong. For example, Stanford Medicine assistant professor Anca Pasca, MD, is using assembloids to study fetal hypoxia, a condition that happens when a fetus doesn’t have enough oxygen, which can contribute to a baby’s increased risk of sudden infant death syndrome (SIDS) and other disorders. Her work has shown that an oxygen deficit can reduce migration of a specific type of nerve cell from one region of the brain to another, impairing the construction of critical neural circuits. Her team also has identified a key substance that could prevent this irregularity, and she hopes to move forward with testing and, eventually, clinical trials.?

Advancing the assembloid model

As sophisticated as the assembloid model is, though, there are limitations to how closely it can replicate human neuron development on a petri dish, lacking blood vessels and other means for deeply absorbing nutrients. One way to solve this is by connecting the assembloid to the brain tissue of a living animal — something that Sergiu’s laboratory has achieved, outlined in research?published?earlier this month. Integrated into a living brain, this more advanced assembloid model can help scientists better understand how electrical activity in a particular nerve circuit of someone with a psychiatric disorder differs from that of its counterpart in a healthy individual, and it can serve as a platform for testing new, and potentially transformative, treatments.

Proactively addressing ethical considerations

The increasing complexity of the assembloid model gives rise to ethical issues that deserve careful consideration. Chief among them: Can brain conglomerations in a dish achieve a level of consciousness? And what is the impact on laboratory animals that receive assembloid implants??

What we know so far is that there are limits to how many organoids can successfully merge in a dish, making it impossible to achieve the complexity of the full human brain. We also know from Sergiu’s research that rats with assembloid grafts didn’t perform any differently on behavioral tests or show any brain abnormalities. Still, the model will continue to progress, and these issues will evolve, as well. The best way to address them is by remaining proactive — as Sergiu has done from the start, consulting with our Stanford bioethicists and participating in national initiatives and discussions guiding the ethics of organoid- and assembloid-associated research.

As Sergiu has said, organoids and assembloids are not brains, but rather dynamic models of how a living human brain works. This unprecedented access for studying neural development is already advancing our understanding of the body’s most complex organ. As we learn more, the potential only grows for developing new drugs and therapies, enhancing our ability to help the many millions who suffer from debilitating mental health disorders today.

These resources provide more information about the assembloid model, its potential for advancing our understanding of human biology, and the need for new psychiatric treatments.

Transplant of human brain tissue into rats could help study autism, other disorders?(The Washington Post). This report provides an in-depth look at Sergiu’s most recent study, recounting how he and his team successfully integrated organoids into laboratory rats and exploring the scientific opportunities presented by their latest research.

Here come the assembloids?(Stanford Medicine?magazine). This piece traces 13 years of research by Sergiu and his team, as they discovered how to generate neurons from skin cells and evolved their model from organoids to assembloids. A short?video?embedded in the article explains how assembloids work and their potential for advancing neurosicence.?

Redirecting the revolution: new developments in drug development for psychiatry?(Expert Opinion on Drug Discovery). This journal article examines reasons that psychiatric drug development stagnated and outlines approaches to reverse the trend, including through insights derived from organoids and assembloids.?

The rise of the assembloid?(Nature). In addition to Sergiu’s brain research, this article discusses how other scientists are using assembloids to better understand organ development and the progression of diseases ranging from COVID-19 to macular degeneration in the eye.