The human brain continues to develop for two decades. To study this prolonged process, researchers have traditionally relied on donated human brain tissue and animal models, both of which have limitations: donated tissue provides snapshots of brain development, and animal brains differ from the human brain in cell-type composition and timing of development.

Despite their increasing utility, organoids have proven challenging to maintain over long periods. Now, researchers have successfully maintained brain organoids for longer than ever before. For over five years, the tissue continued to mature in ways that closely resemble human brain development. By extending the lifespan of these organoids, the researchers create new opportunities to investigate neurodevelopment, model brain disorders, and test potential drugs.

This work is published in Nature in the paper, “Human brain organoids record the passage of time over multiple years.”

Brain organoids have become increasingly important for studying human brain development. “These models allow us to track development over time and examine how different brain cell types emerge,” said Noelia Antón-Bolaños, PhD, assistant professor at UMC Utrecht. So far, most studies have focused on the earliest stages of development because researchers could not maintain brain organoids in culture for extended periods.

Antón-Bolaños and her colleagues investigated how far human brain organoids can continue to mature. However, standard culture conditions did not adequately support neuronal activity over extended periods.

“During human brain development, neurons display spontaneous activity,” Antón-Bolaños explained. “By adapting the composition of the culture medium, we supported that activity, kept the neurons active, and maintained the neuronal populations for much longer.”

Using this approach, the team maintained organoids for over five years. At defined time points, the researchers profiled the cell types present, gene-expression patterns, epigenetic changes, and neuronal activity.

The researchers then examined whether the organoids simply stayed alive or continued to develop. Different brain cell types appeared in the same order as during human brain development, neurons formed increasingly complex connections, and genes became active or inactive at the expected times.

Some of the strongest evidence came from epigenetic changes. “In the human brain, these epigenetic changes accumulate according to a characteristic developmental pattern,” Antón-Bolaños said. “We observed the same pattern in the brain organoids.”

After approximately one year, the organoids displayed features that normally emerge only after birth. “The cells are outside the body, yet they still follow approximately the same developmental timeline as we do—and even more closely than we had anticipated.”

The team also found that mature cells retained a memory of developmental time. “When we dissociated an older organoid and allowed the cells to grow again, they produced the cell types associated with a late developmental stage,” Antón-Bolaños said. “Yet when we combined older cells with younger cells, the older cells regained the ability to produce neurons—but only the types associated with later stages of development.”

The organoids are still developing in the laboratory. The researchers now want to determine how environmental cues, such as stimulation with light, improve further maturation. The field also aims to improve features that remain incomplete, including vascularization and the layered organization of the cerebral cortex.

“We now know that these models have the capacity to continue developing for years,” Antón-Bolaños said. “The next step is to understand how to provide optimal conditions for that capacity to unfold. That will bring us closer to more faithful models of the human brain.”

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