Inspecting the clock of human brain development. Interview with Gabriele Ciceri.

Gabriele Ciceri is a neurobiologist and stem cell biologist and, since 2025, Group Leader at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) in Milan. His post is supported by the Giovanni Armenise Harvard Career Development Award.

Ciceri obtained a PhD in Neuroscience at the Institute of Neurosciences CSICUMH in Alicante, Spain, and then moved to the Memorial Sloan Kettering Cancer Center in New York. There, he developed stem cell-based models to study human neural development and identified an epigenetic mechanism controlling the unusually slow maturation of human neurons.

You lead the Armenise Harvard Laboratory of Stem Cells and Timing of Neural Development in Health and Disease. What is this about?
In the lab, we investigate a largely uncharted but fundamental problem in biology: how cells within developing tissues know what to do and, in particular, how they do it at the right time. How time information is encoded in a biological system has long been considered a largely intractable and fundamentally conceptual problem. Thanks to recent advances, we are finally gaining experimental access to the molecular machinery—a little bit like the gears of a clock—that controls and sets the speed of human development.

Why are you particularly interested in the timing of human brain development?
We study this question in the context of the developing human central nervous system, which is unusually slow to acquire fully mature adult properties—a characteristic of human neurons, which can take many years to mature, and is thought to underlie the emergence of some of the complex cognitive abilities of the human brain. We want to understand the mechanisms that control this developmental timing and how their modulation enables neurons to assemble in a coordinated way into functional circuits.

How do you study these processes in the lab?
We use advanced technologies to generate several distinct types of human neurons with precision. We basically start from human stem cells and guide them to make appropriate choices and become specialized, mimicking and controlling in a Petri dish the fundamental steps occurring during natural neurodevelopment. It’s like making a roadmap, measuring how long it takes to cover a certain distance, and testing hypotheses on what can make this route faster or slower. In the end, we want to unravel the mechanisms controlling neurons’ developmental timing. It is a truly complex challenge: no one has yet managed to generate fully mature human nerve cells in the lab!

Why is it so challenging?
Because the underlying biology is largely unknown. This is a brand new area of research, and the field is just beginning to approach this question systematically. It took us quite some time to make this question tractable in the lab and to integrate the temporal dimension in our experimental models.

What could this research tell us about neurological disorders?
Our research addresses not only a very fascinating aspect of human neurodevelopment, but is also very relevant for several neurological disorders. In fact, it is becoming increasingly clear that several neurodevelopmental conditions arise from alterations in the timing or trajectory of human neural development. We hope our research will allow us to investigate mechanistically how genetic alterations associated with these disorders impact brain development and lead to dysfunction of neuronal circuits. Understanding these mechanisms is a fundamental step toward designing the rationale for future therapeutic strategies.