Paola Arlotta, Ph.D.

Chair, Harvard Department of Stem Cell and Regenerative Biology
Golub Family Professor of Stem Cell and Regenerative Biology, Harvard University
Associate Member, Stanley Center for Psychiatric Research, Broad Institute

The Arlotta lab research program explores the interface between development and engineering of the neocortex, to gain fundamental understanding of both the principles that govern normal cortical development and of previously-inaccessible mechanisms of human neurodevelopmental disease.

Cortical Development and Neurodevelopmental Disease

The molecular logic that generates, maintains, and wires into circuits the multitude of cell types found in the mammalian brain is poorly understood, yet these processes are critical for complex brain function, and their disruption leads to neurodevelopmental disease. Focusing on the mammalian cerebral cortex, our laboratory is interested in decoding the mechanistic principles by which the vast diversity of cortical cell types is established, integrated, and subsequently maintained for the lifespan of the organism. We have identified molecular programs that shape cell-identity acquisition, and were the first to challenge the notion that the identity of postmitotic neurons in the central nervous system is irreversibly set, by showing that they can be reprogrammed from one class into another in vivo. We discovered that cortical neuron class identity also informs the development and functionality of glia, in particular oligodendrocytes and microglia, putting forward a new conceptual framework for the role of neuronal diversity in instructing local connectivity, immune-neuron balance, and the establishment of myelin maps.

Building on this work in the embryo, we have more recently pioneered the development of stem cell-derived brain organoids that model the human cortex, to study previously-inaccessible mechanisms of human neurodevelopment and disease. We demonstrated that human brain organoids in long-term culture (grown for many years in the lab) can generate extensive cellular diversity, following similar developmental trajectories as the endogenous brain, with unprecedented levels of organoid-to-organoid reproducibility. These organoids can achieve advanced neuronal maturation and the generation of spontaneously-active neuronal networks sensitive to sensory stimuli. By creating organoids bearing mutations in different risk genes for Autism Spectrum Disorder (ASD), we have uncovered cell-type-specific neurodevelopmental abnormalities that are shared across ASD genetic risk. In very recent work, we have shown that we can generate chimeric organoids (chimeroids) incorporating cells of many individual donors, and we recently applied this human brain chimeroid model to uncover inter-individual variation in response to disease triggers. In the future, we are excited to bring these discoveries to bear for unearthing poorly understood mechanisms of human brain development and disease.