Seth

My goal is to understand how the developing brain is organized. As a neuroscientist, I’ve interrogated brain function using a range of techniques aimed at understanding different properties of the brain – functional imaging in humans, single unit recordings during behavior, and whole-cell electrophysiology. You can read more about my experience and how it shaped me as a scientist over here.

Recently, I’ve been thinking about the diversity of cell types in the human brain. During development, each of us begins as a single-celled zygote, which divides and eventually gives rise to every neuron in the brain (not to mention every other cell in our body), each with an identical genetic code. Yet, despite identical genetics, the neurons in our brain are remarkably diverse at the molecular level – diversity that defines unique cellular properties (think morphology, localization, projection profile, and neurotransmitter type for example) that can be used to classify the mature cell into a category of cell-type. Once selected, a given neuron’s cell-type identity remains remarkably constant throughout life. This cellular diversity is foundational to the organization of neural networks in our brain, those that underlie perception and thought – all this from cells with identical genetic starting material. How might we understand the development of cellular identity at the molecular level?

To answer this question, I am employing two parallel approaches. The first aims to build new molecular biotechnology to record the history of transcriptional events as a cell acquires its identity without disrupting the development of the cell itself. To do so, I have built a molecular recording device to encode biological events within living cells though coded changes to the cell’s DNA, which are organized over time. This will allow us to better observe development without interfering. The alternate approach is an attempt to instruct development to test our hypotheses about the molecular sequence of events. For this, I use in vitro differentiation of pluripotent stem cells into neurons.

Once we understand how cellular identity is determined, we can leverage that knowledge to direct the differentiation of human pluripotent stem cells into defined cell types – even recapitulating canonical neural circuits in vitro. This access to human neural circuits, combined with cellular reprogramming of patient-derived cells, opens up the possibility of directly interrogating the mechanisms of neuropsychiatric disease at a cellular level for the first time.

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