For the past two decades, Thomas Jessell has worked to understand how nerve cells in the developing spinal cord assemble into functional circuits that control sensory perception and motor actions. Ultimately, his research may provide a more thorough understanding of how the central nervous system is constructed and suggest new ways to repair diseased or damaged neurons in the human brain and spinal cord.
"There is increasingly persuasive evidence to suggest that many neurodevelopmental and psychiatric disorders—from motor neuron diseases to autism and schizophrenia—result from defects in the initial assembly of connections in the developing brain," said Jessell. "By understanding the cellular and molecular processes that control the normal wiring pattern of these connections, we may eventually be able to design more rational and effective strategies for repairing the defects that underlie brain disorders."
Jessell's work has revealed the details of a molecular pathway that converts naïve progenitor cells in the early neural tube into the many different classes of motor neurons and interneurons that assemble together to form functional locomotor circuits. This molecular pathway involves critical environmental signaling molecules such as Sonic hedgehog, and a delicate interplay of nuclear transcription factors that interpret Sonic hedgehog signals to generate diverse neuronal classes. The principles that have emerged from Jessell's studies in the spinal cord have now been found to apply to many other regions of the central nervous system, thus establishing a basic ground plan for brain development. His work has also defined many of the key steps that permit newly generated neurons to form selective connections with their target cells.
One potential strategy for brain repair involves the use of stem cells, and Jessell and his colleague Hynek Wichterle recently demonstrated that mouse embryonic stem cells can be converted into functional motor neurons in a simple procedure that recapitulates the normal molecular program of motor neuron differentiation. Remarkably, these stem cell-derived motor neurons can integrate into the spinal cord in vivo and contribute to functional motor circuits. This work may uncover additional aspects of the basic program of motor neuron development, as well as pointing the way to new cell and drug-based therapies for motor neuron disease and spinal cord injury.
"I enjoy the search for answers to intriguing problems in biology," explained Jessell. "On those rare occasions when a definitive answer emerges, there is great pleasure in having deciphered a small fragment of a much larger and still elusive puzzle. And when frustration comes, it is usually from a sense of impatience—the desire to know answers more rapidly than they emerge."