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Thomas M. Jessell Ph.D. A Moving Story By Steve Mirsky Anyone watching Jamaican sprinter Usain “Lightning” Bolt win three gold medals at the Beijing Olympics may have asked “How can he run so fast?” But there is perhaps an even more intriguing question: how can he—or you—run, or even walk, at all? “The act of walking is a remarkable feat of the nervous system,” says Howard Hughes Medical Institute investigator Thomas Jessell. “To know when to step on a curb and when to avoid obstacles, the brain has to coordinate motor activity with a world of sensory inputs. These sensory and motor computations ensure that for each movement, just the right sets of muscles is activated at just the right time and for just the right duration. And because movement is the mediator of all behaviors, much of the circuitry in the brain and spinal cord is devoted to the problem of motor control.” Jessell strives to understand that motor machinery—he wants to know how nerve cells, also called neurons, grow in embryos, especially in the spinal cord, and then join together into organized circuits that make movement possible. Understanding the neural control of movement can reveal basic principles of nervous system function, and could also lead to the design of more rational therapies for neurodegenerative disorders and spinal cord injury. Jessell’s laboratory at Columbia University Medical Center in New York City looks out over the Hudson River. But he grew up in London, closer to the River Thames. Science and art were in the family; his mother was a conservator of paintings, working at The National Gallery, and so the art of solvent chemistry was always in the air. Jessell’s maternal grandfather was a pioneer in organic synthesis, working in Germany at a time when that country was the center of the discipline. Jessell did his undergraduate work at the University of London, in Chelsea College. “I was influenced early on by an inspiring lecturer in pharmacology, John Bevan, whose lectures brought to life the way in which drugs could manipulate the circuits and functions of the brain. These descriptions provided the first glimpse of a way forward in the broad world of science.” The college’s location in the Kings Road --- the epicenter of the “psychedelic 60s” area gave him the opportunity to do some field observation. “You only had to walk off campus to observe living examples of the influence of drugs on nervous systems and behavior,” he recalls. Then it was off to graduate school at Cambridge University, where he worked with Leslie Iversen asking “how sensory information is conveyed into the nervous system”— focusing on the sensory signals that convey the perception of pain. One key thing that happens in the nervous system is that nerve cells release chemical compounds—neurotransmitters—that bring information to other nerve cells. “In Cambridge, I worked on a newly discovered peptide neurotransmitter named substance P,” Jessell says. “Substance P is expressed by sensory neurons, and its release from nerve terminals in the spinal cord helps to signal painful stimuli”. These early studies also showed that opiates work as analgesic agents in part by inhibiting the release of Substance P and other neurotransmitters in the spinal cord. The sensory signaling of pain and the mechanism of action of painkillers triggered Jessell’s interest in spinal cord circuitry. The scientific environment in Cambridge was varied and rich --- long a world leader in the study of the physiology of the nervous system, the Iversen lab was next door to the Laboratory of Molecular Biology where methods for DNA sequencing were being perfected by Fred Sanger and his colleagues. After finishing his PhD in Cambridge, Jessell moved to Harvard Medical School to study how motor neurons form synapses with target muscles, working with the renowned neuroscientist Gerald Fischbach. “Gerry had made important breakthroughs in understanding how motor neurons formed functional synaptic connections with muscle,” Jessell says. Fischbach’s discoveries came from the ability to grow motor neurons and muscle cells in tissue culture permitting him to observe the formation of connections in real time. “It was quite remarkable to set up an experiment on one day and to come back three days later and detect fully functional synapses” Jessell says. In Fischbach’s lab, Jessell studied how motor neurons direct the organization of the muscle cells’ membranes. To achieve efficient synaptic communication the muscle must have receptors in the right places to receive the chemical transmitters released from the nerve terminal. Through these cellular experiments Jessell, first in the Fischbach lab and then as a member of the Harvard faculty, became convinced that one approach to understanding the organization and function of the nervous system was to decipher how neural circuits assembled themselves during development. The following two decades have seen Jessell approach this fundamental problem. Jessell moved to Columbia University in 1985, and soon after he made a serendipitous observation that focused his attention on the floor plate, an obscure and largely ignored group of cells located at the ventral midline of the spinal cord. In the following years, working with Jane Dodd, Jessell discovered that factors secreted by the floor plate have a profound influence on neural circuit assembly in the spinal cord. “These signals generate neuronal diversity, and direct axonal projection patterns” in this way organizing much of the spinal motor system,” Jessell notes. “One signal assigns identities to motor neurons and interneurons, whereas other signals, notably the netrins, guide axons across the midline, so ensuring that the two sides of the central nervous system communicate with each other” And similar principles operate in the dorsal half of the spinal cord, where roof plate cells have complementary functions to the floor plate. Much of that early work to define the functions of the floor plate were performed by three remarkable post-doctoral fellows, Toshiya Yamada, Marysia Placzek and Marc Tessier-Lavigne. “In a typical embryological experiment,” Jessell explains of work with animals, “the way you find out what a cell group does is to surgically remove it or put it in a different place and see what happens during development.” Yamada, Placzek and Tessier-Lavigne took the floorplate and moved it to a different region around the spinal cord. Suddenly motor neurons appeared in new positions, whereas they are normally confined to the ventral region of the spinal cord. “So it became clear that this small un-prepossessing, cell group secretes signals that organize motor circuits” Jessell says. “Then the search was on for those factors, which pattern neuronal development and make motor neurons.” In 1993 several labs discovered that the sonic hedgehog protein mediates the organizing activity of the floor plate, and it was later shown that this protein functions as a morphogen- inducing different classes of neurons at different concentrations. A gradient forms—the protein concentration is higher closer to the floor plate, lower further away. And the specific concentration of the protein at any point determines which class of neurons is formed in that position. “So it is an economical way of establishing neuronal diversity,” Jessell says. “And because of sonic hedgehog, and similar morphogens, you can predict the eventual fate of a cell by its early position in the nervous system.” Since these early studies, Jessell has gone on to define many of the molecular mechanisms that drive the assembly of the spinal cord’s simple sensory and motor circuitry. Jessell serves on the advisory board and as a member of the Motor Neuron Center at Columbia, which tries to take such basic research findings on motor neuron development and translate them into therapies for neurodegenerative diseases. “I think there are many fundamental issues in development of the spinal cord and circuitry that still need to be understood,” he says. “Ultimately we want to know more about circuit assembly and the synapses between neurons,” he notes. “Within the jungle of networks, how do neurons recognize one set of motor neurons that innervate flexor muscles from another set that innervate extensor muscles.” Networks must be assembled correctly and the right sets of motor neurons have to activate the correct muscles in order for Usain Bolt to run faster than anyone ever has, or for you to simply take a walk.
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