Leading From the Lab: Zuckerman Institute’s Thomas Jessell

Ask Thomas Jessell why he has dedicated his career to understanding the neurobiology of movement, and he puts it in simple terms: “Movement is the overt expression of all behaviors—without movement, intent and desire can be planned and felt but never realized.” Whether it’s the pumping heart or a flashing grin, movement is the culmination of all brain and nervous system activity. “In essence, the nervous system performs one major task,” explains Jessell, the Claire Tow Professor of Neuroscience and of Biochemistry and Molecular Biophysics as well as co-director of the Mortimer B. Zuckerman Mind Brain Behavior Institute. “It converts information extracted from the sensory world, or stored within, into purposeful action through the programmed contraction of muscles.”

Jessell is an authority on the motor circuitry of the spinal cord—the part of the central nervous system that oversees movement, determining just which muscles are to be activated, for how long and in which precise combinations. For over 30 years, working initially with chick embryos and now with mice, he has teased apart the mysteries of how naive neural cells develop into hundreds of distinct classes of spinal neurons, and how they form precise connections with one another, with the brain and with the numerous muscles they control. His research has explored how this exquisite circuitry first takes shape, and how it controls and refines movement once the wiring is complete. His most recent paper, published Feb. 2 in Nature, provides an insight into the strategies and circuits behind the act of reaching for an object, arguably the most sophisticated mammalian motor behavior.

Jessell’s contributions to neuroscience have earned him the inaugural Kavli Prize, the Canada Gairdner Award and just last month the Vilcek Prize in Biomedical Science, given annually to immigrants to the U.S. who make outstanding contributions to science. University President Lee C. Bollinger appointed Jessell to serve as co-director of the Zuckerman Institute along with Columbia’s two Nobel Prize-winning neuroscientists Richard Axel and Eric Kandel.

Kandel is one of Jessell’s greatest admirers. “He has focused on a large and important problem in brain science and brought to bear on it whatever techniques are required. If he needs a new technique he masters it. Nothing intimidates him.”

In March the Zuckerman Institute launched a series of Brain Month public education and community outreach events reflecting the Institute’s commitment to making neuroscience accessible to a broader audience, which will remain a hallmark of its public mission when the Jerome L. Greene Science Center opens on the Manhattanville campus in 2016.

For all his achievements, Jessell maintains a cool, levelheaded perspective on the state of his field. “We’ve made important advances, but at present, answers to most of the key questions in neural science remain the stuff of speculation,” he notes.

He is determined to change this state of comparative ignorance, through his own research and his leadership of the Zuckerman Institute. Most days, he’s up at dawn, “worrying” about what’s going on in his lab and “interrogating” his students and postdoctoral fellows. His intensity is tempered by an irreverent sense of humor. Jessell began a lecture recently by winding up a brain-on-legs and letting the plastic toy totter across the podium. “Here is the human body stripped away of all extraneous parts,” he deadpanned.

Raised in London, Jessell was initially uncertain about whether to follow his mother, a paintings conservator, into the arts or to pursue science as did his German grandfather, a distinguished organic chemist. The choice became clear on arriving at Chelsea College at the University of London, when he became fascinated by the lectures of neuropharmacologist John Bevan, who documented how psychoactive drugs influence brain signaling.

Jessell earned his Ph.D. at Cambridge in neuropharmacology and went to Harvard in 1978 for postdoctoral training in neural development and cell biology, joining the faculty three years later. His move to Columbia in 1985 was driven by a desire to incorporate the emerging tools of molecular biology into his research and by the magnetic pull of Axel and Kandel. “There was a sense that one might achieve fundamentally new things at Columbia,” he reflected.

“Every so often, you make a discovery that shakes you to your foundation and makes you think about a familiar problem in a different light.”
Jessell has had several eureka moments in his career. One insight occurred a few years ago when he was puzzling over the issue of how sensory neurons form precise connections with a small set of motor neurons, bypassing dozens of potential targets. The prevailing view, Jessell explains, was that target cells were recognized by chemical labels expressed on their surface.

To explore this issue, Jessell and his student Gulsen Sumeli used a genetic trick to abolish certain identifying characteristics of motor neurons. Although one potential outcome was the random scrambling of sensory-motor connections, they instead found that sensory neurons still arrived at their correct destination, but on arriving made connections with any motor neurons that happened to be in the vicinity.

Jessell explains this unexpected discovery with a simple analogy. Imagine a weekend morning when you have to meet a friend at the corner of Eighth Avenue and 44th Street in Manhattan. One option couldbe to wander down Eighth Avenue, all the while keeping an eye out for that familiar face. An alternative strategy would be to head directly to the corner of 44th and Eighth with the expectation that the person standing there will be the person you hope to meet. As it turns out, sensory axons in the spinal cord use the latter strategy.

As a research scientist, Jessell has focused on uncovering fundamental biological insights, but his research has also provided a foundation for clinical advances. About 15 years ago, Jessell and his postdoctoral colleague Hynek Wichterle, now a faculty member at Columbia, designed a recipe for efficiently coaxing embryonic stem cells into becoming motor neurons.

This simple discovery has made it possible to generate motor neurons in near-limitless numbers from human cells isolated from healthy subjects and from patients suffering from motor neuron diseases, opening the way to a better understanding of such diseases and hopefully to the design of effective interventions.

Scientific progress tends to come in fits and starts, Jessell observes. “Every so often, you make a discovery that shakes you to your foundation and makes you think about a familiar problem in a different light. And immediately a dozen or more experiments suggest themselves. It is this cycle that reassures, motivates and keeps us busy for the next few years.”