In the developing brain, hundreds of billions of nerve cells, or neurons, must wire together into the precise circuits that allow us to move, think, feel and be. But how do all these neurons manage to make just the right connections? Marc Tessier-Lavigne has been trying to work out the molecular playbook his entire career. Contained in these blueprints may be the secrets to how to rewire an injured brain or spinal cord, or prevent brain degeneration during aging.
During development, newborn neurons send out long cables—called axons—to link with distant targets. For example, neurons that control movement extend their axons down to the spinal cord. That’s like sitting on the Stanford campus and reaching your hand all the way to Yosemite, explains biology professor Susan K. McConnell, who co-taught neural development with Tessier-Lavigne during his stint at Stanford in the early 2000s. “The axons behave as if they’re following some sort of highway or a set of road signs. But the molecular nature of those highways and road signs has been one of the big questions in neuroscience,” McConnell says.
Tessier-Lavigne broke open the field in 1994 when he became the first to identify one of the molecules that directs growing axons. Scientists had long suspected that axons follow a trail of diffusible chemical “smells” wafting from the target cells. “It’s similar to how you would find the garlic festival in Gilroy or the Cinnabon store in the mall,” McConnell explains. Tessier-Lavigne’s team set out to fish the chemical attractant out of ground-up cells from the nervous system. After three years of arduous work, they succeeded in isolating the proteins, which they named netrins, after the Sanskrit word netr, meaning “one who guides.”
The discovery of the netrins touched off a wave of exciting studies: In quick succession, Tessier-Lavigne and others identified several proteins that attract or repel axons, and figured out many of the rules for wiring the nervous system. For example, an axon’s journey is broken into many short segments, and axons can change how they respond to different cues from one segment to the next.
Tessier-Lavigne soon realized that his work might have practical applications: If you understand how nerve fibers grow, then you might be able to regrow them after injury. In humans, neurons in the central nervous system (the brain and spinal cord) don’t spontaneously rewire, but neurons in the periphery of the body do—for example, when someone loses a finger, doctors can sew the digit back on and it works fine. Some animals (such as fish and salamanders) can also regenerate spinal cords. Thus, coaxing a severed spinal cord to reconnect might just be a matter of providing the right molecular cues and conditions.
Several proteins appear to act as roadblocks to axon growth in the adult nervous system. By disabling these proteins, Tessier-Lavigne and others have spurred mammalian brain and spinal cord neurons to sprout axons in a petri dish.
The details of brain wiring are also relevant to neurodegenerative diseases, such as Alzheimer’s. The developing brain initially wires up an excess of axons, some of which are then pruned to refine the circuits. Tessier-Lavigne believes that the same biological pathways that mediate axon death in the embryo may be mistakenly reactivated in Alzheimer’s and Parkinson’s diseases. He has tried to identify the players responsible for neuronal death, as some of these may be targets for drugs.
At Genentech, Tessier-Lavigne witnessed breakthroughs in cancer treatment that came from understanding the molecular nature of cancer. He hopes that a similar story is about to unfold for neurological diseases.
Kristin Sainani, MS ’99, PhD ’02, is a freelance writer and associate professor of health research and policy at Stanford.
