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Research

Barres Laboratory

Ben Barres, MD, Ph.D.

 

 Ben Barres, MD, Ph.D.
Stanford University, Stanford, California

The Barres laboratory is focused on the role of glia (which include astrocytes and oligodendrocytes) in the failure of the central nervous system (CNS) to regenerate. Glial cells, also known as neuroglia, are non-neuronal cells that have varied functions in the CNS, including providing support and protection for nerve cells, forming myelin and destroying pathogens and removing dead neurons.

Dr. Barres became board certified in neurology and then returned to graduate school to do a seven-year PhD at Harvard and a three-year post-doc at University College in London. He says that one of the reasons he left his medical practice for basic research was the extreme frustration of having spinal cord injury patients for whom he could do little.

Years ago, he became very interested in the question of whether glial cells have a more active role in the CNS than what conventional wisdom held; then, it was widely believed that glia were passive work cells that mopped up after neurons. In particular, Dr. Barres and his lab colleagues wondered if glia were active at the synapses (the points at which electrical/chemical signals pass between neurons and other cells). In pursuit of an answer, they found that neurons are amazingly self-sufficient cells; they can keep their morphology as neurons, make dendrites and axons on their own and are excitable and independently able to initiate action potentials. However, the Barres team found that neurons can't form synapses on their own: to do this, they need glial cells! Without glia, they simply can't hook up, wire up; they are connection-less. Neurons have the internal molecular machinery necessary to make synapses but they need a signal from outside to trigger the actual process. So the next question Barres asked was: what is it that astrocytes create that tells neurons to make synapses? It took many years but the first signal his studies identified was a family of molecules called thrombospondins – these proteins are made by astrocytes (especially in the developing brain) and they reappear after injury – for repair of synapses.

Dr. Barres believes that astrocytes control all aspects of synapse formation, function, maintenance and even elimination. Why is this so important? Synaptic connections are damaged and/or lost in disease and will have to be rebuilt; the signals made by astrocytes and the cells they interact with are all potential new drug targets. In the case of spinal cord injury and regeneration, the questions are: will regenerating axons even make synaptic connections? And if they do, will they make the right synapses, the very specific connections they're supposed to make? So in traumatic injury, as in disease, how the body elicits the signals needed to trigger synapse formation is of paramount importance.

The Barres lab also focuses on regeneration – and why axons in the CNS fail to grow back after they're severed. His research suggests this is a problem that is largely glial in nature. Astrocytes that have become reactive and oligodendrocytes (especially in degenerating myelin) are very inhibitory to regenerating axons. Yet there's been very little research into reactive astrocytes and how they actually stop regeneration. Scientists don't even understand how astrocytes know there has been an injury, although the obvious culprit is some kind of signal, perhaps from inflammation.

In addition to his work with glia, Dr. Barres is exploring what role neurons play in regenerative failure. As young cells during development, neurons have an intrinsic capacity to regenerate but as adults, the ability to regenerate their axons has been lost. The Barres lab has shown that this is tied to a genetic program, a switch that results in dramatically slowed growth. He says that "...forever after, those axons can never grow fast again, no matter what you do. No matter what trophic juice you throw on them. No matter how you stimulate them. No matter what you do, they just lost, irreversibly it would seem, the ability to rapidly regenerate their axons. Axon growth failure in the CNS, it's not all glial inhibition. Even if you got rid of all the inhibition ... Those axons, if they grew flat out at this rate, it would take them ten years to grow from the neck back down to the end of the spinal cord. If you could flip the switch and get those axons to grow fast again, maybe they'd grow right over all those supposedly inhibitory molecules."

The research in the Barres lab will dovetail with scientific explorations ongoing in the other Consortium laboratories. Obvious points of intersection include: the Edgerton lab (better understanding how spinal cord cells get signals from glia with a clinical goal of using pharmacology to stimulate spinal cord cells rather than using implanted stimulators); the Fawcett lab (better understanding the molecular signaling that switches on axons during development and better insight into chondroitinase, which appears to promote axon growth and is related to glia); the Schwab lab (axon sprouting, which involves glial cells); the Pfaff lab (motor neurons, axon guidance, how nerve circuitry is formed and how it could be reformed after injury); and the Mendell lab (using its electrophysiological expertise to enhance Barres' own research).

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Continue Christopher Reeve's LegacyPhoto by Timothy Greenfield-Sanders