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Regenerating what cannot be replaced

Victims of stroke and traumatic neurological injury face a difficult problem: healing requires growing new connections. Researchers are working on ways to accelerate and supercharge the mind’s ability to mend.

Stroke representation.

The 65th anniversary of the day the world learned the polio vaccine is safe and effective occurred on April 12, 2020, amid another global infectious disease outbreak. As it happens, intensive care medicine of the kind now saving COVID-19 patients’ lives has roots in the pre-1950s polio epidemics.

There’s another connection between the two infections: neurological damage. Some COVID-19 patients suffer ischemic strokes or other neurological problems like seizures and loss of smell. Some evidence suggests the novel coronavirus can travel to and attack the brain directly. Likewise, in some unlucky polio sufferers, the virus invades motor neurons in the spinal cord, leading to widespread cell death and paralysis of limbs or even the diaphragm.

Still, healing can take place. Stroke and polio survivors as well as people living with spinal cord injury may recover function. Axons sprout; cut nerves can reconnect; paralysis can subside. Sometimes.

Several Yale researchers have spent their careers working to understand the mechanisms of neural regeneration and repair. Over the past two-plus decades, new and powerful forms of microscopy and gene analysis have allowed neurology researchers to compile an encyclopedia of sorts—one that could allow them to manipulate the molecular pathways of damage after neural injury. Their hope: to restore function in survivors of spinal cord injury, stroke, and other devastating neurologic conditions.

“The idea that we could use medical interventions to enhance a process that’s already there—that happened during development in the first place, but then is severely and unfortunately restricted in the mature CNS after injury—is something that I think is very hopeful,” said Stephen Strittmatter, MD, PhD, the Vincent Coates Professor of Neurology, professor of neuroscience, and director of the Cellular Neuroscience, Neurodegeneration, and Repair program.

A growth environment

Paralysis, numbness, speech difficulties, and other disabilities resulting from neurological injury often occur, not as a result of cell death but rather of interrupted connections. Those connections occur at synapses on the tips of axons, the long projections from cell bodies that can traverse a brain or head down a spinal cord or limb.

Being long and thin, axons are vulnerable to injury. A cut axon’s parent neuron can’t communicate across its synapse. That loss in turn disconnects neural circuits and the functions that depend on those circuits.

Yet even in the worst spinal cord injuries, the vast majority of neurons themselves usually survive. If their axons could regrow and reconnect across synapses, nearly all networks and functions could recover. There would be no need to generate new cells.

In the peripheral nervous system, axons often can heal by growing back, at least in part. Nearby glial cells support regenerating axons by delivering nutrients and providing a sense of direction as the growing nerve tips find their targets.

But in the central nervous system, spontaneous axon growth is typically negligible. Mature neurons, though they contain genes whose expression can push axons to grow, don’t usually fire up that machinery in an effective way if their own axons are cut. And something about the environment around an injury site prevents regrowth. Nearby support cells release axon growth inhibitors that block growth, like so much glue fixing neurons in place.

A memorable environment

For decades, Strittmatter has worked to understand and block those environmental barriers to axon regrowth. After discovering the inhibitor Nogo in the myelin sheaths that insulate central nervous system cells, then a receptor to which it binds, his team devised ways to block that “no-go” signaling. Then they developed a strain of mice in which the Nogo pathway doesn’t function. Experiments with those mice offered not only hope for survivors of stroke and spinal cord injury, but also clues as to why the brain so strongly prioritizes stability: it may be done so that important new skills and memories aren’t lost.

Knockout mice whose Nogo inhibitor pathways are disabled or removed develop normally—for the most part. But they show evidence of a nervous system that is more malleable, in a sense more adolescent, than that of normal mice. In particular, they seem less able to remember potential dangers like uncomfortable electric shocks. These mice lend weight to a hypothesis that the central nervous system’s need to maintain enough stability not to forget those foot shocks—or that dangerous predator, or that poisonous plant—might entail a sacrifice of the plasticity required to heal from injury.

Still, the knockout mouse turned out to have an important advantage: if it experienced a stroke or a spinal cord injury, its nerve fibers regrew more readily and it recovered much more function than normal mice do.

That finding led Strittmatter’s team to pursue molecules that can block this inhibition. They developed a soluble receptor decoy called Nogo Trap that mops up inhibitor proteins, preventing them from slowing axon growth. In genetically normal mice who have experienced a stroke or spinal cord injury, injecting this protein leads to better recovery, as in the knockout animals.

In treated animals, axons sprout and grow long distances, while synapses on nerve cell bodies show increased plasticity. “When we intervene with these growth promoters, some fibers that were cut will cross the injury site and go back at least to the general territory where they were before,” Strittmatter said. “But even more so—and probably more important for recovery—they’ll make new connections with fibers above the injury, and cells below the injury will make new connections.”

Now patented, Nogo Trap is being tested for efficacy in people with chronic spinal cord injury, in part because any improvements will be obvious amid an otherwise unchanging neurological situation. Even small changes in function are hugely important to people living with spinal cord injury. With minor improvements in muscle strength, Strittmatter said, “somebody can go from not being able to dress themselves or feed themselves to being able to do so.”


Other Yale researchers are tackling the problem from different directions. If Strittmatter’s research focus is the axons’ environment, that of William Cafferty, PhD, associate professor of neurology and of neuroscience, is on trying to remind neuronal cell bodies how to grow axons.

“If you think about it anthropomorphically, these nerves have forgotten how to grow, because they’ve switched off that program” since early development, said Cafferty, who began his career as a postdoctoral fellow in Strittmatter’s lab. “I’m very interested in how we can encourage adult central nervous system axons to grow again, irrespective of what the environment is.”

One challenge is sheer distance. In early development, animals are small, and the program allowing the nervous system to grow doesn’t need to remain “on” for long. By contrast, Cafferty said, “I’m six-foot-two. If I catastrophically had some kind of injury in my upper spinal cord, the distance that a motor neuron deep within my motor cortex would have to grow would be almost a meter.” On the way, he explained, the axon would somehow have to steer around injured tissue and unrelated neurons.

But Cafferty’s team thinks a workaround might lie in the fact that few spinal cord injuries lead to the nerve being completely severed, or “anatomically complete.” Even when loss of function is complete, the injury is typically partial, with some intact axons persisting along the length of the spinal cord. If there were a way to stimulate or reorganize those intact pathways to replace lost connections, he explained, then axons wouldn’t need to grow far to access areas that have lost input from the brain. Cafferty’s experiments based on that approach have been successful in rodents.

Meanwhile, Marc Hammarlund, PhD, associate professor of genetics and of neuroscience, studies the molecular machinery of axons in Caenorhabditis elegans. This transparent one-millimeter-long nematode sports precisely 302 neurons. Hammarlund’s team can sever individual axons with a laser and study the regenerative process.

Jeffery Kocsis, PhD, professor of neurology and of neuroscience, is exploring cell transplantation to repair central nervous system damage. He has demonstrated in rodents that an intravenous injection of stem cells called mesenchymal stem cells (MSCs), which are derived from bone marrow, can repair damaged microvessels after spinal cord injury and stroke, and improve functional outcomes. These results have important implications for a number of neurological disorders in which the microvasculature is compromised, resulting in brain and spinal cord damage. Kocsis added, “Cells used for therapies are interesting in that they can release nanoparticles called exomes which carry molecular cargoes that can be therapeutic. The exploration of exomes as therapeutic tools in neurological diseases is currently an exciting area of research.”

Beyond the spinal cord

The spinal cord may be a comparatively simple problem. Future challenges may be to intervene in more complex brain deficits resulting from stroke, traumatic brain injury, multiple sclerosis, or degenerative diseases like dementia. “This idea of getting new neural network connections is relevant to a broad range of chronic neurologic deficits in the central nervous system,” Strittmatter said.

But axon repair will remain relevant. Though traumatic brain injury can kill cells, it can also disrupt networks. Repeated mild blows to the head, for example, can rip long fibers traversing the brain. And the lasting neurological deficits that often follow stroke can result from oxygen starvation injury to axons as well as to neuronal cell bodies. “Many times, chronic cognitive and behavioral deficits are actually more related to disconnection than they are to cell loss,” Strittmatter said.

If stem cells, inhibition blockers, or neuronal rewiring prove effective, they still probably won’t be magic cures for injuries to a structure as complex as the central nervous system. “It’s likely that one therapy will not solve everything,” Strittmatter said. “But eventually, three or four therapies, each with benefits, will be added together for more and more robust benefits. I’m certainly optimistic,” he added. “Otherwise I wouldn’t be doing what I do.”