How Scientists Finally Learned That Nerves Regrow

Scientific American

10 hours ago

Billions of nerve cells send signals coursing through our bodies, serving as conduits through which the brain performs its essential functions. For millennia physicians thought damage to nerves was irreversible. In ancient Greece, founders of modern medicine such as Hippocrates and Galen refused to operate on damaged nerves for fear of causing pain, convulsions or even death.
The dogma stood relatively still until the past two centuries, during which surgeons and scientists found evidence that neurons in the body and brain can repair themselves and regenerate after injury and that new nerve cells can grow throughout the lifespan. In recent decades this knowledge has inspired promising treatments for nerve injuries and has led researchers to investigate interventions for neurodegenerative disease.
In humans and other vertebrates, the nervous system is split into two parts: the central nervous system, composed of the spinal cord and brain, and the peripheral nervous system, which connects the brain to the rest of the body.
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Attempts to suture together the ends of damaged neurons in the peripheral nervous system date back to the seventh century. It was only in the late 1800s, however, that scientists began to understand how, exactly, nerves regenerate. Through his experiments on frogs, British physiologist Augustus Waller described in detail what happens to a peripheral nerve after injury. Then, in the 1900s, the influential Spanish neuroanatomist Santiago Ramón y Cajal provided insight into how nerve regeneration occurs at the cellular level. Still, there remained fierce debate about whether stitching nerves together would harm more than help.
It was against the backdrop of bloody world wars of the 20th century that physicians finally made significant advances in techniques to restore damaged neurons. To treat soldiers with devastating wounds that typically involved nerve damage, doctors developed methods such as nerve grafts, in which pieces of nerves are transplanted into the gap in a broken nerve.
Over time physicians learned that some peripheral nerve injuries are more conducive to repair than others. Factors such as the timing, location and size of the injury, as well as the age of the patient, can significantly impact the success of any given intervention. Crushed nerves are likelier than cut ones to be repaired, and injuries that occur closer to a nerve's target tissue have a greater chance of regaining function than those that occur farther away. Take the ulnar nerve, which stretches the entire length of the arm and controls key muscles in the lower arm and hand. A person with nerve damage near the wrist is much more likely to regain function in the arm and hand after undergoing treatment than someone who injures the same nerve near the shoulder, in which case it must regrow from the shoulder all the way to the wrist.
Even today many peripheral nerve injuries remain difficult to treat, and scientists are striving to better understand the mechanisms of regeneration to facilitate healing. One notable development in recent years, according to neurologist Ahmet Höke of the Johns Hopkins University School of Medicine, is a 'nerve transfer,' in which a branch of a nearby nerve is rerouted to a damaged nerve. In cases where, for example, a nerve is damaged far from its target muscle, existing techniques may not be sufficient to enable regrowth across the long distances involved within a time frame allowing for recovery. This detour provides an alternative pathway to regain function. Susan Mackinnon, a plastic and reconstructive surgeon at Washington University in St. Louis, has largely driven the advances in nerve transfer, enabling patients to use their limbs after peripheral nerve injuries that previously would have led to a permanent loss of movement in them.
For instance, Oskar Hanson, a high school baseball player, lost sensation and movement in most of his left arm after a surgery to mend a ligament injury ended up damaging the ulnar nerve in that arm. 'There was zero hope that he would be able to have use of his arm again,' says his mother, Patricia Hanson. But after Mackinnon performed a nerve transfer procedure, most of the function returned. 'She saved his life with that surgery,' Hanson says.
Despite the leaps that were made in treating peripheral nerve injuries, the notion that neurons within the central nervous system—the brain and spinal cord—were incapable of regrowth persisted until the late 20th century.
A pivotal moment came in the early 1980s, when Canadian neuroscientist Albert Aguayo and his colleagues demonstrated that in rats, neurons of the spinal cord and brain stem could regrow when segments of peripheral nerves were grafted into the site of injury. These findings revealed that neurons of the central nervous system can also regenerate, Höke says: 'They just needed the appropriate environment.'
In succeeding years, neuroscientists worked to uncover what, exactly, that environment looked like. To do so, they searched for differences in the peripheral and central nervous systems that could explain why the former was better able to repair damaged neurons. Several key differences emerged. For example, only injuries within the central nervous system led to the formation of glial scars—masses of nonneuronal cells known as glial cells. The purpose of these scars is still debated, however.
Today the search for the specific mechanisms that prevent or enable neuron regrowth—in both the body and the brain—remains an active area of investigation. In addition to uncovering the processes at play in humans, scientists have pinpointed molecules that enable nerve cell repair in other organisms, such as 'fusogens,' gluelike molecules found in nematodes. Researchers are attempting to harness fusogens to help with difficult-to-treat human nerve injuries.
Modern neuroscientists have also challenged another long-standing doctrine in the field: the belief that the adult brain does not engage in neurogenesis, the creation of brand-new nerve cells.
Early clues for neurogenesis in the brain emerged in the 1960s, when researchers at the Massachusetts Institute of Technology observed signs of neurons dividing in the brains of adult rats. At the time, these findings were met with skepticism, says Rusty Gage, a professor of genetics at the Salk Institute for Biological Studies in La Jolla, Calif. 'It was just too hard to believe.'
Then, in the early 1980s, neuroscientist Fernando Nottebohm of the Rockefeller University discovered that in male songbirds, the size of the brain region associated with song-making changed with the seasons. Nottebohm and his colleagues went on to show that cells in the animals' brains died and regenerated with the seasons. Inspired by these findings, researchers looked for signs of adult neurogenesis in other animals. In 1998 Gage and his colleagues revealed evidence of this process occurring in the brains of adult humans—specifically within the hippocampus, a region linked with learning and memory.
Although support for adult neurogenesis in humans has amassed over the years, some experts still debate its existence. In 2018 a team co-led by Arturo Alvarez-Buylla, a neuroscientist at the University of California, San Francisco, who had worked with Nottebohm on songbirds, published a study stating that the formation of new neurons was extremely rare, and likely nonexistent, in adult human brains.
Still, there's a growing consensus that neurogenesis does happen later in life —and that this growth appears to be largely limited to certain parts of the brain, such as the hippocampus. This past July a team at the Karolinska Institute in Sweden reported that the molecular signatures of precursors of neurons, known as neural progenitor cells, were present in the human brain across the lifespan—from infancy into old age. Researchers are now trying to understand the purpose of these budding nerve cells and asking whether they might offer clues for treating neurodegenerative disorders such as Alzheimer's disease. Some scientists are even exploring whether, by targeting neurogenesis, they can improve the symptoms of psychiatric conditions such as post-traumatic stress disorder.
Understanding that a neuron can regrow and be repaired and identifying details of that process has been a great achievement, says Massimo Hilliard, a cellular and molecular neurobiologist at the University of Queensland in Australia. The next step, he adds, will be figuring out how to control these processes: 'That's going to be key.'