HARVARD GAZETTE ARCHIVES

Images show optic nerve regrowth in rats (top) without oncomodulin (the new compound found by researchers) and (bottom) with oncomodulin.

Researchers at Harvard Medical School and Children's Hospital Boston have isolated a molecule that stimulates the regrowth of damaged adult nerve fibers, providing new hope for those suffering from nerve damage and from neurodegenerative diseases.

Adult nerve fibers in the brain, spinal cord, and optic nerve - all parts of the central nervous system - are notoriously difficult to repair once damaged. In extreme cases, such as spinal cord injury, such damage can be responsible for devastating paralysis.

Led by Associate Professor of Neurosurgery Larry Benowitz (right), researchers, including lead author Yuqin Yin (left), identified a mysterious protein that stimulates the regrowth of damaged adult nerve fibers. (Staff photo Stephanie Mitchell/Harvard News Office)

Led by Associate Professor of Neurosurgery Larry Benowitz, researchers identified a mysterious protein whose effects were first noticed seven years ago when injured optic nerves spontaneously began to regenerate in some of their experimental animals.

One of several surprises in this work, Benowitz said, is that the protein, oncomodulin, does not belong to any known family of growth factors, but to an entirely different family of proteins.

It took time not only to identify oncomodulin, but also to figure out the right conditions for the molecule to be effective. Oncomodulin works best in the presence of two other molecules, and even better when substances known to inhibit adult nerve growth are neutralized. So far, oncomodulin has been proven to work on retinal ganglion cells - which connect the eye to the parts of the brain responsible for processing visual signals - and at least one other type of nerve cell.

The research, reported in the May 14 online edition of the journal Nature Neuroscience and scheduled for release in print in June, was led by Benowitz. The first author is Instructor in Neurosurgery Yuqin Yin, who conducted most of the studies reported in the article. Other Harvard investigators include Research Fellow in Surgery Barbara Lorber and Research Fellow in Ophthalmology Toru Nakazawa. Other participants include colleagues at Children's Hospital, the Massachusetts Institute of Technology, and the University of Missouri.

The pursuit of oncomodulin began when researchers testing another molecule they hoped would stimulate injured nerve fibers to grow back after optic nerve damage noticed there was regeneration not only in the experimental animals but also in some of the controls, which had only received an injection of saline solution.

The researchers eventually realized that they had inadvertently nicked the lens of the eye while making their injections, creating an inflammatory response in both the experimental and control cases. They traced the regeneration to immune system cells called macrophages that were responding to the injury. They then cultured macrophages and isolated the proteins secreted by the cells.

Among these proteins was oncomodulin, which initially didn't appear to be very promising, Benowitz said, as there was no indication from previous studies that oncomodulin could act to stimulate nerve growth. The more they investigated its effects, however, the more they realized oncomodulin was indeed a growth factor, and a very strong one.

"Much to our surprise we found it's a powerful stimulator of axon growth," Benowitz said.

Though encouraging, there is much more work to do before oncomodulin can be declared a potential tool for nerve repair, Benowitz said. The experiments conducted by him and his team illustrated significant nerve growth using oncomodulin in both cell cultures and in laboratory rats.

But it remains to be seen, he said, whether nerve fibers that regenerate after treatment with oncomodulin would restore lost sight in laboratory animals. His experiments were conducted to identify oncomodulin and to explore how well it helps damaged nerves regenerate. In order for the nerves to be functional, he said, the nerve fibers would not only have to grow long enough to re-connect the eye and the brain, they'd also have to connect to the proper locations in the brain that process visual signals.

A further limitation, he said, is that this treatment would not replace any nerve cells that had died due to injury.

Still, Benowitz said, researchers are just starting to probe the possibilities of nervous system repair with oncomodulin. Between his own research and work being done on nervous system repair around the world, Benowitz said he remains cautiously optimistic that science will find new ways to help those suffering nerve damage.

"This is one step along the way," Benowitz said. "For people who are in need of treatments, this is one part of a pretty big effort, a worldwide enterprise focused on this. And the whole enterprise gives me hope."

alvin_powell@harvard.edu

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