A Protein Called Sonic the Hedgehog

Videogame superstar Sonic the Hedgehog is making a comeback-this time as a brain protein.

Instead of Sonic fighting evil digital villain Dr. Robotnik, however, chemical engineering professor David Schaffer hopes that this Sonic will eventually be battling brain diseases.

Last year Schaffer published his discovery that the Sonic Hedgehog protein, first determined as a protein to cause mutations in flies in 1993, also played a significant role in cell division.

"For the past six of seven years we've been studying adult neuron stem cells-these cells are population cells that exist in the brain that divide and generate new neurons in our brains," Schaffer said. "We're interested in a couple of questions-why does the brain need new neurons in the first place, can we use these cells to regenerate tissue, and what are the signaling factors that control the function of the cells?"

Researchers discovered a couple of years ago that Sonic Hedgehog is a major regulator of neuron cells. The body uses the Sonic protein in multiple tissues for development, such as the skin, hair, intestine, pancreas and brain, from the embryo stage to the adult stage. Schaffer's investigation focuses on Sonic's role in the brain.

"To regenerate tissue, or replace a lot of neurons, you need to mass-produce the cell, and then you need to take those mass-produced cells and induce them to differentiate them into neurons. So we're very interested in Sonic Hedgehog because we found it's a powerful way to mass produce the cells initially," Schaffer said.

The body's delivery of the Sonic Hedgehog protein to the brain stimulates stem cell divisions, and the brain transforms the cells into neurons. These new neurons provide a pool of healthy cells to replace the dying neurons that cause brain damage.

Sonic could have a profound effect on cases in which the brain suffers from dying neurons. Such examples include Alzheimer's, Lou Gehrig's disease, Huntington's, stroke and other brain injuries from trauma.

"We're interested in general in identifying factors that control cell function, so for example if we want to regenerate tissue for an Alzheimer's victim, as Alzheimer's is caused by the death of neurons, we identify the factors that cause cell to proliferate, and then the factors that cause the cell to differentiate, so you can find the cell division and proliferation signal. We're in the business of identifying factors that control a cell function," Schaffer said.

At the beginning, Schaffer and his team compiled all the possible factors that could have an affect on adult neuron cells.

"We screened a few of the usual suspects that play major roles during neural development, and this one ended up having very significant effects, and it's one of the ones our lab has been focusing on," Schaffer said.

He studied the Sonic protein first in cell culture dishes, in which he could add other proteins to study the results.

"You really want to prove it really is having an effect on the brain, so that's where animal work comes in," Schaffer said.

Schaffer tested and observed the Sonic Hedgehog protein in mice to see if it was having the same effect in the brain as it was in cell culture. It was in animal testing that Schaffer encountered what he said was the most difficult obstacle in his experiment.

The scientists at first delivered the Sonic Hedgehog protein directly to the mice, but soon discovered that the protein quickly degraded within the body, not permitting enough time for observation.

To solve this problem, Schaffer turned to another approach. He injected the gene encoding the Sonic protein into mice, thus allowing the protein to be continually produced and allowing scientists to study cell divisions over the course of several weeks.

The results in the mice experiments reflected the positive outcome in the culture dish.

"We've actually tripled the stem cells in the brain, and thus as a result tripled the neurons in the brain, which is a pretty significant finding. It really hints at future use of these cells for regeneration," Schaffer said.

Schaffer also says the most daunting task to come is identifying the full set of signaling molecules that control cell function, and understanding how they work in a concerted way to orchestrate cell function and cell development.

"Since these cells were very recently discovered, and the stem cell field is very young, it will probably take a decade or more before these cells can be used to repair tissue. There's still an enormous amount of work that needs to be done before we can understand what makes these cells tick, exactly how they function within the body," Schaffer said.

Karen Lai, Brian Kaspar and Fred Gage collaborated with Schaffer on this experiment.

Tags: