BY JAMIE TALAN
STAFF WRITER
November 7, 2005

Walking, grabbing a pen, bending over to tie a shoe. For most people, these everyday functions seem so easy. But until now, scientists really couldn't explain how motor neurons are born to find their precise job in the body. There are 100 different types of motor neurons, each destined to hook up to a specific muscle in the body.

Now, in a landmark finding that could have huge implications for a variety of diseases - from paralysis to Lou Gehrig's disease - scientists at Columbia University Medical Center have discovered a set of genes that assign a role to specific types of motor neurons. This was no small discovery: Just taking a step calls on 50 different muscle groups.

So how does the human body generate such an extreme diversity of motor neurons, and how do they find the right home?

According to Dr. Thomas Jessell, a Howard Hughes Medical Institute investigator and professor of biochemistry and biophysics at Columbia, a family of genes, with a surname of Hox, holds the key to motor neuron development, differentiation and specialization. Before this finding, which appears in the latest issue of Cell, all that was known was that Hox genes controlled many aspects of the overall body plan.

Jessell and colleagues discovered that 21 of the 39 Hox genes are involved in making all the different types of motor neurons and getting them to where they need to be. "It tells us the basic workings of how the nervous system is wired up," Jessell said. "It also gives us a new target for treating diseases that damage the motor neurons."

With all the work under way in trying to understand and treat Lou Gehrig's disease, formally known as amyotrophic lateral sclerosis (ALS), the Hox discovery could immediately open the door to new avenues of research. "In order to understand how ALS develops, we have to unravel this genetic process," Jessell said. "This paves the way to asking how this takes place."

Many groups of motor neurons are progressively damaged in ALS. The damaged motor neurons can no longer communicate with muscles. The result is paralysis. No one knows why these motor neurons are so vulnerable to attack. But once this process starts, it's lethal. The average ALS patient is dead within five years.

But as Jessell pointed out during an interview last week, some groups of motor neurons are spared in the disease. For instance, virtually all patients retain their ability to move their eye muscles, which are also controlled by motor neurons. For some, this is their final means of communication, using their eyes as their voice, or even guiding a computer cursor to type. If scientists could identify specific Hox genes that regulate these eye muscles, it may be possible to develop a strategy to protect those more vulnerable motor neurons.

It's possible that certain Hox mutations could be involved in the disease, Jessell said. Or the patterns of gene expression - how these genes make proteins - could be altered to bring about the devastating symptoms. "By knowing the basic molecular wiring programs, one may be able to change the identity of motor neurons to see if it protects or damages them."

At present, there are no treatments that stall the disease process. At a recent meeting at Cold Spring Harbor Laboratory's DNA Learning Center, a dozen ALS patients and their families had an opportunity to question some of the leading scientists in the field.

David Deutsch, a 37-year-old biology teacher from West Sayville, was diagnosed 18 months ago. He experienced the first signs while in the hospital with viral meningitis. His thumb muscles began to twitch. It didn't go away. "I was strong as an ox," he said recently. The muscle weakness has now spread to his arms and shoulders. For now, his legs remain strong, but the motor neurons send chaotic messages to the muscles, causing involuntary movements of his legs. His balance is shot. Most of his time awake is spent in a wheelchair.

With no therapies on hand, he looks to research. "I look forward to steering the research in the direction of hope," Deutsch said. On the ALS treatment horizon: stem cells that deliver growth factors that could nourish motor neurons, or the muscle itself.