InsideMS; Summer 2002; Vol. 20, Issue 3
When medical science finds a way to stop all MS attacks—what then? Will it be possible to repair the damage MS has already done? This question has propelled neurologist and molecular neuroscientist Stephen G. Waxman, MD, PhD, professor and chairman of Neurology at Yale University, throughout his career. As an acknowledgment of his painstaking, groundbreaking research on nerve fibers that have lost their protective myelin coat and become, in medical terms, demyelinated, the American Academy of Neurology and the National Multiple Sclerosis Society awarded Dr. Waxman the prestigious 2002 John Dystel Prize for MS Research, on April 16, in Denver, Colorado.
Dr. Waxman, who also directs Yale’s PVA/EPVA Center for Neuroscience and Regeneration Research Center of Yale University in West Haven, Connecticut, says the path to his current work reaches back to his medical student days in the 1970s. While attending the Albert Einstein College of Medicine, he became enamored of the work of Dr. Andrew Huxley, the Nobel Prize–winning physiologist who discovered the sodium channel.
“When I did some of my first research in London, I got to meet Huxley,” Dr. Waxman recalled. To his disappointment, his hero had left the field of sodium channels. “At that time it was a mystery why,” he said.
Nevertheless, young Dr. Waxman was inspired to devote his life to studying nerve impulse conduction in normal, demyelinated, and regenerating nerve fibers.
Nerve Conduction 101
To understand this work, it’s necessary to learn a little about nerve conduction. Nerve fibers (or axons) are like long chutes that act as delivery pathways for electrical signals traveling from one site to another within the central nervous system (the brain and spinal cord) or from the central nervous system to sites all over the body. Running along the axons are clusters of different kinds of pore-like molecules designed to admit particles—or ions—of salts or minerals.
Chief among them are sodium channels. They allow electrical signals to be created. Each sodium channel has a kind of trap door that opens and closes to let through sodium ions in response to signals from the axon. As Dr. Waxman explained, “Some sodium channels open and close slowly, some rapidly, some have an on/off switch that’s easy to turn on, others have a switch that’s hard to turn on.”
A second type of pore-like molecule is the potassium channel. Potassium channels act as a brake. Sodium channels and potassium channels operate together, generating sequences of precisely timed nerve impulses that carry information within the brain and spinal cord. Dr. Waxman’s early research showed that when the axon’s protective myelin sheath is damaged, as happens in MS, the exposed parts of the axon don’t contain enough sodium channels to power nerve conduction. The lost or weakened nerve messages cause many MS symptoms such as poor vision or loss of motor power.
Genes run the show
Dr. Waxman wanted to know what happened next. “We learned there are 10 different genes in the nerve cell’s DNA that produce different sodium channels. When an axon is damaged, the sodium channel genes that should be turned on are turned off, and those that should be turned off, turn on. The cell produces the wrong kind of channel. It’s like putting a type A battery into a radio that needs a type C.” The damaged nerve cell may continue to fire in an inappropriate buzz, like static on a radio, or pins-and-needles, or numbness, or pain.
Studying laboratory animals, Dr. Waxman and his colleagues recently found that special nerve cells in the brain called Purkinje cells also produce the wrong kind of sodium channels in lab animals that had lost their myelin. When the researchers studied autopsy tissues from people with MS, they found the reason why: “Something linked to the MS was causing a sodium channel gene to turn on inappropriately,” Dr. Waxman said. When this “off” gene is turned on, the cell activity becomes strikingly perturbed and it fires in inappropriate patterns. “The Purkinje cells are supposed to fire in a precise pattern, enabling us to play piano, do gymnastics, or throw a football,” he explained. “In a person with MS, these essential cells may talk nonsense to each other, and that causes loss of coordination.
“If we can learn how to control these genes or the channels they produce, we may be able to improve function in people with MS.”
Dr. Waxman’s research has also revealed that damaged axons can reorganize themselves and establish new sodium channels, even in areas that have been stripped of their myelin. The new channels restore the ability of the axon to conduct electrical impulses. “This prompts us to ask what triggers this process,” said Dr. Waxman. “Can we induce this change? In other words, can we develop therapies that will cause people with MS to have remissions?” Dr. Waxman and his research team are searching for the “promoters”, or switches, that control the production of new sodium channels.
In a third area of research, Dr. Waxman is looking into ways to rescue nerve fibers before they die. It is now well known that some nerve fibers degenerate, or even die, in MS. Researchers think this may be the cause of permanent disability. Dr. Waxman’s research suggests that nerve fibers die when calcium ions flow, in inappropriately large amounts, into nerve fibers. Dr. Waxman’s research has identified the molecules that permit this damaging inflow of calcium. “Our hope is to develop drugs that will block the pathway, and protect the axons by keeping the calcium out,” he said. “If we can do that, we have a good chance of preventing degeneration and loss of axons in the brain and spinal cord.”
A science fiction world
Twenty years after meeting Dr. Huxley in London, Dr. Waxman discovered why his hero had left the field of sodium channels. In 1995, Dr. Waxman edited a medical text called The Axon, for which Dr. Huxley wrote an introductory chapter. “In the 1960s, any idea of analyzing the sodium channels by the methods of molecular neurobiology would have seemed to us to be science fiction,” Dr. Huxley wrote. “Any idea that such work would be relevant to humans was beyond science fiction,” he said privately.
“Today, we’re living in his ‘science fiction,’” Dr. Waxman said. “The
molecular revolution has given us powerful research tools. Hopefully, we
can make all this science relevant to humans, especially to people with
© 2002 The National Multiple Sclerosis Society