Pioneering research on the causes of an MS attack: the 2006 John Dystel Prize for Multiple Sclerosis Research for Dr. William A. Sibley.

What triggers an MS attack? Not one of those short-term spikes in MS symptoms that resolve in a few hours or by the next day, but the full-court exacerbation of neurologic symptoms that can mean a person is unable to walk or see or even hold a pencil and doesn't improve for 48 hours or more. What was the trigger? Hostile co-workers? Impossible teenagers? Too many worries? Or was the damage done by air pollution, high-tension wires, vapor from amalgam fillings?

Questions like these can haunt people with MS and those who care about them. When something so unwanted happens people naturally try to find a way to understand and perhaps control the situation. And sometimes they grasp at myths, like those last three ideas.

In different forms, questions about what triggers an MS attack also haunt MS researchers. Definitive answers could lead to therapies, to prevention strategies, and ultimately to the long-sought basic understanding of the MS mystery. No one in MS research has grappled with this longer--and arguably more fruitfully--than Dr. William A. Sibley, of the Arizona Health Sciences Center.

By normal career standards, Dr. Sibley would be long retired from the fray. Instead, as he enters his 82nd year, he is co-investigator in yet another National MS Society research grant so that he can work with Dr. John D. Kriesel of the University of Utah on a new approach to identifying MS triggers. Using recently developed, highly sensitive PCR technology, they will look for evidence linking specific viruses involved in the common cold to the onset of MS attacks. They will home in on a group of RNA viruses called picornoviruses, and particularly a subgroup called rhinoviruses. (More than 200 different viruses cause common colds.)

A pivotal achievement

This April, the National MS Society and the American Academy of Neurology jointly bestowed the 2006 John Dystel Prize for Multiple Sclerosis Research on Dr. Sibley for his groundbreaking work recognizing the role of upper respiratory viral infections in triggering MS attacks. The upper respiratory infection, or URI, is an ordinary cold. While evidence directly linking stress to the onset of MS attacks has proved elusive for decades, Dr. Sibley's rigorous eight-year study of people with MS and healthy controls, conducted from 1976 to 1984, showed that one-third of all new MS attacks were preceded by a cold.

Since that time, these findings have been confirmed by studies at major research centers in Maryland, Rotterdam, Nottingham, and Gothenberg. Concurrently, Dr. Sibley's research failed to find any connection between physical trauma and MS onset or MS attacks.

However, the trigger itself--the specific cold virus responsible--has managed to elude all the lab methods available up to now. The actual mechanism through which an MS attack is provoked by a virus is also not yet pinned down, although there are persuasive theories about how certain viruses can re-stimulate a sensitized immune system.

A clue to the role of interferon

Dr. Sibley's 1984 finding has had powerfully important "unintended consequences" in the years since. It led directly to the development of three of today's disease-modifying drugs--the three that are based on interferon: Betaseron, Rebif, and Avonex.

Some 20 years before the study linking viral URIs and MS attacks, Dr. Sibley and Dr. Fred Wheelock were the first investigators to find interferon molecules in the human bloodstream. Back then, the recently described molecule had received its funny name because it was seen to "interfere" with viral replication.

Once it was understood that virus infections triggered MS attacks, Dr. Sibley quickly proposed that interferon could be used to tamp them down. The first tests were conducted in 1986.

To everyone's surprise, the interferon tested, IFN gamma, made MS attacks worse. This was not a good answer for people with MS, but it was an important clue for immunologists. In time, investigators teased out the answers as they learned how the interferons work to regulate immune system functions. Some of them--IFN gamma, for example--step up the system. But others, notably IFN beta, dampen immune responses.

IFN beta, tested in a nationwide trial from 1988 to 1993, proved to have a remarkable ability to reduce attack rates and prevent new lesions seen in the MRI scans of people who were treated with it. This was something no other MS treatment had ever been able to do. Dr. Sibley was the leader of the analysis group that reviewed the successful outcome of the multicenter trial that led to marketing Betaseron in 1993. Avonex and Rebif, also forms of IFN beta, came into clinical use later in the 1990s.

A different strategy for control

"We believe there are some loose ends in MS research," Dr. Sibley told InsideMS. "We describe MS as an autoimmune disease, a smoldering inflammation that produces new lesions, or areas of injury, now and then for no obvious reason. But evidence that MS attacks may not be entirely random comes from focusing on a specific type of MS attack called retrobulbar neuritis. This is an MS exacerbation characterized by vision symptoms. Information about these attacks is generally very good because people call their doctor fight away when they have vision loss, and they know exactly when the attack began.

"Studies from four hospitals in northern climates--Minnesota, Cleveland, and Stockholm--have shown that this type of attack is least common in the winter months, and then peaks in the spring. Seasonal data from Cleveland, collected with Dr. Joseph Foley, showed a double peak, with MS attacks most common in spring and again in late summer/early fall. Rhinovirus infections don't occur in midwinter. Instead, they fit this same seasonal pattern."

If their scientific hunch pays off, Dr. Kriesel and Dr. Sibley envision a therapy for MS that would approach the disease from a completely different direction than that of the current drugs.

"We currently judge treatment by how much it reduces inflammation," Dr. Sibley explained. "All the disease-modifying drugs modulate the immune response. Tysabri does a remarkable job of reducing inflammation in the brain, but it does so at a cost. As we've seen, it reduces the brain's protection against another virus. We may need to accept that risk in order to control MS. But suppose we could approach the problem by eliminating or reducing the power of the environmental trigger?"

Informed speculation

"What I expect is that different people with MS will prove to respond differently to various types of virus. In fact, each person might have an individual profile. If so, that might actually simplify matters. Assuming John Doe always responds to rhinovirus number 3 by developing an MS attack, we might be able to tailor an immunization to rhinovirus number 3 just for him.

"We haven't done the study yet, so this is all speculation--speculation based on data that we believe is accurate."

The National MS Society is proud of having funded Dr. Sibley's informed speculations since 1962, including important support for the 1976-84 study. In addition to the viral trigger study Dr. Sibley continues his involvement in a long-term follow-up of people who were enrolled in the original IFN beta trial that began in 1988.

RELATED ARTICLE: In honor of John Jay Dystel.

The $15,000 John Dystel Prize is the only annual international prize for MS research achievement. It is given jointly by the National MS Society and the American Academy of Neurology, and is funded by the Society's John Dystel Multiple Sclerosis Research Fund. National Board of Directors honorary life member Oscar Dystel and his late wife, Marion, established this fund in 1994 to honor their son, John, a lawyer whose promising career was cut short by progressive MS. Dystel family funds are also supporting a program of clinical fellowships for nurses.

John Dystel died of MS complications in June 2003.

Currently, John's sister Jane is continuing the family's tradition by joining her father in promoting research for a cure and efforts to improve care for people living with severe MS. A third generation has also begun participating. Jane's son, Zachary, recently contributed gifts he received for his Bar Mitzvah to the as yet unfinished work of the National MS Society.

Martha King is the editor of Inside MS.