Unconventional wisdom

By Erin Biba, a New York-based freelance writer whose work regularly appears in publications such as Scientific American and Newsweek.

It was in total contrast to her traditional, buttoned-up personality. She was sent to a psychiatrist, but just two weeks later had completely lost her ability to speak. The young woman was rushed to the hospital and within 24 hours was unable to swallow and had become completely paralysed down one side of her body. She had multiple sclerosis (MS).

“This was a time when we could do nothing for people with MS,” says Dr. Stephen Hauser, one of her physicians and now the chair of Neurology at the University of California in San Francisco. He was a young resident, recently out of school, and witnessing this bright young woman — the same age as him — deteriorate so quickly had a huge impact on him.

It was this moving experience that spurred Hauser to dedicate his life to figuring out a way to treat this disease so future patients might not have to face the same fate. “My last visit with her was about a year later in our local rehabilitation hospital across the street. She was still paralysed, could only speak a couple of words, had a stomach tube for feeding, a tracheotomy for breathing assistance and was in a wheelchair. That was the face of aggressive MS a generation ago.”

Nearly 40 years later, the treatment landscape has evolved and doctors are now able to do more to ease or slow the irreversible accumulation of the disease. But a cure has not been found and the most effective medicines used to treat MS also carry the risk of serious side effects.1 Patients struggling with this life-long illness need more options and thanks to decades of research by Hauser and others, we now have a much deeper understanding of how the disease works.

Multiple sclerosis affects about 700,000 people in Europe.2 It’s the leading cause of non-traumatic disability for young people and for reasons that aren’t known, it is most prevalent in countries that are farthest away from the equator.3,4 MS is usually diagnosed between the ages of 20 and 40 - and it’s much more prevalent in women than in men.3,5

Scientists are still unsure what triggers the disease. However, they do understand how it causes the most common symptoms, which are fatigue, difficulty walking, impaired vision and bladder issues.6 Multiple sclerosis is caused by what amounts to an out-of-control immune system.

Normally, elements of the body’s immune system, called T cells and B cells, are floating around in the body looking for foreign invaders that cause infections. Their job is to notice these outsiders, call in other parts of the immune system, and together disarm the infection-causing intruders.7

In a healthy body this immune response goes on everywhere except inside the brain and spinal cord, which have a special barrier that is designed to protect them from any harmful intruders that are circulating in the blood. But in people with MS, that barrier becomes compromised and immune cells enter the brain.7 The cells begin attacking myelin, a protective sheath that exists around the nerve fibres in the brain and the brain experiences localised inflammation. As the myelin degrades, scar tissue, or plaques, build up as the brain attempts to repair the damage the immune system has done.9 As a result, the signals between the brain and body are compromised, the body doesn’t function as it normally should, and symptoms tend to get worse over time.10

The way that we currently treat MS is to try and stop or slow the immune system attack on the myelin. This approach was adopted in the late ‘70s and has remained the standard of care ever since. At the time, several different researchers had shown that T cells, a type of white blood cell that acts against foreign bodies in the immune system, could be used to transfer inflammatory diseases from one mouse to another.7 The inflammatory disease was similar to MS and so scientists believed they had found the key to the myelin breakdown in the brain.

Transferring the disease from one mouse to another genetically identical one “redirected the entire field,” says Hauser. “This really proved to much of the scientific community that T cells were necessary [in causing MS].”

And so, from that point forward, treatments for MS focused on targeting T cells. According to Dr. Paulo Fontoura, Global Head Clinical Development, Neuroscience at Roche, “Most MS research and clinical development programs were focused on T cells because those cells were what the model of the disease depended on. There was finally a biological target to pursue to help people living with this debilitating disease.”

But as no one had been able to create an MS brain lesion (or plaque) using T cells alone, Hauser and other researchers in the field speculated that perhaps these weren’t the only parts of the immune system responsible for the disease. Maybe there was more to be found. After all, though it seemed clear that T cells played a role, no one knew exactly what triggered MS, so replicating it in living models was extremely difficult.

It wasn’t until 1998, nearly 18 years after the original T cell hypothesis became accepted, that the researchers finally achieved it. Hauser and his colleagues Norman Letvin, who was the head of the Harvard-affiliated New England Primate Research Center at the time, and Luca Massacesi, a postdoctoral fellow in Hauser’s lab, completed a series of experiments in which they managed to create a brain lesion that looked exactly like MS.11 It was a pivotal moment that allowed them to study the disease more closely.

“We were now at a point where we thought that we had a surrogate for MS,” says Hauser. A model that really was indistinguishable from what was happening in human beings. The key, he says, was to focus on the tissue changes in the brain — the MS plaques. And for the first time, they felt confident they had created an MS-like plaque.

As they pushed forward with additional experiments to understand more about the underlying biology of the disease, Claude Genain of the University of California San Francisco, and Cedric Raine at Albert Einstein College of Medicine, joined the team. They eventually found that it was not just T cells, but also the immune system’s antibodies present inside the brains of MS patients that enabled the exact replication of the MS plaque. By looking closely at these antibodies and their role in the disease, Raine saw that T cells seemed to be responsible for opening the blood-brain barrier to allow antibodies into the central nervous system, where they attached to the myelin sheaths and began digesting and destroying them.11

Though this hypothesis had been considered in the past, the combination of how difficult it was to replicate MS and support for the established T cell theory meant few people were attempting the same types of experiments as Hauser and his colleagues. Finally, another way of treating MS seemed possible as the role of a completely different type of cell entered the picture.

The antibodies in the affected brains were part of a line of cell evolution that originates with B cells, a component of the immune system. The B cell goes through several stages of evolution throughout its life and in the final stage, some of the cells become plasma cells. Plasma cells are an important component of the immune system as they produce antibodies that specifically target and kill invaders such as bacteria or viruses.12

However, it seemed that in MS, the plasma cells were making antibodies that attack proteins in the brain that form the myelin sheath, which protects and supports the brain’s nerve fibres. In other words, T cells and B cells were taking up residence in the brain and working together to degrade its protective systems.13

They would need to study it further to get to the point where this discovery might help patients, but the scientific community was so rooted in its T cell treatment approach that there was very little appetite to consider other research angles. Hauser’s attempts to secure academic funding for a trial that would study B cell treatment in humans fell on deaf ears. “We had 15 years of efforts in this direction, but it was very clear that there was no way the federal government would have supported this trial because everyone knew that T cells cause MS,” says Hauser.

They needed to find a partner who was willing to take a chance on an idea that had promise, but not proof. At the time, Genentech, a future member of the Roche Group, had recently finished conducting research on targeting B cells in other diseases. It was a shot in the dark, but Hauser began conversations with the company to see if they’d be willing to do proof-of-concept patient trials targeting the B cells thought to be involved in MS. To his surprise, Genentech agreed. “In retrospect, it was shocking,” Hauser says. “It’s stunning that Genentech agreed to go forward [with an early phase clinical trial]. They estimated that the chance of success was less than 15 percent, but there were enough supporters to approve the study. I think they did it because they thought patients needed it. It was worth doing.”

The next “Gadzooks!” came when the results were finally revealed. “It was an amazing moment for all of us,” says Hauser, but what they saw wasn’t exactly as they had hypothesised. Though it seemed clear that B cell targeted treatment had the potential to significantly help people with MS, the trial showed that the effect was not produced by inhibiting the antibodies produced by plasma cells as expected, but rather resulted from targeting a small percentage of specific B cells before they aged into those antibody-producing plasma cells. “It told us that B cells that are passing from the blood into the brain are the key to understanding relapsing MS. It completely moved the immunobiology of the field toward a laser focus on B cells,” says Hauser.11

Thanks to this discovery, Hauser and his colleagues believe that by formulating an immunotherapy treatment to eliminate that small percentage of specific B cells, they might be able to stave off the plaque generation that MS causes in the brain without damaging the immune system as a whole. And because those B cells are free-floating in the blood, they would be much easier to target than plasma cells.

Currently, many doctors wait until the disease is more advanced before prescribing higher efficacy medicines because of the serious safety risks associated with them. But specialists are now starting to think that treating earlier in the course of the disease could have the greatest impact on reducing the accumulation of nerve damage and delaying the progression of MS.

After three decades of research, we have seen that even well-established scientific approaches can ultimately turn out to be missing a large chunk of the picture. For Dr. Hauser, his only regret is that the B cell discovery didn’t come sooner. Nonetheless, armed with this new information, he and his colleagues continue to work diligently to determine the trigger for MS and hopefully, one day, perhaps even find a cure.

References

1. Mayo Clinic. Multiple Sclerosis Treatments and Drugs. Last revised July 10, 2014. Retrieved September 2, 2015 from

2. European Multiple Sclerosis Platform. MS Facts. Available at:

3. Multiple Sclerosis International Federation. Atlas of MS. Last revised April 24, 2015. Retrieved September 2, 2015 from

4. Simpson S, et al. Latitude is significantly associated with the prevalence of multiple sclerosis: a meta-analysis. J Neurol Neurosurg Psychiatry 2011;82;1132-1141

5. Multiple Sclerosis International Federation. Atlas of MS. Last revised April 24, 2015. Retrieved September 2, 2015 from

6. Mayo Clinic. Multiple Sclerosis Symptoms. Last revised July 10, 2014. Retrieved September 2, 2015 from

7. National Multiple Sclerosis Society. T Cells. Retrieved September 2, 2015 from

8. Minagar A, et al. Blood-brain barrier disruption in multiple sclerosis. Mult Scler, 2003; 9: 540-549. Available at

9. National Multiple Sclerosis Society. What is Myelin? Retrieved September 2, 2015 from

10. Brück W. The pathology of multiple sclerosis is the result of focal inflammatory demyelination with axonal damage. J Neurol 2005; 252 Suppl 5:v3-9. Available at

11. Hauser SL. The Charcot Lecture | beating MS: a story of B cells, with twists and turns. Mult Scler 2015; 21: 8-21

12. Calame KL. Plasma cells: finding new light at the end of B cell development. Columbia University Medical Center 2001; 1103-1108. Available at

13. Weber MS, et al. Cooperation of B cells and T cells in the pathogenesis of multiple sclerosis. Results Probl Cell Differ. 2010;51:115-26. Available at