Moving Toward Convictions
Risk VI: New strategies to root out the cause of MS
If the hunt for causes of multiple sclerosis were a simple murder mystery, investigators might be having an easier time cracking the case. The disease detectives must identify the multiple agents, rather than a lone perpetrator, that lead to the disease—and unravel how the culprits work individually and together. To complicate the inquiry further, each contributor might begin causing damage decades before the disease begins. And finally, the ultimate test of causation—restraining or removing a suspect and assessing whether the disease diminishes in response—isn’t generally practical because methods do not exist to contain most of the candidate troublemakers.
Nonetheless, MS investigators have drawn up an inventory of top suspects, which include a lack of vitamin D (see “The Sunshine Suspect”), the Epstein-Barr virus (EBV) and the infectious mononucleosis that it can cause (see “Viral Villain”), certain genes (see “Genetic Associations” and “Nature, Nurture, and What’s in Between”), female gender (see “Discriminatory Disease”), smoking, and stress (see “Where There's Smoke (and Stress), Is There Fire?”). To build a case against these characters, researchers are measuring the strength of the associations between the potential wrongdoers and the illness, and they’re asking whether the putative scoundrels act before the disease begins and how they might set it off.
MS has been studied for more than a century, and the lineup of potential MS triggers that have been scrutinized includes everything from cats to the mumps. At the moment, however, several characters in addition to those mentioned above rank relatively high on researchers’ lists, including microbes that naturally inhabit the human gut, retroviruses that reside within human DNA, and, strangely enough, a lack of parasitic worms. While some investigators are pursuing a case against these agents, others are employing new strategies to assess multiple possibilities at once. They study pediatric MS patients and people at high risk of MS, because the culprits might be more obvious in these groups. Finally, questions have emerged about factors that clearly contribute to MS risk, but whose mechanisms are unknown; for example, why does onset tend to occur in early adulthood or middle age? By tracking multiple suspects in myriad ways, investigators hope to uncover some answers.
Many microbes live peacefully within their hosts. However, microscopic critters in the guts of patients with autoimmune diseases that include inflammatory bowel disease, rheumatoid arthritis, and type 1 diabetes appear to exacerbate those maladies. Last year, researchers stumbled on a clue that gut flora might contribute to multiple sclerosis as well. They studied lab mice that spontaneously develop an MS-like demyelinating disorder and noticed that it failed to develop in a group of “germ-free” mice; in contrast, most animals that harbored normal gut microbes came down with the disease within 8 months (Berer et al., 2011).
The disease, called experimental autoimmune encephalomyelitis, developed promptly once the researchers colonized the “germ-free” mice with commensal microbes. Although the pathway from microbe to disease remains uncertain, the authors suggest that intestinal flora similarly play a role in triggering MS. The researchers suggest that future studies should identify microbes that might increase the risk of MS. This avenue of inquiry could provide the basis for new, noninvasive treatment strategies, they add.
Other questionable characters also dwell inside humans: ancient viral sequences called human endogenous retroviruses (HERVs) that reside within DNA. They became suspect when multiple investigators found bits of their RNA sequences in the blood and brain tissue of MS patients (Antony et al., 2011; Christensen, 2005). In one small study, blood from all 39 MS patients harbored signs of a particular type of HERVs, the HERV-W family, whereas 7 of 11 of patients with other inflammatory neurological diseases tested positive for these viruses, and the sequences rarely appeared in healthy individuals (Dolei et al., 2002). At the moment, researchers aren’t sure whether or how HERVs might give way to MS. One idea is that some stimulant—perhaps herpesviruses, such as EBV—drives HERV expression, which in turn incites the immune system to fight the virus in a way that damages the surrounding tissue (Christensen, 2005). This idea is supported by observations that, in laboratory dishes, retroviruses activate certain inflammatory proteins (Christensen, 2005).
Although some studies point toward infectious agents as contributors to MS, others point toward their absence. The dearth of childhood exposure to microbes might partly account for higher rates of MS in the industrialized world. This concept, called the hygiene hypothesis, proposes that infections protect people from inflammatory diseases when the encounters take place early in life. This phenomenon might occur for a number of reasons—among them, infections in youth appear to shift a person’s immune system toward a “quieter” state (Correale and Farez, 2011). In addition to bacteria and viruses, common parasitic worms such as Trichuris trichiura and Schistosoma mansoni might help prevent and tame MS as well as other diseases characterized by excess inflammation. For this reason, several Phase II clinical trials are under way to test whether MS patients who ingest eggs from the parasitic “pig whipworm” Trichuris suis develop fewer new lesions than those given a placebo (for example, see clinical trial identifiers NCT01413243 and NCT0064574 and “AAN Final Roundup”).
For these possibilities and others, investigators are gathering evidence through surveys, experiments, and computational models designed to test the likelihood that one agent interacts with another (see “Whodunit?” for methods of deduction). Researchers are also trying to figure out when each factor exerts its effects. Timing presents a particularly difficult obstacle: Experiments rarely run for decades, and retrospective studies can yield false associations because confounding events occur in the intervening years. Still, probing this issue is worthwhile, experts say. “One of the most important questions when we think about risk factors is when do these factors act and at what point is the horse out of the barn and it’s too late to intervene,” says Amit Bar-Or, a neuroimmunologist at the Montreal Neurological Institute and Hospital at McGill University in Montreal (who is an Accelerated Cure Project Scientific Advisory Board member). “If we want to prevent the disease, it’s essential to know when to act.”
To overcome the hurdle of time, researchers have turned to patients who acquire MS prior to age 18. This approach narrows the gap between cause and effect, and according to some researchers, these cases could be informative for another reason. “When the disease starts early in pediatric cases of MS, it means these individuals have faced a higher exposure to environmental risk factors, and perhaps have a higher load of genetic risk factors,” says Emmanuelle Waubant, a neurologist at the University of California, San Francisco. In other words, the culprits might stand out more clearly from the crowd. Only 3% to 5% of all MS cases are pediatric, but children experience the same basic disease as relapsing-remitting MS, Waubant says. Indeed, children and young adults with MS tend to have low blood concentrations of vitamin D, a history of EBV infection, and the genetic variant HLA-DRB1*1501 more commonly than healthy individuals—much as older patients do (Yeh et al., 2009).
With improved techniques for analyzing immune system components and gene expression, Waubant and her colleagues have embarked on a multi-institutional NIH-funded study to nail down the characteristics of pediatric MS patients. The project will assess genetics as well as vitamin D levels, sun exposure, infections by EBV and other common viruses, weight, age, and exposure to cigarette smoke, stress, toxins, and pets, among other factors. The differences between pediatric and adult MS patients might also prove informative. For example, boys and girls younger than 10 years old experience the same likelihood of disease, suggesting that puberty-related boosts in female hormones might account for the gender disparity seen in adult MS. “This is a unique opportunity to look at multiple factors at the same time,” Waubant says. “We know the disease is quite complex, and so I think a study like this on pediatric MS will be very exciting.”
Researchers are devising additional strategies to avoid the blurring effects of time so that they can more clearly link suspects to the disease. Some researchers, for instance, are focusing on individuals who are at substantial and imminent risk of MS. At Harvard School of Public Health in Boston, epidemiologist Alberto Ascherio collects information about people who have experienced their first neurological sign or symptom—such as weakness on one side or a loss of vision caused by an inflamed optic nerve. After one of these clinically isolated syndromes, a person might or might not acquire MS within several years, and Ascherio wants to know whether any particular risk factors can predict which CIS patients will get the disease. This method can’t rule out potential candidates because some agents might act before a person’s first clinical episode. Nonetheless, positive correlations might open avenues of research into how to prevent MS in this high-risk population.
Every story in this series on Risk Factors portrays a snapshot of the field, and each one is bound to change as ongoing studies chip away at the mystery of MS. We at the Multiple Sclerosis Discovery Forum will keep you updated as new research, hypotheses, and strategies emerge. As technical advances give way to new ideas about what causes MS, science inches ever closer to arresting this debilitating disease before it starts.
Previous article in series: "Where There's Smoke (and Stress), Is There Fire?"