Multiple sclerosis (MS) remains one of the most complex neurological conditions with no known cure. Affecting over 33,000 Australians and 2.8 million people globally, MS continues to baffle scientists and clinicians alike. While environmental factors, genetics, and viral infections have all been linked to MS, no single cause has been confirmed.Now, a world-first study from the University of South Australia may finally crack part of the code. For the first time, researchers are using a genetic selection method called recall by genotype to understand why some people exposed to the same virus go on to develop MS while others don’t.At the heart of the study is a long-suspected culprit: the Epstein-Barr virus (EBV), best known for causing glandular fever. More than 90% of the global population gets infected with EBV at some point. Yet only a small fraction develop MS. That’s where the mystery lies- how can one virus lead to a life-altering autoimmune disease in a select few?Dr. David Stacey, who leads the study, believes the answer may lie in our genes. “It’s like studying the immune system’s blueprint before the disease starts,” he said. The goal is to identify how individuals’ genetic make-up alters their immune response to EBV—and whether that difference tips the scale toward developing MS.What Is the ‘Recall by Genotype’ Approach?This isn’t just another observational study. The team is using an innovative approach known as recall by genotype, a first in MS research. In simple terms, they’ll analyze the DNA of more than 1,000 participants who have never been diagnosed with MS. These individuals will then be grouped into high-risk and low-risk categories based on their genetic predisposition to MS.From there, researchers will compare how the immune systems in these two groups respond to EBV exposure.“By grouping people based on their genetic profile, we expect to find those with a high genetic risk for MS will also show biological differences—even if they don’t have the disease,” explained Dr. Stacey.This could help pinpoint biomarkers—early warning signs in the body that MS may be developing long before symptoms appear.Why This Study Could Be a Game-Changer?MS is a central nervous system autoimmune disorder. It causes the immune system to attack the protective sheath covering nerve fibers, resulting in symptoms like fatigue, muscle weakness, poor coordination, vision problems, and cognitive changes. But the progression of the disease is highly unpredictable.This study, funded by MS Australia’s Incubator Grant program, aims to do more than just explain risk. It could transform the way we approach MS—shifting from reactive care to proactive detection and even prevention.“If we can identify biological markers before symptoms begin, that opens up new possibilities for early interventions or therapies that could delay or stop disease progression altogether,” said Dr. Stacey.Does High Genetic Risk Mean Someone Will Develop MS?With genetic research comes another layer of complexity: how much risk information should be shared with participants? Dr. Stacey acknowledges that just because someone has a high genetic risk doesn’t mean they’ll definitely develop MS. That brings up ethical and legal challenges. “If we identify people who are at risk of developing MS, we need to consider how—and whether—to share that information, particularly as it may not yet be clinically actionable,” he said.Part of the study will address these questions and help lay the groundwork for responsible, patient-centered practices in future genetic research.While this study is based in Australia, its implications are far-reaching. MS is a leading cause of neurological disability among young adults worldwide. The hope is that by identifying the biological chain of events leading to MS, scientists can develop tools that apply globally—regardless of geography, ethnicity, or background.According to Rohan Greenland, CEO of MS Australia, “Our mission is to accelerate research and improve outcomes for every person living with MS.” This project exemplifies that vision by targeting the earliest stages of the disease—before symptoms even appear.If the pilot is successful, it will inform a much larger, more ambitious study. Researchers plan to refine how genetic risk scores are calculated, validate their findings across diverse populations, and develop standardized operating procedures for similar studies worldwide.This could also inspire studies into other autoimmune conditions like lupus or type 1 diabetes, where viral triggers and genetic susceptibility are believed to intersect.The world's first “recall by genotype” study in MS research is underway in Australia. By linking genetic risk to immune response against the Epstein-Barr virus, scientists aim to answer a longstanding medical mystery: why only some people develop MS. The findings could pave the way for earlier detection, targeted therapies, and ethical frameworks for sharing genetic information—all with global implications.