Today (April 5), the Breakthrough Prize Foundation announced the recipients of the 2025 Breakthrough Prizes. Dubbed the “Oscars of Science,” these prestigious awards celebrate groundbreaking discoveries in science that advance our understanding and treatment of human disease.
This year, one of the Life Sciences prizes was jointly awarded to Alberto Ascherio, an epidemiologist at Harvard University, and Stephen Hauser, a neurologist at the University of California, San Francisco, for their contributions in transforming the understanding and treatment of multiple sclerosis (MS). Ascherio identified Epstein-Barr virus (EBV) as the leading risk factor for MS, while Hauser established the role of B cells in the disease and developed B-cell-based treatments.
“This work has taken me on the journey of my life. It's been a long journey with many lessons, and gratitude was the number one emotion,” said Hauser.
A Devastating Diagnosis: Multiple Sclerosis
MS is a chronic, debilitating neurodegenerative disease where the immune system attacks the myelin sheath, the protective layer around nerve fibers. This damage disrupts communication between the brain and the body. MS has several forms and its progression is unpredictable. While some people experience mild symptoms like fatigue and limb numbness for years, others may quickly develop severe disabilities.
Clinicians recognized MS as an autoimmune disease but struggled to identify its exact cause. Fifty years ago, no effective therapies existed, making an MS diagnosis especially grim—most patients faced reliance on walkers, wheelchairs, or even bed confinement within 15 years of a diagnosis.
This harsh reality left a deep impression on Hauser, then a neurology resident in the 1970s. One day, he stepped into an emergency room and pulled back the screen to a heartbreaking scene—Andrea, a 27-year-old woman with MS, laying in a hospital bed, unable to speak, swallow, or move the right side of her body.
“I remember thinking this was the most unfair thing I had ever seen in medicine,” said Hauser. This moment cemented his resolve to devote his career to MS research.
Early Struggles in Understanding Multiple Sclerosis
Scientists first observed characteristic neurological damage associated with MS in the late 19th century, but its cause remained unclear. Separately, scientists in the 1930s explored why viral infections and rabies vaccination occasionally resulted in a rare complication of brain inflammation–encephalitis. Since this vaccine was prepared from rabbit spinal cords, researchers immunized animals with normal brain proteins, triggering immune cell infiltration and demyelinated lesions that characterized human encephalitis.1
This animal model for MS, known as acute experimental allergic (now “autoimmune”) encephalomyelitis (EAE), became the replica for human MS.2 Expanding on this work, serum (pure antibodies produced by B cells) from EAE animals did not transfer the disease, leading the field to conclude that T cells were responsible for causing EAE, and by extension, MS.3
Neurologist Stephen Hauser receives the 2025 Breakthrough Prize in Life Sciences for his work in establishing the role of B cells in multiple sclerosis and developing B-cell based treatments.
University of California, San Francisco
In contrast, for many years antibodies were used as markers for MS. However, it was widely accepted that B cells had no role in the disease's development. Hauser explained, “That was the thinking of the field: B cells were protective, they weren’t the culprits.” However, when Hauser compared brain tissue changes in EAE mice to the tissue of his MS patients, he noticed that they looked nothing alike. EAE models did not exhibit the same pathology seen in human MS, which led him to suspect another underlying factor.
In the 1980s, Hauser collaborated with classmate Norman Letvin, who developed immunologic tools for marmosets—animals more genetically similar to humans than mice—to create an MS model that was more reflective of the human disease.4 They injected animals with brain proteins and an adjuvant of heat-killed Mycobacterium tuberculosis, to boost the immune system to induce brain lesions.
However, after a decade of research, the animals seemed completely resistant to brain inflammation. Their first breakthrough came when Hauser's postdoctoral researcher, Luca Massacesi, suggested using a different regimen of two Bordetella pertussis injections in addition to their adjuvant for immunizing the animals—and it worked.5
Although they had induced the MS-like lesion, they couldn't replicate it using T cells, despite trying various approaches, including cloned T cells and brain-reactive T cells. Then, another postdoctoral researcher, Claude Genain, proposed investigating B cells, which had previously been overlooked. To their surprise, transferring B cell antibodies successfully replicated the MS lesions.6 Their findings demonstrated that while T cells initially disrupted the blood-brain barrier, it was the B cells and the autoantibodies they produced that ultimately attacked the myelin sheaths in MS. This discovery upended long-held beliefs about the role of B cells in MS and marked the beginning of a new understanding of the disease.
While Hauser and his colleagues investigated how B cells drive nerve damage in MS, Ascherio, another young physician, embarked on a path that would eventually lead him to study the links between viruses and neurodegenerative diseases like MS.
The Viral Infection Link to Multiple Sclerosis: A Paradoxical Mystery
Ascherio’s career as a physician began in the field of tropical medicine and epidemiology, where he treated diseases in countries such as Nicaragua and Mozambique. During his time in Nicaragua, he investigated an outbreak of paralysis in children and discovered that a neurotoxic plant was to blame. “This was my first epidemiological investigation in the neurological field that contributed to my increasing interest in neurological diseases.”
Later, while pursuing a PhD in epidemiology, Ascherio shifted his focus to MS. “Multiple sclerosis is a very intriguing disease. It’s very rare in the tropics, so in the places where I was working, there was basically no MS in Africa and Central America. The disease gets more frequent when you move away from the equator.” As he delved into the literature, epidemiological studies revealed a striking pattern: When people migrated from low-incidence regions to high-incidence ones, their MS risk increased dramatically. While researchers had yet to pinpoint the cause, many suspected infectious agents, including bacteria and viruses, played a role.
Of the potential culprits, one virus stood out to Ascherio—EBV, the cause of mononucleosis, or kissing disease. EBV is a common childhood infection, with an estimated 90 percent of the global population having been infected. Once contracted, the virus establishes a latent, lifelong infection, hidden within B cells.7 Ascherio suspected a link between EBV and MS, and upon comparing EBV antibody levels in people with MS, he found that they were higher than those in the control group.8
Epidemiologist Alberto Ascherio receives the 2025 Breakthrough Prize in Life Sciences for his work in identifying EBV as a leading cause of MS.
Steven McCaw
While Ascherio’s EBV observation appeared to fit the observed pattern of MS, another prominent idea, the hygiene hypothesis, offered a different explanation. It proposed that a high level of hygiene during childhood would prevent early EBV infection, but would also prime their immune system toward a higher risk of autoimmune diseases like MS. Despite this, Ascherio remained unconvinced as his studies suggested the opposite effect. “I think that paradox was the strongest clue that there was something wrong with this hypothesis and that something else was at play,” said Ascherio.
Determined to explore this further, Ascherio launched a longitudinal study to track MS development in individuals with and without EBV infection. The biggest challenge was finding a large enough EBV-negative population, given the virus’s high prevalence. In 2000, he partnered with the US military and used samples from the Department of Defense’s serum repository (DoDSR). At the time, the DoDSR held over 60 million blood samples from more than 10 million service members, most under 20 at the start of the study.
His goal was clear: Do people who never contract EBV also remain free of MS? His team determined the soldiers’ EBV status from their first sample and monitored MS onset during active duty. “The simplicity [of the study] is its strength,” Ascherio noted.
After a decade of research, his team reported in 2010 that MS risk was extremely low in EBV-negative individuals but rose sharply after infection.9 While the results did not initially attract widespread attention, subsequent studies by Ascherio and other researchers strengthened the connection between EBV and MS. These studies demonstrated an increased MS risk after infectious mononucleosis, elevated serum EBV antibody titers in patients with MS, and reports of the presence of EBV in MS demyelinated lesions.10-12
In 2022, further analysis of military serum samples confirmed that MS risk increased 32-fold after EBV infection but remained unchanged after infection with other viruses. Levels of neurofilament light chain, a biomarker of MS-related nerve damage, rose only after EBV infection—often before symptoms appeared. These findings were the strongest evidence that exposure to EBV was necessary to provoke MS.13
Against the Odds: Revolutionizing Multiple Sclerosis Treatment and Renewing Hope
As Hauser and Ascherio challenged longstanding theories, Hauser recalled the deep prevailing sense of pessimism, even nihilism, surrounding MS, remarking that another leader in the field wrote, “The best way to ruin one’s career is to propose a treatment for MS.”
Undeterred, Hauser aimed to evaluate rituximab, a monoclonal antibody therapy for B cell lymphoma, to see if selectively targeting B cells could benefit MS patients. However, the study section at the National Institutes of Health dismissed the idea as “biologically implausible”.
Despite skepticism, Hauser found a willing partner in Genentech, though the odds remained stacked against them: The study was predicted to have less than a 15 percent chance of success. Then, team was instructed by the Food and Drug Administration to reduce their cohort size and administer only a single 1,000 mg dose of intravenous rituximab.
“We thought that the primary culprit were likely B cell-produced antibodies, and it would take a long time for those destructive antibodies to winnow down after we killed B cells,” Hauser said. “We decided to go forward, nonetheless, hoping to see just a shadow of a benefit.”
Instead, the results were extraordinary.14 Even with one dose, brain inflammation nearly disappeared, demonstrating that B cells, not their antibodies, were the only explanation for this effect. Encouraged by this breakthrough, Hauser and his colleagues developed second-generation antibodies better suited for long-term use, leading to the creation of ocrelizumab and later ofatumumab—safer, more effective options for chronic treatment of MS.15,16
“The MS story is one of the great success stories of modern clinical neuroscience,” said Hauser. “[MS] has been thought to be too complicated to be able to understand in a molecular way that has a chance for success with application, and that has all changed.”
Ascherio acknowledged that, despite the odds, having strong conviction and determination to press forward has proven rewarding, providing valuable insights not only for researchers but also for MS patients. While the exact mechanisms of how EBV triggers B cells to attack myelin sheaths remain unclear, the growing understanding is still highly beneficial.
The combination of three drug therapies has sparked new hope for MS patients, while Ascherio’s recent research suggests the possibility of treating MS with antiviral drugs—or even preventing it with an EBV vaccine. Compared to Andrea’s grim prognosis decades ago, today’s patients have far better chances for an improved quality of life.
- Rivers TM, Schwentker FF. Encephalomyelitis accompanied by myelin destruction experimentally produced in monkeys. J Exp Med. 1935;61(5):689-702.
- Kabat EA, et al. The rapid production of acute disseminated encephalomyelitis in rhesus monkeys by injection of heterologous and homologous brain tissue with adjuvants. J Exp Med. 1947;85(1):117-130.
- Kabat EA, et al. Studies on acute disseminated encephalomyelitis produced experimentally in rhesus monkeys. III. J Exp Med. 1948;88(4):417-426.
- Genain CP, Hauser SL. Creation of a model for multiple sclerosis in Callithrix jacchus marmosets. J Mol Med. 1997;75(3):187-197.
- Massacesi L, et al. Active and passively induced experimental autoimmune encephalomyelitis in common marmosets: A new model for multiple sclerosis. Ann Neurol. 1995;37(4):519-530.
- Genain CP, et al. Antibody facilitation of multiple sclerosis-like lesions in a nonhuman primate. J Clin Invest. 1995;96(6):2966-2974.
- Thorley-Lawson DA. Epstein-Barr virus: Exploiting the immune system. Nat Rev Immunol. 2001;1(1):75-82.
- Ascherio A, et al. Epstein-Barr virus antibodies and risk of multiple sclerosis: A prospective study. JAMA. 2001;286(24):3083-3088.
- Levin LI, et al. Primary infection with the Epstein-Barr virus and risk of multiple sclerosis. Ann Neurol. 2010;67(6):824-830.
- Thacker EL, et al. Infectious mononucleosis and risk for multiple sclerosis: A meta-analysis. Ann Neurol. 2006;59(3):499-503.
- Levin LI, et al. Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA. 2005;293(20):2496-2500.
- Hassani A, et al. Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells. PLoS One. 2018;13(2):e0192109.
- Bjornevik K, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301.
- Hauser SL, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008;358(7):676-688.
- Hauser SL, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376(3):221-234.
- Hauser SL, et al. Ofatumumab versus teriflunomide in multiple sclerosis. N Engl J Med. 2020;383(6):546-557.
