Pulse
The MS Lesion Project
A Mayo Clinic researcher is leading an international initiative to better understand multiple sclerosis.
Last year, Claudia Lucchinetti, M.D., and William Hu, M.D., of Mayo Clinic, wrote in the journal Seminars in Immunopathology that the last decade had seen a resurgence of interest in examining the lesions of inflammatory demyelinating central nervous system disorders. What the authors did not mention was that Lucchinetti herself was the reason for much of that interest.
Since 2000, Lucchinetti, chair of the division of multiple sclerosis (MS) and autoimmune neurology and a professor of neurology at Mayo Clinic, has led a group of scientists that is delving anew into the pathology of MS by systematically examining tissue from brain biopsies and autopsies. Called the MS Lesion Project, the group includes scientists from the United States, Germany, and Austria who are working together to understand MS at the cellular level with the hope that new knowledge might lead to new therapies. That work has resulted in fresh thinking about how MS progresses and how it might be treated.
Time, Tissue, and Talent
Lucchinetti’s inspiration for this research was a patient she cared for while she was doing her residency at Mayo 15 years ago. The young mother presented with a very rare form of the disease known as Marburg MS, which quickly took her life. Upset about the death of the woman, perplexed that a disease could behave in such an aggressive fashion, and frustrated that she couldn’t do more to help her patient, Lucchinetti began to wonder why MS affected people so differently.
She decided she needed to study its neuropathology if she was ever going to find ways to limit its effect on patients. Fortunately for her, Mayo Clinic happened to have a large collection of brain tissue samples, as its world-renowned neuropathology department often was asked by physicians at other medical centers to weigh in on patient diagnoses. Over the years, the group had amassed hundreds of the paraffin-embedded and formalin-fixed slides.
After her neurology residency, Lucchinetti headed to Vienna, Austria, as a Mayo Foundation scholar to work with two of the world’s leading MS neuropathologists, Hans Lassmann, M.D., director of the Brain Research Institute at the University of Vienna, and Wolfgang Bruck, M.D., of the University of Gottingen in Germany. She brought with her some of the tissue samples, and the three investigators realized that together they had a unique opportunity. “We had a critical mass of tissue, coupled with the expertise and time to focus on this,” Lucchinetti says. “That laid the foundation for our cardinal observation that there were four distinct patterns of tissue injury among subsets of MS patients.”
Their work suggested a new direction for MS research, which until then had focused on finding a single cause for the myelin damage associated with the disease and, hence, a single cure. Lucchinetti and others realized that if different mechanisms caused the tissue damage, different therapies might be needed to treat different patients.
By 1998, those ideas had caught the attention of the national MS Society, which convened a task force to explore whether examining MS lesions further might explain why people experienced the disease so differently. Its recommendation was to establish an international research collaborative to find answers.
In 2000, the Society funded the work that Lucchinetti and her colleagues had begun in Austria, and the MS Lesion Project was born. Lucchinetti continues to direct this project, which is based at Mayo Clinic. It has since grown to include researchers at a number of medical centers around the world and has garnered funding from the National Institutes of Health.
In the decade that followed, MS Lesion Project researchers have continued to collect brain tissue samples from autopsies and biopsies and analyze them using microscopy. They’ve categorized more than 400 according to the four types of lesion patterns they first identified. In collaboration with investigators at Harvard University, they’ve studied antibody reactivity in relation to the different MS patterns using microarray technology. They also have found that one of the four patterns responds dramatically to plasma exchange, a treatment used for patients with severe MS relapses who do not respond to steroids. In addition, they continue to study the complex relationship between inflammation and myelin and nerve cell damage. The project has resulted in the publication of a spate of papers and a database containing clinical, radiographic, genetic, and pathologic information on more than a thousand MS patients.
Their work also has drawn criticism. “The concept of pathogenic heterogeneity has been somewhat controversial,” Lucchinetti says, admitting that several groups have challenged their assertion that there are four different patterns of myelin damage in MS.
Lucchinetti says her group has now done a study that explains why at least one other group has not been able to find such differences. “Our initial body of work was based on early MS,” she says. Other groups have looked at later stages of the disease.
Examining tissue from patients with both early and late-stage disease, Lesion Project researchers have discovered that the level of disease activity changes over the course of the disease. In the early relapsing stage, when the lesions are more active, they do show the four distinct patterns of demyelination. In later stages, when the lesions are less active, there’s a uniform pattern of tissue damage, which may contribute to disease progression.
Lucchinetti presented these findings at the American Academy of Neurology’s annual meeting in Toronto last month.
Remembering Marburg
Despite her extensive research commitments, Lucchinetti considers herself a clinician first and a scientist second. She says she’s always thinking about what she can learn from patients and take back to the lab, and how she can apply what she’s learning in the lab to helping her patients. “It’s kind of a bidirectional thing,” she says, noting that she tries to share with patients what she knows about whether or not a therapy might be effective at their stage in the disease and why.
Lucchinetti says she hasn’t forgotten about the woman with Marburg MS who first inspired her. Interestingly, when she first arrived at the Viennese research institute back in 1995, she was greeted by a photo of Otto Marburg, who had described the lethal variant of MS that had killed her patient. It turned out that he had done his work there as well. Although Lucchinetti doesn’t want to make much of that coincidence, she obviously saw it as a reminder of the work that needed to be done and perhaps confirmation that she was on the right track and in the right place. “I just know that my experience taking care of her as a neurology resident led to me asking some very fundamental scientific questions,” she says.
Lucchinetti hopes answers to those questions will one day translate to better lives for people with MS. “It’s why I’m doing this work,” she says. “What gets me going is what I see in the clinic.”—Carmen Peota