Welcome to Issue 1 of The BIG Brief: a periodic digest of what is top of mind at Project BIG.
Our mission is to unlock the cause and cure for MS and other neurological and autoimmune diseases through a unique clinician-scientist collaboration across disciplines. Our team of scientists, researchers, neurologists, immunologists, radiologists, microbiologists, psychologists, and patient advocates at Stanford are engaged in some of the most high-impact and exciting Brain-Immune-Gut (BIG) research taking place anywhere. The BIG Brief will include a snapshot of their worlds as well as a curated collection of articles that have captured our attention.
Spotlighted: Get It Dunn
Jeffrey Dunn, MD, FAAN, Division Chief and Professor of Clinical Neuroimmunology at Stanford University and Multiple Sclerosis Chair of the American Academy of Neurology, shares his vision and the innovative ways that Project BIG is bringing the lab to the clinic on its quest to unlock the Brain Immune Gut axis and find the cause and cure for MS. In his own words:
Project BIG is the name we have given to the Brain, Immune and Gut research initiative at Stanford University. It is our quest to find the cause and cure of multiple sclerosis (MS). The impacts of MS are profound and wide-reaching. There are nearly one million people diagnosed with MS in the United States alone. MS remains the second leading cause of disability among young adults. It is a lifelong and life changing disease that has likely been with us for centuries. Given the prevalence and far-reaching burden of illness of MS, it is reasonable to ask, why have we not yet discovered what causes MS? Why do we not yet have a cure?
These two questions spurred the blueprint for Project BIG. We acknowledged that the lack of breakthrough discovery has not been from lack of interest, commitment, talent or will. Rather, it is the idiosyncrasies of MS itself that have rendered its solution elusive. To overcome this challenge, we must disrupt the conventional infrastructure of academic medicine. We need to renew our entire approach and investigate according to a novel paradigm. We must take an entirely different path to achieve an entirely different result. Project BIG is our roadmap. These are some of the ways that project BIG inverts the status quo:
Whatever MS is, it is unique to humans. While animal models can help our understanding of disease mechanisms, if we are to succeed in discovering the cause and cure for MS, we must look to where it lives. Our clinic must become our lab. A mandate of project BIG is that dedicated clinic research coordinators be embedded in specialty MS clinics in order to facilitate real-time assessment and robust clinical annotation to combat the time lag that is an inherent weakness of many existing biorepositories. Project BIG transcends this weakness by bringing the lab to the clinic, and directing our clinicians to function with the alertness of scientists.
Multiple Sclerosis is a disease of process and product. For the 85% of MS patients who have a relapsing course, relapses are driven by a pro-inflammatory coordinated immunologic cascade. It is this immune attack directed against myelin of the central nervous system that causes a patient’s symptoms and lead ultimately to neurologic disability. It is therefore imperative we “catch” this relapse in real time. Relapses don’t just occur during business hours. Project BIG has designed a team-based interdisciplinary and collaborative approach by which our availability assures 24/7/365 coverage. We will be there when MS rears its unwelcome head. In this way, too, facile though it may seem, our study architecture transcends the weaknesses of prior protocols.
MS is a highly heterogeneous disease. In fact, although we refer to MS as a “disease,” it is actually better conceptualized as a syndrome. The defining commonality across people with MS is that the body’s immune system attacks the central nervous system in at least two or more places at least two or more times. The immune pathways that mediate these attacks are very likely different from one person to another. MS is not one size fits all. The cells, cytokines, antibodies, antigens form the nodal basis for an interactome that may be comprised of thousands of unique effector sequences. In truth, there may be hundreds or thousands of MS subtypes. Our ability to achieve optimized outcomes depends on our ability to treat the individual according to their own unique immunologic fingerprint. A functional cure must offer a patient-specific arrest of all relapses. Today, an effective treatment for one patient may not be the most effective for another. Our endeavor to match optimized therapy to the individual represents the true practice of personalized medicine, and our path to real therapeutic progress.
The design of Project BIG anticipates that we will analyze MS down to its finest level of individual granularity and according to unique personal immuno-prints. To do this, we have recruited a team of leading scientists and innovators at Stanford University as our partners and collaborators. You can learn more about them here. As an interdisciplinary team, we have pledged to work together in shared open access. Laboratory and clinical data will be collected cohesively and longitudinally in an advanced multimodal database to enable real-time assessment of changing disease status over time.
Our discoveries will be shared as regular updates; as a stakeholder and supporter, this will give you the opportunity to join us in our quest, to be part of our team, and to learn right alongside us in partnership. Project BIG is for all of us. Finding the cause and cure of MS and advancing science across the Brain-Immune-Gut axis is an initiative we all care about deeply. This is not a simple endeavor. It will take a village. We invite you to join with us. We need you. What lies ahead promises to be the adventure of a lifetime!
Bookmarked: MS News
Going grey. Much of the research focus in MS has been on the white matter and relapsing-remitting forms of the disease. But, by examining the movement into the brain of T cells that target myelin (present in white matter) and β-synuclein (present in grey matter), researchers are shedding more light on the progressive forms of the disease and the role of grey matter proteins on MS and other neurodegenerative diseases. (More: You can read the original article here)
7T does what 3t couldn’t. High-strength 7T MRI scanners are more sensitive to cortical lesions than conventional 3T MRI scanners. The 7T MRI scanner has already proved impactful, demonstrating 1) cortical lesions predominately developed in the cortical sulci and 2) total volume of cortical lesions was a predictor of disability. (More: You can read the original article here). (Want even more? You can also read a review on the association between pathological and MRI findings in MS here)
Stratification using immunobiological and radiological markers. A possible disease stratification method using combined 3T MRI imaging data, neuropathology analysis, and cerebrospinal fluid measurements has been identified. Recent findings suggest that there might be a CSF/MRI pattern that can act as proxy for meningeal inflammation and be used to stratify patients by level of inflammation and cortical lesion load at diagnosis at the time of diagnosis. (More: The original abstract can be found here)
The capacity for repair. The importance of early diagnosis and treatment in MS was reiterated in a recent study showing the limited ability of cells to regenerate in the brains of patients with MS. However, in the same study, researchers found that, unlike what has been seen in animal models, it appeared as though the remyelination of lesions that does occur was spurred by existing oligodendrocytes. “We were highly surprised that humans proved to be so different from the animals that have been studied. In humans, there is very limited regeneration of oligodendrocytes, but they seem to have a greater capacity to contribute to repair.” (More: The original study can be found here)
Broader BIG (Brain-Immune-Gut Axis)
Gut & brain crosstalk. An understanding that the body’s microbial community can influence the brain and behavior and play a role in dementia and other disorders has generated scholarly and popular excitement. In this relatively new space, “We have the edges of the puzzle, and we’re now trying to figure out what’s in the picture itself.”
Sex differences in AD. Key sex differences in Alzheimer’s disease (AD) pathology offer insights not only into differential burden and impact of the disease on women and men (Why do women show a faster cognitive decline than men?) but also harbor implications for the diagnosis and management of AD (Could women and men benefit differentially from disease-modifying therapies?)
Neurodegenerative diseases and pseudomedicine. A January JAMA Viewpoint generated much conversation about limitations in effective treatments for neurodegenerative diseases, such as Alzheimer’s disease. From interventions targeting unsubstantiated etiologies of disease to treatments for brain health piggybacking questionable supplements onto known dementia interventions, there is no shortage of treatments for neurodegenerative diseases lacking an evidence base.
|Listen| Sleep is your superpower. In this 19-minute TED talk, sleep scientist Matt Walker discusses the far-reaching impacts of sleep on everything from memory to the immune system. “Sleep loss will leak down into every nook and cranny of your physiology, even tampering with the very DNA nucleic alphabet that spells out your daily health narrative.”
Initiated
Patient consents for Project BIG are well underway and already yielding key insights.The progress, severity and specific symptoms of MS in any one person cannot yet be predicted, and it is not known whether the disease has a single or multiple causes. Nonetheless, various genetic, immunologic, environmental and infectious factors are suspected to contribute.
Impacted
“When you live with a degenerative illness, no symptoms are mild.” A person with MS wants doctors to know that even though symptoms might be categorized on scales ranging from mild to severe in textbooks and outcome measures, this distinction can be invalidating for patients. “The appointment could have been different if I’d been asked ‘How do these symptoms affect your life?; as well as ‘What symptoms are you experiencing?'...Every new symptom I experience, regardless of severity, has a huge emotional impact on me.”
Noted
With this year's record-breaking summer heat wave upon us, it is important to remember that warm temperatures can temporarily exacerbate MS symptoms. The National MS society shares some strategies for beating the heat.
Quoted
"Better is possible. It does not take genius. It takes diligence. It takes moral clarity. It takes ingenuity. And above all, it takes a willingness to try."
Atul Gawande (2010), Better: A Surgeon's Notes on Performance
Committed
The support of our community of donors has been awe-inspiring. Unlocking the many mysteries of MS will yield important new insights on the immune mechanisms of the brain and underlying causes of immune dysregulation more broadly. This initiative leverages the world-class human capital, interdisciplinary ethos, and culture of translational medicine that Stanford is recognized for. If you know of an individual or foundation that may choose to support this work, please let us know.
With Gratitude,
Lily Sarafan, Founding Partner & Project BIG Evangelist
Do you have an article or content that you would like to see in the next BIG Brief? Send an email to editor@projectbig.com. Questions? Contact us or visit our FAQs.
Live well,
Shadi Gholizadeh, PhD, MPH & The BIG Brief Editorial Team
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