Welcome to Issue VI of The BIG Brief — a periodic digest of what is top of mind at Project BIG.
As a reminder, 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. The BIG Brief provides updates and a curated collection of articles that have captured our team's attention.
Spotlighted: Recent Achievements
We wanted to share a few key achievements and updates with you, our stakeholders and supporters, starting with an update from The Lily Sarafan Director of Neuroimmunology, Clinical Professor, and Chief of Neuroimmunology, Dr. Jeffrey Dunn:
What a year! Even as we faced unprecedented health challenges, 2022 was a year that saw the greatest forward progress in our understanding of multiple sclerosis (MS) since the advent of MRI. Researchers at Harvard showed that contracting the Epstein Barr virus (the virus that causes mono) is a necessary first step toward developing MS. But this can’t be the whole story, because 19 out of 20 people get infected with EBV, but only 1 out of 340 people get MS. So why do some people get MS, but most don’t?
Our team at Stanford, doing research that you supported, found that in fighting off the EBV infection, humans can develop antibodies against a specific protein on the surface of the Epstein Barr virus. Antibodies against this protein called EBNA-1 can then cross react with a normal protein in the brain called glial cell adhesion molecule (GCAM). Led by our brilliant scientists, Tobias Lanz and Bill Robinson, with the blood and CSF of new onset MS patients we cared for in clinic, our Stanford team has established that “molecular mimicry” is the likely causal pathway of MS.
This is ground-breaking work. I’m writing today to thank you for your support this past year. The key to our success was the broad arc of collaboration we were able to establish between clinicians and scientists. This is the core of Project BIG: enabling clinicians and scientists to break out of their respective siloes and work together. Working bedside to bench, our translational discovery paves the way for new and potentially more effective therapy for MS, including the possibility of using mRNA vaccines (as we did for COVID) as future MS treatment.
The year ahead looks even more promising. Our group is planning to investigate the role of a newly discovered cell type that appears to modulate autoimmunity. This might lead to a completely novel line of cellular therapy for MS as we pursue its cure. We also plan to assess in greater depth the mechanisms by which Vitamin D appears to modulate the human immune system. The key to success is bringing clinicians and scientists together in this pursuit. That is what your support for Project BIG allows.
There are rays of sunlight bursting through the clouds that are lifting the spirits and giving realistic hope to so many. As we approach year’s end, we give thanks, for you, for your interest, for your support, and for your investment in improving human lives.
Here are just a few of the many exciting projects underway:
We shared last time that a team including Project BIG's Jeffrey Dunn, MD, William Robinson, MD, PhD, and Lawrence Steinman, MD demonstrated that the Epstein-Barr virus (EBV) triggers MS. Dr. Robinson and Dr. Steinman also published a Science Perspective that discusses another study with evidence that EBV triggers the development of MS. These findings have important implications for personalized medicine for people with MS and the possibility of a vaccine for EBV even eradicating MS. Dr. Steinman noted, "If the virus is the target of the immune response that's going in an unwanted way in the MS brain, why not get rid of the virus?"
Working with the Davis lab (a Project BIG Collaborator), Stanford researchers led by Jing Li, PhD reported on a novel newly discovered cell type that modulates autoimmunity in humans. The KIR+CD8+ T lymphocyte eliminate autoreactive CD4+ regulatory T cells that serve as the effector cells for celiac disease, COVID associated vasculitis, and MS. This regulatory CD8+ T cell suppresses self-reactive pathogenic CD4+ T cells, and may open the door to a completely novel cellular-based therapy for autoimmune diseases including celiac disease, long COVID, and MS.
Earlier this year, Project BIG benefactor and Stanford trustee Lily Sarafan made a philanthropic investment to Sarafan Chemistry, Engineering, Medicine, and Human Health (Sarafan ChEM-H). In October, chemist Carolyn Bertozzi, PhD, Baker Family Director of Sarafan ChEM-H, was awarded the 2022 Nobel Prize in chemistry for her pioneering work in bioorthogonal chemistry.
BOOKMARKED: MS NEWS
EBV and MS: funding and next steps. Following up on the recent research highlighting the causal link between EBV and MS, Professor Gavin Giovannoni describes what is needed in terms of funding the next phase of this research.
"Cleaning" MS debris. Researchers have identified a neuroprotective microglial response with implications for preventing and reversing damage seen in neurodegenerative diseases, such as MS and Alzheimer's. Using a mouse model of MS, the researchers showed that a molecule called SYK is involved in the removal of myelin debris that would otherwise contribute to dysfunction.
Two biomarkers predict relapsing MS. An evaluation of several biomarkers in people with MS showed that two, CHI3L1 and CXCL13, were found to be strong prognostic predictors of relapsing MS and could potentially be used to inform treatment path.
Learning more about bacteria in MS. An innovative international study looked at the gut bacteria in people living with MS and controls living in the same household who were not genetically related. The study was able to identify a number of gut bacteria associated with MS as well as changes in bacteria in response to specific treatments. This opens the door to mechanistic studies exploring what exactly these bacteria are doing.
BROADER BIG (BRAIN-IMMUNE-GUT AXIS)
The claims of possible data manipulation in the context of a foundational 2006 paper in Nature that identified Aβ*56 as a toxic oligomer causing dementia symptoms in rats is leading to important discussions ranging from the public's trust in science to the pressures of academia. However, many researchers are emphasizing that regardless of the allegations, there is enough support and important work being done in the field of oligomers and amyloid proteins and cognitive decline outside of Aβ*56 to not cause any major disruption in the research underway.
Memory prosthesis. Using an electrode placed in the brain, an experimental study showed that hippocampal stimulation not only was associated with improved memory performance, but was even more beneficial for people with memory problems.
Sleep and Circadian Function as Modifiable Risk Targets. Given the prevalence of sleep and circadian function disorder, the potential for sleep as an intervention target in the prevention of dementia is discussed.
| Watch | Dr. Dunn discusses EBV & MS for the Seattle Science Foundation. In this fascinating one hour lecture, Dr. Jeffrey Dunn discusses his and his collaborators' research showing that Multiple Sclerosis may be caused by Epstein Barr virus infection. Learn more in this informative Grand Rounds lecture at the Seattle Science Foundation.
QUOTED
"Above all, don't fear difficult moments. The best comes from them." ― Rita Levi-Montalcini
COMMITTED
Will you consider renewing your support for Project BIG on this Giving Tuesday?
We know that you show your generosity by giving your support, advocacy, money, time, and voice to many worthwhile causes and passions. Whether it’s by forwarding our The Big Brief newsletter, telling someone about our mission to unlock the cause and cure for multiple sclerosis and our commitment to high impact research, or making a 100% tax-deductible gift to Project BIG via Stanford Healthcare, we would love to count on your support as this year comes to end. We are grateful for the support from our generous community donors and hope to continue building on this momentum to achieve BIG results. If you know of an individual or foundation that may choose to support this work or would like to discuss making a leadership level gift, please let us know.
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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