Welcome to Issue 2 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 provides a snapshot of their worlds as well as a curated collection of articles that have captured our team's attention.

Spotlighted: Meet Mark Davis, PhD

Dr. Mark M. Davis is the Director of the Stanford Institute for Immunology, Transplantation and Infection (ITI), a Professor of Microbiology and Immunology, and a Howard Hughes Medical Institute Investigator.

Tell us what you do, and what your role is in Project BIG?
I come from the basic science world, where I have had training or experience in chemistry and molecular biology, biochemistry, and cell imaging. Immunology has been a great field to use these skills, and most of my focus over the past 35 years has been on T lymphocytes and how they work. While we worked almost exclusively with mice for most of that time, a lot of our recent work has been focused on developing good tools and methods for studying T cells in important human diseases like MS. MS is thought to be a very T cell driven disease, and while a lot is known about certain T cells that are important in causing the disease, we recently discovered another type of T cell that suppresses these disease-causing cells in a mouse model. We see evidence of a very similar type of suppressive T cell being active in MS, and we're excited about what this might mean for future treatments and hope this gives us a better understanding of why some drugs work for some patients and not others. So being a part of Project BIG is perfect for us, since it allows our team to learn more about this devastating disease and share what we know. I also think that the future of research into diseases is going to be very team dependent, since there are many skill sets — including those that are clinical, scientific, and technical — needed to make progress.

What MS or broader brain, immunology, or gut research are you most excited about right now?
Well, I’m an immunologist, mostly, so it's definitely the area that interests me most, particularly the T cell side of things. But no one can be an island in this effort; we all have to learn from each other to make further progress.

How did you end up working in the brain, immunology, or gut fields, and how long have you been in this field?
I got the bug for this type of work mid-grad school. My first lab experience wasn't working out at the time, so I was looking for something that could excite me and also help me transition into gene work, which was just starting to take off. There happened to be a lab nearby working on antibodies in the immune system that had an open position. The opportunity came at the right time and proved to be a great fit, and I've never looked back!

What do you like most about your job?
Many aspects! The freedom to pursue work that is fascinating and important; the fun of breaking down big problems into reasonably solvable bits, and coming up with something new; and being able with bright young people who want to change the world!

What do you find most challenging about your job?
The big problems are always hard (the easy ones have already been done!). They require a lot of focus and often new technology to crack them, as well as pooling knowledge and brain power. But when it works, you know you’ve made a difference that many people can then benefit from. That’s very satisfying.

What is the kindest thing that someone has done for you?
Research can be a very discouraging activity, with lots of setbacks, especially when you are starting out. Mostly you just have shrug these off, learn from your mistakes and keep going. But every so often a mentor or friend would offer encouragement, and let you know that they believed in you, and had no doubt that you would be successful, ultimately. Even when things were most discouraging for me, there were people that would be very encouraging in this way, and it meant a lot.

What is the best piece of advice you have ever received?
“There’s always room at the top.” Ed Koza (after many others had warned me about the perils of a research career!).

What is something about you that would surprise others?
In college I wandered in to competitive fencing, where I found that I had a previously unappreciated talent for stabbing people! You had to come up with a viable strategy in a very short time. And if you got it right, you won. If not you lost. Focus was key, as was strategy. Very useful in research!

Bookmarked: MS News

CD8 T cells offer protection in a mouse model of MS. While CD8 T cells are most known for their role in killing infected, foreign, or abnormal cells, they have been exposed as also having the ability to inhibit CD4 T cells and protect against MS in a mouse model of the disease. The study authors, including the subject of this issue’s Spotlight, Dr. Mark Davis, suggest that these findings may also apply to humans given the coordination of CD4 and CD8 T cells in MS. (More: you can read the original article here).

ECTRIMS2019 wrapped in the Fall, giving us a glimmer of many exciting findings and innovations. One study found that monthly injections of ofatumumab led to a 50% reduction in relapse rates and a greater than 90% reduction in active brain lesions when compared to teriflunomide in relapsing-remitting MS and secondary progressive MS. A panel challenged how relapses are defined and assessed and called for a more refined classification of relapse that integrates cutting edge clinical imaging and biomarkers. Another study examined risk factors for developing secondary progressive MS and found that exposure to disease modifying therapies was a significant protective factor; less time to initiation of disease modifying therapies was also associated with a reduced risk of conversion to secondary progressive MS.

Projection neurons may explain MS brain shrinkage. Using a technique called single nuclei RNA sequencing, scientists have been studying the changes in gene activity that take place inside the nucleus of brain cells associated with MS lesions. They found that nerve cells called projection neurons, that play a key role in communicating information in the brain, are particularly prone to damage, and that as these cells die off, brain mass becomes smaller. Immune cells were facilitating much of the damage. David Rowitch, the led scientist for the study, commented, “This suggests that cell therapies targeting these immune cells could protect projection neurons and provide a novel treatment for progressive MS.” (More: You can read the original article 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.” (the original study can be found here)

Why don’t we have a vaccine against autoimmune diseases? A review discusses the considerations for developing a vaccine for autoimmune diseases, such as MS and RA. Factors contributing the challenge of developing such a vaccine are highlighted, such as the fact that unlike vaccines for infectious diseases, which are generally preventive and designed for immune-naïve people, vaccines for autoimmune diseases would be therapeutic and developed for people with an existing inflammatory immune response. Because there may be different mechanisms driving the disease for different people, identifying the target for an autoimmune vaccine has proven complex.

Stem cell therapies: hype or hope? After celebrity Selma Blair went public with her decision to undergo hematopoietic stem cell transplantation, public fascination with stem cell therapies is on the rise, while the MS community remains largely cautious but curious. A preliminary study found that nonmyeloablative autologous hematopoietic stem cell transplantation was more effective in delaying disease progression than disease modifying therapy for patients relapsing-remitting MS. Given the rise in stem cell clinics making unproven claims and offering dubious therapies (you can read the original research here), the relatively nascent and experimental stage of research in this area, and small number of patients who would be suitable candidates for the procedure, there is a need for accessible and relevant information provided to patients about these therapies.

Broader BIG (BRAIN-IMMUNE-GUT AXIS)

The menopause and Alzheimer’s link. Dr. Lisa Mosconi shares the roots of her interest in Alzheimer’s in women and the link between Alzheimer’s and menopause in an in-depth interview. Using the knowledge that Alzheimer’s affects more women than men and is triggered in midlife, Dr. Mosconi has been looking at brain scans of women before and after menopause to track the differences in pre-menopausal and menopausal brains. She discusses the role of everything from hormone to processed foods in the risk for developing Alzheimer’s.

The womb factor. An evolutionary theory is tying the disproportionate rate of autoimmune diseases in women to the placenta. The pregnancy-compensation hypothesis posits that women’s bodies evolved to both turn down and ramp up the immune system throughout adult life in order to provide simultaneous protection to the mother from harmful pathogens and protect the growing fetus and placenta from rejection. However, as the number of pregnancies adult women experience has dramatically declined over time, “…without a more or less constant pushback from placentas during pregnancies...the immune system can get too aggressive, too ramped up. It starts looking for things to attack that aren’t dangerous, which is how autoimmune diseases set in.” (You can read the original article here).

Targeting the immune system to treat Alzheimer’s. With research advocating for the potential role of the immune system and the potential of a viral infection trigger in Alzheimer’s disease, there has been a growing interest in exploring the immune system as a target for the treatment of dementia. The focus on the immune system is a departure from the amyloid hypothesis that has focused on the rule of the accumulation of amyloid plaques in the brain. Neuroscientist Arnon Rosenthal described, “Instead of trying to remove the pathological proteins, we are recruiting the immune system to treat the disease for us.”

[Listen] A stroke of insight. In this 18-minute TED talk, brain researcher Jill Bolte Taylor discusses her experience after suffering massive stroke and observing her brain functions start to collapse in real time.

The eureka moment. Are there things that we can do to spur greater creativity and the much longed for scientific Aha! moments? In this short piece, the role of stepping away from a problem in order to allow theories and ideas to incubate and grow is discussed. “Lighten up and let your mind roam” is a takeaway from this piece that we are loving.

Initiated

Using a broad interdisciplinary collaborative model with a tight interface between clinicians and scientists, Project BIG seeks to identify the patient's unique "immuno-fingerprint" as a step toward the true practice of precision medicine. Hundreds of patients have been enrolled and the BIG database is yielding key discoveries.

Impacted

“I wanted health professionals to share all the information they had, and to be clear when they had no answers.” A patient shares his thoughts on the importance of transparent information and peer support in coping with a new diagnosis. He shares, “As with many other chronic conditions I need to take control of my health and be vigilant to changes—to monitor myself and report anything new to my health professional. To do this, I need to know everything about my condition, especially about the expected progression and treatments.”

Quoted

““If you find a path with no obstacles, it probably doesn’t lead anywhere””

— Frank A. Clark

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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