Multiple Sclerosis Discovery -- Episode 63 with Dr. Helen Tremlett

[intro music] Host – Dan Keller Hello, and welcome to Episode Sixty-Three of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m Dan Keller. We’ve just passed the winter solstice. What better time than the shortest daylight hours of the year to check in with research at the University of British Columbia on sunlight and MS? Today we talk with Dr. Helen Tremlett who is exploring sun exposure over a person’s life course and how that syncs with their MS risk and disease course. In the weekly papers section on the MS Discovery Forum, this week’s list includes nearly 150 newly published research reports that could lead to better understanding and treatment of MS and related disorders. We selected four papers as editor’s picks. In one paper, researchers think they may have the first experimental evidence that MS may start with damage or loss of myelin-making cells in the brain and spinal cord. In this new mouse model of progressive MS, experimentally damaged brain cells make it hard for the mice to walk. The mice recover when their brain cells repair on their own. Six months later, the MS-like disease returns. In the study, the team showed that nanoparticles targeting the autoimmune reaction prevent the second phase of the disease. The study shows support for an “inside-out” model of MS. That’s different from the “outside-in” model, in which some aspect about the immune system goes wrong and then initiates the attack on myelin-making cells. The paper is published in Nature Neuroscience by collaborating researchers from Northwestern University and the University of Chicago. To grow and be healthy, all human cells need a signaling molecule named mTOR, named for the mammalian target of rapamycin. That’s true for myelin-making cells, or oligodendrocytes, as listeners may remember from an earlier podcast interview with Dr. Wendy Macklin. The ability to make myelin seems to depend on a key part known as mTOR complex 1, also called its raptor subunit. In a very basic advance, scientists have determined the atomic architecture of the raptor, or mTORC1, piece. The details are reported in the journal Science and provide a structural basis for studying mTORC1 function. In another editor’s pick, a review of cases of pediatric neuromyelitis optica, or NMO, showed that new international diagnostic guidelines applied well to children. Unfortunately, they also found that children with NMO have delayed treatment and worse short-term outcomes compared to those with MS. The authors urged immediate adoption of the guidelines to select the best treatment and improve outcomes. In the fourth editor’s pick, researchers found a potential new target to protect axons in a mouse model of neurodegeneration in multiple sclerosis. The target is a pore in the mitochondria, the cellular battery that provides energy. They designed a molecule to block the pore and showed it helped protect neurons and improved the mice’s mobility, all with minimal immunosuppression. The paper by mostly UK researchers is published in the Journal of Biological Chemistry. Now, let’s take a look at the latest Drug Development Pipeline updates. The drugs with important additions and changes are dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and rituximab. One update reflects findings from post-hoc analysis of clinical trial data showing that the positive effects of fingolimod are apparent quite soon –within months – after initiation of treatment. [transition music] And now to our interview. I spoke with Professor Helen Tremlett, Canada research chair in neuroepidemiology and multiple sclerosis at the University of British Columbia when we were at the ECTRIMS conference in Barcelona in October. She has been studying sun exposure over the course of the lifetime and its relation to MS risk. While MS may affect an individual's likelihood to go out in the sun, studies may also need to consider the influence of sun exposure before the disease develops. Interviewer – Dan Keller What are you doing in this area? Interviewee – Helen Tremlett So I was presenting at ECTRIMS yesterday on a really interesting study based out of the Nurses' Health Study, and this was a collaboration from my group in Vancouver and Harvard School of Public Health; and that's Alberto Ascherio's group and Sandy Munger. So we were looking at sun exposure over the life course and associations with multiple sclerosis. So here we were looking at both aspects of the spectrum, if you can imagine; we were looking at sun exposure and future risk of multiple sclerosis, but also once an individual has developed multiple sclerosis, we were looking at the impact that potentially has on an individual in terms of their propensity to go outdoors in the daylight hours, outdoors in the sun. MSDF Right. So it may be the cart is before the horse in that sense; not that sun exposure is causing it, but their disability is causing less sun exposure? Dr. Tremlett We were looking at both sides of the equation. And I think it is important, particularly in a disease such as MS where onset of MS is a little bit fuzzy, I think, to look at sun exposure of the life course is important, and certainly our findings are indicating that. Because you want to know sunlight exposure in MS risk, but you also want to know, once someone's developed multiple sclerosis, how that influences their behavior outdoors and what implications that has if you're then trying to design the study to look at what causes MS. You need to be really careful who you recruit, because if that person has already changed their behavior, then that may influence your findings, and you're not then actually looking at what causes MS at all, you're just looking at a consequence of the disease. So I guess that's the first part of why we wanted to do that. And the second part is if having MS, if having a chronic condition, does influence your propensity or ability or desire to go outside, what consequence could that have for your health in terms of maybe your serum vitamin D levels or your melatonin levels, and that may have a consequence in terms of long-term health. MSDF You segmented people by where they were and at what ages. Dr. Tremlett It was pretty interesting. So, first of all, over ages 5 to 15, we found there that there was a 48% lower risk of MS for women living in high, relative to low, ambient UVB areas during their sort of childhood and early adolescent years. So that was pretty interesting. But we found, kind of to our surprise because it goes against other studies that are out there, we found that time spent outdoors in summer or winter wasn't significantly associated with MS risk in that age group, 5 to 15 years. But what we didn't realize is that it wasn't until we combined that outdoor behavior with the UVB, then we could see that there was an association. So we found that less time spent outdoors in summer in low ambient UVB areas—that was associated with a two-fold increased risk of multiple sclerosis. That was an important step for us; I mean, it might, you know, sound obvious to combine those two, but it was an important step because other studies in smaller geographical areas such as Tasmania, or there's a study out of Norway in a small region of Norway, they can find an association between time spent outdoors in summer/winter and MS risk. But I think we couldn't find it in the US, because the US is at such a diversity of latitudes – the study spanned over 14 US states – so it wasn't until we looked at that outdoor behavior in context of ambient UVB that we could find the association. And then, I suppose, our next step was to look at outdoor behavior over the life course. And this was really interesting, that we found some avoidance behavior was apparent in later life in multiple sclerosis. And maybe that comes as no surprise to people, but I think our numbers are interesting to put a concrete figure on it. So, for instance, by age 50, our MS cases were 60% less likely to report high relative to low outdoor exposure compared to controls, and that was in winter and in summer. So the bottom line is people with MS, once they have MS, are not going outside as much, so they're not getting that UVB exposure, so potentially they're not making that vitamin D and serum vitamin D. And then the winter exposure's important as well, because potentially they're not getting the same melatonin production and inhibition, and that may have a really important role in terms of immunology, the circadian rhythm and your sleep cycle, which, again, all knocks back into overall health and immunology of MS. And there have been some presentations actually at this conference looking into melatonin and its association with relapses in MS, and that's pretty interesting. MSDF There's even some emerging thought that sleep is essential for good brain function in terms of taking out the garbage – glymphatics and things like that. So melatonin disturbances may actually have some further consequences in an inflammatory brain disease. Dr. Tremlett And there's some interesting studies, not that we did but others have done, looking at shift work and risk of MS. And shift work may be associated with increased risk of MS. Maybe melatonin ties into that as well. MSDF Is there also potentially an effect, besides on vitamin D and melatonin, that sun exposure itself has an effect on the immune system, maybe suppressing it? Dr. Tremlett Yeah, modulating it in some way. No, absolutely. We don't really know the mechanism. I mean, the obvious one would be sun on human skin at the right time of year on the right skin color can result in really high levels of serum vitamin D being produced. Sunlight exposure the minute it actually hits the skin surface can have a direct immunomodulatory effect. And then, obvious, sun hitting the eye. Melatonin is one of the pathways in there that may then impact the immune system. MSDF Is it possible to make any conclusions or even recommendations at this point? Dr. Tremlett No. It's an observational study, and we do actually need to do more analysis on this group of individuals. The main recommendations we could make from this study is informing how to design future studies, and also two things you could take from this in terms of recommendations. First of all, we saw sun avoidance behavior in individuals once they've developed multiple sclerosis. That's really important because it really means that if you want to look at what is causing MS, do not take serum vitamin D levels or look at skin cancer risk, for instance, in individuals who already have MS, because they've already changed in compare to controls, adding further somehow differences are related to what causes MS, because these individuals have already changed their behavior because they've got a chronic disease. So that's the first statement, which might be a no-brainer for some people, but it's amazing how many studies are still published like that in the MS literature at the moment. And I suppose the second piece is trying to understand if we are going to do an interventional study, what time period in an individual's life or within a population do you need to target in order to change the course and prevent the disease from occurring? And we're trying to understand that more, looking beyond the window age 5 to 15, look more into adulthood to see if ambient UVB is associated with MS risk later in life and into adulthood. And others have shown that there does seem to be an association even into adulthood, which is exciting because if you do want to do an intervention study, then you haven't necessarily missed the boat because you've not intervened during childhood. But, I mean, the real question is how do you intervene and what with? And that's another topic in itself. MSDF We'll leave that for another day. Thank you. Dr. Tremlett Thank you very much. [transition music] Next week, we'll continue our discussion with Professor Tremlett when she'll talk about her preliminary studies on pediatric MS patients and their gut microbiomes. Until then, thank you for listening to Episode Sixty-Three of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Carol Cruzan Morton. Heather McDonald curated the MSDF drug database updates. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations. Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances. We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to [email protected]. For Multiple Sclerosis Discovery, I'm Dan Keller. [outro music]