Multiple Sclerosis Discovery -- Episode 8 with Dr. Wendy Macklin

[intro music]   Host – Dan Keller Hello, and welcome to Episode Eight of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with researcher, Wendy Macklin, whose team studies myelination and demyelination in zebrafish and mouse animal models. But to begin, here is a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.   As listeners may already be aware, a new study suggested that infection with HIV is associated with a lower risk of developing MS. Researchers looked at a large sample of hospital records and found that individuals infected with HIV had a 62% lower risk of MS than HIV-negative individuals who were matched for age, gender, region, and socioeconomic status. The researchers think that antiretroviral drugs might be causing the protective effect, though it’s possible the infection with HIV itself somehow protects against developing MS. Antiretroviral drugs may attack some ancient viral genes thought to trigger MS and other autoimmune diseases.   Science journalist, Ricki Lewis, covered a study of patients with a rare mitochondrial eye disease that may be entwined with MS. The disease called Leber hereditary optic neuropathy, LHON, is a degenerative eye disease that causes progressive loss of vision. But in some patients, the disease can also cause MS-like symptoms. Researchers performed MRIs on patients with LHON and found that their white matter lesions resembled MS, possibly providing an early snapshot of MS. The similarity of the diseases has also led some researchers to question whether they share a pathogenesis, but the rarity of LHON and MS developing in the same person is shifting the opinion towards calling any comorbidity of the diseases just a coincidence.   In a recent post in MS Patient, Ph.D., blogger Griselda Zuccarino-Catania followed up her feature on DMTs in pregnancy with her own personal debate on whether to continue her DMT while breastfeeding. In her post, she profiles researcher Thomas Hale, who studies drug concentrations in breast milk. He’s found that concentrations in a woman’s blood plasma are associated with the concentrations in her breast milk. These levels can be used to assess the risk any drug might have to infants.   [transition music]   Now for the interview. Science journalist, Carol Morton, met with Wendy Macklin at the Glia Meeting in Cold Spring Harbor, New York. She and Dr. Macklin discussed new research in myelination using the mTOR cell apoptosis pathway, the feasibility of a remyelinating drug, and her work with an unusual animal model for modeling MS – the zebrafish. [Note: the word "apoptosis" is incorrect and should not have appeared in the introduction to Dr. Macklin's interview. While it's impractical to remove it from the already-released audio podcast, we are correcting the error here, in this transcript.--Editor]   Interviewer – Carol Morton There are not that many MS researchers who work with that.   Interviewee – Wendy Macklin No, and there are times when you have to suggest that there is relevance to multiple sclerosis for looking at little two-inch fish. But they do. They provide really important information because you're not even looking at the two-inch fish; you're looking at the little, teeny tiny larva and embryos, but they are optically clear. So some of the new technologies use these green fluorescent proteins that originally were identified in jellyfish that make the jellyfish fluoresce at night. If you shine a certain wavelength of light, they turn green. And so, you can do that in a live animal, in a live fish; and in fact, some of the stuff that we were hearing today was even doing it in the mouse, but there you have to actually be able to get the microscope so you can actually see into the mouse brain. But in the fish, everything is transparent; so you can see it no matter what. So you just put the fish in a microscope environment, and you can watch cells, and you can take movies of cells moving, cells trying to make new processes, and cells wrapping around axons. And so you can watch this in realtime.   MSDF You recently had a really interesting paper. Do you want to talk about...?   Dr. Macklin So that paper came out of a project that we'd started a long time ago that was focused on understanding how one particular protein, Akt – which does many, many things in cells – regulates oligodendrocytes, which are the cells that make myelin. And it does many things; we thought it was involving in a survival element; and so we thought maybe we could find things that would help the oligodendrocytes survive immune attacks, survive things better and not die. And so we created a mouse where we overexpressed that protein in the oligodendrocyte. And instead, actually, what happened it did not change the survival of the cells at all; it changed how much myelin they made. And in fact, it drove the cells to make too much myelin. And in fact, if that becomes pathologic, the animals actually die when they're about a year old because they have too much myelin, and it's filling up their brain. So it's a dramatic change. And so, then we began to drill down to see well what is it about that molecule because it does many things? This particular hypermyelination syndrome was really feeding down through the mTOR pathway. And so, if you knockout parts of the mTOR pathway in the oligodendrocytes, the spinal cord is far worse and makes much less myelin and does not really generate the right kind of myelin. Whereas other parts of the brain are doing just fine or seem to be doing just fine. So one of the questions is why is this anymore damaged by this change in the cell? So the oligodendrocyte is identifying an axon and then wrapping around and making myelin, and that's what's the key question in MS is how to make sure that cell continues to make myelin. And we now have a system where we have changed the axons in some way – using again this mTOR pathway – and those axons don't encourage the oligodendrocyte to make myelin. So now we have a system where we can go in and try and figure out well what's fundamentally changed about those axons that they say don't myelinate me; whereas the oligodendrocytes in other parts of the nervous system are doing just fine making myelin.   MSDF Now after the session this morning, I'm actually wondering if myelin making is now the goal, or has the goal…is the goal changing as people find out more for for therapeutic?   Dr. Macklin I would say we don't know. So if you look in MS tissue, you see that where there's demyelination there still are oligodendrocyte progenitor cells, and there still are the cells that are trying to make myelin, the premyelinating cells. There's small numbers relative to the normal tissue, and they don't make myelin. So is that because we don't have enough cells? Is that because they have an inhibitor that's preventing them in that environment, or because they're not getting some positive signal? So I would still say the question of understanding how myelination is regulated has huge clinical relevance.   MSDF Recently you went to another meeting that was really focused on myelination as a therapeutic problem, a therapeutic target.   Dr. Macklin Right.   MSDF In addition to knowing what's happening with the cells and the molecules in the environment in the brain, there's some other issues in getting myelin-making drugs through clinical testing.   Dr. Macklin Yeah. In contrast to many of the other neurologic diseases, there are disease-modifying drugs out there for MS, but they almost all – at the current time – hit the immune component, which is absolutely essential and is definitely important. But even if you got rid of 100% of the immune component of MS, you still would have damage in the brain. And there is a good deal of evidence that the myelin not only does it allow better conduction of these axons, but it also provides all sorts of support. Metabolic it's providing energy to the axons; it provides a great many things to the axons that help the axons survive, which are part of the neurons. So if there is really still serious damage, you want to figure out some way to repair that. And so there are a couple of clinical trials actually going on right now that are looking at drugs that might enhance the remyelination in patients. And so, some of the things that we're doing – looking both in the fish as well as in the mouse – are pathways that could be targeted for therapeutics that might help you to enhance myelination. One of the big themes that came out of that meeting last month was that if you had the perfect therapy for remyelination – you know that it works well in the zebrafish; you know it works well in the mouse – you can get other models that allow you to look at remyelination in a number of different contexts. You have to get those to patients and see if they actually do create new myelin. In patients, the problem is that the current imaging modalities for patients, MRI, is measuring water. And where you have myelin there is less water because of the way myelin works. It's hard to know exactly why there's less water where you're looking in MRI. So there's a variety of different approaches. There's new techniques with MRI. There's even some new PET techniques – which are clearly experimental at this stage – to try to really be able to show new myelin. And part of that meeting was really if we had the perfect therapy how would we prove it in a clinical trial? You can show clinical improvement, which is great, but is that because of you've changed the immune system, because you've changed other aspects of the patient, or you really have new myelin? That's currently still a really hard problem in terms of the the clinical end of things to really be able to prove that. Nevertheless, people are developing these kinds of drugs, and as I said a couple of them are in clinical trial right now.   MSDF Looking at your animal models, the ways that you have evaluating more or less myelin are ways are ways that can't be translated to people…   Dr. Macklin Well some of them are. I mean that's really where some of this work is going is trying to figure out how to use either MRI or PET imaging of live animals, and then you can go and test. And you think you have a signal that tells you you have increased myelin then you can actually go in and check and see – at the tissue level – is there really new myelin? So you can validate some of these imaging modalities that way. But you you will always have to go eventually to the patients and be able to really demonstrate that that particular way of imaging the tissue proved in in an animal model really does mean something in the patient as well.   MSDF I've seen those little mouse MRIs.   Dr. Macklin They're so adorable.   MSDF They are.   Dr. Macklin And they definitely show you something. They definitely show you something. And some of the PET work…the PET work is more specifically directed to myelin so you can have a PET ligand, which shows up in PET imaging, that just literally binds only to myelin or binds predominantly to myelin, and it will go into the tissue, and it will bind there. And that actually gives you some fairly discrete imaging that because you know it's a molecule that only binds to myelin when you see that signal in a particular place you know that that is myelin. And if you see more of a signal, then you know that that's more myelin. So those are really interesting approaches, and they're very much more directed to being able to specifically say that's myelin that you're seeing. But in the clinical context, those kinds of approaches are being worked on, but they're still very early stages. In terms of trying to set up a clinical trial, those kinds of approaches may be the way you'll go eventually, but today you couldn't do it that way.   MSDF Anything else that I should be asking, or that you wanted to add that would in in this context that would be interesting?   Dr. Macklin Well I mean I think at this stage  there are other issues of the question of so much of the work is done on myelination, which is crucial during development, and it's absolutely essential. And problems with normal myelination during development result in really serious brain problems. There are ways to study developmental myelination: in the fish, in the mouse, in a variety of different ways. And then there's a series of adult ways of getting rid of myelin to look at remyelination. And so, the overwhelming perspective has always been well whatever you learn from the myelination during development would be exactly what you would need to know about for the remyelination in the adult. And much of that's true. I mean you have to get the cells, you have to get the cells to proliferate, you have to get them to the right place. But there are now data that suggest that there are definite differences in the way the adult cells are responding to their overall environment, which is totally different than from the developmental environment. The cells may be very similar, but in the developing environment the many things are changing all of the time – the nerve cells, all of the different cells are changing, the brain is getting bigger – there's all sorts of changes. And in a damaged adult brain, you see certain differences that do seem to be real in terms of the way the signaling pathways are that would regulate how the myelin is generated in the remyelinating context versus in the developmental context. So we do need to go back and forth even the ones of us who work on the fish. We need to be able to look and see some adult context that's a demyelination/remyelination context that those same things that you're seeing developmentally are important in the adult.   MSDF That is interesting because I have heard people say well you recapitulate, you want to recapitulate the…   Dr. Macklin Yes, and it does. It…   MSDF …the developmental pattern.   Dr. Macklin Right.   MSDF So that's interesting in that. Okay, well that's fabulous. Well, thank you for taking the time to do this.   Dr. Macklin Okay. Certainly.   MSDF It was wonderful.   Dr. Macklin I hope it's useful for you.   MSDF Okay, great.   [transition music]   Thank you for listening to Episode Eight 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 Robert Finn. Msdiscovery.org is part of the non-profit 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].   [outro music]