Podcast appearances and mentions of rusty gage

Nick talks to Dr. Rusty Gage, a neurobiologist at the Salk Institute whose lab studies how genes & environment interact to influence brain development, including the process of adult neurogenesis. They discuss: what neurogenesis is and how it works; lifestyle factors that influence neurogenesis, such as exercise, intermittent fasting, etc.; molecular pathways involved in neurogenesis; depression & PTSD; memory formation and the function of newly born adult neurons; and more.Try Everyday Dose, high-quality coffee & matcha altneratives with functional mushrooms & other supplements.Support the showSign up for the free weekly Mind & Matter newsletter:[https://mindandmatter.substack.com/?sort=top]Learn how you can further support the podcast: [https://mindandmatter.substack.com/p/how-to-support-mind-and-matter]

In this episode of The Stem Cell Report, sponsored by Bio-Techne, we will explore the modeling of complex human neuropsychiatric diseases such as autism, bipolar disorder, and others using stem cell-based, three-dimensional culture models of the brain and its development. Martin Pera will be joined by Drs. Carol Marchetto and Rusty Gage, experts in the normal and pathological development of the brain. Carol Marchetto is an Assistant Professor in the Anthropology Department at the University of California, San Diego and an adjunct Assistant Professor at the Salk Institute. Rusty Gage is the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease and the President of the Salk Institute for Biological Studies. He has received numerous awards and recognition for his research including his appointment as a Fellow of the National Academy of Medicine. He is a former president of the ISSCR and a current member of the Stem Cell Reports Editorial Board. HostMartin Pera, PhD – Editor-in-Chief, Stem Cell Reports and The Jackson LaboratoryTwitter: @martinperaJAXGuestsCarol Marchetto, PhD, University of California, San Diego, USA Rusty Gage, PhD, Salk Institute for Biological Studies, USA  Supporting ContentReaching into the toolbox: Stem cell models to study neuropsychiatric disordersEthical, Legal, and Regulatory Issues Associated with Neural Chimeras and OrganoidsAbout Stem Cell ReportsStem Cell Reports is the Open Access journal of the International Society for Stem Cell Research (ISSCR) for communicating basic discoveries in stem cell research, in addition to translational and clinical studies. Stem Cell Reports focuses on original research with conceptual or practical advances that are of broad interest to stem cell biologists and clinicians.Twitter: @StemCellReportsAbout ISSCRWith nearly 4,500 members from more than 70 countries, the International Society for Stem Cell Research is the preeminent global, cross-disciplinary, science-based organization dedicated to stem cell research and its translation to the clinic. The ISSCR mission is to promote excellence in stem cell science and applications to human health.Twitter: @ISSCRAcknowledgementsISSCR StaffKeith Alm, Chief Executive OfficerYvonne Fisher, Managing Editor, Stem Cell ReportsKym Kilbourne, Director of Media and Strategic CommunicationsJack Mosher, Scientific AdvisorVoice WorkBen SnitkoffMusic@Konovalov

Rusty Gage is a professor and Salk’s president as well as one of the world’s most renowned authorities in neuroscience. Aside from discovering neurogenesis, Gage has made many critical discoveries in the fields of genetics, mental disorders and aging-related dementia, like Alzheimer’s. In this episode, he talks about what it’s like to lead both a research lab and one of the top scientific research institutes in the world.

Alysson Muotri and top geneticists Rusty Gage and Miles Wilkinson explore the fact that ninety-nine percent of human DNA doesn't code for anything used by the human body. Series: "Stem Cell Channel" [Science] [Show ID: 33492]

Alysson Muotri and top geneticists Rusty Gage and Miles Wilkinson explore the fact that ninety-nine percent of human DNA doesn't code for anything used by the human body. Series: "Stem Cell Channel" [Science] [Show ID: 33492]

Alysson Muotri and top geneticists Rusty Gage and Miles Wilkinson explore the fact that ninety-nine percent of human DNA doesn't code for anything used by the human body. Series: "Stem Cell Channel" [Science] [Show ID: 33492]

Alysson Muotri and top geneticists Rusty Gage and Miles Wilkinson explore the fact that ninety-nine percent of human DNA doesn't code for anything used by the human body. Series: "Stem Cell Channel" [Science] [Show ID: 33492]

Kavli Institute for Brain and Mind co-director Rusty Gage and symposium co-chair Jennifer Lippincott-Schwartz deliver opening remarks for the Imaging the Brain, from Molecules to Circuits and Beyond symposium. Series: "Kavli Institute for Brain and Mind" [Science] [Show ID: 33293]

Kavli Institute for Brain and Mind co-director Rusty Gage and symposium co-chair Jennifer Lippincott-Schwartz deliver opening remarks for the Imaging the Brain, from Molecules to Circuits and Beyond symposium. Series: "Kavli Institute for Brain and Mind" [Science] [Show ID: 33293]

Introduction to the Extraordinary Variations of the Human Mind symposium. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Science] [Show ID: 32449]

Introduction to the Extraordinary Variations of the Human Mind symposium. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Science] [Show ID: 32449]

Introduction to the Extraordinary Variations of the Human Mind symposium. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Science] [Show ID: 32449]

Introduction to the Extraordinary Variations of the Human Mind symposium. Series: "CARTA - Center for Academic Research and Training in Anthropogeny" [Science] [Show ID: 32449]

Fred Gage är professor vid Salk Institute i USA och en av forskarna bakom upptäckten att det kan bildas nya celler i hjärnan även hos vuxna människor. Gage berättar här om hur nycellsbildningen är något som vi faktiskt kan påverka själva.

November 10, 2015 Rusty Gage joins us from the Laboratory of Genetics at the Salk Institute to talk about neuron and neuron circuit generation and regeneration in adults. Duration: 34 minutes Discussants:(in alphabetical order) Alfonso Apicella (Asst. Prof, UTSA) Michael Foret (grad student, UTSA) Gary Gaufo (Assoc. Prof, UTSA) Annie Lin (Asst. Prof, UTSA) Christopher Rhode (grad student, UTSA) Jacqueline Shay (grad student, UTSA) Charles Wilson (Prof, UTSA) acknowledgement: JM Tepper for original music.

[intro music] Host – Dan Keller Hello, and welcome to Episode Fifty-One of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller. This week’s podcast features Dr. Luke Lairson of Scripps Research Institute, who discusses discovery of small molecules to induce remyelination and, in particular, some muscarinic receptor antagonists currently approved for other indications. But first, here are some new items in the MS Discovery Forum. According to our curated list of the latest scientific articles related to MS, 114 such articles were published in the first two weeks of August. We selected a few of these articles as our Editor’s Picks. One is a longitudinal study of gray matter lesions and cortical atrophy in MS published in PLOS ONE. The investigators obtained MRIs at baseline and five years later from subjects with clinically isolated syndrome, early and late relapsing-remitting MS, and secondary progressive MS, and examined lesion placement and cortical thinning in the different disease subtypes. To see this publication and the other articles we selected, go to msdiscovery.org and click on Papers. Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week, we added 1 new trial, we updated information on 2 other trials, and we added 12 other pieces of information. The drugs with important additions and changes are ATX-MS-1467, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta-1a, and interferon beta-1b. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline. [transition music] And now to the interview. Dr. Luke Lairson is an assistant professor at the Scripps Research Institute and a principal investigator at Calibr, the California Institute for Biomedical Research, in La Jolla. We spoke at the research institute. Interviewer – Dan Keller Dr. Lairson, we're talking about the potential for remyelination. And your institution is taking a very systematic and maybe novel approach. Can you describe how you're going about looking at possible ways to induce remyelination? Interviewee – Luke Lairson Sure. So we're using a phenotypic assays to look for small molecules that selectively induce the differentiation of the precursor cell population which is required for remyelination, which are the so called oligodendrocyte precursor cells or OPCs. We developed imaging-based assays where we could look for small molecules that selectively induce that differentiation phenotype. MSDF And how are you going about screening compounds, and what is your institute set up to do? Dr. Lairson So at Scripps and Calibr we have the capacity to screen on a million compound scale capacity to look at molecules. In this particular assay, we do it in a 3D four-well format, which limits us to screening collections on the scale of hundreds of thousands. And to date, we've screened about 200,000 compounds with this assay. MSDF In terms of multiple sclerosis, what are you looking at now? Dr. Lairson From our preliminary screen of our collection of bioactive compounds, including FDA-approved drugs and drugs in late-stage clinical development, we identified a series of compounds for which OPC differentiation had not been previously reported, which are muscarinic receptor antagonists, which are clinically approved drugs and which work in the central nervous system. And we demonstrated a number of these compounds work in two different rodent models of remyelination in MS. And we're currently developing these as a lead class of compounds as a combination therapy when combined with existing immunosuppressant drugs, including Gilenya. MSDF What compounds have you focused on most? There's a multitude of approved antimuscarinic agents. Dr. Lairson Right. So this is actually a a critical point. So we identified a number of compounds which had antimuscarinic activity, which were active in our OPC differentiation assay. We used pharmacology to demonstrate that the antagonism of M1 or M3 receptor subtype is a required component of the mechanism of these drugs. However, we think that there's a second target, and it's a dual mechanism action through which these drugs are acting, which we're currently trying to elucidate what that second target is to fully characterize the mechanism. That second target actually provides the opportunity to identify compounds that have a potential to have a better therapeutic index in vivo. So the lead compound we published was benztropine. Jonah Chan's lab at UCSF later showed that clemastine also works, which was in our paper, as well. So these are drugs that have been demonstrated to work in vivo. What we did after we published that is we then looked at every compound that we could get our hands on that had antimuscarinic activity – specifically targeting M1/M3 receptor subtypes – and then characterized their activity in the OPC differentiation assay and, as well as profiling their potency on the M1/M3 receptor subtypes, with the goal of looking for compounds that have an optimal therapeutic index in terms of on-target toxicity. So benztropine induces OPC differentiation in the low micromolar range, but it antagonizes M1 and M3 receptors in the low nanomolar range so there's a discrepancy there. And we think that the on-target toxicity of antimuscarinic activity is going to limit the therapeutic potential of these drugs. We've since identified other FDA-approved drugs for which that index is improved and we compounds with approximately 100-fold improvement in therapeutic index, which we've demonstrated in the EAE model are active. And we're currently evaluating them in combination with immunosuppressant drugs to identify an optimal combination, which could well be benztropine or clemastine but may be another FDA-approved drug. MSDF You're at very early stage in terms of clinical utility of these things in MS. But is there any way to separate out the negative antimuscarinic effects that affect people taking drugs for overactive bladder and various other things from their therapeutic effect? Or is it really intrinsic to attacking that receptor? Dr. Lairson That's the key point. So we do think that it's that on-target toxicity which is going to potentially limit this class of compound, which is why we're looking for these other compounds and where we have an improved therapeutic index of inducing remyelination versus antagonizing those receptor subtypes. And likely this class of drugs – and any class of drugs that induces remyelination – is going to have to be used in combination with immunosuppressant drugs. It will require a careful clinical evaluation to figure out which combination will be the most effective and what doses will be safe. MSDF But you also have been doing T-cell assays I take it in looking at benztropine in your work. So what goes on with immune modulation? Is there any effect there? Dr. Lairson So we did extensive studies with benztropine to evaluate its activity in not just T-cell biology but also macrophage biology both in vitro and in vivo. And we found benztropine had no affect on in vitro or in vivo T cell numbers or activity in terms of cytokine production. It has no affect on macrophage polarization in vitro or in vivo, including looking at spinal cords of animals. We don't think that it's acting through a peripheral immune system effect. We can't rule out an important concept that came out at a recent meeting was we need to look at the affect of these compounds on microglial cell activation in the brain and also in astrocyte activation. MSDF So it looks like it's a pure remyelination effect at this point and not really an immunosuppressive effect, which would argue for having to use it in conjunction with today's drugs for MS. Dr. Lairson Correct, that's our current reasoning, yeah. MSDF Have you looked at other models other than cuprizone? Dr. Lairson Yeah, we looked at the EAE…PLP-induced EAE model of relapsing-remitting MS, and we've looked at the MOG model of progressive MS and the cuprizone model. Yeah, those are the models we've looked at to date. MSDF With similar results? Dr. Lairson The compounds we've evaluated have all been active in in those models. MSDF Do you have an idea of the mechanism of action how this is actually working in the oligodendrocyte precursor cells? Dr. Lairson Downstream of the muscarinic receptor…so as I said, based on pharmacology, these classes of compounds – these neurotransmitter receptor modulating agents – are notoriously pleiotropic in that they had multiple receptor subtypes in the brain. So benztropine, for example, it hits nicotine and histamine receptors in this dopamine reuptake inhibitor in addition to being an antimuscarinic. We've shown that those activities are not responsible for inducing OPC differentiation. However, as I said, we've identified multiple compounds that do inhibit muscarinic receptors – specifically receptor subtypes 1 and 3 – that do not induce OPC differentiation. So we think there's a second target; we're actively trying to identify what that second target and downstream mechanism is. MSDF Do you think the same compound would attack both targets, or are you going to need to give multiple compounds to hit multiple targets very selectively as I would think would be the hope? Dr. Lairson The existing compounds we have the argument is that they are hitting both of these targets to induce the differentiation. In that, there's a number of compounds that do hit the M1/M3 receptors that do not induce differentiation, which argue that you need both. The compounds we've identified fortuitously hit both of the necessary targets. MSDF In the antimuscarinic field, often the goal is to be very selective and limit activity at different receptors, but it sounds like you want some overlap here. Dr. Lairson Exactly. We've also initiated some medicinal chemistry where we're trying to see if we can dial in potency for the second target. So we know if benztropine is active on muscarinic and low nanomolar can we improve its potency in the OPC assay by dialing in potency on that second target? MSDF By modifying the molecule? Dr. Lairson Yeah, so making analogs of existing active antimuscarinic agents and then evaluating their activity in the OPC differentiation assay, as well as evaluate their antimuscarinic activity. MSDF Are you hoping that the same active part of the molecule hits both receptors, or have you ever considered making a bifunctional molecule that would be best at both receptors? Dr. Lairson If we knew what the other receptor was, we could potentially address that, or you could argue a bifunctional versus having two unique compounds so it would be you'd have to evaluate that in vivo I think, yeah. The other argument for moving away from this is that as soon as you make a change to that compound it's no longer an approved drug, and you have to go through the rigor of bringing that to the clinic. MSDF Now in your screening, you're using a lot of drugs – a lot of compounds at this point – that have already passed phase 1 screening or phase 1 clinical testing, and this has shown safety. Does that speed up do you think the approval process if these things look active? Dr. Lairson It does. So UCSF has actually initiated a phase 2 trial to evaluate clemastine in MS. So they were able to immediately proceed from a screening result to a clinical trial because it's an approved drug. MSDF And just about Calibr, your institute. You have full facilities for taking this from screening up to what stage? Dr. Lairson Up to the rodent proof of concept stage. So we have a high throughput screening facility, as I mentioned, and then we have a medicinal chemistry group, a pharmacology group where we can do pharmacokinetics in-house and then in core biology. So we take it to the rodent proof of concept. MSDF Do you do any synthetic chemistry, or this is all screening of existing molecules? Dr. Lairson Yeah, we do significant amount of synthetic chemistry so we have a group of 20 chemists – medicinal chemists – that are making analogs. And we do a significant amount of contract research to get compounds and analogs made. MSDF What have we missed, or what do you think is important to add, if anything? Dr. Lairson The other aspect of our program is we've identified novel compounds for which their mechanism of action is unclear. So we've identified multiple scaffolds. We've focused on three of those, which have been subjected to medicinal chemistry optimization. So we identified screening hits, which we were unable to evaluate in the rodent models due to their pharmacokinetic property. But we've now identified analogs of those compounds which are potent in the OPC assay, in which we can achieve reasonable levels in the brain. So we're currently evaluating those in these preclinical rodent models. And once we demonstrate efficacy there, we'll then go and evaluate their mechanism of action. MSDF You test these compounds first in a phenotypic sense to see if they actually do something that you want done. And then you trace it back to mechanism of action? Dr. Lairson Correct. That's our general approach for a lot of assays. So rather than looking at a validated, biochemical target, typically we'll just look for small molecules that induce the cell fate decision that we're interested in. For me, personally, it's the most interesting part of the project is I’m figuring out how those compounds that we rule out known mechanisms how they're actually acting. So we do the mass spec-based proteomics to figure out the specific protein target. And then we use standard cellular molecular biology techniques to elucidate the downstream mechanism of action. MSDF So I suppose the phenotype you're looking for in the case of this research we've been discussing is remyelination. How do you look for that activity? Dr. Lairson The remyelination activity in vitro? We use a co-culture assay, which we collaborate with Rusty Gage at Salk where we pre-differentiate neurons in a dish and then co-culture with our oligodendrocyte precursors plus or minus drug and then look at the ability of those drugs to enhance the rate of myelination of co-cultured axons. MSDF And you just stain the cells in vitro looking for myelin production or myelin basic protein? Dr. Lairson Exactly, yeah. So we just look at myelin basic protein co-localization with axon. MSDF Very good. I appreciate it, thanks. Dr. Lairson Absolutely. Thanks very much for your interest. [transition music] MSDF Thank you for listening to Episode Fifty-One 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. 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 editor@msdiscovery.org. [outro music]

What does exercise and experience do for the brain? Improving maternal care, the brain networks of impulsive behaviour and the rewards of sharing experiences with friends! Plus turning hair into nerve cells to help beat Alzheimer's and we find out what keeps a Nobel Laureate up all night. Like this podcast? Please help us by supporting the Naked Scientists

What does exercise and experience do for the brain? Improving maternal care, the brain networks of impulsive behaviour and the rewards of sharing experiences with friends! Plus turning hair into nerve cells to help beat Alzheimer's and we find out what keeps a Nobel Laureate up all night. Like this podcast? Please help us by supporting the Naked Scientists