Brian Kim Brain Body Lecture

Summary

Highlights

• Brian Kim's lecture dove deep into the complex sensation of itch, touching on its psychological and physiological roles 🎤.
• Itch signals a combination of internal and external stimuli, providing clues to both protective and pathological processes 🤔🔍.
• Recent research highlights specific neural circuits and receptors involved in itch, distinguishing it from similar sensations like pain 🧬.
• Innovative approaches in treatment have seen successes, especially through targeting cytokine activity and its pathways in chronic itch conditions 💊.
• Kim's presentation emphasized the multi-disciplinary nature of itch, integrating insights from dermatology, immunology, and neuroscience 📚🌐.

Key Takeaways

• Brian Kim explores the sensation and perception of itch from a neurological and immunological standpoint 🧠✨.
• Itch involves key interactions between the brain, body, and immune responses, revealing fascinating insights into sensory perception 🎯🔬.
• Understanding how sensory nerves and cytokines work together opens potential pathways for novel treatments for chronic itch conditions 🚀💡.
• Therapeutic successes using drugs like monoclonal antibodies show promise in effectively treating conditions like eczema and atopic dermatitis 🌟🎉.
• A strong interplay exists between mental health and physical sensations, with itch being a critical example that needs further exploration 👩‍⚕️🧘‍♂️.

Overview

Chapters

• 00:00 - 00:30: Introduction to Brian Kim's Lecture The chapter titled 'Introduction to Brian Kim's Lecture' sets the tone for a lecture series by Brian Kim, focusing on the topic of the sensation and perception of itch. The session is part of the Brain Body Lecture Series, a platform known for its insightful discussions. The speaker, Brian Kim, is introduced as the main presenter for the day. During the introduction, there's a mention of balloons, hinting at a celebratory atmosphere, possibly due to someone's birthday.
• 00:30 - 01:00: Brian Kim's Background and Research Focus Chapter 1: Brian Kim's Background and Research Focus - The chapter discusses the recruitment of Brian Kim from Washington University around a year ago to lead a program focused on the intersection of sensation, itch, and immunology. His research encompasses the fields of neuroscience, immunology, and dermatology, highlighting the complex interactions between neural circuits and peripheral systems.
• 01:00 - 01:30: Sensation, Perception, and Itch The chapter explores groundbreaking research on the role of sensory nerves in neuroinflammatory processes. It highlights how these nerves can use classic neurotransmitter signaling pathways, commonly studied by neuroscientists, to control local neuroinflammation. This represents an innovative, out-of-the-box approach to understanding sensory nerves and neuroinflammation.
• 02:00 - 03:00: Nobel Prize Discoveries Related to Senses Dr. Brian Kim is about to present his work related to Nobel Prize discoveries connected to human senses. The context suggests a speech or presentation at an event where Scott Russo has also played a significant role, possibly in forming a new center focused on this field. Dr. Kim expresses excitement and gratitude for the opportunity to present and congratulates Scott on the establishment of the center. The atmosphere seems enthusiastic, with attendees present physically.
• 03:00 - 04:00: Pain vs. Itch: Importance and Functionality The chapter begins by addressing the increasing relevance of the topic, particularly over the last five years. The speaker mentions having numerous disclosures related to the subject. The fundamental question posed is how humans sense the world around them, which sets the stage for the exploration of the topics of pain and itch in the chapter.
• 05:00 - 07:00: Why Itch is a Conserved Sensation The chapter discusses the sensation of itch and its significance as a conserved sensation across different organisms. It explores the intersection of immunology and neuroscience, indicating how the study of itch not only aids in understanding this particular sensation but might also shed light on other sensory experiences. The chapter underlines the importance of integration between different scientific disciplines, noting the awarding of Nobel Prizes in the area of sensory science as a testament to the field's importance.
• 07:00 - 10:00: Itch and Medical Conditions This chapter discusses the contributions of David Julius and Arden Patapudian to physiology and medicine, specifically their discoveries related to the sensory perception of temperature and touch. The narrative briefly considers the importance of the five senses, pointing out how even though they are crucial, we may not always consciously acknowledge them.
• 10:00 - 13:00: Peripheral Nervous System and Dermatology The chapter discusses the peripheral nervous system and dermatology, specifically focusing on sensory experiences like pain and itch. It addresses how certain conditions, such as mutations in pain receptors, affect sensation. Despite initial thoughts that insensitivity to pain might be a superpower, the example of Ashley Blocker—who was born with a mutation and cannot sense pain well—illustrates that such insensitivity may lead to unintentional self-injury.
• 13:00 - 18:00: New Discoveries in Itch Biology In this chapter titled 'New Discoveries in Itch Biology,' the discussion begins with a real-life example of a toddler who bites her fingers, leading to them being bandaged. This highlights the role of pain as a crucial protective measure, allowing us to avoid harmful stimuli. The chapter then delves into the less understood phenomenon of itching. One of the most common questions asked during talks about this topic is why humans experience itchiness. While there is no definitive answer yet, the chapter suggests that at least two minimal explanations could potentially exist, though these are speculative at this point.
• 18:00 - 22:00: Research on Atopic Dermatitis and Inflammation The chapter delves into the research on atopic dermatitis and inflammation. It explores the reasons behind certain noxious stimuli's ability to be sensed in a non-aversive manner, such as the presence of disease-borne insects. Unlike immediate aversive stimuli like a bee sting, these stimuli encourage sensing the environment without immediate avoidance, allowing a brief tolerance. Furthermore, the chapter highlights the increasing awareness of the role of itch sensations, especially as people age and experience organ failure or other body failures, uncovering itch as a common signal in such deteriorating conditions.
• 22:00 - 27:00: Type 2 Cytokines and Sensory Neurons The chapter discusses the role of type 2 cytokines and sensory neurons in the sensation of itch, emphasizing its dual nature as both an external and internal signal of something potentially being wrong in the body. The chapter suggests that itch, as a symptom, is highly conserved evolutionarily, indicating its significant biological importance.
• 27:00 - 33:00: Therapeutic Applications and Clinical Trials This chapter dives into the reasons why the sensation of itch is retained across vertebrates, despite evolutionary changes. It highlights the importance of sensation and also delves into the complexities that arise when these sensations malfunction. The chapter further discusses the clinical significance and research conducted on seemingly vestigial cell types like innate lymphoid cells and basophils, emphasizing their roles in therapeutic applications and clinical trials.
• 33:00 - 39:00: The Role of Neuropeptides and Inflammation The chapter discusses the role of neuropeptides and inflammation, highlighting the impact of residual or vestigial systems on modern health issues. It underscores how even seemingly minor physiological processes can become problematic when they are activated and cannot be turned off, particularly focusing on conditions where itch is a central issue of morbidity. The chapter points to conditions like atopic dermatitis (eczema) and other conditions like no talger parasitica as examples where itching is significant, detailing the need for understanding these processes to better address patient problems.
• 39:00 - 45:00: The Brain-Body Connection in Itch This chapter discusses the brain-body connection in the context of itch. It explores various conditions associated with itching, ranging from inflammatory ones like prurigo nodularis to neuropathic and uremic pruritus, particularly in dialysis patients. Although not all conditions are covered, the chapter emphasizes the diversity of itch conditions, some of which will be revisited later. It also delves into the intriguing question of how the skin senses itch.
• 45:00 - 51:00: Exploring New Therapeutic Frontiers in Itch The chapter titled 'Exploring New Therapeutic Frontiers in Itch' delves into the speaker's initial focus on the autonomic nervous system due to their medical training. It underscores the role of the peripheral nervous system in regulating physiological functions such as heart rate, breathing rate, and gastrointestinal motility. Despite this focus, the chapter also hints at the importance of the somatosensory nervous system, suggesting a possible shift or expansion in understanding towards new therapeutic developments related to itch management.
• 51:00 - 57:00: Closing Remarks and Q&A The chapter discusses the evolution of the sensory nervous system, focusing particularly on its role in skin sensation. The discussion highlights that this is not typically emphasized in dermatology education. The explanation is provided in simple terms, from both dermatological and neuroscience perspectives, detailing how different nerve fibers, such as the 'a beta' and 'a delta' fibers, are responsible for transmitting various mechanical sensations.

Brian Kim Brain Body Lecture Transcription

• 00:00 - 00:30 why don't we get started um thank you all for coming to the brain body lecture series to keep in the spirit of such an amazing session uh we've got brian kim here to visit and to give his uh lecture to us today on the sensation and perception of itch so um i don't know why we have these these balloons here but i think it's somebody's birthday party today so
• 00:30 - 01:00 we're here to celebrate so um anyways we we recruited brian kim here about a year ago from wash u he's come in to um develop and lead an amazing program on sensation itch and immunology his work spans the gamut of neuroscience and immunology and dermatology so i think in the spirit of brain and body brian really encapsulates that really complex interface between neural circuits and peripheral systems and
• 01:00 - 01:30 immunology so he's been doing really groundbreaking research on understanding how sensory nerves can co-opt kind of classic neurotransmitter signaling pathways the things that we all neuro scientists study on a regular basis to control local neuroinflammatory processes it really is kind of an outside of the box innovative new way of thinking about how sensory nerves or neuroinflammation in general
• 01:30 - 02:00 can uh can operate so without further ado i'd love to bring up to the stage dr brian kim to present his work thanks again for coming yeah thank you uh thanks to scott russo um and uh it's great to see people in the flesh as well um and uh yeah congrats to scott on the formation of this center uh i am i was very excited to hear about the center because i think it's
• 02:00 - 02:30 very timely and i think a lot of the stuff that we do is inadvertently really kind of integrating into this and i'll try to speak to that a little bit throughout the talk and yeah we'll just get right into it i have a number of disclosures uh quite a number uh as itch has really become a big topic in in the last five years in particular so the first kind of fundamental question is for us has become how do we sense the world around us
• 02:30 - 03:00 and how does this inform itch and perhaps even other sensations and that's how i'll try to kind of end the talk but uh as an immunologist it's interesting because most of what i'm talking about really falls within the domain of neuroscience traditionally and as we know when we think of the five senses there are have been a number of nobel prizes awarded in these different domains and most recently uh the nobel prize
• 03:00 - 03:30 in physiology and medicine this fall to david julius and arden patapudian for the uh discovery of how we sense temperature via trip channels and uh touch via the piezo receptors and uh it's really it's really obvious immediately as to why the five senses are important for the most part but it's actually it's funny when we think of the five senses we don't even really immediately think of
• 03:30 - 04:00 pain and certainly not itch which probably falls within the domain of touch uh but what what happens when we actually have mutations in in receptors for pain it's actually one would he might think at first that this is actually a bit of a superpower but it really isn't we know that uh ashley blocker shown here who actually was born with a mutation and can't really sense pain very well would injure herself and in fact as a
• 04:00 - 04:30 toddler would bite her fingers and that is why she's actually bandaged in this picture so actually pain of course is very very important uh as a protective measured so that we know how to avoid certain kinds of traumatic or harmful stimuli but then it becomes even less clear though as to why we itch and this is something i'm probably asked the most when i give a talk is why we actually itch the short answer is we don't exactly know but we can actually speculate there's probably two at least minimal
• 04:30 - 05:00 reasons one is to actually sense certain kinds of noxious stimuli such as disease-borne insects in the environment in a way that's not so aversive like a bee sting so that's not immediately makes you want to avoid the environment but allows you to sense the environment feel that something's wrong and still remain within a perhaps a limited amount of time but the other that we appreciate more and more in modern day is that as we get older as organs fail as different parts of the body fail actually itch is actually a final common
• 05:00 - 05:30 pathway and it's why it's such a common symptom as a chronic pathology and actually itch is also in a way to tell ourselves that something might actually be wrong so in a way uh itch has an extra receptive component to to sense things from the outside world but also from inside the body that there's something wrong as well as there's a interceptive component to it as well so we think but these this is speculation but one thing's for sure is that itch is highly conserved and it's really thought
• 05:30 - 06:00 that all vertebrates itch so it this has this evolution has not done away with the sensation but notwithstanding the kind of homeostatic and uh reasons for why we need certain things like sensation but what i spend most of my time as a physician doing is understanding what happens when these things go really awry and um i actually believe or not spent most of my career studying things that were seemingly vestigial like innate lymphoid cells and basophils and um and the
• 06:00 - 06:30 one criticism sometimes is that you might be studying something vestigial but the issue is that even in modern days things that are seemingly residual can cause a tremendous amount of problem for patients if these things actually are turned on and can't turn off and uh here is just a small list of conditions in which itch is actually central morbidity these include atopic dermatitis or as or eczema which i'll speak to other conditions like no talger parasitica where you itch in the middle of the back it's why the back scratcher
• 06:30 - 07:00 was invented uh perigo nodularis uh they range from inflammatory to more neuropathic um there's also uremic parietas patients who are on dialysis will itch with high penetrance i'm not going to go over all the different conditions here but really just to list that there are many many itch conditions and some of them will come back later in the talk so when we think about itch how does the skin sense itch it's actually interesting because
• 07:00 - 07:30 i again i'm not a neuroscientist so i actually really was when we think about the peripheral nervous system i was originally much more acquainted with the autonomic nervous system and i think that that was because i was trained as a physician so the idea was that heart rate breathing rate gastrointestinal motility these are all things that in an efferent fashion regulate the uh the um different physiologies within tissues but ironically despite the fact that on the right the somatosensory nervous
• 07:30 - 08:00 system is essentially mostly evolved for the skin i didn't really think about this a lot and it's not something in the field of dermatology for example we we are taught or focused on but in very very overly simplistic terms uh almost embarrassingly simplistic and from a neuroscience standpoint uh you know we know that the somatic sensory nervous system has different kinds of nerve fibers that can sense things from mechanical sensation by way of a beta fibers to a delta fibers and as we get to the polymodal on myelinated
• 08:00 - 08:30 c-fibers we find that they are truly quite polymodal and can sense everything from uh pain itch and temperature and a whole host of different sensory modalities and it's really just a subset of these c fibers a small subset that actually mediate itch and um the question though is why has not itch been studied uh for very long um why is this such a new area in many ways itch is actually a very kind of trivialized sensation it's not
• 08:30 - 09:00 one that physicians in particular took very seriously but what's changed and why we are taking it much more seriously it really starts with the science and it's really the discovery of um it's fairly itch selective if not even in specific pathways such as the mass related g protein coupled receptors in the periphery a whole family of g protein coupled receptors that mediate itch and perhaps other processes as well and then also the discovery by markoon's group of brain natural peptide
• 09:00 - 09:30 as being a major neuropeptide from these peripheral neurons dumping into a spinal cord and being very itch specific does discovery of gastrointestinal peptide receptor as well as those neurons being very specific in the spinal cord circuit and then additionally people are now working on identifying foci within the brain that actually receive these edge signals for perception but it's really with the the scientific uh accomplishments that it then
• 09:30 - 10:00 made us believe that itch was actually tractable a misconception was that it was simply a mild form of pain so it wasn't going to be a specific distinct molecular target but all this was overturned with these discoveries and i think it really put um itch biology on the forefront and what i'm going to talk about later is how we've had a lot of actual therapeutic success in a very short amount of time so our laboratory has always been focused on understanding what actually what are the initial events that trigger
• 10:00 - 10:30 inflammation at a barrier surface and using skin as a model paradigm and that was really where my most of my post-doctoral work focused on but when i started my laboratory we became really interested understanding how does inflammation trigger something like itch and how can this represent in a a model in which inflammation and neurodysfunction or perhaps even a sensing inflammation uh can occur and this can be kind of a weighted way to understand this through
• 10:30 - 11:00 itch and to study this we used atopic dermatitis or eczema as a model disease it's one that i started treating um very early on in my career in a specialized manner it's very common it's you if you don't have it you know someone who has it and um very likely a family member in a severe forms can be incredibly debilitating it's an atopic disorder so actually clusters with other allergic disorders like food allergy asthma and all other emerging conditions as well
• 11:00 - 11:30 such as eosinophil esophagitis but when we first started studying this disease it was actually very limited in what we could do topical steroids are kind of the mainstay therapy it was not one that dermatologists necessarily enjoyed treating uh because it was difficult but that's changed quite a bit in the last few years but itch was always the central symptom and it is uh certainly the major morbidity so um when we first came to uh study this disease using more of a
• 11:30 - 12:00 immunological lens we knew a few things we knew that there are allergenic or environmental stimuli that can activate this arm of the immune system the th2 cell axis these are t cells that have antigen specific receptors but still what the antigen is remains very elusive but what we knew that was that in a modular fashion what we referred to back then is th2 cell associated cytokines il4 5 and 13 will actually trigger all coal cascade of inflammatory events including the
• 12:00 - 12:30 production of ige ige has reacted to a variety of different environmental allergens in all the atopic disorders and then also these cytokines can directly damage the barrier but uh we became interested in actually understanding how the barrier itself can directly engage with the immune system and this the clues came by way of the cytokines alarm in cytokines like il-33 and tslp which actually immediately can sense a barrier breach and then is released
• 12:30 - 13:00 from the barrier and we knew at that time that it was potently the cytokines were currently activating these pathways and this led to the kind of my early work which is understanding then that innate cells like group 2 and 8 lymphoid cells are ilc2s which are hardwired during embryonic development into different tissues we discovered them for the first time in the skin and as being major sources of vile 5 and 13 but also that rare circulating basophils which when i was in medical school i was
• 13:00 - 13:30 taught it was a vestigial cell as a vestigial kind of relative of the mast cell actually come into skinned um and are major sources of violence iv and this uh in recent years after uh i started my laboratory we came to appreciate that these canonical what we now refer to as type 2 cytokines because innate cells actually are major sources of them not just the adaptive th2 cell that these canonical type 2 cytokines can actually directly communicate with the sensory nervous
• 13:30 - 14:00 system they employ downstream jack signaling pathways that we typically think about in immunology more than neuroscience to actually uh mediate these kinds of processes and and now we know that the therapeutic blockade of these cytokines is very very important across in a pan allergic fashion but just to highlight some of the uh ways in which you can approach this was we uh this is actually my first graduate
• 14:00 - 14:30 student landon etchan we took very kind of low-tech approach we just simply extracted dorsal riganglia and in collaboration with steve davidson we're able to get cataract human donor uh drg and just look at by rt pcr for whether they express these different receptor components in fact they do il4 receptor alpha which is the uh receptor for oil 4 and 13 we can also detect l13 receptor alpha 1 and then the canonical kind of itch or
• 14:30 - 15:00 perigen receptor l31 receptor we could also just use as a positive control to identify uh within the sensory nervous system we can never detect il5 receptor in the drg though it's been reported within the actual no-dose ganglia that it is expressed indicating that maybe actually some functional heterogeneity across different uh tissues but uh we we just did kind of traditional calcium imaging to then test whether these cytokines are actually functional on these sensory neurons and we can then
• 15:00 - 15:30 uh detect response to recombinant il-4 and mouse drg as well as human drg and you can see here that uh this neuron is not only responsible to dial for but also capsaicin indicating that in fact this is a v1 positive neuron and we model this in mice and we use a very well now well established model of atopic dermatitis like disease in which mice are treated with a vitamin d analog it actually induces expression of these alarm and cytokines
• 15:30 - 16:00 and then it potentially activates the immunological events that are mirrored in human atopic dermatitis they develop rash histopathologic features and immunologic cellular features but if we just do aren't just bulk rna sequencing in the skin with the induction of this disease we see key type 2 cytokines the alarm cytokines chemokines and keratin alterations that have been already well reported in human atopic terminitis from particularly from translational groups like emma gutman here
• 16:00 - 16:30 at mount sinai but importantly for us these mice develop behavioral itch and they develop scratching behavior that's highly elevated and chronically so so whenever you look at these mice they are spontaneously scratching at any moment the great thing about studying uh itch and mice is that it's very objective because they are they have no idea that that's what you're actually uh doing in humans the problem is a lot of kind of cortical processing can affect it quite a bit but
• 16:30 - 17:00 in mice you can eliminate that element and so the the way we kind of interrogate this is we use uh sodium channel 1.8 cree mice and then we can flux out different receptors in the peripheral sensory neuronal compartment and in this case we were able to actually delete il4 receptor alpha just in the peripheral sensory neurons and we found that in fact that the scratching bots are
• 17:00 - 17:30 greatly reduced but also the disease severity and i'm actually going to come back to this point so it's been a number of years since we did this work um interestingly a question that was brought up by the reviewer was is this really due to a reduction in scratching or is this really a is this something independent of the scratching pathology and it was actually a really good point we didn't really want to get into that at that point but i'm going to come back to this in a second but we know that drugs monoclonal
• 17:30 - 18:00 antibodies that actually target this receptor are highly effective they actually have unprecedented efficacy for atopic dermatitis and actually they have really revealed how important itch is in these diseases and have had unprecedented effects on the attenuation of itch uh in the interest of time and showing this the way we think that actually the static particularly il 4 and 13 work is that they actually sensitize the nerve to a whole host of other parity and so it's not so much that these cytokines are all periodogens
• 18:00 - 18:30 and necessarily slam the nerve and cause a lot of itch but they actually uh what we think is they actually change the membrane uh depolarization in a way they depolarize the membrane in a way that make them much more sensitive to a whole host of stimuli so the simple way to think about what this drug might do is actually may actually anesthetize the nerve to a whole host of other different stimuli but in parallel to the work we're doing which we took we're taking a very kind of candidate based approach
• 18:30 - 19:00 that um uh other groups like uh patrick earnforce neuroscience groups were actually just taking doing single cell rna sequencing across different ganglia and i'll show this here in a bit how this kind of plays out but i'd like to think of them as somewhat dispassionate towards itch that they're very objective neuroscientists and and they were finding that some of the most readily identifiable neurons at the single cell level are actually these
• 19:00 - 19:30 itch specific neurons or per receptors and they would classify them as um and i won't get into this but non-peptidergic 1 np2 mp3 and i just color coded them for you and in fact what was great is that the single cell studies actually confirmed a lot of traditional functional studies uh suggesting already that there's modularity of these neurons with regard to how they respond to different periodogens so not just every nerve responds to the same thing but one of the things that landon observed early on was that the alpha receptor alpha was
• 19:30 - 20:00 selectively expressed on these edge neurons but also very broadly so across these different subsets and uh that actually provoked a hypoth a clinical hypothesis for us that taking to putting these this all together we thought maybe it's not just an atopic dermatitis story maybe that the fact that these type 2 cytokines are so conserved that maybe this is more of an itch phenomenon and we can actually broadly target
• 20:00 - 20:30 many different kinds of itch disorders and one condition we're interested in this condition called paragon nodularis this is actually very different from atopic dermatitis where you start with inflammation or a rash in the skin that leads to itch these patients actually i primarily achieve and then they secondarily damage their barrier to give themselves very distinct modules this is a patient of mine this is actually not very dramatic if you google it it's incredibly dramatic what they can do themselves the idea here is if you actually duct tape these patients they would never develop these nodules they'd
• 20:30 - 21:00 be very very distressed but they wouldn't develop these nodules so it's really this kind of scratching reflex that actually triggers a lot of pathology of course there's inflammation once they trigger this kind of pathology but the primary genesis of this is thought to be itch and so what we actually proposed to regeneron who actually had pioneered the development of diplomab early on was we said we think that this drug should be used towards patients with other itch conditions like paragon algolias at the time the company was not really aware of
• 21:00 - 21:30 what this was this is the itch landscape we're really at the leading edge of even defying these conditions um and what happened was actually i i designed an investigate-initiated trial i'm not much of a clinical trials but i felt that we should really push this went back and forth they agreed to fund it but what happened at that point was there were enough case reports coming out that dupilumab was effective for paragon nodularis that they decided to go straight to phase three and in fact the
• 21:30 - 22:00 phase three was just uh well it was a home run uh met all the key primary and secondary end points this is reported in the fall the prediction is this drug will be approved by the end of the year so this is fantastic because you have a condition that was ill-defined no fda approved conditions and were really if it weren't for the science we would not have been able to kind of embolden this kind of um exploration even in the clinical space so i think this is a good example that the science really the thread here is that the science is
• 22:00 - 22:30 what's really leading the way and at every step um but also we see patients what i see mostly now in my clinic on the upper east side is chronic parietals of unknown origin these are actually patients who are more elderly the same way that a lot of elderly individuals will start to develop a lot of neurodysfunction they start to itch they don't actually have much in the way of an atopic history they're incredibly debilitated by this because there's no adaptation a topic to monetize patients from childhood have itched so they actually have a lot of plasticity they can actually adapt to it these patients
• 22:30 - 23:00 are very very distressed um often suicidal and uh they look like this so they just scratch where they can reach and then where they can't they spare themselves and uh if and then anecdotally out of our clinic off label patients were treated to pilunav actually improved um we did a retrospective study uh to look at over a 30-month period just out of my clinic all the patients who had severe seven or greater over time and they all did quite well
• 23:00 - 23:30 um so as you can imagine um being a bit of an instigator we we were pushing really hard for regeneron to do this as well and so they've actually partnered with sanofi and for this drug and now they've actually opened up another clinical trial which started enrolling in march so i hope that in a year or so i'll report back a very similar kind of positive outcome but at the time independent of this aisle four story one of the things that
• 23:30 - 24:00 we did know is that dupilumab was not approved there's no blocker for this receptor but we there were jack inhibitors two jack inhibitors tophascitinib and roxylignit one for rheumatoid arthritis and rexella for myeloproliferative disorders and if you look at the single cell rna sequencing dataset you find that actually these itch nerves actually do highly express jack downstream jack one and we know that many of these cytokine receptors are in fact dependent on jack one downstream but you zoomed to just in the last year
• 24:00 - 24:30 and other groups like steve davidson here and ted price have actually identified that there are itch specific neurons also within human drg as well that are readily identified and one of the things that we can't quite figure out is why they keep coming up so cleanly in these single-celled sets it's kind of interesting they're actually uh you know the thing we're a little perplexed by is the why they're so well represented um and i have some theories about that so but
• 24:30 - 25:00 one of the things you see jack one here uh comes up very uh readily so it so we think that there's a lot that's translating from the mouse to human i think we're very lucky and a lot of this is due to the fact that type two immunity is a very ancient uh arm of the immune system and itch is a very primitive kind of reflex but we took a similar approach here and we deleted jack one in the peripheral neurons and here's where it differs we see no effect on the inflammation we see exquisite effect on the itch but
• 25:00 - 25:30 no effect on the inflammation in contrast to when we deleted at first after alpha so that reviewer was right um had they really pressed it we would have been in a lot of it would have caused a lot of angst back then but but you know we we kind of come back to this concept and um and and i'll i'll address what i think is going on and what we actually know is that many many cytokines uh go through jack one and the idea was really kind of medieval we thought okay uh we've identi
• 25:30 - 26:00 it took us several years to publish a paper on one or two cytokines being involved in itch in a very specific way if we add up every cytokine this is going to take forever we want to just try to cure itch or treat it right so we wanted to go downstream to just really choke it off and one of the predictions we made we like to make a lot of predictions uh based on the mouse modeling is that we thought that because of the breath there would be broad activity rapid because you're choking off more and potency with this
• 26:00 - 26:30 and then you zoom to the last year and the phase three clinical trials have gone actually head to head so the jack one selective inhibitor patterns that went head to head with depilomab it actually this downslope here shows that in fact much more rapid reduction in itch um and then abrasive nib is another jack one selective inhibitor now with the up stroke here you see that high dose of abrasion that does outpace uh duplicate shown here in green it does catch up though later on um so
• 26:30 - 27:00 there's probably other things going on as well but we actually early on shared a lot of our mouse data with the um jack effects on the nerve with uh insight corporation and actually was we're trying to get actually oral rock solid for our patients with this chronic paritis and in these conversations what actually ended up happening was a bit of a bait and switch uh we ended up designing a phase two dose-ranging study with
• 27:00 - 27:30 topical rh nib for atopic dermatitis but the nice thing was we could actually design the trial in a way that we were reading out itch in a very high resolution manner because we knew what we were trying to look for here and not just as an anti-inflammatory agent and this drug is now approved as of last fall and it was actually the first jack inhibitor approved in the field of dermatology so this was a another kind of big win that kind of fell out of this the science but we were able to get tofu synthetic for these patients with
• 27:30 - 28:00 cpuo and again just scratch marks where they're itching the scratch marks go away very anecdotal cohorts of severe patients before and after this is by no means anywhere near a clinical trial uh but of course as you would imagine uh companies are now jack and companies are now approaching us about whether they should go forward with this um in light of the fact that um regeneron keeps kind of moving ahead very quickly but i think what we're appreciating is that
• 28:00 - 28:30 that there's if you think about itch we think of in a very simplistic terms that the cytokines hit the the receptors and they can trigger it or amplify itch and it's just this kind of uh unidirectional kind of afferent mechanism but what we also know is that these itch nerves actually are very much uh peptidergic so they actually have the capacity to release neuropeptides into the tissue like cgrp but other neuropeptides as well and depending on the receptor and depending on the way in which this nerve
• 28:30 - 29:00 is hit we think is that there are ways in which neuropeptides are released to either activate or even for that matter regulate negatively regulate inflammation and so we're really understanding at the receptor level what's going on actually is very important and that's why we think actually the jack one deletion is there's a discrepancy with dial four receptor alpha and we are understanding this um we have data to support this concept now uh and it's a very
• 29:00 - 29:30 interesting uh area and the other thing to consider here is that there are many many different sensory uh apathy's right there's pain there's itch there's irritation across the tissue across the body and whether this kind of we always think of this irritation as a subjective phenomenon where we're often clinically a bit dismissive of we want things that are really objective histology biopsy radiology but the question we have to ask is
• 29:30 - 30:00 you know whether it's rheumatology or these other fields whether a chronic um kind of pathologic sensory state itself in and of itself could not be pro-inflammatory uh and this is something i think we have to really consider and actually uh along the lines of the center does this work its way all the way up to the brain right so so you know can some focus in their brain
• 30:00 - 30:30 thread all the way back to the skin and and you know promote other kinds of fibromyalgia disorders so so i think you know this is a concept i think that's kind of on the frontier but you know what we're saying is that cytokine blockade jack inhibition we know that this is anti-inflammatory but what we're really proposing very strongly now is that th these are just as much neuromodulators and they can actually be tailored to be even more neuromodulatory if that's how we think of these agents and and this is certainly the way the companies are thinking of it in fact they're even
• 30:30 - 31:00 marketing increasingly the drugs in this fashion as well again they weren't conceived that way at all um in the interest of time not showing this work but i just wanted to highlight you know what i've talked about so far is in the setting of chronic inflammation how local cytokine processes will drive through jack or other pathways uh chronic itch at this neuroimmune interface but what we've also identified in diseases like atopic dermatitis is that the systemic inflammation will actually trigger systemic activation of basophils
• 31:00 - 31:30 and this will actually result in the basophils being activated and primed in a way that they respond to ige and override the the response of mast cells in the tissue and actually activate a totally alternative leukotriene c4 circuit so this has nothing to do with kind of classical histamine as the etch mediator and it starts to explain heterogeneity of even ige responses so kind of classic allergic pathways and this this seems to be a very very potent kind of peritogenic pathway and
• 31:30 - 32:00 i'm not the only one saying this this was discovered by mark hoon who showed using chemogenic activation of mast cells that this pathway is very important and recently isaac chewet as well from harvard medical school so we don't generally believe our data until other people reproduce it and and so i'm starting to get very bullish on this pathway now um in light of the uh the the work of others but also one of the things that i want to highlight i mentioned the
• 32:00 - 32:30 mrgprs that actually uh led to discovery of kind of and the conceptual advance that there are it specific receptors in the peripheral sensory nervous system but some of them do land on the immune system as well and what's interesting what i think is quite beautiful actually is that mrgprb2 in mice is very specific for mast cells and muscles have always been associated with neurons and actually my buddy brad undum one of my favorite neuroscientists says he he considers mast cells uh a neuron
• 32:30 - 33:00 i kind of agree with him and what's interesting is that mrgbrb2 is on a host different mast cells throughout the body and it's very selective mrgprx2 is the ortholog in humans so there are actually less mrgprs in humans which also indicates we think that there's much more polymodality of these receptors what's interesting about mr gprb2 is that it explains a lot of reactivity that we misattributed to ige to a whole host of
• 33:00 - 33:30 different kinds of allergens turns out many different endogenous exogenous peptides as well as drugs and synthetic drugs can activate this pathway on mast cells and it can cause non-histaminergic itch also kind of pseudo-anaphylactic reactions so it's actually explaining a whole new paradigm of allergy but there's also another receptor mrgpr a6 in mice that's only on basophils and this is something that we're exploring in as well and
• 33:30 - 34:00 what's interesting is if you take mrgpr a6 reporter mice this is in collaboration with shinzondong if we gate on the mrg very six cells actually they're entirely all basophils they're they're not mast cells or eosinophils um so they're c kit negative they're c f negative but also as i mentioned the kind of uh contracted repertoire of mr gprs in humans what we think is actually mr gbrx2 if we actually get on human blood
• 34:00 - 34:30 uh there's actually uh these are also fc epsilon receptor cd123 positive basophils largely so what we think is that mrgpr b2 and a6 being divergent and specific for mast cells and basophils and mice are actually shared as mrgprx2 in humans and represent the receptor at least in part on basophils in circulation and mast cells and tissues and this is a interesting concept we we we're struggling to get r1 funded on this people have very strong opinions
• 34:30 - 35:00 about this so it just gets clobbered but eventually i'm sure um we'll get it through but um but anyway that's something we're exploring but um one of the things that i want to highlight is that the cis ltr2 doesn't pan out also within um in human drg and if you go back to steve davidson's data sets you can see these are the itch neurons il31 ra positive uh the co-receptor osmr um but yeah you find cis cltr2 is very
• 35:00 - 35:30 much in fact enriched on on these neurons as well as the um brain natural peptide that marcoon discovered so with this is just again just trying to cross validate we really love to mine other people's data sets but i want to just pivot in the last part is to uh moving beyond kind of classical um periodogens and talking about some of the opioid signaling pathways as well and one of the things that we at least appreciate within the skin and it's been well established by people like sarah ross and others was that
• 35:30 - 36:00 that there's a balance between the mu opioid and the kappa opioid pathway so these are very distinct pathways and the immune opioid pathway we do know even clinically often triggers itch so if people get morphine whether in the periphery or even the spinal cord it can actually trigger itch uh very intensely and we can talk about why that is in part it's because that the the actual probably the c fibers do respond to this uh to the new opioids but the capital opioid is actually counter balancing so
• 36:00 - 36:30 actually agonizing the capital good receptor pathway actually tends to counterbalance the mu opioid pathway and has been considered very much a um an itch target for a long time and it's really to kind of balance this out within the skin but what's interesting is that and there are actually drugs that aren't necessarily the most optimal like naltrexone that block the mu opioid and it's been used as a not a great strategy but a bit of a desperate strategy to treat itch um and then there are
• 36:30 - 37:00 um uh other drugs that have been around for a while like the torphenol which activate uh the kappa opioid but also antagonize the mu opioid i actually use this in the clinic it works here and there um there's a new drug called now buffing uh which i'll come back to in a bit which is similar but much better with much better kind of pharmacokinetics and then there's diphthalicephalon now furophene i think is approved actually in japan for uremic in patients on dialysis
• 37:00 - 37:30 so there are agents here and i'm going to speak to this a little bit but if you actually go back to the single cell and sequencing data sets what's interesting is is that if you look at the kappa opioid receptor we actually don't find although it's been reported we don't actually find it we can't detect it within the c fibers there may tend to be mainly on the mechanoreceptors whereas in contrast the mu opioid receptor is more on these c fibers so they're kind of inverted um this could be a bit controversial
• 37:30 - 38:00 controversial because as i mentioned others have reported that it's on these c fibers and it might actually be acting directly on them but again this is not our data but um this kind of suggested to us there might be a slightly different mechanism action and and this is something we're exploring but notwithstanding that the diphthaliceflyn the pure capital opioid receptor agonist has actually been improved in the last year for monetary severe paritis in patients on dialysis and um but we also were working with
• 38:00 - 38:30 cara therapeutics and exploring this in atopic dermatitis what we really think what we really thought was this was primarily just a neuromodulator but this was something that we're trying to kind of settle and if we if these mice actually develop 80 like disease what we find is that if we treat them with high dose diphthong kepler no effect on the inflammation if we do flow cytometry we see no effect as well but one of the things we noticed is that dfk was incredibly potent we actually see a difference at baseline even in
• 38:30 - 39:00 terms of scratching it was shockingly potent to me i was really surprised to be honest um and so then this is work from masada tamari in the lab and so we just looked within 30 minutes we see actually a reduction in the itch so we think okay there's no way this is anti-inflammatory um you know this is just way too way too fast um and and we and again we saw no effect on the inflammation and they they're in parallel while we were doing this um cara was running a phase two dose ranging study uh in
• 39:00 - 39:30 atopic dermatitis and one of the things i said to them is i don't think a neuromodulator in atopic dermatitis is a great idea because you have inflammation hitting the nerve lots of paretogens seems like an uphill battle you know the reason why the other drugs i mentioned are working so well is they are still an anti-inflammatory sure they're neuromodulatory but they're still taking care of the the root cause with a pure neuromodulatory drug and an inflammatory disorder this is probably not the greatest idea so what they baked into the trial was another primary endpoint is to look at patients with
• 39:30 - 40:00 milder inflammation so less than 10 percent body surface area well it turned out that was the only end point in which it actually worked so it you actually have to get to the milder disease to see an effect of the drug so again we were used this is all informed by our mousework so um so i get very upset when people say mouse study models don't matter because we've been doing this a long time now and helping companies do the right thing because these trials are incredibly expensive
• 40:00 - 40:30 and um but in parallel they also were very responsive to me i said you guys should do a purely neuropathic edge condition like notalja peristetica which is not inflammatory you itch on the back it's why the back scratches have invented there's probably people in this room that have it they didn't know it until i mentioned it uh and some people it's very severe they can't concentrate they have trouble focusing and actually the phase two trial for this was actually very successful and um just did they just came up with the results three weeks ago so this will invariably go to phase
• 40:30 - 41:00 three hopefully the first fda approved drug for uh notality parasitica so and we think at least putting it all together we think there are itch stimuli that might go through jack or not and you know we can activate there are things that activate it but with diphthalic keflan it you know mimics endogenous opioids that activate the capital opioid pathway and we think probably through mechanoreceptors actually sort of gates out itch so in a way it's a way to kind of we scratch to suppress itch and it's
• 41:00 - 41:30 through the mechanoreceptors so we think that this is a form of kind of pharmacological scratching uh and and hopefully results in less pathology within the skin but it's interesting even before all these recent results came out i i wrote this perspective for neuron because there were so many people asking me these questions why is itch suddenly big why does it matter and why are why is pharma suddenly so big on it so i wanted to kind of address it in a very succinct manner and and even and one of the reviewers actually commented i'm not so sure it's
• 41:30 - 42:00 translational uh or revolutionary i'm sorry but i said you know i i kind of pushed back i said it is pretty revolutionary in the sense that the hit rate has been so high with these trials and with such little investment from a funding standpoint because this isn't like the most highly funded area of nih at all so the return on investment has actually quite been quite tremendous um and so it's a very very exciting area but it extends beyond that if you actually look within the vagal ganglia um again you see these itch neurons pop
• 42:00 - 42:30 up as as kind of top hits even within the vagal ganglia and we know that what roughly what 80 percent of the vagus nerve is actually sensory again something that i never really thought and so the and then if we look if masada looks just using trip v1 reporter mice we find that you can't actually distinguish the vagal ganglia from the drg so they basically look kind of the same so they seem to have a very kind of similar sensory machinery but along these lines the now buffing uh
• 42:30 - 43:00 the the kappa opioid agonist uh uh and mixed uh mule beard antagonist from another company actually had very good phase two data on chronic cough and what we think is that cough is probably very similar to itch and a lot of the kind of uh cellular molecular machinery similar so we're starting to think of are these are other sensations within the body much more akin to itch than than we think and so we know that we're studying somatic afferents in the skin but then there are these vagal
• 43:00 - 43:30 efferents they're these spinal visceral afferents which we know very little what they do at all and they probably innervate so when we're looking to drg we often are assuming we're reading this out but we're forgetting about this part so how does this all come together this is this is i think it's a very rich area of exploration it's quite a frontier i don't think people know much about this at all uh if you go into the trigeminal ganglia we find itchner's in the trigeminal genga which is not a surprise but what's interesting is this in this study they looked in the context of migraine
• 43:30 - 44:00 headaches and as you go from mouse to human they can become much more peptidergic so so the human nerves again more polymodal uh i have a c dr are very enriched for cgrp again how are migraine headaches really kind of pro-inflammatory are they you know how much is sensory and how much is pro-inflammatory so um so i think this is a very interesting area and we like to think of itch as maybe itch is a big problem we estimate anywhere from a 50 to 100 billion dollar problem on uh for pharmaceutical
• 44:00 - 44:30 industries but there are many many disorders that have sensory uh pathology that we are actually kind of ignored in the clinic but well i think what we can say is that itch is actually uh revealing how these are actually quite worthy um conditions that we can actually potentially go out after so you know we started with asking what causes chronic itch you know we then delved into kind of fundamental neuroimmunology uh i think we've been able to inform and
• 44:30 - 45:00 accelerate the therapeutic development and uh and even design clinical trials towards fda approval but we've also been able to reverse translate to get at more kind of more other kind of fundamental biology and um you know i just want to comment you know here's the body and here's the brain and there's a lot in between but i think the the key is understanding where are the frontiers and i think there's been so much great work done within these specific domains i mean there's no question to me neuroscience has been
• 45:00 - 45:30 incredibly fruitful but i think we want to understand you know we were just focused from here to here you know and it's just been a very very rich uh kind of um frontier for us and you know can we connect this all together and that's kind of how i think uh you know we can work all together through centers like like this uh brain body center and um you know i just want to end by just thanking all the people who did the work i highlighted the individuals who led the work that i showed here today our collaborators our
• 45:30 - 46:00 funding agencies and happy to answer any questions thank you okay great so we'll take questions from the room first and people online if they have
• 46:00 - 46:30 questions um just put them in your chat i will take a quick look and feel them as we go so we'll start with questions in the room and then pivot to online sure hi brian uh amazing talk my uh question is related to mental health and itching because you know i because it's bi-directional right the conditions like ptsd there's a lot of itch sensation at
• 46:30 - 47:00 least from what i know but then you you also mentioned that um with some of these drugs um the distress aspect of it is reduced so in your clinic or animal models like um do you see this connection and what level is it in regards to certain mental health conditions like absolutely yeah unequivocally in patients unequivocally so um i've actually thought that a lot of patients had presented to me i had no doubt that they were itchy but i thought they had deeply rooted kind of mood disorders because
• 47:00 - 47:30 they were so profound when we were able to actually get their itch better they actually completely recovered and and and so i have stories i can tell you lots of stories i i had patients come in with lymphoma uh you know uh that was undiagnosed for a year and a half that were put on um antipsychotics um so so it's very yeah so they have a huge effect clinically and that's something scott scott and i actually talked about this um you know the brain is pretty scary to me so uh so i say you
• 47:30 - 48:00 know i can't do a lot of these behavioral assays to look at more mood defects or even cognitive defects right and and you have to wonder how much of these peripheral stimuli actually can rewire even in the brain people talk about even in central sensitization no one's proven that in the itch field yet i know it's big in pain but you know no one's proven that it's just the concept we assume away from the pain field so yeah there's a lot that we're interested in um and you know furthermore how does this
• 48:00 - 48:30 then go the other way right um so there's a lot of complex uh interplay um but yeah i i'm very interested in that especially you know with optogenetics and you know uh stereotactic targeting of these areas um thanks brian so
• 48:30 - 49:00 in your talk i think you nicely sort of alluded to this idea of itch being a cause or a symptom of something so so i understand for example that you know if you have an inflammatory condition skin condition that itches and you have that need to scratch right but so how do you think about sort of the advantages of having an itch where it doesn't really potentially lead to pustules or sort of a dermatologic problem like you're playing the piano
• 49:00 - 49:30 and all of a sudden your nose itches and you and you just are fighting you cannot stop playing the piano to scratch your nose and it's and it takes all sort of will to not uh to scratch your nose because then you'll stop playing so sort of how how how do you sort of think about these kinds of issues because i think during your talk i probably scratched myself 15 times just listening to you speak but i'm not going to get a dermatological condition about this so what are sort of
• 49:30 - 50:00 the advantages of this is it a grooming thing is it some residual just overall how do you think about this yeah it's it i mean it's clearly protective against parasites mites and you see if you have a dog you'll see that dogs actually scratch quite a bit um and they actually some of the biggest blockbuster drugs for itch are in canines so um two of them il-31 antagonists and a jack inhibitor so um so yeah it is protected and there is actually a a contagious component that's
• 50:00 - 50:30 protected so socially if i am scratching it's presumed by you instinctively that i actually might have scabies or body last or something and you start scratching so that you don't get infested i think you know so i think there's there is a contagious element to it um that that is socially protective the other interesting thing though is it's very socially aversive and scott and i were talking about this like the the mice don't like to be around other itchy mice like
• 50:30 - 51:00 um you know humans you know uh if someone's scratching in the subway people don't tend to sit next to them so there's an incredible amount of actually social stigma but it's very hardwired into us so i think it is productive but it's protected i guess things that we you know we already kind of know we don't want to be around um so yeah but the other thing about your piano analogy is that there's a lot of suppression so whereas a concentration cortical suppression there's lots of ways that itch actually can be suppressed
• 51:00 - 51:30 throughout the day that's what's very hard to study in patients so interesting we actually done studies with mit where we actually use touchless technology to match count scratching in humans but we also have video cameras patients are consented they actually you know it truly is a reflex they scratch in their sleep they don't know it um in and there's there's some discrepancy in terms of what they think they're doing and what they're really doing so yeah there's a lot of it really kind of gets at all so kind of
• 51:30 - 52:00 fundamental questions of what does it mean to be conscious and unconscious with regard to what is a reflex but doesn't have to be a reflex can be initiated by a thought or someone talking about it so it has a lot there's a lot to be still studied i think in it i i think it's a pretty fundamental it brings out some good fundamental questions so this is i'm already thinking about a million things that we can do together this is a great discussion i'm going to pivot to some of the online questions the first one is from two who
• 52:00 - 52:30 um who asks whether there are biomarkers black perhaps molecular biomarkers that could be used to characterize itch that's the holy grail not every pharmaceutical company wants to know you know yeah it'd be great it's hard it's hard though um yeah so you're talking to peop a psychiatric researcher so yeah i have none exactly uh the second question is from olivier masso um where does the lymphatic system fit
• 52:30 - 53:00 in this paradigm of itch yeah i don't know there's lots of things that people ask about we don't know what the lymphatic system uh we don't know a lot about the vasoregulation in general too uh you know the blood supply and how that plays into it uh and and we also don't know how much the autonomic nervous system does in this and we know that there's a lot of autonomic triggers probably but we still don't even know how they say you know i only talked about somatosensory and then what we also i'm
• 53:00 - 53:30 just gonna say about stuff we don't know microbiome we don't know either so there's a lot of hot topics in itch that have not been explored so yeah um okay i'm gonna get one more in here actually we've got two more three more um next one is from supinda who wants to know how do you currently balance anti-inflammatory and anti-neuropeptide meds for a.d treatment in children yeah it's in it it should at this point be really mostly the
• 53:30 - 54:00 anti-inflammatory agents that in my opinion which they all do have some neural activity so in children dupilumab is approved now for uh down to six months so i think that's a game changer um in terms of atopic march there's some suggestions from pre-clinical studies that you might even prevent the onset of asthma and other subsequent allergic disorders so for kids that's going to be the strategy so far neurologic strategies um
• 54:00 - 54:30 we have yet to be uh determined and as i mentioned i showed the kappa opioid diphthalic kaplan is kind of the first one um we have two more questions if that's okay with you um hi brian thank you for a great talk can you elaborate on side effects of systematically targeting jk in patients jack inhibitors yeah the issue with jack in there systemically we know this is that there's there's a significant but small but very
• 54:30 - 55:00 significant increase across the board a lot of things cardiovascular events blood clots cancer infection so they are immune suppressive that's the issue with them um the other question is for us could you just target the nervous system uh there are potentially ways you could do that but you know they weren't conceived to do that they were really tailored for autoimmunity so the people were trying to get the anti-inflammatory immune suppressive
• 55:00 - 55:30 properties from them but yeah so that's an issue with the systemic jack universe and they all have a fda black box label because of that thank you um last question then um this is from crystal for the dupilum i can't say the name of that trial have they looked into if itching resume or increase back to normal baseline after stopping using drug yeah in general i have a lot of experience in atopic dermatitis it it comes right back
• 55:30 - 56:00 so there's no remittive property yet to be determined for these really more neuropathic conditions because the question the kind of question is these people weren't itchy and then they became a chain it's quite persistently actually months years so is there any way you can turn it back all right is there any way that you can rewire them unclear as yet all right um i guess if there's no more
• 56:00 - 56:30 questions then we'll wrap it up grace thank you thank you thanks everyone