# Michelle Monje: The Brain in Long Covid and Cancer

An episode of [Ground Truths](https://invisiblenetwork.ai/podcast/1728526108), 25 Feb 2024, 44 min.

Audio: https://api.substack.com/feed/podcast/141977828/21f0ceed9f5785f0f4e93444fead50f4.mp3

Transcript with audio and relevant external links, recorded on 6 Feb 2024 Eric Topol (00:05): Hello, this is Eric Topol with Ground Truths, and I have a remarkable guest with me today, Professor Michelle Monje, who is from Stanford, a physician-scientist there and is really a leader in neuro-oncology, the big field of cancer neuroscience, neuroinflammation, and she has just been rocking it recently with major papers on these fields, no less her work that's been on a particular cancer, brain cancer in kids that we'll talk about. I just want to give you a bit of background about Michelle. She is a National Academy of Medicine member, no less actually a National Academy of Medicine awardee with the French Academy for the Richard Lounsbery Award, which is incredibly prestigious. She received a Genius grant from the MacArthur Foundation and is a Howard Hughes Medical Institute (HHMI) scholar, so she is just an amazing person who I'm meeting for the first time. Michelle, welcome. Michelle Monje (01:16): Thank you. So nice to join you. Long Covid and the Brain Eric Topol (01:18): Well, I just am blown away by the work that you and your colleagues have been doing and it transcends many different areas that are of utmost importance. Maybe we can start with Long Covid because that's obviously such a big area. Not only have you done work on that, but you published an amazing review with Akiko Iwasaki, a friend of mine, that really went through all the features of Long Covid. Can you summarize your thoughts about that? Michelle Monje (01:49): Yeah, and specifically we focused on the neurobiology of Long Covid focusing on the really common syndrome of cognitive impairment so-called brain fog after Covid even after relatively mild Covid. There has been this, I think really important and exciting, really explosion of work in the last few years internationally trying to understand this in ways that I am hopeful will be beneficial to many other diseases of cognition that occur in the context of other kinds of infections and other kinds of immune challenges. But what is emerging from our work and from others is that inflammation, even if it doesn't directly initially involve the nervous system, can very profoundly affect the nervous system and the mechanisms by which that can happen are diverse. One common mechanism appears to be immune challenge induced reactivity of an innate immune cell in the nervous system called microglia. These microglia, they populate the nervous system very early in embryonic development. (02:58): And their job is to protect the nervous system from infection, but also to respond to other kinds of toxic and infectious and immune challenges. They also play in healthy conditions, really important roles in neurodevelopment and in neuroplasticity and so they're multifaceted cells and this is some population of those cells, particularly in the white matter in the axon tracks that are exquisitely sensitive it seems to various kinds of immune challenges. So even if there's not a direct nervous system insult, they can react and when they react, they stop doing their normal helpful jobs and can dysregulate really important interactions between other kinds of cells in the brain like neurons and support cells for those neurons like oligodendrocytes and astrocytes. One common emerging principle is that microglial reactivity triggered by even relatively mild Covid occurring in the respiratory system, not directly infecting the brain or other kinds of immune challenges can trigger this reactivity of microglia and consequently dysregulate the normal interactions between cells and the brain. (04:13): So important for well-tuned and optimal nervous system function. The end product of that is dysfunction and cognition and kind of a brain fog impairment, attention, memory, ability to multitask, impaired speed of information processing, but there are other ways that Covid can influence the nervous system. Of course there can…

## Transcript

[0:05] SPEAKER_02: Hello, this is Eric Topol with Ground Truths and I have a remarkable guest with me today, Professor Michelle Monje who is from Stanford, a physician scientist there and is really a leader in neuro-oncology, the big field of cancer neuroscience and neuro-inflammation and she has just been rocking it recently with major papers in these fields, no less her work that's been on
[0:35] SPEAKER_02: a particular cancer brain cancer in kids that we'll talk about but I just want to give you a bit of background about Michelle she is a National Academy of Medicine member no less actually a National Academy of Medicine awardee with the French Academy for the Richard Landsberg Award which is incredibly prestigious she received a genius grant from the MacArthur
[1:03] SPEAKER_02: and is on the Howard Hughes Medical Institute support HHMI scholar.
[1:09] SPEAKER_02: So she is just an amazing person who I'm meeting for the first time.
[1:14] SPEAKER_02: Michelle, welcome.
[1:16] SPEAKER_00: Thank you.
[1:16] SPEAKER_00: So nice to join you.
[1:18] SPEAKER_02: Well, I just am blown away by the work that you and your colleagues have been doing, and it transcends many different areas that are of utmost importance.
[1:29] SPEAKER_02: Maybe we can start with Long Covid because that's obviously such a big area.
[1:35] SPEAKER_02: Not only have you done work on that, but you published an amazing review with Akiko Iwasaki, a friend of mine, that really went through all the features of Long Covid.
[1:46] SPEAKER_02: Can you summarize your thoughts about that?
[1:49] SPEAKER_00: yeah and and you know specifically we focused on the neurobiology of long covid you know focusing on the really common syndrome of cognitive impairment so-called brain fog after covid even after relatively mild covid and there has been this i think really
[2:06] SPEAKER_00: Important and exciting explosion of work in the last few years, internationally trying to understand this in ways that I'm hopeful will be beneficial to many other diseases of cognition that occur in the context of other kinds of infections and other kinds of immune challenges.
[2:27] SPEAKER_00: But what is emerging from our work and from others is that inflammation, even if it doesn't directly initially involve the nervous system,
[2:36] SPEAKER_00: can very profoundly affect the nervous system and the mechanisms by which that can happen are diverse but one common mechanism appears to be
[2:46] SPEAKER_00: Immune Challenge Induced Reactivity of an innate immune cell in the nervous system called microglia.
[2:52] SPEAKER_00: And these microglia are, you know, they populate the nervous system very early in embryonic development and their job is to protect the nervous system from infection but also to respond to other kinds of toxic and infectious and immune challenges.
[3:08] SPEAKER_00: They also play in healthy conditions really important roles in neurodevelopment and in neuroplasticity.
[3:14] SPEAKER_00: and so you know they're they're they're sort of multifaceted cells and there's a this is some population of those cells particularly in the white matter in the axon tracks that are exquisitely sensitive it seems to various kinds of immune challenges so even if there's not a direct nervous system
[3:33] SPEAKER_00: The Brain in Long Covid and Cancer Neuroscience
[3:55] SPEAKER_00: Microglial reactivity triggered by even relatively mild Covid occurring in the respiratory system, not directly infecting the brain or other kinds of immune challenges can trigger this reactivity of microglia and consequently dysregulate the normal interactions between cells in the brain.
[4:13] SPEAKER_00: So important for well-tuned and, you know,
[4:17] SPEAKER_00: Optimal Nervous System Function.
[4:19] SPEAKER_00: And the end product of that is dysfunction in cognition and kind of a brain fog, impairment in attention, memory, ability to multitask, impaired speed of information processing.
[4:32] SPEAKER_00: But there are other ways that COVID can influence the nervous system.
[4:35] SPEAKER_00: Of course, there can be direct infection.
[4:37] SPEAKER_00: We don't think that that happens in every case.
[4:39] SPEAKER_00: It may not happen even commonly, but it certainly can happen.
[4:44] SPEAKER_00: There is a clear dysregulation of the neurovasculature.
[4:48] SPEAKER_00: The immune response and the reaction to the spike protein of Covid in particular can have very important effects on the vessels in the nervous system and that can trigger a cascade of effects that can cause nervous system dysregulation and may feed directly into that reactivity.
[5:03] SPEAKER_00: of the Microglia.
[5:05] SPEAKER_00: There also can be reactivation of other infections, previous for example herpes virus infections, EBV for example, can be reactivated and trigger a new immune challenge in the context of the immune dysregulation that Covid can induce.
[5:21] SPEAKER_00: There also can be autoimmunity.
[5:25] SPEAKER_00: We're learning all the different ways Covid can affect the nervous system, but autoimmunity, there can be mimicry of some of the antigens that Covid presents and unfortunate autoimmunity against nervous system targets.
[5:41] SPEAKER_00: And then finally, in severe Covid, where there is cardiopulmonary compromise, where there is hypoxia and multi-organ
[5:56] SPEAKER_00: So many different ways and probably that is not a comprehensive list.
[6:00] SPEAKER_00: It is certainly not a mutually exclusive list.
[6:03] SPEAKER_00: Many of these interactions can happen at the same time in the same individual and in different combinations.
[6:10] SPEAKER_00: You know, we're beginning to wrap our arms around all the different ways that that Covid can influence the nervous system and cause this fairly consistent syndrome of impaired attention, memory, multitasking and executive function.
[6:23] SPEAKER_02: Yeah, well, there's a lot there that you just summarized, and particularly you highlighted the type of glia, the microglia that appear to be potentially central, at least a part of the story.
[6:35] SPEAKER_00: you also made analogy to what you've seen with chemo therapy chemo brain maybe you could elaborate on that yeah absolutely so you know I've been studying the the cognitive impairment that can happen after cancer therapies including chemotherapy but also radiation and immunotherapy and each time we you know develop a new model and dig in to understand what's what's going on and how these cancer therapies influence the nervous system microglia emerge as
[7:03] SPEAKER_00: you know sort of the unifying principle microglial reactivity and the consequences of that reactivity on other cell types within the nervous system and so understanding that microglia and and their reactive state to toxic or immune challenges was central to chemotherapy induced cognitive impairment at least in in preclinical you know models in the laboratory and confirmed by human tissue studies I worried at the very beginning of the pandemic that we might begin to see something
[7:31] SPEAKER_00: that looks a lot like chemotherapy-induced cognitive impairment, the syndrome that is characterized by impaired attention, memory, executive function, speed of information processing, and multitasking.
[7:42] SPEAKER_00: And when just a few months into the pandemic, people began to flood neurologists' office
[7:49] SPEAKER_00: Complaining of exactly this syndrome, I felt that we needed to study it.
[7:53] SPEAKER_00: And so that was the beginning of what has become a really wonderful collaboration with Akiko Iwasaki.
[7:59] SPEAKER_00: I reached out to her, kind of cold called her in the midst of the deep Covid shutdown in 2020 and said, hey, I have this idea.
[8:07] SPEAKER_00: Would you would you like to work with me?
[8:08] SPEAKER_00: And she's, as you know, just a thought leader in Covid biology.
[8:13] SPEAKER_00: And she's been an incredibly wonderful and valuable collaborator along the way.
[8:18] SPEAKER_02: Well, the two of you pairing up is kind of, wow, you know, that's a powerful combination, no question.
[8:26] SPEAKER_02: Now, I guess the other thing I wanted to get at is there have been many other studies that have been looking at Long Covid, how it affects the brain.
[8:35] SPEAKER_02: The one that's frequently cited, of course, is the UK Biobank, where they had CT or MRI scans before in people, fortunately, and then once they had
[8:47] SPEAKER_02: The Brain in Long Covid and Cancer Neuroscience
[9:16] SPEAKER_02: Potential Effects of Covid on the Brain.
[9:20] SPEAKER_00: Yeah, absolutely.
[9:21] SPEAKER_00: And I will say that I think, you know, all of the studies are actually quite parsimonious.
[9:27] SPEAKER_00: They all really kind of point towards the same biology, examining it at different levels.
[9:31] SPEAKER_00: And so that UK Biobank study was so powerful because, you know, in what other context would someone have MRI scans of, you know, across the population and cognitive testing prior to the Covid pandemic and then have paired same individual tests after?
[9:49] SPEAKER_00: a range of severity of Covid infection.
[9:53] SPEAKER_00: So it was just an incredibly important data set with control individuals in the same cohort of people.
[9:59] SPEAKER_00: This longitudinal study has continued to inform us in such important ways.
[10:04] SPEAKER_00: And that study found that there were multiple findings.
[10:08] SPEAKER_00: One is that there appears to be a small but significant atrophy in the neocortex.
[10:17] SPEAKER_00: Two, that there are also abnormalities in major white matter tracks.
[10:23] SPEAKER_00: And three, that there is particular pathology within the olfactory system.
[10:29] SPEAKER_00: And we know that Covid induces, as a very common early symptom, this loss of smell, anosmia.
[10:38] SPEAKER_00: and then together with those structural findings on MRI scans that individuals even with relatively mild acute disease exhibited long-term deficits in cognitive function and that fits with some beautiful epidemiological studies that have been done across
[10:57] SPEAKER_00: Many thousands of individuals in multiple different geographic populations underscoring this consistent finding that Covid can induce lasting cognitive changes and as we begin to understand that biology it fits with those structural changes that are observed.
[11:15] SPEAKER_00: We do know that the olfactory system is particularly affected and so it makes sense that the olfactory system would show those structural changes.
[11:23] SPEAKER_00: The neocortical and
[11:25] SPEAKER_00: you know white matter changes evident on MRI fit with what we found you know microscopically at the cellular and molecular level that you know highlighted a loss of myelinating oligodendrocytes a loss of myelinated axons a deficit in hippocampal new neuron production
[11:47] SPEAKER_00: All of those findings kind of fit together with the structural changes that the UK Biobank study highlighted.
[11:54] SPEAKER_00: So, you know, clearly this is a disease that has lasting impacts and the challenge is to understand those better so that we can develop effective interventions for the many, many millions of people who are still struggling with, you know, decreases in their cognitive function long after Covid exposure affecting the world population.
[12:17] SPEAKER_02: Yeah that's a great summary of how the biobank data UK aligned with the work that you've done and I guess the other question just to round this out is you know for years we didn't think the brain had an immune response system right and then
[12:36] SPEAKER_02: There's been a wake-up call about that and maybe you could summarize what you know there.
[12:40] SPEAKER_00: Absolutely, yes.
[12:42] SPEAKER_00: The brain is not, we used to call the nervous system an immunoprivileged site and it is not, you know, it is not hidden from the immune system.
[12:48] SPEAKER_00: It has its own and distinct immune system properties, but it's very clear from work by Yoni Kipnis and others that there are in fact lymphatics in the nervous system.
[12:59] SPEAKER_00: These are in the meninges.
[13:01] SPEAKER_00: It's also become increasingly clear that there is a
[13:06] SPEAKER_00: unique bone marrow niche in the skull from which many of the you know lymphocytes and other kinds of immune cells that survey and surveil the brain and spinal cord you know that's that's where they come from that's where they develop and that's what they return and the lymphatic drainage of the nervous system you know goes to distinct places like the posterior cervical lymph nodes we are now understanding the sort of trafficking in and out of the nervous system
[13:33] SPEAKER_00: of Cells and and certainly understanding how that changes in the context of Covid you know how those cells may be particularly responsive you know to to the immune challenge initiated in the respiratory system is something that is an area of deep importance and active exploration and in fact
[13:55] SPEAKER_00: Some of my ongoing collaborations and ongoing lab work focuses on exactly this question.
[14:01] SPEAKER_00: How does the trafficking from the brain borders into the nervous system change after Covid?
[14:10] SPEAKER_00: And how does potentially cellular surveillance of the nervous system contribute to the persistent microglial reactivity that we observe?
[14:22] SPEAKER_02: And do you have any hunch on what might be a successful, worthwhile therapy to a candidate to test prospectively for this?
[14:30] SPEAKER_00: I think it's too early to nominate candidates, but I think that the biology, the molecular and cellular biology is underscoring a role for particular cytokines and chemokines that are initiated by the immune response in the lung.
[14:47] SPEAKER_00: and, you know, clear cellular targets.
[14:49] SPEAKER_00: The goal, you know, I think the central goal being to normalize the neurovasculature and normalize microglial reactivity.
[14:56] SPEAKER_00: And so the question in this disease context and in others becomes how can we kind of molecularly coach, you know, these reactive cells to to go back to doing their normal jobs, to being homeostatic?
[15:07] SPEAKER_00: And and that's the challenge.
[15:09] SPEAKER_00: But it's a it's a surmountable challenge.
[15:11] SPEAKER_00: It's one that I think that, you know, the scientific community can figure out.
[15:14] SPEAKER_00: and it will be relevant not only to Covid but also to many other consequences of immune challenges including other post-infectious syndromes.
[15:25] SPEAKER_00: It's not only Covid that causes long-term cognitive and other kinds of neurological and neuropsychiatric
[15:33] SPEAKER_00: Consequences.
[15:33] SPEAKER_00: We saw this after the influenza pandemic in 1918.
[15:38] SPEAKER_00: We've seen it after many other kinds of infectious challenges.
[15:42] SPEAKER_00: And it's important as we prepare for the next pandemic, for the next global health challenge that we understand how the long term consequences of an immune response to a particular pathogen play out.
[15:58] SPEAKER_02: No question.
[15:59] SPEAKER_02: And that, I guess, also would include myalgic encephalomyelitis and
[16:02] SPEAKER_02: all the other post infectious post viral syndromes that overlap with this now to switch gears because that work is just by itself extraordinary but now this is other field that you are a principal driver leader and that is cancer neuroscience I didn't even know they had boards in neuro-oncology I thought neurology was enough but you got board certified in that too but this
[16:32] SPEAKER_02: Field is just exploding with of interest because of the ability for cancer to cells to hijack neurons and neural circuits which you know I guess the initial work goes way back but more recently the fact that gliomas were you know just electrically charged and so
[16:56] SPEAKER_02: Maybe you can frame this because this has not just amazing biology, but it's also introducing all sorts of therapeutic opportunities, including many ongoing trials.
[17:08] SPEAKER_00: Yes yes and thank you for asking me about it it's certainly one of my favorite things to think about and perhaps as a bridge between you know the the cognitive impairment that occurs after Covid and other inflammatory challenges and the neuroscience of cancer I'll just highlight that maybe the common theme is it's important to understand the way cells talk to each other and that they you know these sort of molecular conversations are happening you know on multiple scales and
[17:34] SPEAKER_00: in unexpected ways and they shape pathophysiology in a very important way.
[17:40] SPEAKER_00: so kind of continuing on that theme we've known for many many years for decades in fact that the nervous system and its activity shapes the development of the nervous system and actually it doesn't just shape the development of the nervous system where perhaps it's intuitive that you know the activity within the nervous system might you know sculpt the way that it forms but it turns out that innervation is critical for
[18:05] SPEAKER_00: Development broadly, that innervation is necessary for organogenesis and that this is becoming clear in every organ that's been studied.
[18:15] SPEAKER_00: And so it stands to reason, given that kind of perspective on the role that neuronal activity plays in normal development
[18:23] SPEAKER_00: Plasticity, Homeostasis and Regeneration of many different issues that the activity of the nervous system and those principles can be hijacked in the context of cancer, which is in many ways a disease of dysregulated development and regeneration.
[18:38] SPEAKER_00: And so, you know, I'm a neuro-oncologist.
[18:41] SPEAKER_00: I take care of children with a very terrible form of brain cancer called high-grade glioma.
[18:47] SPEAKER_00: And, you know, the most common form of high-grade glioma in kids occurs in the brain stem.
[18:52] SPEAKER_00: It's called diffuse intrinsic pontine glioma.
[18:55] SPEAKER_00: It's really the worst disease you can imagine.
[18:58] SPEAKER_00: and understanding it has kind of been the need to understand and treat it has been kind of a guiding principle for me and so taking a big step back and trying to wrap my arms around the biology of these terrible high grade gliomas like glioblastoma like diffuse intrinsic pontine glioma
[19:14] SPEAKER_00: I wondered whether nervous system activity might influence cancer the way that it influences normal development and plasticity.
[19:23] SPEAKER_00: And as soon as we started to leverage tools of modern neuroscience like optogenetics to ask those questions to modulate the activity of neurons in a particular circuit and see how that influences cancer proliferation and growth, it was clear how very important this was.
[19:39] SPEAKER_00: uh that you know act the active neurons and various subtypes very robustly drive the it drives the growth of these brain cancers and so you know trying to understand the mechanisms by which that occurs so that we can target them therapeutically it it's become clear that the tumors don't just respond to activity regulated growth signals they do there are those you know peregrine factors but that in brain cancer the cancers actually
[20:07] SPEAKER_00: Integrate into the neural circuits themselves that there are bonafide electrophysiologically functional synapses that form between various types of neurons and high-grade glioma cells where discovering the same can occur in brain metastases from different organs and that this principle by which neuronal activity drives the cancer
[20:30] SPEAKER_00: is playing out in other tissues.
[20:32] SPEAKER_00: So right when we made these discoveries about glioma, within this few years, discoveries were made in prostate cancer, in gastric cancer, colon cancer, skin cancer, pancreatic cancer, it seems that innervation is critically important for those tumors.
[20:50] SPEAKER_00: And not just for their growth, but also for invasion, metastasis, even initiation in diseases
[20:58] SPEAKER_00: that are driven by particular oncogenes there's an intersection between the power of those oncogenes to cause the cancer and the necessary environment
[21:08] SPEAKER_00: for the cancer to form and that appears to also be regulated by the nervous system in very powerful ways.
[21:14] SPEAKER_00: So, you know, the exciting thing about recognizing this relatively unsettling feature of, you know, cancers is that as we understand it, the neuroscience of cancer becomes an entirely new pillar for therapy to combine with, you know, immunotherapy and more traditional cytotoxic therapies and we've been missing it until now.
[21:36] SPEAKER_00: and so the the opportunity exists now to leverage medicines that were developed for other reasons for indications in neurology and cardiology and psychiatry you know medicines that target neurotransmitter receptors and ion channels that it turns out have a role in in some forms of cancer now each cancer has its own biology so different types of neurons different neurotransmitters different neuropeptides play specific roles in that tissue context but
[22:05] SPEAKER_00: that the principle is the same.
[22:07] SPEAKER_00: And so as we understand each cancer, we can start to understand what neuroscience inspired medicines we might leverage to better treat these tumors.
[22:17] SPEAKER_02: Yeah, I mean, it's amazing as a cardiologist to think that beta blockers could be used to help people with cancer.
[22:23] SPEAKER_02: And of course, there are trials and and some studies in particular cancers in that.
[22:28] SPEAKER_02: So one of the things that people maybe not outside outside of oncology
[22:35] SPEAKER_02: don't follow these these papers about hallmarks of cancer there's been two editions major editions of the hallmarks of cancer and recently in the journal Cancer Cell Douglas Hanahan and you wrote a classic about that the hallmarks need to be revised to include you know neuroscience and maybe you could elaborate on that because it seems like this is like a missing frontier that isn't acknowledged by
[23:05] SPEAKER_00: you know some of the traditional views of cancer absolutely so you know I think number one I want to just give a shout out to Doug Hanahan and that the role that this you know
[23:17] SPEAKER_00: The Hallmarks of Cancer, which is a review article that he wrote and has become sort of the Bible, if you will, of cancer biology, you know, really out, you know, laying out common principles across cancer types that, you know, have provided a framework for us to understand this complex and, you know, diverse heterogeneous set of diseases.
[23:36] SPEAKER_00: And so it was very exciting when he reached out and asked if I wanted to write this perspective, you know,
[23:44] SPEAKER_00: as an emerging hallmark of cancer.
[23:49] SPEAKER_00: And as we examine them from that, we examine the neuroscience of cancer from that heuristic set of principles, this framework of principles of cancer biology, it's clear that there is a neural influence on the vast majority of them.
[24:06] SPEAKER_00: We now understand from this exciting and burgeoning field
[24:10] SPEAKER_00: that you know the nervous system can regulate cancer you know unregulated proliferation, it promotes you know proliferation and growth, it promotes invasion and metastasis, it alters the immune microenvironment, it can both
[24:25] SPEAKER_00: Promote pro-tumor inflammation through neurotransmitter signaling.
[24:29] SPEAKER_00: It can also help to modulate anti-tumor immunity.
[24:34] SPEAKER_00: The crosstalk between immune cells, cancer cells and the nervous system are complex, profound and I would argue incredibly important for immunotherapeutic approaches for cancer.
[24:46] SPEAKER_00: and at the same time that there are these diverse effects of the nervous system on cancer, cancer also influences the nervous system.
[24:55] SPEAKER_00: And so there's really this bi-directional crosstalk happening by which neurons in an activity dependent way, either in short range local neurons or in long range, down a nerve or across a circuit, promote the pathophysiology of the cancer
[25:14] SPEAKER_00: and and you kind of know it's beneficial because the cancer does many different active things to increase innervation of the tumor um there is in a variety of different tissue contexts and disease states elaboration of um of nervous inner you know nervous system interactions through cancer derived either axonogenic or synaptogenic factor secretion
[25:38] SPEAKER_00: the nervous system remodels the nerves it remodels the neural circuits to increase you know the the connectivity of the nervous system with the cancer and also to increase the activity of the of the nerves to increase the excitability of a neuron and this contributes to not only driving the cancer but to many of the really important symptoms that patients face with cancer including you know tumor associated seizures as well as cancer associated pain
[26:06] SPEAKER_02: Yeah I mean this is actually you know so unusual to see a whole another look at what cancer is about I mean it's just you know this is about as big a revision of thinking as I've seen at least in many many years and the fact that you pulled this together by kind of the new hallmarks also made me wonder because you know a number of years ago we went through this
[26:34] SPEAKER_02: Angiogenesis story whereby like this cancer can hijack blood vessels and promote its growth and as you know very well a lot of these anti-angiogenic efforts didn't go that well that is they maybe had a small impact overall but they didn't you know change the field in terms of successive therapy I wonder
[27:01] SPEAKER_00: if this is going to play out very differently what are your thoughts about that because there's lots of shots on goal here and the trials have sprouted out very quickly to go after this yeah i think it's important to to recognize you know various micro environmental effects on the cancer including the nervous system effects as one piece of a puzzle uh that
[27:26] SPEAKER_00: we need to put together in order to effectively treat the disease and I think to effectively treat particularly very aggressive cancers we need to you know hit this from multiple angles and effective strategies will need to include you know targeting cell intrinsic vulnerabilities of the cancers as most traditional and targeted therapies are focused on doing right now together with
[27:49] SPEAKER_00: you know decreasing the the strong growth and metastasis you know influencing effects of the nervous system I think that's one pillar of of the um of therapy that we really have been missing and that represents an important opportunity as well as leveraging the power of the immune system which perhaps will only work optimally particularly for solid tumors
[28:12] SPEAKER_00: if you also address the nervous system influences on immune cells and so I think that you know it's part of a holistic approach to effective therapy for tumors we have so far failed to treat with you know kind of single agent or you know one-dimensional kinds of approaches we need to
[28:29] SPEAKER_00: target not only the cell intrinsic vulnerabilities, the immunotherapeutic opportunities, and the nervous system mechanisms that are influencing all of that in really important ways.
[28:38] SPEAKER_00: So I think it's important to design clinical research for, you know, in the context of cancer neuroscience with that holistic view in mind.
[28:46] SPEAKER_00: We don't think one strategy is going to be curative for difficult to treat tumors.
[28:52] SPEAKER_00: I don't think that blocking
[28:54] SPEAKER_00: Neuron to Glioma Synapses in Glioblastoma and DIPG will alone be sufficient, but I do think it may be necessary for other therapies to work.
[29:01] SPEAKER_02: Yeah, I think that a perspective of in combination is is exceedingly important.
[29:07] SPEAKER_02: And, you know, now the overall there's a big fixation, if you will, about revving up immunotherapies, various ways to do that.
[29:16] SPEAKER_02: We talk about that in a moment, but without attention to the the
[29:21] SPEAKER_02: Neurogenic side of this might be a problem.
[29:23] SPEAKER_02: Now, that gets me to the tumor type that you have put dedicated effort, which is this pediatric pontine tumor, which is horrendous, invading the brainstem.
[29:37] SPEAKER_02: And you've even done work with engineering T cells to go after that.
[29:42] SPEAKER_02: So you cover all the bases here.
[29:44] SPEAKER_00: um can you tell us about where that stands because if you can prevail over that perhaps that's one of the most challenging uh tumors of of people there is yeah absolutely so you know just a few words about this tumor for those who don't know um diffuse intrinsic pontine glioma and other related tumors that happen in the thalamus and the spinal cord are the leading cause of brain tumor related death in kids this is a
[30:08] SPEAKER_00: Universally Fatal Tumor Type that tends to strike school-aged children and it's the worst thing I've ever seen in medicine.
[30:15] SPEAKER_00: I mean it really has been something that since I saw in medical school I just have not been able to turn away from.
[30:21] SPEAKER_00: And so studying it from many different perspectives, both the cell intrinsic vulnerabilities, the microenvironmental
[30:29] SPEAKER_00: opportunities for therapy and and and also the immunotherapeutic opportunities it became clear to me that for a cancer that diffusely infiltrates the nervous system forms synapses with the circuit that it is invading and integrates into those circuits in the brainstem and spinal cord that the only way to really effectively treat it would be a very precise and powerful targeted approach and so immunotherapy was a very attractive you know
[30:59] SPEAKER_00: set of approaches because you know in the best case you have an engineered t-cell or other immune cell that can can you know go in and kind of like a special forces agent you know just find the cells and disintegrate them from this you know synaptically integrated circuit that has formed
[31:15] SPEAKER_00: And so I began to search for cell surface targets on this particular type of cancer and found that one of the antigens for which many immunotherapy tools had already been made because it's prevalent in other kinds of cancer
[31:34] SPEAKER_00: was very highly expressed on on diffuse midline gliomas including diffuse intrinsic pontine glioma and so this target which is a sugar actually it's a diacylic anglioside called GD2 is extraordinarily highly and uniformly expressed on on DIPG because the the oncogene that drives DIPG and other related tumors which is actually a um
[31:56] SPEAKER_00: a mutation in genes encoding histone H3 which causes broad epigenetic dysregulation strongly upregulates the synthesis genes for GD2 and so it's a really ideal immunotherapeutic target because it's on every cell and it's at extraordinarily high levels and so you know again speaking to the importance of collaboration right when we made this discovery one of the leaders in in chimeric antigen receptor T cell therapy CAR T cell therapy
[32:23] SPEAKER_00: named Crystal Makel head to Stanford and her office is in my building.
[32:28] SPEAKER_00: So I walked over and knocked on the door and said, do you want to work on this together?
[32:32] SPEAKER_00: And so we've been working together ever since and found that, you know, indeed, you know, CAR T cells targeting GD2 cure our mice models, which is
[32:41] SPEAKER_00: something I have never seen you know I have never seen anything as effective but it's always easier to to help a mouse than to help a person and so you know we knew that that the clinical translation would be challenging we also knew that it would require you know intentionally causing inflammation in the brainstem that's already compromised neuro critical care
[33:07] SPEAKER_00: I'm gonna not use the word nightmare but you know it's it's a set of challenges that you know to think about really carefully and so we spent a lot of time and collaborated with our neurocritical care colleagues our neurosurgical colleagues and and developed a protocol that had many you know we anticipated this this neurotoxicity of causing inflammation in the brainstem and we had many kind of safety measures you know built in in an anticipatory way gave the
[33:35] SPEAKER_00: Therapy only in the intensive care unit and had many safeguards in place to treat anticipated hydrocephalus and other consequences of inducing inflammation in this particular region of the nervous system.
[33:51] SPEAKER_00: And over the last four years, we began this trial at the beginning of the pandemic in June of 2020.
[33:58] SPEAKER_00: So that was its own unique set of challenges.
[34:02] SPEAKER_00: We've seen some really incredibly exciting, promising results.
[34:07] SPEAKER_00: We've presented, we've published some of our early experience.
[34:10] SPEAKER_00: We're getting ready to present the larger experience and we've presented this at meetings.
[34:16] SPEAKER_00: We've seen some kids go from wheelchair bound to walking in a matter of weeks.
[34:21] SPEAKER_00: It's been just incredible.
[34:22] SPEAKER_00: Wow, that's phenomenal.
[34:25] SPEAKER_00: Reduced to Nearly Nothing.
[34:27] SPEAKER_00: And other kids have had less robust responses.
[34:30] SPEAKER_00: Therapy has really helped some kids and it's failed others.
[34:34] SPEAKER_00: And so we're working very hard right now to understand what factors affect this heterogeneity in response so that we can achieve
[34:44] SPEAKER_00: The Brain in Long Covid
[35:00] SPEAKER_00: Mechanisms but there there's also I think really important influences of neurotransmitters and neuropeptides on the immune response against central nervous system cancers in you know in the central nervous system and so we're working hard to kind of understand that crosstalk and and develop strategies to optimize this promising therapy but it really has been you know one of the
[35:22] SPEAKER_00: One of the highlights of my professional life to see kids with DIPG and spinal cord diffuse melancholomas get better even for a while.
[35:33] SPEAKER_00: Something I hoped at some point in my career to ever see.
[35:37] SPEAKER_00: And having seen it now so frequently in our trial patients, I'm really hopeful
[35:42] SPEAKER_00: that this approach will be part of the answer.
[35:44] SPEAKER_00: And I'm hopeful for sort of the future of immuno-oncology for solid tumors in general.
[35:50] SPEAKER_00: I think when we understand the tumor microenvironment, we'll be able to leverage these really powerful therapies in a better way.
[35:58] SPEAKER_02: Wow.
[35:58] SPEAKER_02: Yeah.
[35:59] SPEAKER_02: I mean, if anybody was to try to crack the case of one of the most challenging cancers ever seen, you would be that person.
[36:09] SPEAKER_02: Now, speaking of collaboration,
[36:13] SPEAKER_02: I didn't know this until I was getting ready to have the conversation with you, but your husband, Karl Deisseroth, is like the optogenetics father.
[36:25] SPEAKER_02: He is another exceptional, rarefied leader in neuroscience.
[36:32] SPEAKER_02: So do you collaborate with him?
[36:34] SPEAKER_00: we do collaborate and in fact you know i so i met carl when i was um a medical student and he was an intern in psychiatry so we go back uh fairways we're both md phd students at swanford and um we've been collaborating for many many years in many different ways so you know both in the clinic uh i met him when i was a sub i in neurology and he was the psychiatry intern you know on biology but um we collaborated when he was a postdoc and i was a graduate student um on
[37:04] SPEAKER_00: you know some some you know neurobiological studies we have four children we have I have one step for children that that I can take full credit for and so we collaborated on five kids for a while I I really wanted because he he is such an he is such an amazing scientist he is such a you know
[37:27] SPEAKER_00: Thought Leader in Neuroscience and as I started my own independent laboratory I wanted to not be entirely in his shadow and so you know I did make it a point to do I used optogenetics but I took the course and you know bought the tools and did it all myself
[37:47] SPEAKER_00: I really wanted to be kind of independent in the beginning.
[37:50] SPEAKER_00: Now that my career in my laboratory is a bit more established, we are formally collaborating on some studies because he's a brilliant guy.
[37:59] SPEAKER_02: Well, I think that you fit in that category too.
[38:04] SPEAKER_02: And a bit more established is maybe the biggest understatement I've heard in a long time.
[38:08] SPEAKER_02: The body of work you've done already at a young age
[38:14] SPEAKER_02: is just beyond belief and you're on a tear to do you know have big impact and you know many across the board and as you said um many things that you're learning about the brain with all of his challenges um will apply to cancer generally will apply to hopefully someday a treatment that's effective for long covid it affects the brain um and and so many other things so
[38:40] SPEAKER_02: Michelle, I'm so grateful to have had this conversation.
[38:44] SPEAKER_02: You are an inspirational force.
[38:47] SPEAKER_02: You've covered a lot of ground in a short time.
[38:51] SPEAKER_02: And between you and your husband, I don't know that that's got to be the most dynamic duo of neuroscience that exists on the planet and the human species, I guess.
[39:01] SPEAKER_02: And I just can't imagine what those those kids of yours are going to do when they grow up.
[39:07] SPEAKER_00: I'm biased, but they're pretty great kids.
[39:10] SPEAKER_02: Well, thank you for this.
[39:12] SPEAKER_02: And I think the folks at
[39:14] SPEAKER_02: I get to listen to this will certainly get charged up.
[39:18] SPEAKER_02: They'll realize the work that you're doing and the people you collaborate with and making cold calls to people.
[39:25] SPEAKER_02: You know, that's another story in itself that how you can get transdisciplinary efforts when you just approach somebody who's doing some good work.
[39:35] SPEAKER_02: Another lesson just kind of hidden in our discussion.
[39:39] SPEAKER_02: Thanks very much.
[39:40] SPEAKER_00: Oh, thank you.
[39:41] SPEAKER_00: It's wonderful to talk with you, Eric.

Shows are listed from Apple Podcasts' charts and directory, and Podcast Index where it is used. Every show and episode belongs to its publisher and plays from the publisher's own feed; this site hosts none of them.