 Boom, what's up everyone, welcome to Simulation, I'm your host Alan Sakyan. Very excited to be talking about heart and brain diseases and how we can in advance understand the pathologies happening to our body, live longer and healthier. We have Dr. Karunia Kandimala joining us on the show. Hello. Hello. Thank you for coming on. Really appreciate it. It's such a pleasure. Thank you to Kishore for introducing us, your cousin, yes, and you also have your daughter visiting as well into the Bay Area and it's nice she's visiting Berkeley, yes, yes, and your background is very cool. You've been an associate professor in the Department of Pharmaceuticals at the University of Minnesota for the last seven years, also a research collaborator at Mayo Clinic. You were previously also visiting scientists and an adjunct professor in the Department of Neurology at Mayo Clinic and you've been now focusing on macromolecular pharmacokinetics related to Alzheimer's disease and metabolic syndrome and developing nanotech for diagnosis and treatment of cerebral vascular disease. So this is very important for us to understand this affects one out of every six of us by the age of 65, one out of every two of us by the age of 80. So this is a big deal for us to be able to have, you were teaching earlier about the preventative steps that we can take in order to prevent the onset of neurodegenerative diseases. So Karunia, let's start off on a big history perspective. We find ourselves as stewards of Earth, we have eight billion of us now, there's exponential technology happening, we have so much great science that can help us. What's your current take on this state of humanity? I have a very optimistic perspective. I think humanity is progressing and actually moving the frontiers in science as well as in technology. Previously people only used to live up to 50 to 60 years of age, but now we are expected to live about 80, so that's a real possibility. With those advances also come challenges, so because Alzheimer's is one of the diseases of aging. So if a person is above 70, there is a 15% chance, but above 80, there is almost a 50% chance of getting Alzheimer's. So those challenges could be also consequences of the progress we have been making. But at the same time, the science is evolving at a rate to a level where humanity is probably getting ready to face these challenges and solve them eventually. Yes, yes. And the relationship between the heart and the brain to what affects the heart as something that is bad is very much so associated with affecting the brain as something is bad. And that's something that you found with type 2 diabetes and that will continue talking about through this conversation. These are the two of those central organs to our existence and our health. So, Karunia, you're right, the scientific frontier is pushing us in the direction of being able to solve these tough challenges, we're very excited for that. What has been your journey to get to the point of your fascination and your interest with solving these challenges? I think it's the fascination to deal with the unknown. So I have a natural tendency to gravitating towards what is unknown and what's more challenging. So as a consequence, I get myself in trouble every now and then and I still remember one of my professors when I was doing my doctoral study at the University of Iowa. He commented looking at my project, which is to investigate how drugs permeate from nose to brain. So like say for example, drugs of abuse and therapeutic molecules also could permeate once they're in the nasal cavity into brain. So the pathways that they take to reach the brain are poorly understood. So my PhD thesis was investigating what those pathways are and how body can protect itself from being bombarded by these molecules. You know, if it's drug, then it's beneficial, but it could be toxin too. For example, manganese, aluminum, all those metals could get into brain through inhalation. Viruses could get into brain via the nasal pathway. So my thesis was to investigate that and the professor was used to ask me like, so how long do you want to stay here? You know, is it a 10-year project or is it a five-year project? So it was risky, but that's what was the driving force. Likewise, when I moved to being a faculty member, again, I started looking into the pathophysiology of Alzheimer's. Instead of treading the known or well-investigated path, I started a different direction, which I felt is probably what might be the earliest risk to neurodegeneration, which is insults to the vasculature, to the blood vessels. In the brain blood vessels, the brain is heavily perfused, which means there is almost a small blood vessel for every neuron in the brain, because neurons need nourishment and they generate a lot of byproducts that should be cleared from the brain. And vasculature, the blood vessels can do that very well. One blood vessel for every neuron? Every neuron. That's how dense the blood vessels are in the brain, because brain needs a lot of energy, which is supplied in the form of glucose. So that supply is consistently maintained by the blood vessels. The blood vessels are bringing the glucose into the brain. Yes. So we have almost 100 billion plus of these little micro blood vessels, micro vasculature, that brings the glucose up, that powers the brain, and it brings oxygen. Oxygen, which is very critical. So unless the blood vessels are functioning very well, it's hard for the brain to get that nourishment. And also a lot of byproducts are generated, a lot of metabolites. If they start accumulating in the brain, it's very hard to maintain what we call homeostasis, which is the balance in the brain. So blood vessels again remove all those breakdown products into the bloodstream so that they could be eliminated. So this should be functioning very, very effectively for proper brain physiology. Yes, yes. So then simultaneously as our blood is bringing up the glucose and oxygen, it's bringing down the build-ups. The build-ups, yes. Of the toxic products. And this is fat, cholesterol, and then the amyloid protein build-up. Right. Amyloid protein is also regarded as one of those byproducts of brain metabolism. So we don't know what the function is, but we do know that it is there in every brain, amyloid protein is there in every brain. But in Alzheimer's brain, it is overproduced because the blood vessels or the brain itself is not able to clear them, so they start accumulating and cause problems. One of the problems they could cause is killing the neurons. Yes, yes. Okay, so for you, how did it come up for you the moment for I want to be focused on this specifically? Yeah, again while I was doing my doctoral work, one of the reasons we were investigating, you know the purpose of investigating nos-to-brain delivery of molecules is to look at resolving the issues associated with Alzheimer's. Because in Alzheimer's disease, one of the first brain areas that are affected is the olfactory system. It's the olfactory system, interesting for our nose, for us being able to process what we smell. For able to smell, basically. So, an Alzheimer's patient. Why? Do we know why? We don't know why, but we could see some connections and sort of guess associations at this point. So olfactory system is the only part of the central nervous system that's exposed to the environment. This. Right. Is the only... What about taste? Is it not... It is not directly the part of the central nervous system. Taste is not... You have the neurons, of course supplying the nerves that are supplied to the brain. The tongue for the taste perception, but it is not a directly exposed part of the central nervous system. No, we have nerves being supplied to all over the body. But in the olfactory system, the olfactory neurons are actually exposed to the environment. And that's right up here. Right up. These olfactory neurons. Roof of the nose. Yeah. And then... Okay, interesting. Okay. So you can actually trace the area, the olfactory processing part of the brain all the way to... You can trace the... The roof of the nasal cavity. So the roof of the nasal cavity. Yeah. Where the olfactory epithelium is located. Interesting. Yeah. These senses that we have to process our environments are very, very interesting. Right. So... And how we're building new senses is very interesting. Right. Yeah. Now, take us to your teaching... You actually started hinting at what is... If the blood vessels themselves have issues with bringing up the glucose and bringing up the oxygen, that that process can start deteriorating. Actually, you were teaching me earlier, and this is an important point to teach, that it's 90... No, that's 100%. There's 100% failure rate in clinical trials for Alzheimer's disease. And that's because we're not doing it early enough. Right. Yeah. So most of the therapies that went into phase three clinical trials, I'm talking about the novel treatments of Alzheimer's. And our conventional treatments to actually those we call colonist-raised inhibitors that are available on the market, but they deal with sort of temporary effects caused by Alzheimer's disease, but they don't address the root cause. But one of the attempts that were made to address the root cause is to therapeutically remove the toxic amyloid proteins that accumulate in Alzheimer's brain. So and that removal is done by antibodies against the amyloid beta proteins. So many of those antibodies went into clinical trials, but failed in phase three clinical trials. The antibodies are trying to go and remove the amyloid protein buildup, and we're doing it too late in the process. That is sort of the reasoning that scientists are coming up to explain the failure of those clinical trials. But there could be several aspects associated with it. One is amyloid accumulation could be a consequence of some pathological damage that really caused problems. Yes. So it could be a bystander, but genetic data clearly shows that amyloid is a critical part of the Alzheimer's pathology. So it's a, you know, there could be a sort of a shift in the role of amyloid proteins very early on in the disease and then compared to that in later portions. So unless we know and understand what that shift is, it's very hard to time when the therapy should be administered. Yes. Yes. And let's pull up our images that help us explain what we're talking about. Okay. Yes. So these are the stats you were mentioning earlier affecting one in every six people above 70 years and one out of every two people above 80 years now. Interesting. First patient diagnosed by Dr. Alois Alzheimer, 100 years ago, so 1920-ish, interesting. And do you know the story of how Alois Alzheimer, how did, how did, is this a he? Is this a she? Yeah, she used to complain. She? She. Is the, is the professor or is the doctor? The doctor is Alzheimer. Oh, but is the doctor a he or Auguste is a she? The doctor is he, Auguste is she. Is she? Okay. And yeah, and how, yeah, how did she and he, how did, how did Alois understand Auguste's issue? How did he open her to understand that? Yeah, no. So he provided the first clinical documentation of the cognitive loss in Alzheimer's patient. So she used to complain, confusion, memory loss, all the classical changes that we are seeing now in Alzheimer's patients. Then Dr. Alzheimer went beyond just the clinical investigation. He, in fact, looked at the autopsy brain of Auguste. Oh, interesting. Yes. And then he noticed those plaques in the brain 100 years ago. Wow. And later on, since the past 30 years, scientists all over the world have been investigating what those plaques are made of. And then how are they causing, how are they associated with Alzheimer's pathophysiology? So we've identified now that those plaques are made of amyloid beta proteins. And those beta proteins, they are, they aggregate very rapidly. And those aggregates, the small aggregates, could be very toxic compared to amyloid beta protein that hasn't aggregated, that remains as a monomer, what we call just one molecule. So it's not that toxic. But when it starts aggregating, those aggregates can be very, very toxic. And several scientists have even compared them to be prions, again, that have tendency to aggregate and those prions cause mad cow disease. Interesting. So this is an 100 years ago, we're talking autopsy is what started our scientific understanding of the memory loss of these issues. This is very important because these are those, this is how you get to an edge of science is that you have to take initiative and and do things like do an autopsy and find these these amyloid protein buildups. And this is the plaque is specifically the last 30 years. He's saying we're under state, we're diving into understanding the plaque that's building up and causing the plaque causes the neurons to die because and what's the relationship with the tangles as well. It might not be the plaque that's problematic. It might be those oligomers before plaque formation that are distributed all over the brain that could be causing the problem. Plac, according to many scientists, could be a protective mechanism. So body is actually encapsulating those proteins into a plaque and which is then not that toxic. Plac formation could be a protective mechanism similar to like formation of atherosclerotic plaque in the blood vessels. That could be a protective mechanism, but when it's when it grows bigger, it blocks the blood vessels and cause problems. So it's, you know, as in these cardiovascular diseases, instead of actually removing the plaque, we tend to address issues that promote the generation of the plaque. But in case of Alzheimer's, we might be doing it in a different way. We are trying to deal with the plaque formation and trying to clear or break that plaque down rather than addressing the issues that have caused the problem, that have caused the plaques. So according to our investigations, the cerebrovascular damage could be one of the contributing factors to that eventual buildup of plaques in the brain. Yes. The healthier these billions of microvascular chur that's carrying the glucose and oxygen up, the healthier that that is, the less of the plaque buildup that even occurs in the first place. So this is again, this is coming to preventative medicine. The health care that you're wearing. And how do we then keep the billions of microvascular chur healthy to what's our what's our strategy? Yeah, we have known this for all along, right? It's a right exercise and a right amount of exercise and food. Yeah. And sleep. Huge. Yeah, sleep. But there was a study published in Science that demonstrated sleeplessness can promote amyloid buildup in the brain. So again, suggesting that those are all, the healthy lifestyle is the key to protect the person from these neurodegenerative diseases. Yes. Yes. Ronny, let's go to that next image too. Okay. And this is kind of, as we're talking, you mentioned earlier, the fact that we typically don't think of one little microvascular chur with blood vessel for every single neuron in the brain. That's a very interesting point. So that's called this blood brain barrier. And that's right, you know, that really starts right about at where the initial part of the brain starts. So usually all the blood vessels that are supplying blood to the brain, they have endothelial membrane. What does that mean, endothelial? Endothelium is the cell lining of the blood vessels. Okay. Interesting. All the blood vessels are lined by endothelial cells, a single layer of endothelial cells. Difference between the brain blood vessels and the blood vessels in the periphery and other parts of the body is that the endothelial cells in the brain blood vessels are all sealed together. Interesting. So there are no gaps, they prevent the movement of any molecules non-specifically to get into the brain. They prevent the movement of bacteria, movement of viruses. Interesting. Any extraneous substances, unwanted substances from getting into the brain. Because brain cells, they don't have ability like the peripheral cells to protect themselves. Neurons are highly specialized. They do what they, you know, they do, they functions very, very systematically and with high fidelity. So they don't have the same capacity to handle the abuses like the peripheral cells. So they need protection, they need a certain environment to function effectively. All that is maintained by other cells, other supporting cells. And endothelium, endothelial cell is one of the most critical supporting cells. Fascinating. Endothelial cells are what, they're lined very tightly in the blood as it's going up to the brain. They're very tightly, and that prevents the bacteria and other things that the body cells can fight against. The brain neuron cells can't fight against because they're super focused on activity in the brain, that the brain has to do. This is very interesting. So then in the body, the endothelial. So there are gaps. There are gaps. So that nutrients could go in and out, likewise the metabolites, the toxic substances could get out quite easily. But in the brain, we don't have those gaps. As a consequence, brain needs specialized systems to send material and to send signals in and out of the brain. And then this called blood-brain barrier is then because you can't send a molecule through the blood up into the brain. Unless brain needs it. Interesting. So it won't take molecules unless the body already considers it like an endogenously made substance that then, so you can kind of trick the blood, the brain to taking it. Right. So glucose, you know, brain is 3% of body's weight, but then it consumes 15% of glucose. So- I've heard that numbers as high as 25, is that, could it be? Could be depending on the condition. But at a normal physiological level, on average, it's about 15%. So for all that glucose to get into brain effectively, the blood-brain barrier has glucose transporters functioning, again, with high fidelity. You know, there cannot be any damage to those glucose transporters, otherwise the brain could suffer from lack of nutrition. And this is where insulin is a big key. I would like to, again, make a distinction there. Those glucose transporters, they don't listen to anyone. They don't even listen to glucose. They're independent of glucose. So the glucose transporters in the periphery, in the body, they respond to insulin. They need insulin to act, for them to, you know, actually insulin signals them to take up glucose. Yes. Those glucose transporters are insulin dependent. Like in the muscle, for example, it is insulin dependent uptake of glucose, but in the brain, it occurs independent of insulin because insulin goes up and down in the body, depending on the time of the day, depending on the consumption of food, insulin levels keep going up and down. If the glucose transporters at the blood-brain barrier is listening to insulin, then there will be a huge shift in the amount of insulin getting into brain, depending on the condition of the periphery. So it's a very steady for the brain, but the body is much different in response, interesting. So this functioning is actually regulated by blood-brain barrier, which is the endothelium. Then there are other cells in the blood vessels called perisides. So perisides are like supporting cells to the endothelium. And then we have, that's part of the vasculature. We have the endothelium and then the perisides in the blood vessels. On the brain side, we have astrocytes and neurons. So all those four cells, they function together. So we call that a neurovascular unit. So neurovascular unit communicates and then it actually coordinates all the regulatory functions that are happening between the periphery and the brain. So any damage done to the neurovascular unit could be problematic, and we believe that it could be the earliest damage done to the brain in Alzheimer's brain. For those four cells to be miscommunicating? Miscommunicating. Yeah. Okay. Interesting. CBF means free blood flow? So what is depicted in this figure is the response, the connection between endothelium, the blood-brain barrier, and the neuronal response. So we call this neurovascular coupling. So these are so interlinked that here when the neural response is triggered, it could be triggered by many activities, like even opening eyes could trigger neuronal response in the visual cortex. So once that neuronal response is triggered, then neurons present in that brain region needs nourishment, oxygen, and then they generate byproducts, they should be removed very, very quickly to accomplish that function, the blood vessels are dilated. In that region. Interesting. And then they supply more blood carrying the nutrients and also to bring the metabolites out. So that response is what we call neurovascular response, and that's measured by change in the cerebral blood flow. When you have neuronal response, very quickly you could see changes in the cerebral blood flow. So this is the main signal that's captured on functional MRI to actually relate to which part of the brain is functional under certain stimulation. So this should be done very, very predictably, but in diseases like Alzheimer's disease, that neurovascular coupling is disrupted. Yeah, interesting. Yes. Okay. So then let me see if I can do this. So then the neurovascular coupling, when you're meditating, you close your eyes and you decrease the amount of blood and glucose that's flowing to your visual cortex. And so then the visual processing part of your brain, the neurovascular there, it narrows because it doesn't need the processing because your eyes are closed. It might not narrow, but it stays at rest. At rest. In the fMRI you can see that there's less blood that's moving to that part of the brain. Okay. And then once you open your eyes again, you can see in the fMRI that more blood flows there for the processing. And then in a brain where the cell communication isn't working as well, then it's not as the ability for the blood to move into that part of the brain is it's miscommunicated. Yeah. Okay. So that's the demands of the neurons. So if it's happening over a period of time, then the neurons could die off in that region. Interesting. Yeah. If the miscommunication happens for long periods of time, then that causes the neurons to die. Okay. Okay. Cool. Let's move on. Yeah. This is a good way of explaining the normal versus the Alzheimer brain, yeah. So you have the material transport and the signaling going on or carried on by the blood brain barrier between periphery and the brain. So you have all that communications very well laid out in the normal brain. But then in Alzheimer's brain, that communication system is all disrupted. As a consequence, you could see the, you know, like you see on a highway, you could see the build up. You could see the traffic that's slowing down. And if that traffic, if those cars are amyloid proteins, then they get backed up. And once the amyloid proteins are together and if the concentration is growing in the brain, they could aggregate. Those aggregates could cause problems in the neurons. And then eventually can lead to the neuronal death. Yeah. Yeah. This analogy is very powerful for, you know, we're talking about diseases of heart and brain. This similarly affects our heart as well as when you see the build up versus this free flowing. The traffic analogy is very powerful. Thank you. Yeah. It's a really good one. And so we want, we want to keep our heart vasculature as well as our brain neuro vasculature. We want to keep this moving like very smooth traffic. And then these things of really powerful sleep, good nutrition, good exercise, these are the things that keep the amyloid build up down. Right. Yeah. The physiological response is robust as a consequence the build up will not happen in the first place. So once that already, once it started happening, then it's, it might be very hard to clear and repair all the mechanisms that are responsible for, for the smooth flow like what you're referring to. Yes. Yes. When you, when you go back to the reason why many of the Alzheimer's therapies might be failing. Yes. The therapies that are focused on getting rid of the plaques might be failing could be due to the fact that the traffic, the build up could be corrected. But then what caused that build up is still not addressed. Yes. In this sense, the neurons might not recover from the damage that has been done a while ago. And it's again very important to notice that now we have clinical tools to see if the amyloid is building up in the brain. So we could use petimaging to investigate the amyloid build up in the brain. And we clearly know now that the build up starts 20 years before the cognitive changes are evident. Wow. So 20 years before. So what damage is done within that 20 years is not clearly understood. So build up could be starting as early as age 40 even really. Could be, yeah. Could be as young as that. If there is familial Alzheimer's disease, it's much earlier. Like usually the subject could suffer from Alzheimer's when he or she is about 50. Yeah. If it's familial, we're caused by mutations in the genes. But most of the disease is sporadic, which means that we don't know what the cause is. Wow. This is a very, very important for all of those that are listening, that are in their adolescent years in their 20s and even in your 30s, really experience life to the fullest now as best as you can because even if we're not even realizing that the cognitive decline is slowly occurring, it really is building up even if we're not noticing the decline. Right. Yeah. Right. Things happening without any notice and then all of a sudden there could be changes in cognition. By then it might be already too late. Yeah. Yeah. Do we have one more? Yeah. We have the one more image as well, the last one that we can pull up to. And this one's actually supposed to be a video, but we didn't get the video so you can explain it as an image. So what this picture is showing is the movement of vesicles, movement of whatever cell, whatever nourishment cell gets that is trafficked from one part of the cell to the other part. So that is handled by what we call microtubules. Microtubules. So these microtubules like each streak is like a microtubule. So microtubule is like a railroad track. It directs that movement from the center of the cell to the edge of the cell. So we can consider this as the center and then moving towards the edge. The edge, yeah. Yeah. So in a normal cell that flows very smoothly. Yes, yes. But when the cells are exposed to amyloid beta proteins, then you could see that those railroad tracks. Oh, wow. This is just crisscross. Yeah, these are way less. The communication, like you were saying, it looks like the communication is horrible here. Right. Like it's just being messed up. And the communication here is like looking like smooth. We know what's, we can almost predict where it's going here. It's a disaster. It looks like a disaster. And so then this is where you can see that amyloid plaque buildup. Well, you know, these are actually the blood-brain barrier endothelial cells. And these are the theothelial cells. So these are supposed to move proteins, not only amyloid beta proteins, but also a lot of HDL proteins, a lot of the iron-carrying proteins like transferent insulin. Interesting. They should be moved from the bloodstream into brain. If that's what is going on in the endothelial cell, then they will never reach brain in required proportions. And those are all growth factors. Neurons need them for good functioning. Iron, HDL. HDL, and even insulin. And even insulin. Yeah. Because insulin is a growth factor. It not only regulates insulin, it also regulates the mitogenic activity, what they call is cell growth, self-division, all those are regulated by insulin. So that's the reason why when insulin signaling is disrupted, you could see the cancer cells growing. Yeah. So in Alzheimer's it's the opposite problem because there is problem with insulin signaling the cells start to die. And what other techniques are you using along with your students, along with, you know, University of Minnesota and Mayo Clinic, what techniques are being used especially in the field of nanotechnology to both understand the pathophysiology but also to then go and do preventative because the nutrition and exercise and sleep is a very common mantra that civilization chants. Look in a nanotech perspective what could be done at age 30 to 40 to get us to that homeostatic capacity of like a 15 year old to keep us healthy. So the reason why we started developing nanoparticles for the treatment and diagnosis of Alzheimer's disease and to look at the buildup of those amyloid proteins in the blood vessels is looking at the examples from nature. For example HDL particles, HDL particles are nanoparticles. So they take up, they actually clear cholesterol from various cells and then they carry the cholesterol to liver. So nanoparticles could have the ability to interact with the endothelial surface, the blood-brain barrier, and they might be able to alter some of these processes. They could signal a change. Signal a change. That's one thing. One aspect is nanoparticles could carry a contrast agent for MRI, PET, to show us where the problem is in that endothelium so that we could detect the trouble early on. Interesting. Yes, yes. And then if you can detect where the problems are at then you can then go and target those specific areas and fix them. And then signaling this in young ages, you said in PET scans, and okay, interesting. So we are developing novel probes to see if there is any problem with the endothelial function. Can we spot that early on so that we might be able to repair the damage? And this is where I would like to bring the association between Alzheimer's disease and type 2 diabetes. So there is a clear epidemiological evidence that these two diseases are related, but we don't know how they're connected mechanistically. So we know that in the periphery, in other tissues, type 2 diabetes could cause problems to the endothelium, could cause problems in the endothelial cells. But what it does to the brain blood vessels is poorly understood. So if there is a problem with insulin signaling, you know type 2 diabetes causes insulin resistance. If there is a problem with insulin signaling in the brain blood vessels, all the functions are most of the functions that we've been talking about could get disrupted because they're connected to insulin signaling. So if we manage to find how they're pathologically connected, the type 2 diabetes and Alzheimer's, one big advantage could be we might be able to repurpose diabetes drugs to treat Alzheimer's, at least very early on. So that's one of the motivations behind our work. Can we repurpose, reuse those drugs to treat the neurodegeneration? Yes, yes. Is that because then similarly to how a drug that is assisting with issues with the cardio vasculature, with the heart disease areas and issues can then also be used for similar processes with the brain? Similar processes. So you know with the diabetes, the same problems again, HDL lowering, LDL increase, insulin resistance, all those are very, very, they cause problems to the vasculature. So using the same tools and similar understanding, we might be able to look at neurodegeneration with a different, in a different perspective because instead of just focusing on what goes on in the brain, it might be important for us to look at the aspects that could directly interfere with the brain function. And you know nowadays the National Institutes of Health has been investing resources into investigating the cerebrovascular contributions to Alzheimer's disease. And still the field is in its infancy and more work needs to be done in that direction. Yes, more funding for the National Institute of Health and for the National Institute of Nutrition. We're aiming to set up, shout out to Dr. Jun Yoon in that process because it's very interesting that you bring up this, the connection between the heart and brain disease and how if we understand their connection better we can tackle them together better. This is very important. Karni, this has been such an interesting conversation together and I'm really grateful that we ended up sitting down with you on the show while you're in the area. It's a pleasure. Thank you so much. And we have a couple questions that we like asking at the end of our episode. One of the questions that we like asking is if you think we are alone in the cosmos. Of course we are not and we have known that. But assuming that there are people like ourselves is probably far-fetched but I don't think we are alone in the cosmos. There might be living beings elsewhere in the galaxies but what they are, how they are is probably a frontier that has been untouched so far. Yes, yes. And then the second question we like to ask is if you think we are in a simulation. Absolutely, you know, I believe that we are in a simulation but then is someone else doing it or are we doing it to ourselves? You know, in the sense are we forced to act in a very particular way or have we programmed ourselves to do certain things whether we like it or not? Do we have real independence over our thinking? So all those really, you know, makes me believe that we could be in a simulation but that could be self-inflicted. It might not be someone else really playing with us or might be, who knows, right? You know, I'm open to, you know, after looking at this many unknowns. I'm so open to considering ideas that I'm not aware of currently. So, but you know, whichever way it will be fascinating to know. Yes, correct. Oh, high level of open-mindedness and poking with science at the truth. Yes, yes. And then the last question we like to ask is what do you think is the most beautiful thing in the world? Human mind, I believe, is the most beautiful thing. I might be biased, but the mere thought of the motivation to know actually is what convinces me that it's the most beautiful thing. And that's one of the reasons why I focus on Alzheimer's research because at the end of life, a person, you know, what is he accumulating, he or she? Not wealth, not, you know, fame, name, all those things are very ephemeral. But for that person, what really matters are the memories or the feelings or the connections. But in this disease, it's such a devastating disease that all those are lost. And to me, that's the real loss. So that's the reason why that's what motivates me to really find out if we could do something about it. It's crazy how well these devices keep the memory, almost 100% efficiency. But our brain doesn't keep with that efficiency. And on our deathbed, we are typically only remembering just very sparse life events. But if we can be able to remember all of these experiences, feelings and memories that we had and be able to store it for children to be able to access in the future and understand, that's just a very interesting. Well, what about the memories that we don't want to remember? You know, this brain has a self-protection mechanism. There's a lot you can't do about the trauma you experienced. Yeah, but we don't want to remember because it's causing pain. But whatever causes pain might not be not everything is bad. For example, there are a lot of painful memories that humanity has gone through. If we forget them, then we keep repeating. We keep getting into those painful memories. So memory, whether it's good or bad to a person or to a community, to society, is a valuable resource and that's all we have. That could bring up the murder rate, though. You know, if we remember these dark experiences and we continuously remember them and then, you know, oh, I've been through this shit before and nothing happens, nothing gets done. And then our self-protective mechanism goes into effect again and we use violent measures to make sure that these memories don't happen again. We have had several guests, like, you know, Coco McKenzie and other people that have said that. On the other side of the traumas are sometimes the greatest treasures. And it's very important to actually integrate the learning experiences into the code of ourselves and the civilization in total. Even at the microcosm, you know, nowadays I believe that, you know, because we mentor graduate students and that's our legacy. And those are our, you know, graduate students will carry through their learning the collective memory of our experience and of our work. So nowadays I feel that they should be more trained to handle bad memories, failures, because if they're handled well, there could be success lurking underneath. Yes, yes. And this is a whole nother conversation on how to best be able to integrate these traumas, you know, maps and other psychedelic studies we've been experimenting with. There's been lots of interesting ways to integrate. And did we get any questions I see on YouTube? Yes, Charlie Sportello, watching in Akron, Ohio, asks if there's any connection between aluminum foil and Alzheimer's disease? Yeah, excellent question, Charlie. I think about 15, 20 years ago, it was believed that magnesium, aluminum, all those metals getting into brain could cause Alzheimer's. And there have been several studies looking at the role of metals in how amyloid proteins aggregate. In fact, amyloid beta aggregates in the presence of metals. But aluminum per se has been ruled out as the prime cause. But metals do play a role, particularly copper and zinc. Then a metal chelator that can get rid of the metals from the brain also failed in the clinical trial. So that might not be the only reason. But we cannot totally rule out the role of metals in neurodegeneration. But aluminum foil is probably, you know, is very safe. Because it's the aluminum that gets into, that's inhaled or that somehow can bypass the blood-brain barrier and gets into brain. It could be problematic. But that has also been ruled out as a major cause. Interesting. That was it. Thank you, Charlie. Thank you, Charlie. Yeah, it's nice everyone for tuning in that. We do have questions. Feel free to ask the questions in the YouTube and Facebook chats. We'll ask our guests the questions live on set. Karunia, thank you so much for coming onto the show. This has been such a pleasure. Thanks for having me. Thank you for teaching us about heart and brain disease and about Alzheimer's disease and about how we can really start tackling this at a greater level. We really want to thank everyone for tuning in. Thank you so much. Let us know your thoughts in the comments below and what we were discussing. Go and share more with your communities, your families, your friends on the internet. Get more people talking about this and really pushing the frontier of science in these domains. Let's do it together. Everyone inspire young people to get more involved. Huge shout out to Ron Vargas, our producer and director. Thank you very much. We love you very much, Ron. And no cut, no cut, no thumbs up from you. Yeah, I love you too. There's the cut and thumbs up. We love you very much. Thank you. And also support the artists and entrepreneurs that you believe in. Support them in your communities. Help them grow. Help them stay afloat. Simulations links are below. We need your help as well. 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