Talking Biotech Podcast 392 Renewing This Old Brain - Dr. Jean Hebert === Hi everybody, and [00:00:01] Kevin Folta: welcome to this week's Talking Biotech podcast by Colabra. Now as we age, one of the hallmarks of the process is our brains not working as well as they used to, and experiencing some elements of cognitive decline that are based upon various aspects of changes that are occurring at the cellular level. A lot of these changes are not reversible and. Uh, manifesting is different elements of neurological change that result in cognitive decline sometimes as different diseases, different disorders that are seeming to become more prevalent as we age and as the aging population grows. But can you reverse this? And it seems like today's guests says you can't. Today we're going to speak with Dr. Johnny Bear. He's a professor in the Department of Neuroscience in the Department of Genetics at the Albert Einstein School of Medicine and the author of Replacing Aging. Welcome to the podcast, Dr. Eber. [00:01:03] Jean Herbert: Oh, thanks for having me. Great to be here. Yeah. [00:01:06] Kevin Folta: I really appreciate it because brains are a frequent topic these days, especially with respect to neurodegenerative disease and some of the underlying causes that we talk about, which really are rather intriguing. But this is the flip side. This is trying to get back what we lost, and let's go back to the basis of this. What is aging, particularly at the cellular level? [00:01:30] Jean Herbert: Yeah, I mean, first, getting back to what we lost in the. Of regaining function, right? So if our cognitive performance declines with age, that's what we want to reverse. Um, you know, if we've lost some memories or, or some functionality, uh, depending on how that was lost, you know, we may not get it back unless we relearn it. Um, yeah. But what is. Uh, you know, that's, that's a good question and it can be defined many different ways, and many different people define it different ways. You can look at the whole organism, right? You, you can't run as fast, you're more wrinkled. You're stiffer. That's all aging. Um, and people also define it at a cellular level. So the metabolism of cells, um, the epigenome of cells, which you may have heard. Uh, the mitochondria of cells, the telomeres of cells, uh, you know, many aspects of cells, uh, show, uh, features that are, um, that accumulate over time that we would call aging. But I think the more important level, uh, at that we need to look at aging at is the molecular level. The macro molecular level. That's, I believe, Aging occurs and is largely, uh, ignored by, um, the field of, of life extension, aging, longevity. [00:03:02] Kevin Folta: Well, what exactly is happening at that level that you think is a really a priority that others might be missing? [00:03:10] Jean Herbert: Yeah, so I mean, there are, uh, sarcastic forms of damage that accumulate. They're non enzy. Um, there's no repair machinery encoded in our genes to fix them. So no matter how much we play with our genes and our epigenome, we're not addressing that damage. And this is damage to proteins, carbohydrates, uh, dna. Of course that's been well documented. Uh, but for the proteins and carbohydrates, a lot of that is outside the cells. So in the extracellular environ, Um, and that's what I'm referring to as largely being ignored by the, the field of, of longevity and aging. [00:03:54] Kevin Folta: Okay. So these are things that are present in an extracellular context that either are being, um, I guess you maybe post translationally modified in a way that changes their [00:04:06] Jean Herbert: function. Well, post translationally invokes a certain form of normal regulat. Right post-translational modification of proteins is something that's encoded by enzymes. More often than not, what I'm talking about is sarcastic damage, so there's forms of oxidation, gly, carbonation, carbonation, ization. There's all these forms of damage that accumulates as we age in these proteins, and those haven't been addressed yet by any approach. That we hear about the more popular approaches that we hear about in the longevity field, and if we don't address that damage, we know that we will continue to age at the same rate and reach a ma the same maximal lifespan. [00:04:56] Kevin Folta: I see. So is it, you know, and I, I know a little bit about brains. Is it really maybe an accumulation of the damage stuff that isn't being properly turned over? Like, you know, synuclein alpha and those kinds of things that accumulate in Lewy body dementia where you have an extra, uh, accumulation of proteins that should go away that don't. [00:05:16] Jean Herbert: Yeah, this, uh, happens in the brain. It happens all over the body, though, uh, not necessarily the aggregates that you're referring to. Those, some of those may be brain specific and they are a part of the problem. You're absolutely right. Uh, but the damage that accumulates, um, to the macromolecules of the extracellular environment occur all over the body. Collagen is the most abundant protein in our body, and we know very. All these forms of damage that it accumulates over time, that make it resistant to degradation by normal enzymes that we have. Um, so it just sits there getting worse and worse, and we get stiffer and stiffer and, you know, get, we get old and this is very bad for ourselves. So even if we put young cells into this old environment, guess what? They behave like old cells. These experiments have been done for several tissues in the body. And the converse is true. You can take old. So they have an old epigenome, they have old Tels, they have old mitochondria, et cetera, et cetera. And you put them in a young environment and they behave like young cells. So I think this extra cellular environment, you know, is really underappreciated and just trying to target, you know, the cellular function is gonna fail. We need to target at at a tissue. Um, uh, the, the, the damage that accumulates. [00:06:38] Kevin Folta: Um, okay. So, yeah, this is kind of interesting. So it really is about the context of the cell that is getting some sort of messaging from its extracellular environment. Is it really a question of, um, specific metabolites or signaling molecules or something that is informing the cell? It's old and it matches what it knows from the inside, that it's old, like it's internal clocks like you mentioned, uh, epigenome or methylation status or uh, telomere length, these things. Is it that now when that old environment is shaking hands with an well, an old cell shaking hands with the old environment, it says, I'm in an old. [00:07:18] Jean Herbert: Yeah, partly right. You, you mentioned like the signals that that cells receive cells are the, the viability and functions of cells are, um, very dependent on the signals they're getting from the extracellular, they're extracellular environment and they will adjust accordingly. And, and so a uh, you know, an old environment will start telling a cell that, Hey, Uh, this is, there's a lot of damage here. You should become inflamed. And so the cells show signs of inflammation. You know, not surprisingly they're doing what they're supposed to, and they, they will change their, uh, epigenome and, and, uh, other aspects of their metabolism and function accordingly. Um, so yeah, they're, they, they, they do kind of, uh, interact. [00:08:10] Kevin Folta: Okay, so we've talked about, you know, collagen, you mentioned, uh, relatively simple molecule compared to, or tissue compared to the brain, and that's really where your work is, uh, centered. And so why is the brain the most attractive target for revitalization? [00:08:28] Jean Herbert: It's, it's actually, uh, the hardest target as you, you might expect, right? The, the human brain is one of the most complex structures known to. Um, so yeah, why target the brain? Well, you know, one might argue that the brain is the organ that is most dear to us, um, because it, it houses, uh, our self-identity, uh, our, our memories, who we are, um, our highest cognitive functions, and, and not to mention consciousness. Um, so you can, you know, theoretically replace. The whole body without the, without replacing the brain with a new body. And you would still, as far as you could tell, be the same person. Um, so you can't do that with the brain. So the brain is irreplaceable, um, in terms of it's still being you or my brain still being me. Um, so that's why I think, uh, we're tackling the brain because others, Um, taking approaches of replacing the other body parts, the old body parts with new body parts that will make potentially our whole body young again, but not our brain. So someone needs to figure out how to reverse all this damage that accumulates over time in the brain, and we think we can do that. Uh, we think we have a, a method of. [00:09:59] Kevin Folta: Yeah, so you're starting with the hardest nut to crack, but it, it also seems to me, we just, with my limited understanding of brains, is that it also seems to have the least plasticity. And that when you have a stroke, the damage is slow to, to recover, um, like a severed spinal cord or c n s problems that, that doesn't normally repair. Um, I know people are working on that, but, uh, how do you achieve goals of, of repairing something that seems to be terminally differentiated and not most likely to want to be able to reju? [00:10:36] Jean Herbert: Right. So plasticity in the sense of being able to repair itself. The brain is terrible at, um, plasticity in the sense of, um, encoding information. It's amazingly plastic. So you mentioned stroke. So there's been studies where stroke to the language center, for example. Sort of rather traumatically and in a short period of time, destroys the language center. Those individuals show very little recovery because there was no time for this mechanism of plasticity to re-encode that information elsewhere. So if you compare that to individuals of the same age, they can be of advanced age as well, that have destruction of the same amount. Tissue in the language center, but progressively over time due to, for example, a benign glioma that grows from a pinpoint out and eats away at that tissue. Those individuals never lose the ability to speak because every day they're speaking every day. The tumor's growing slowly. The ability, uh, for language, um, translocates to a different part of the. And this has been well documented. So at that level, there is tremendous plasticity, um, and functions can move seamlessly without the individual even noticing from one, you know, part of the brain. So one neural substrate to another. Um, and, and that's what is one of the reason, one of the two reasons why we. We can progressively replace brain tissue, hence removing both the cells and their extracellular environment progressively replace that over time without losing a continuity of self or a continuity of function in the brain. And in so doing, you know, completely reverse the, the, the old brain tissue with young brain. [00:12:40] Kevin Folta: Okay, so that sets the table really beautifully. How, how are you doing this? It seems like, uh, where do you get new brain tissue from to introduce to that old brain? [00:12:51] Jean Herbert: Yeah. So this is the second reason why we think we can do this, because we didn't do it in the first place, right? The brain that's in your skull. The brain that's in my skull. No scientist or engineer made. Where did it come from? It came from a rather simple sheet or, or a few sheets of cells, um, early in fetal development. That's a fairly simple biological structure, and that sheet gave rise to the mature, uh, brain or, or, you know, the neocortex is what we're focused on. That's, you know, the, where the highest cognitive functions. So a, a simple sheet of cells gave rise to this wonderful tissue that can encode, you know, these, these higher learning, uh, and, and thinking processes and consciousness. Um, so we don't have to kn know how to put together all those mature, um, structures. We can use this very immature structure. And let it do what it normally does. And to date our lab and many others have been transplanting these fetal like cells, uh, not, not very often tissues, but cells. And they do remarkably well in the adult environment after transplantation. So they project long distances to normal target. They synaptically integrate, um, and they, uh, show, uh, good evidence of, uh, functionality. Uh, for example, if you put them in the visual part of the brain, uh, over time they will respond to visual stimuli. Um, so, so that's the second reason. So you can change the substrate of function progressively over time if you do it over, you know, a long enough period of. And you can put in new tissue that I think if we do it right, can en, you know, encode function and, uh, And, and be useful to [00:14:53] Kevin Folta: the, to the individual. Well, this is a really good spot to take a break, so it sets the table beautifully for what comes next. So we're speaking with Dr. Jean Abeer. He's a professor in the Departments of Neuroscience and the Departments of Gen, department of Genetics at the Albert Einstein School of Medicine. And we're talking about replace. Worn out brain parts, um, and, and some of the new breakthroughs, which are suggesting that it just may be possible. This is the Talking Biotech podcast by Collabora, and we'll be back in just a moment. And now we're back on the Talking Biotech Podcast by Collabora, and we're talking to Dr. Jean Heber. Hey Bear. He's the professor at the Albert Einstein School of Medicine and the author of Replacing Aging, and we're talking about the prospects of how do you restore a brain and. Organ or Yeah, I guess an organ that is really thought to be rather steadfast and and rigid in terms of its development and in terms of its structure. That its structure and function are closely tied. And so how do you mess with that in a way that doesn't destroy what's already there and actually makes a brain do what it's supposed to do while still rejuvenating it and providing some new life in that old structure. And before the break we were talking about. How fetal cells have the capacity to deliver plasticity and kind of assimilate with brain tissue in the context in which they're placed. And so are these experiments, uh, done in vitro or are these actually in vivo experiments where fetal cells have shown that they can articulate correctly with the context where they're placed? [00:16:38] Jean Herbert: Yeah, these are, uh, primarily in vivo, experi. We generate the cells now from, uh, these human, um, embryonic like cells, and we can differentiate them into precursor brain cells that resemble these fetal brain cells. And then we try to reassemble them in a structure that is, um, just like the fetal tissue that gives rise to our brains. Uh, and we've rebuild that fetal light tissue inside an adult brain. So we don't make it in a dish and then transplant it. We actually build it inside the, uh, the, the, the brain where there's damage. [00:17:22] Kevin Folta: Okay. So the, are these mostly, uh, animal models that you're working with? [00:17:26] Jean Herbert: Yes. Yes. We're, we're not ready to go in humans [00:17:30] Kevin Folta: yet. I could use a few if you were. I was, uh, but if you were talking about mouse, um, I was assuming mouse or rat model, or [00:17:38] Jean Herbert: is this a Yeah, mostly [00:17:39] Kevin Folta: mouse. Yeah. Yeah. So you're, you're having mice that are showing some sort of a deficiency, or is this like an induced damage that you're doing that then you're able to repair [00:17:48] Jean Herbert: with the fetal? So we work with, uh, stroke models, Alzheimer models, but more often than not just for reproducibility, we make a physical lesion where we, um, you know, just take out small sections of brain that we try to rebuild. [00:18:06] Kevin Folta: Okay, so you can actually see how a mouse is specifically impaired with, and I know that that medical folks and psychologists do this all the time. You can tweak parts of the mouse's brain change behavior and then, uh, and so you're able to do that, create some sort of a physical lesion that then can be repaired by the addition of fetal cells. [00:18:29] Jean Herbert: Yes, although we will not claim to achieve repair yet, and I don't think anybody can, uh, justifiably claim repair yet. Uh, primarily because when people are putting the cells in, as we have done thus far, there's missing certain precursor cell types. It's not just, you know, the nerve cells or neurons in the brains. There's all the support cell types that are necessary for function. Those are often. Um, the organization of the cells hasn't been, uh, good enough yet to encode, uh, normal information processing. And so those are the areas that we need to improve upon. Those are the areas that we're working on, um, before we think that we can claim any type of repair. [00:19:18] Kevin Folta: Yeah, so if I, I guess if I'm thinking about this as my, put my developmental biologist hat on, you're putting in a highly plastic stem cell type that is not necessarily differentiating into the suite of different cells that would be required in the correct proportions to be able to do functionally what the tissue does in the context of the. Yeah, [00:19:44] Jean Herbert: exactly. So that's what most people have done so far. We've done some of that too, where we're putting in basically one, uh, stem-like cell type or, or stem cell. But really we should be putting in, uh, multiple STEM types. Some for the vasculature, some for neurons, some for those support cells. Uh, that can be grouped into, you know, a lia category is what they're called. Um, you know, so we need precursors for all these major cell types, uh, to be present in the right ratios, as you mentioned, and then also in the right, uh, cytal architecture. So meaning that they, they can't just be jumbled in a mess. They're normally there in, in an organized pattern. And we have. Uh, recapitulate that organized pattern for information processing to occur normally. And you know, it, we think we can do that. It's just a matter of, um, At perfecting the, the approach. [00:20:47] Kevin Folta: Yeah, it seems, it seems to me, again, with my developmental biologist hat on, that coming up with those kinds of structural connections would be the real challenge. Because this happened originally when you were, you know, day X of gestation, where it was part of the context of a normal time series of gene expression and other events that were occurring that probably have been shut off ever. And so now you're trying to, uh, put a heterologous cell type into the context of a differentiate, terminally differentiated cell in a complex organ and expecting it to kind of take on the right identity. And I, I can see the challenge here, but am I really overstating the complexity of this and that you have evidence that it is starting to work in this, uh, really complicated. Yeah, [00:21:36] Jean Herbert: no, we're not, we're not asking these cells that we're putting in to do anything different than they normally would. And the nice thing is they don't seem to care whether they're in the fetal environment or the adult environment. They follow their developmental program. Right. So we're, we're not trying to change that. We're taking advantage of it. Because to date it seems that these cells, uh, will do what they do during development and develop, um, into the right cell types project to the right parts of the brains and, and make the right type of connections. Um, so that's all inherently programmed in these cells, uh, and they seem to do it even in the adult to a large extent. And, and you know, there, there's a probably, um, at least a half dozen labs that have shown this at this point. So it's very encouraging that we, you know, and it, it was a bit of a surprise that they would do this in the adult, um, But hey, great. You know that that'll help us along [00:22:43] Kevin Folta: well. As, as a plant biologist, it's no big surprise because we have plant, uh, stem cells, not cells in the stem, but, but dedifferentiated cell types that you can, depending upon the hormone gradient they're placed in, and the context placed in can differentiate into a number of different tissues because of their toe to potency. So it seems like in something complicated like a brain, maybe there's ways to stumble into this too, but what about things like vascularization? You require, uh, some level of angiogenesis before you can support, uh, you know, nerve function and, and is that step one bridge too far? [00:23:22] Jean Herbert: Uh, no. So we have evidence that that can be done as well, and that's one of the reasons that we, we build our fetal like tissue in, in the adult. Uh, and we include in that tissue vascular precursor cells. So within the tissue, those cells quickly form vessels and they fuse with the host vasculature to circulate blood and keep our graft alive. This doesn't happen if you try to build the tissue in the dish and then transplant it. So that's one of the advantages of our approach, is we've rebuild it in a live animal where vascularization occurs. Fast enough to support survival of the tissue. [00:24:05] Kevin Folta: And what about microglia? I know that you've read in some of your work that there is a attempt to genetically engineer micro microglia to take on more advanced functions. Can you touch on that a bit? [00:24:18] Jean Herbert: Yeah. So you know that that's, um, glee are very important to, uh, rebuilding this fetal like tissue. They're one of the earliest cell types present in the fetal. So it's certainly, uh, you know, when I talk about these multiple precursor cell types, so early microglial precursors are included in that and, and, uh, important for the development of the fetal tissue. Uh, so we're including it there. Um, now we have other applications for microglia that you're alluding to here with genetic reprogramming. Um, so that's not replacing tissue to reverse aging, but it's to deliver, you know, Biologic drugs to the brain under any disease condition, uh, that can't otherwise get to the brain. So these biologic drugs don't cross the blood-brain barrier by and large. Uh, and so there's no delivery mechanism for getting them there. So we have this, uh, sort of, uh, side project where we engineer microglia to produce a biologic of. Maybe it's an anti-inflammatory factor, maybe it's angiogenic factor, maybe, you know, it could be anything. Uh, but then the microglia, when we put them in, we have a, a way of having them spread throughout the brain and replace existing microglia. Um, and so the brain, you know, has the normal amount of microglia except. The microglia that we put in are secreting, um, a, a factor, a therapeutic factor that would otherwise be hard to distribute into the brain tissue. [00:26:00] Kevin Folta: That's, uh, really cool. So what is a good example of one of these therapeutic factors that maybe shows promise in a mouse model? [00:26:08] Jean Herbert: So, you know, I, I think the more, uh, canonical one is a neurotrophic factor. There's, there's several that have been used in preclinical studies. Um, you know, there's brain derived neurotrophic factor, glial derived neurotrophic factor. Uh, and those have been shown, at least when you inject them locally into the mouse brain that has features of Alzheimer's, uh, to, to, uh, help curb the disease progress. And people would have wanted to use these in humans, but they're very inefficient, these factors at crossing the blood-brain barrier. And you don't wanna go around injecting, you know, doing array injections throughout the whole brain to get them in there cuz you'll end up doing more damage than doing good. So, so we need some way of delivering those, um, factors and that's what we're, uh, working on with that project. [00:27:03] Kevin Folta: That's interesting. But are, are there, um, specific viruses? I think about like, you know, the, uh, bacterial or the, uh, viral meningitis virus. Um, these do work in the central nervous system. And are there viral vectors that do that kind of work as well? [00:27:19] Jean Herbert: Uh, yeah, but the viruses don't spread, uh, throughout the brain like microglia do. I mean, microglia are really, uh, impressive. You can do like one little superficial. Injection and, um, they'll just, you know, spread and, and, and cover, you know, the, the whole tissue. Uh, whereas virus, you know, if you inject it will only go so far. And again, if you inject it systemically, very little of it makes it into the, the brain tissue, per se. Um, so yeah, viruses are a little more limited and they can be associated, of course, with inflammatory responses. Um, mm. You know, have other side effects? [00:28:02] Kevin Folta: Well, I, I really love these kinds of shot down the field, you know, moonshot projects because, uh, you know, maybe, uh, someday this will be a very practical therapeutic that you can go receive to reverse brain deficits. But are there other collateral things that you've learned from this about just the way a brain functions and repairs? [00:28:23] Jean Herbert: Yeah, I'm just constantly amazed by, you know, the, the, the two pillars on which our projects are built on. And that is the plasticity of the adult human brain to, to, to seamlessly move, uh, functions over time from one area to another. Even something like personality. So, uh, talking to a clinician recently who had a patient with a, an astrocytoma the size of, uh, an orange. Uh, in, in the, uh, in, in his two frontal lobes. Uh, and, um, you know, which, if that was sudden damage that occurred there, that that individual would've completely changed their personality. But in this case, uh, never lost, uh, the personality. You know, they were always the same person to everyone that knew them, uh, you know, said they were the same. You know, grandpa's the same, even though. You know, has that damage in the front of his brain, of course. Um, you know, that, that's, that's pretty impressive, that level of plasticity and that's very encouraging to us. And then the second thing is just, you know, that these fetal like cells, uh, just seem innately eager and program to do, uh, to, to build new tissue for us if we place them in the right organization of ratios. So we're very encouraged that, you know, we can get there with, with a fair amount of further tweaking. But, but yeah. Tweaking nonetheless. Uh, do you [00:29:55] Kevin Folta: realistically think that this is something that you may see in your career? [00:30:01] Jean Herbert: Yeah, I'm hopeful. Um, you know, I, I, I. I wouldn't say it's a guaranteed, uh, it's very hard to predict the pace of progress, right? Uh, you, you, you must be familiar with that. Uh, speaking to scientists in different areas, sometimes it accelerates much faster than expected and sometimes, you know, there's hardly any measurable progress for a long time. Uh, so it is hard to predict. Uh, I think it's. Um, and I'm, I'm very excited by the idea that we can reverse brain aging with this progressive, um, tissue replacement. And if we can reverse brain aging, then, you know, I think the rest of the body, uh, there'll be ways of, of replacing, um, old parts with new parts just like you would, uh, a used car. So that way we could, you know, extend life. Enjoyable life in good health for much longer time. [00:31:00] Kevin Folta: Now it's, it's really a good note to go out on because I know a lot of folks listen to the podcast because they find a topic that appeals to them. Uh, maybe a, a parent with cognitive decline or someone's starting to suffer from Alzheimer's or ALS or whatever, and they start to look for information online. And the fact that there's something on the horizon. Is very comforting to them. And, and maybe it's not tomorrow, but science has a funny way of surprising us with its fits and spurts of progress and, uh, it at least gives people some hope that maybe there's something on the future. So I really appreciate you taking the time to talk to me today. So thank you very much for spending the time and best wishes going forward. [00:31:40] Jean Herbert: Yeah, thanks so much. It was a pleasure being on. And [00:31:44] Kevin Folta: for our listeners, thank you very much for listening to The Talking Biotech podcast. Do me a favor. Go on Twitter and retweet this, go on Facebook and share it with some friends. The idea that we may be able to repair the damage that time does to our brains is pretty exciting, even if it seems like it's in an infancy, because science tends to surprise us. And, uh, you never know what's gonna happen next. Just to know that these things are on the horizon can bring a lot of hope to a lot of people with, uh, significant problems. So thank you for listening to The Talking Biotech podcast, and we'll talk to you again next.